A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent Patients With Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

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Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
1
 
Clinical Study Protocol with Amendment 03
Study Number TV46000-CNS-30072
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable Suspension 
(TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent 
Patients with Schizophrenia
A Randomized, Double-Blind, Placebo-Controlled Study on Efficacy, Safety, and 
Tolerability of TV-46000 in Adults and Adolescents with Schizophrenia
A Study to Test if TV-46000 is Effective for Maintenance Treatment of Schizophrenia
(The RISE Study – The RIsperidone Subcutaneous Extended-release Study)
Efficacy, Safety, and Tolerability Study (Phase 3)
IND number: 124384;
NDA number: 213586;
BLA number: Not applicable; EudraCT 
number: 2018-001619-65
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol Amendment 03 Approval Date: 19 April 2020
Protocol Approval Date: 14 December 2017
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 (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
(SOPs).
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.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
2
AMENDMENT HISTORY
The protocol for Study TV46000-CNS-30072 (original protocol dated 14 December 2017) has 
been amended and reissued as follows:
Global Amendment 03
19 April 2020
(863 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 9.5.4.2. Sensitivity Analysis;
Section 10. Quality Control and Quality Assurance;
Appendix C. Quality Control and Quality Assurance;
Appendix F. Lost to Follow-Up;
Administrative Letter 03
09 February 2020

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
3
Global Amendment 02 with 
Revision 01
16 October 2019
(649 patients enrolled to date)
Global Amendment 02
02 September 2019
(584 patients enrolled to date)
Letter of Clarification 02
27 June 2019
Global Amendment 01
06 December 2018
(184 patients enrolled to date)
Letter of Clarification 01
26 June 2018
Local Amendment 01 for 
Bulgaria
28 May 2018
(6 patients enrolled to date)
Protocol with Revision 01
15 February 2018
(0 patients enrolled to date)
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
4
INVESTIGATOR AGREEMENT
Original Protocol Dated 14 December 2017
Clinical Study Protocol with Amendment 03
IND number: 124384;
NDA number: 213586; BLA number: Not applicable; EudraCT 
number: 2018-001619-65
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable Suspension 
(TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent 
Patients with Schizophrenia
(The RISE Study – The RIsperidone Subcutaneous Extended-release Study)
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the Protocol Amendment 03 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 IMP and the conduct of the study. I agree to keep 
records on all patient information, investigational medicinal products (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

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
5
SPONSOR PROTOCOL APPROVAL

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
6
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 14 December 2017
Clinical Study Protocol with Amendment 03
IND number: 124384;
NDA number: 213586; BLA number: Not applicable; EudraCT 
number: 2018-001619-65
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable Suspension 
(TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent 
Patients with Schizophrenia
(The RISE Study – The RIsperidone Subcutaneous Extended-release Study)
I have read the Protocol Amendment 03 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 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 IMP and the conduct of the study. I agree to keep 
records on patient information, IMPs shipment and return forms, 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.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
7
CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV46000-CNS-30072
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable 
Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and 
Adolescent Patients with Schizophrenia (The RISE Study – The RIsperidone Subcutaneous 
Extended-release Study)
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 124384
New Drug Application (NDA) Number: 213586
Biological License Application (BLA) Number: Not applicable
EudraCT Number: 2018-001619-65
EMA 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 (EV) code for the IMP, if applicable: SUB10335MIG
Type of the Study: Efficacy, Safety, and Tolerability Study (Phase 3)
Indication: Maintenance treatment of schizophrenia in patients currently treated with oral 
antipsychotics
Is this study conducted to investigate the New Use of an approved, marketed product? No
Number of Investigational Centers Planned: Approximately 80
Countries Planned: The study is planned to be conducted in North America and Bulgaria.
Planned Study Period: Q2 2018 to Q4 2020
Number of Patients Planned (total): The total number of patients planned to be enrolled into 
Stage 1 is approximately 860 adults (18 years of age and above), to achieve approximately 520 
adults  randomized to Stage 2. As an event-driven study, it may be possible to randomize more 
than 520 adult patients, as long as Stage 2 of the study ends when the number of events among 
adults reaches at least 90 (see Sample Size Rationale). 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 at screening, who have a 
confirmed diagnosis of schizophrenia, are clinically stable, and are eligible for risperidone 
treatment.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
8
Primary and Secondary Objectives and Endpoints 
Objectives
Endpoints
The primary objective of this 
study is to evaluate the efficacy
of TV-46000 during 
maintenance treatment in adult 
patients with schizophrenia.
The primary efficacy endpoint is time to impending relapse. 
Relapse is defined as 1 or more of the following items:
Clinical Global Impression–Improvement (CGI-I) of ≥5 
(greater than or equal to minimally worse, ie, minimally 
worse, much worse or very much worse), AND
an increase of any of the following individual Positive 
and Negative Syndrome Scale (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
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 increase of ≥4 on the 
combined score of these 4 PANSS items (conceptual 
disorganization, hallucinatory behavior, suspiciousness, 
and unusual thought content) since randomization;
hospitalization due to worsening of psychotic symptoms 
(including partial hospitalization programs), excluding 
hospitalization for psychosocial reasons
Clinical Global Impression-Severity of Suicidality (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
violent behavior resulting in clinically significant self-
injury, injury to another person, or property damage
A key secondary objective of 
this study is to evaluate the 
efficacy of TV-46000 during 
maintenance treatment in the 
total population (adults and 
adolescents)  and in adolescent 
patients with schizophrenia.
Key secondary endpoints are:

time to impending relapse (as defined under the primary 
objective) in the total population (adults and adolescents)

impending relapse rate at week 24 

percentage of patients who maintain stability at endpoint

percentage of patients achieving remission at endpoint

observed rate of impending relapse at endpoint 

Drug Attitudes Inventory 10-item version (adult patients 
only)

Schizophrenia Quality of Life Scale (SQLS) (adult 
patients only)

time to impending relapse in adolescent patients with 
schizophrenia 

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
9
Objectives
Endpoints
A secondary objective of this 
study is to evaluate the safety 
and tolerability of TV-46000 in 
the total population.
The safety variables include adverse events, extrapyramidal 
symptoms (EPS), risk of suicide events, depression symptoms, 
injection pain and other injection site reactions (local 
tolerability), vital signs, laboratory tests, physical examination, 
electrocardiogram (ECG) measurements, body weight, rescue 
medication use, time to all-cause discontinuation, all-cause 
discontinuation rates and discontinuation rates due to adverse 
events (tolerability), and the following rating scales:
Abnormal Involuntary Movement Scale (AIMS)
Simpson-Angus Scale (SAS)
Barnes Akathisia Rating Scale (BARS)
Columbia Suicide Severity Rating Scale (C-SSRS)
Calgary Depression Scale for Schizophrenia (CDSS)
CGI-SS
A secondary objective of this 
study is to evaluate the 
pharmacokinetics (PK) of oral 
risperidone and TV-46000 
after administration of multiple 
doses in adults, adolescents, 
and the total population.
The pharmacokinetic endpoints are the plasma concentrations 
of risperidone, 9-OH-risperidone, and total active moiety (sum 
of risperidone and 9-OH-risperidone).

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
11
Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Study Design: This is a double-blind, randomized, relapse prevention study comparing 
a therapeutic dose of TV-46000 sc (every month [q1m] and every 2 months [q2m]) with placebo 
sc (q1m) in a 1:1:1 ratio.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
12
Patients will undergo screening procedures/assessments within 30 days before the start of 
Stage 1. They should have had a diagnosis of schizophrenia for >1 year (diagnosis must be 
reconfirmed by Structured Clinical Interview for DSM-5 [SCID-5]) and have been generally 
responsive to antipsychotics in the past year based on investigator judgement (and discussions 
with family members, caregivers, or healthcare professionals as applicable). 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.
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. 
Patients can be accompanied by caregivers to visits.
Stage 1: Oral conversion and stabilization stage (12 weeks). Patients not already on oral 
risperidone or injectable risperidone (RISPERDAL CONSTA, Janssen Pharmaceuticals, US PI) 
and on any antipsychotic (other than clozapine), and who can benefit from conversion to oral 
risperidone based on the investigator’s judgement, will be converted to oral risperidone 
(2 to 5 mg/day) to ensure that they 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 
who are already on risperidone but can still benefit from the study based on the investigator's 
judgement will also undergo the oral stabilization stage. Open-label oral risperidone (2 to 
5 mg/day) will be used to stabilize patients to the treatments (the dose will be based on clinical 
judgement). Patients will come to the clinic for 4 visits (weeks -12, -10, -8, and -4) for dose 
adjustments; however, additional visits may be required for dose adjustments. Patients will be 
assessed by 
. Additionally, 
telephone contacts will take place at weeks -6 and -2, or more frequently if required in the 
judgement of the investigator. 
Stability on risperidone, while also adequately controlling for symptoms of schizophrenia, will 
be assessed at baseline and is defined as meeting all of the following criteria for at least 4 
consecutive weeks prior to the baseline visit:

outpatient status


 
 


Blood samples for plasma drug concentration will be collected during the in-clinic visits (besides 
screening) and adverse event inquiry will be performed at all visits and telephone 
calls/teleconferences (TCs).

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
13
If a patient withdraws from the study prior to the randomization 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.
Stage 2: Double-blind maintenance stage (variable in duration). Stabilized patients (see 
definition above) will be randomized to receive TV-46000 q1m sc injections, TV-46000 q2m sc 
injections, or placebo q1m sc injections in a 1:1:1 ratio. Patients that require a stabilization dose 
below 2 mg/day will not be randomized in the study. Also, as a precautionary measure, 
adolescent patients that will require a stabilization dose of more than 4 mg during the 
stabilization stage will not be randomized. Patients in the TV-46000 groups will receive a dose 
of TV-46000 (q1m or q2m) that is equivalent to the oral dose on which they were stabilized in 
Stage 1. The maximal dose administered to adult patients will be equivalent to an oral 
risperidone dose of 5 mg/day, and the maximal dose administered to adolescents will be 
equivalent to 4 mg/day. Patients randomized to TV-46000 q1m or placebo sc will receive an sc 
injection of TV-46000 or placebo, respectively, at baseline and every 4 weeks (q4w) thereafter. 
Patients randomized to TV-46000 q2m will receive a TV-46000 injection at baseline and every
8 weeks (q8w) thereafter and a placebo sc injection 4 weeks after baseline and q8w thereafter to 
ensure blinding of the doses and durations of the TV-46000 injections and the placebo injections.
The study will continue on an outpatient basis, and telephone contacts will take place weekly 
between clinic visits. If, in the judgment of the investigator, the patient is likely to relapse or 
pose a danger to himself/herself or others, that patient may be invited for an unscheduled visit 
and/or hospitalized if needed, and treatment with the study drug may be discontinued. 
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. Randomized 
patients, 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. Patients 
who remain relapse-free when the study is terminated should be invited to perform the End-of-
Treatment (EoT) visit within 4 weeks of the last injection. Therefore, a patient is considered a 
study completer if he or she experienced impending relapse or remained relapse-free at the time 
of study termination.
During the conduct of this study, an Independent Data Monitoring Committee (IDMC) will
review accumulating unblinded safety and pharmacokinetic data on a regular basis, as detailed in 
the IDMC charter, to ensure the continuing safety of the study patients and study conduct issues. 
The specific details regarding the IDMC sessions will be outlined in the IDMC charter. 
Brief Summary of Study Design for the Trial Registry(s): The purpose of the study is to 
evaluate the efficacy, safety, and tolerability of different dose regimens of TV-46000 
administered sc as compared to placebo during maintenance treatment in adult and adolescent 
patients with schizophrenia. The study will include male and female patients, 13 to 65 years of 
age at screening, who have a confirmed diagnosis of schizophrenia, are clinically stable, and are 
eligible for risperidone treatment. Patients will be randomized to receive doses of TV-46000 
q1m, TV-46000 q2m, or placebo q1m sc injections in a 1:1:1 ratio. Patients randomized to 
TV-46000 q1m or placebo will receive an sc injection of TV-46000 or placebo, respectively, at 
baseline and q4w thereafter. Patients randomized to TV-46000 q2m will receive a TV-46000 sc 
injection at baseline and q8w thereafter and a placebo sc injection 4 weeks after baseline and
q8w thereafter to ensure blinding of the doses and durations of the TV-46000 injections and the 

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
14
placebo injections. The doses of TV-46000 will be equivalent to 2 to 5 mg/day of oral 
risperidone. The primary efficacy endpoint is time to impending relapse, which will be measured 
by CGI-I, PANSS, and CGI-SS scores, hospitalization due to worsening of psychotic symptoms, 
or violent behavior. The duration of patient participation in the study will include up to 4 weeks 
of screening, 12 weeks of the oral conversion/stabilization stage, and a double-blind maintenance 
stage. The double-blind maintenance stage will be variable in duration, with patients continuing 
until they experience a relapse event; meet 1 or more of the study discontinuation or withdrawal 
criteria; or remain relapse-free at the time of study termination. Patients will subsequently 
complete all end-of-study assessments. When the study ends, eligible patients may be offered the 
opportunity to enter the TV46000-CNS-30078 extension study to assess the long-term safety and 
tolerability of extended-release risperidone. If they choose to enter the extension study, they will 
not need to complete the follow-up/exit visits in this study. For all other patients, there will be 
2 follow-up/exit visits that will take place at 4 weeks and 8 weeks after the last dosing visit. 
During the follow-up/exit period, patients will be treated according to the investigator’s 
judgement.
Method of Randomization and Blinding: Patients will be randomized to receive doses of 
TV-46000 q1m sc injection, TV-46000 q2m sc injection, or placebo q1m sc injection in a 1:1:1 
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). The doses of 
TV-46000 will be equivalent to 2 to 5 mg/day of oral risperidone (equivalent to the oral dose on 
which the patient was stabilized in Stage 1). As a precautionary measure, adolescent patients that 
will require a stabilization dose of more than 4 mg during the stabilization stage will not be 
randomized. Patients randomized to TV-46000 q1m or placebo sc will receive an sc injection of 
TV-46000 or placebo, respectively, at baseline and q4w thereafter. Patients randomized to TV-
46000 q2m will receive a TV-46000 sc injection at baseline and q8w thereafter and a placebo sc 
injection 4 weeks after baseline and q8w thereafter to ensure blinding of the doses and durations 
of the TV-46000 injections and the placebo injections.
Patients and investigators will remain blinded to the identity of the treatment administered to 
each patient. Due to the differences between the TV-46000 product and placebo, an unblinded 
nurse, not associated with rating the patient (including assessment of the injection site if needed) 
and 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 unblinded nurse will 
 in a room
separated 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.
The sponsor’s clinical personnel (and delegates) involved in the study will be blinded to the 
identity of the IMPs until the database is locked for final analysis and the IMP assignment is 
known. 

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
15
In the event of an emergency (ie, where knowledge of the study drug assignment is needed to 
make treatment decisions for the patient), the treatment group and dose to which the patient has 
been allocated can be determined by accessing the Interactive Response Technology (IRT) 
system.
Pharmacokinetic sample analysis and drug concentration calculations will be performed during 
the course of the study.
 
. 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate
Test IMP:
 
 
 
 
 
 
In general, 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 oral risperidone 2 to 5 mg/day per 
the conversion table below. Patients that will require a stabilization dose below 2 mg/day will not 
be randomized in the study. The maximal dose administered to adult patients will be equivalent 
to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents will 
be equivalent to 4 mg/day. As a precautionary measure, adolescent patients that will require a 
stabilization dose of more than 4 mg during the stabilization stage will not be randomized.
Several investigational centers may be selected by the sponsor (based on the centers’ capabilities, 
sponsor's considerations, and prior clinical experience with injectable medication) for injection 
of study drug in the back of the upper arm, instead of the abdomen, to all or some of the enrolled 
patients at these sites (approximately 20% of the study patient population). 
Conversion Table Between Oral Risperidone and TV-46000 Doses
Frequency of TV-46000 
Administration
Oral Risperidone Doses and Corresponding TV-46000 Doses
2 mg/day
3 mg/day
4 mg/day
5 mg/day 
(Adults Only)
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 arm and the left. 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 dosing manual.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
16
Reference IMP: None
Placebo IMP:
 
 
 
 
 
 
 
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
Storage conditions
 
 
 
 
 
 
Unit dose strength(s)/dosage level(s)
Treatment
Dosing volume (mL)
 
 
 
Further dosing instructions are detailed in the pharmacy manual.

Placebo-Controlled Study - Schizophrenia
Clinical Study Protocol with Amendment 03
Study TV46000-CNS-30072
17
IMP name
Test IMP
Placebo IMP
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
q1m or q2m injections per the 
patient’s assigned treatment 
group.
The injection will be administered 
by an unblinded independent 
nurse
q1m injections per the patient’s 
assigned treatment group.
The injection will be administered 
by an unblinded independent 
nurse
Packaging
Manufacturer
 
 
.
Duration of Patient Participation and Maximal Exposure to IMP: The duration of patient 
participation in the study will include up to 4 weeks of screening, 12 weeks of the oral 
conversion/stabilization stage, and a double-blind maintenance stage. 
Patients are expected to participate in the study for its entire duration, and undergo the scheduled 
visits and assessments as detailed in the protocol. 
The double-blind maintenance stage will be variable in duration, with patients continuing until 
they experience a relapse event; meet 1 or more of the study discontinuation or withdrawal 
criteria; or remain relapse-free at the time of study termination. 
When the study ends, eligible patients may be offered the opportunity to enter the long-term 
TV46000-CNS-30078 extension study to assess the safety and tolerability of extended-release 
risperidone. 
If patients choose to enter the extension study, they will not need to complete the follow-up/exit 
visits in this study. For all other patients (ie, patients who experience a relapse event, meet 1 or 
more of the study discontinuation or withdrawal criteria, or do not consent to join the extension 
study), there will be 2 follow-up/exit visits that will take place at 4 weeks and 8 weeks after the 
last dosing visit. During the follow-up/exit period, patients will be treated according to the 
investigator’s judgement.
Study Duration: Approximately 30 months, from Q2 2018 (first patient in) to Q4 2020 (last 
patient out). 
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.

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Plans for Treatment or Care after the Patient has Ended Participation in the Study:
In case the patient is withdrawn from this study, no further treatment is planned by the sponsor 
after the patient completes their participation in this study. Patients will be advised to return to 
their primary physician for additional treatment. Patients may be treated in the meantime per 
investigator judgment and instruction as applicable.
When the study ends, eligible patients may be offered the opportunity to enter the long-term  
TV46000-CNS-30078 extension study to assess the long-term safety and tolerability of 
extended-release risperidone. This extension study is beyond the scope of this protocol, and a 
separate protocol was issued for  it.
Inclusion Criteria: Patients may be enrolled in this study only if they meet all of the following 
criteria: 
a.
The patient has a diagnosis of schizophrenia according to the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for >1 year (diagnosis 
must be reconfirmed by SCID-5) and has had ≥1 episode of relapse in the last 24 
months.
b. The patient has been responsive to an antipsychotic treatment (other than clozapine) 
in the past year based on investigator judgement (and discussions with family 
members, caregivers, or healthcare professionals as applicable).
c.
[Revision 1] The patient has provided written informed consent and is competent to 
do so.  For adolescent patients, written informed consent has been provided by each 
patient’s parent or legal guardian, and written assent has been provided by 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, tablet ingestion, sc depot 
injection, and discontinuation 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 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.
[Revision 1]The patient is a male or female of any ethnic origin, 13 through 65 years 
of age at screening.

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k. [Revision 2] The patient has a body mass index between 18.0 and 38.0 kg/m2, 
inclusive, at screening.
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 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 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:

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 and intrauterine hormone-releasing system; these need to be 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 follow-up procedures and assessments as specified in this 
protocol.
Randomization Criteria:
The following criteria are randomization criteria and must be fulfilled at the baseline visit before 
randomization, in addition to other relevant inclusion criteria: 

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p. The patient has not experienced mental or physical deterioration, which prevents 
participation in the study per investigator judgement.
q. The patient has demonstrated good compliance in following protocol requirements 
during Stage 1.

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). 
r.
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
Exclusion Criteria: Patients will not be enrolled/randomized in this study if they meet any of 
the following criteria:
a.
The patient has a current clinically significant DSM-5 diagnosis other than 
schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar 
disorder, delirium, dementia, 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, 
clinically significant tardive dyskinesia, or other medical condition that would expose 
the patient to undue risk.
d. [Revision 1] 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 RNA 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 currently has or has 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.

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g. The patient has a significant risk of violent behavior based on the patient’s medical 
history or investigator’s judgement.
h. The patient has a significant risk of committing suicide based on the patient’s medical 
history or 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 previously participated in a Teva-sponsored clinical study with 
TV-46000.
j.
The patient has a clinically significant deviation from normal in the physical 
examination.
k. The patient has clinically significant findings in biochemistry, hematology, ECG, or 
urinalysis results. 

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 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 the medications prohibited in this protocol.
Statistical Considerations
Sample Size Rationale: Median time to impending relapse was observed to be 7 months in the 
placebo group in a similarly designed study (Kane et al 2012). Assuming a similar placebo effect 
in this study, as well as a hazard ratio of 2.50 (placebo vs each TV-46000 arm) and a 
randomization ratio of 1:1:1 (q1m:q2m:placebo) with 2 primary hypotheses to be tested (q1m vs 
placebo and q2m vs placebo) at a 2-sided alpha of 0.050, the total number of events across 
treatment groups that will attain a statistical power of at least 90% to meet success criteria in 
both comparisons (East 6 [Version 6.3] manual, 2014) is 90 relapse events. This number of 
events will need to be observed during Stage 2 of the study in the ITT analysis set (adult 
patients). The sample size rationale is based on the adult patients. There is no estimation of the 
sample size in the adolescent population, and their number is not known at this time.
 

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Primary Efficacy Analysis: Time to impending relapse will be calculated as the earliest date the 
patient meets ≥1 of the impending relapse criteria minus the randomization date plus 1. Data 
from patients who did not relapse will be censored at the last valid assessment. Time to 
impending relapse for TV-46000 and placebo will be compared using the stratified log-rank test 
at the significance levels described (see Multiple Comparisons and Multiplicity). Hazard ratios 
and their 2-sided 95% confidence intervals (CIs) for TV-46000 q1m and q2m versus placebo will 
be analyzed using a Cox proportional hazard model, with treatment and the aforementioned 
stratification variables as the factors (see Method of Randomization and Blinding). 
Kaplan-Meier curves will be provided to present impending relapse rate data over time. The 
primary analysis will be conducted on the population of adult patients.
Sensitivity Analysis: A sensitivity analysis will be conducted to assess the impact of large 
intervals between the previous assessment and the assessment at the time the first relapse was 
observed via the interval censoring method. Sensitivity analysis will also be conducted by 
tipping point analysis, that imputes time to relapse for dropouts (for reasons suspected to be
related to relapse) with increasing risk to relapse, compared to similar patients in the same 
treatment group that continue treatment. The per-protocol analysis set will also be used to as a 
suplemental analysis to evaluate the primary efficacy variable. Details will be provided in the 
statistical analysis plan.
Key Secondary Efficacy Analysis 1: Time to impending relapse in adult and adolescent patients 
will be assessed similarly to the Primary Efficacy Analysis. The Cox proportional hazard model 
will include patient age group (if applicable) along with treatment, and the aforementioned 
stratification variables as the factors. The details about the Type-I statistical error control will be 
discussed in Multiple Comparisons and Multiplicity.
Key Secondary Efficacy Analysis 2: Impending relapse rate at week 24 will be estimated using 
the Kaplan-Meier method and calculated as 1 minus the proportion of adult and adolescent 
patients free of impending relapse events at week 24. The Greenwood formula will be used to 
calculate standard errors for impending relapse rates at week 24, and the pooled standard errors 
will be used for hypothesis testing using z statistics, assuming that the differences between TV-
46000 and placebo follow a normal distribution of large samples.Type-I statistical error control 
will be discussed in Multiple Comparisons and Multiplicity.
Key Secondary Efficacy Analysis 3: The analyses of the proportion of patients who maintain 
stability at endpoint in Stage 2 will be described in the statistical analysis plan. Type-I statistical 
error control will be discussed in Multiple Comparisons and Multiplicity.
Key Secondary Efficacy Analysis 4: The analyses of the proportion of patients achieving 
remission at endpoint in Stage 2 will be described in the statistical analysis plan. Type-I 
statistical error control will be discussed in Multiple Comparisons and Multiplicity.

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Key Secondary Efficacy Analysis 5: The observed impending relapse rates at endpoint will be 
compared between groups using the Cochran–Mantel–Haenszel (CMH) test adjusting for 
stratification variables. Type-I statistical error control will be discussed in Multiple 
Comparisons and Multiplicity.
Key Secondary Efficacy Analysis 6: Change from baseline of DAI-10 at endpoint will be 
compared between groups using repeated measures ANCOVA. Type-I statistical control  will be 
discussed in Multiple Comparisons and Multiplicity.
Key Secondary Efficacy Analysis 7: Change from baseline of SQLS at endpoint will be 
compared between groups using repeated measures ANCOVA. Type-I statistical control will be 
discussed in Multiple Comparisons and Multiplicity.
Key Secondary Efficacy Analysis 8: Time to impending relapse in adolescent patients will be 
assessed if the number of randomized adolescents will be at least 10, with clinically sufficient 
exposure. The method will be similar to the Primary Efficacy Analysis. The details about the 
Type-I statistical error control will be discussed in Multiple Comparisons and Multiplicity.
 
 
 
 
 
 
 
 
In the event that prefilled syringes become available during the study, data relating to the ease of 
dosing administration will be listed.
Multiple Comparisons and Multiplicity:
At the final analysis after at least 90 relapse events, a fixed sequential (hierarchical) testing 
approach will be implemented. The first primary efficacy hypothesis comparing q1m to placebo 
will be tested with a 2-sided alpha of 0.05; if significant, the second primary efficacy hypothesis 
comparing q2m to placebo will be tested with a 2-sided alpha of 0.05. If the first primary 
hypothesis test fails to reach statistical significance, no further formal hypothesis testing will be 
performed. 
Type-I error will be further controlled for the key secondary endpoints by employing the fixed 
sequential (hierarchical) approach to the secondary endpoints. Accordingly, secondary endpoints 
will be analyzed only if primary efficacy endpoints have a p-value less than or equal to alpha of 
0.05.  

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For the key secondary endpoints, if the resulting 2-sided p-value from the first comparison is 
significant, then the next comparison of interest will be interpreted inferentially at the same alpha 
level. This process will continue either until all comparisons of interest are interpreted 
inferentially or until the point at which the resulting 2-sided hypothesis is insignificant at the 
same alpha level. At the point where a comparison is found to be insignificant, no further 
comparisons will be interpreted inferentially. Further details about the Type-I statistical error 
control for the key secondary endpoints will be discussed in the statistical analysis plan.
There will be no multiplicity control for all other exploratory efficacy endpoints, which will be 
tested at a nominal 5% level.
Safety Analyses: Safety analyses will be performed on the safety analysis set.
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 test IMP (ie, reasonable 
possibility 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 treatment group. 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 EPS scale scores (BARS, AIMS, and SAS) 
and CDSS during Stage 2, will be presented using descriptive statistics by treatment group. 
Adjustment to stratification factors may be conducted as appropriate. 
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.
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.
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.
Safety data collected in Stage 1 will also be summarized using descriptive statistics in the 
enrolled patients set.
Selected safety data will also be presented by site of injection (abdomen vs arm) and by age 
group (adolescents [ages 13-17] and adults [18 years of age and above]), as applicable.

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Separate summaries for adolescent patients may be presented separately for some analyses, as 
applicable, and will be described in the Statistical Analysis Plan.
Tolerability Analysis: 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. 
All-cause discontinuation rates and discontinuation rates due to adverse events (dropout rates) 
will be calculated as the number of patients who withdrew early, and the number of patients who 
withdrew early due to adverse events, respectively, divided by the number of patients in each 
treatment group and will be presented using descriptive statistics.
Time to all-cause discontinuation will be calculated as the discontinuation date minus the 
randomization date plus 1. Kaplan-Meier curves for the time to discontinuation as a result of all 
causes will be plotted.
Separate summaries for adolescent patients might be presented separately for some analyses, as 
applicable.
Pharmacokinetic Analysis: Blood samples will be collected from all patients for quantitation of 
the plasma concentrations of risperidone, 9-OH-risperidone, and total active moiety, at 
weeks -12, -10, -8, and -4 in Stage 1, at baseline, every 4 weeks in Stage 2, and at the follow-
up/exit visits. During Stage 2 of the study, blood samples for PK assessment will be taken within 
an hour prior to sc dose administration.
 
 
 
 
 
 
 
 
 
 
  
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 the 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. Drug concentrations over time [C(t)] reported by time (visit) and treatment (q1m, q2m, 
and oral) will be presented using descriptive statistics (n, mean, standard deviation, median, 
minimum, geometric mean, and coefficient of variation).
Additional pharmacokinetic parameters may be determined if data permits. 

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In addition, the pharmacokinetics of TV-46000 (and if data permits, also of oral risperidone) will 
be evaluated by using a population pharmacokinetics approach and reported separately from the 
main study report. 
Pharmacokinetic/Pharmacodynamic Analysis:
 
 
 
Biomarker and Pharmacogenetics Analysis: Biomarker and pharmacogenetic analysis plans 
and results will be outlined in a separate document.
Planned Interim Analyses: There will be no interim analysis in this study. 

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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................4
SPONSOR PROTOCOL APPROVAL ...........................................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS........................................................................................................34
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................37
1.1.
Introduction.................................................................................................................37
1.2.
Findings from Nonclinical and Clinical Studies.........................................................38
1.2.1.
Nonclinical Studies.....................................................................................................38
1.2.2.
Clinical Studies...........................................................................................................39
1.2.2.1.
Clinical Pharmacology Studies...................................................................................39
1.2.2.2.
Clinical Safety and Efficacy Studies ..........................................................................40
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 ................................................41
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................43
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................43
2.2.
.......................................................................45
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
4.2.
Patient Exclusion Criteria...........................................................................................67
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................68
4.3.1.
General Withdrawal Criteria.......................................................................................68

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4.3.2.
Study-Specific Patient Withdrawal Criteria and Procedures......................................70
4.3.3.
Pharmacokinetic Sampling in Case of Patient Withdrawal........................................70
4.4.
Replacement of Patients .............................................................................................71
4.5.
Rescreening.................................................................................................................71
4.6.
Screening Failure........................................................................................................71
5.
TREATMENTS..........................................................................................................72
5.1.
Investigational Medicinal Products Used in the Study...............................................72
5.1.1.
Test Investigational Medicinal Product......................................................................72
5.1.1.1.
Starting Dose and Dose Levels...................................................................................72
5.1.1.2.
Dose Modification and Dose Stratification ................................................................73
5.1.2.
Placebo Investigational Medicinal Product ................................................................73
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs...................75
5.2.1.
Storage and Security...................................................................................................75
5.2.2.
Labeling......................................................................................................................75
5.2.3.
Accountability.............................................................................................................75
5.3.
Justification for Investigational Medicinal Products..................................................76
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................76
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................76
5.4.
Other Medicinal Products/Non-Investigational Medicinal Products..........................76
5.5.
Treatment After the End of the Study.........................................................................77
5.6.
Restrictions .................................................................................................................77
5.6.1.
Activity .......................................................................................................................77
5.6.2.
Specific Beverages......................................................................................................77
5.6.3.
Blood Donation...........................................................................................................78
5.7.
Prior and Concomitant Medication or Therapy..........................................................78
5.8.
Procedures for Monitoring Patient Compliance .........................................................79
5.9.
Randomization and Blinding......................................................................................80
5.10.
Maintenance of Randomization and Blinding............................................................81
5.10.1.
Maintenance of Randomization..................................................................................81
5.10.2.
Blinding and Unblinding ............................................................................................81
5.10.3.
Data Monitoring Committee.......................................................................................82
5.11.
 
82
6.
ASSESSMENT OF EFFICACY ................................................................................83

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6.1.
Assessments of Efficacy.............................................................................................83
6.1.1.
Clinical Global Impression–Improvement (CGI-I) ....................................................83
6.1.2.
Positive and Negative Syndrome Scale (PANSS)......................................................83
6.2.
Other Assessments......................................................................................................83
6.2.1.
83
6.2.2.
Quality of Life Scales .................................................................................................83
6.2.2.1.
.............................................................83
6.2.2.2.
................................84
6.2.3.
84
6.2.4.
Personal and Social Performance Scale (PSP) ...........................................................84
6.2.5.
Healthcare Resource Utilization.................................................................................84
6.2.6.
Clinical Global Impression of Severity ......................................................................85
7.
ASSESSMENT OF SAFETY.....................................................................................86
7.1.
Adverse Events ...........................................................................................................86
7.1.1.
Definition of an Adverse Event..................................................................................86
7.1.2.
Recording and Reporting of Adverse Events .............................................................87
7.1.3.
Severity of an Adverse Event .....................................................................................87
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............88
7.1.5.
Serious Adverse Events..............................................................................................88
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................89
7.1.5.2.
Expectedness...............................................................................................................89
7.1.5.3.
Reporting a Serious Adverse Event............................................................................90
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................92
7.1.7.
Protocol Deviations Because of an Adverse Event ....................................................92
7.2.
Pregnancy ...................................................................................................................92
7.3.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................93
7.4.
95

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7.4.2.4.
Prolactin......................................................................................................................95
7.5.
Physical Examinations................................................................................................95
7.6.
Vital Signs ..................................................................................................................96
7.7.
Electrocardiography....................................................................................................96
7.8.
Assessment of Local Tolerability and Pain ................................................................96
7.8.1.
Erythema and Edema Assessment..............................................................................97
7.8.2.
Induration and Nodule Assessment ............................................................................97
7.8.3.
Injection Pain Intensity Assessment ...........................................................................97
7.9.
Assessment of Suicidality...........................................................................................97
7.9.1.
Columbia Suicide Severity Rating Scale (C-SSRS)...................................................98
7.9.2.
Clinical Global Impression-Severity of Suicidality....................................................98
7.10.
Study-Specific Assessments of Safety........................................................................98
7.10.1.
Abnormal Involuntary Movement Scale (AIMS).......................................................98
7.10.2.
Barnes Akathisia Rating Scale (BARS) .....................................................................99
7.10.3.
Simpson-Angus Scale (SAS)......................................................................................99
7.10.4.
Calgary Depression Scale for Schizophrenia (CDSS)................................................99
7.11.
Other Assessments......................................................................................................99
8.
ASSESSMENT OF PHARMACOKINETICS/ PHARMACODYNAMICS/ 
BIOMARKERS/ PHARMACOGENOMICS ..........................................................101
8.1.
Pharmacokinetic Assessment....................................................................................101
8.2.
Pharmacokinetic/Pharmacodynamics Assessment ...................................................102
8.3.
...................................................................102
8.4.
Pharmacogenetics .....................................................................................................102
9.
STATISTICS ............................................................................................................103
9.1.
Sample Size and Power Considerations ...................................................................103
9.2.
Analysis Sets.............................................................................................................103
9.2.1.
Enrolled Patients Set.................................................................................................103
9.2.2.
Intent-to-Treat Analysis Set......................................................................................104
9.2.3.
Extended Intent-to-Treat Analysis Set......................................................................104
9.2.4.
Per-Protocol Analysis Set.........................................................................................104
9.2.5.
Safety Analysis Set...................................................................................................104
9.2.6.
Pharmacokinetics Analysis Set.................................................................................104
9.3.
Data Handling Conventions......................................................................................104

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9.3.1.
Handling Withdrawals and Missing Data.................................................................105
9.4.
Study Population.......................................................................................................105
9.4.1.
Patient Disposition....................................................................................................105
9.4.2.
Demographic and Baseline Characteristics ..............................................................105
9.5.
Efficacy Analysis......................................................................................................105
9.5.1.
Primary Endpoint......................................................................................................105
9.5.2.
Key Secondary Endpoints.........................................................................................106
9.5.2.1.
Time to Impending Relapse in the eITT Analysis Set..............................................106
9.5.2.2.
Impending Relapse Rate at Week 24........................................................................106
9.5.2.3.
Percentage of Patients Who Maintain Stability at Endpoint ....................................106
9.5.2.4.
Percentage of Patients Achieving Remission at Endpoint........................................107
9.5.2.5.
Observed Rate of Impending Relapse at Endpoint...................................................107
9.5.2.6.
Drug Attitudes Inventory 10-item Version...............................................................107
9.5.2.7.
Schizophrenia Quality of Life Scale.........................................................................107
9.5.2.8.
Time to Impending Relapse in Adolescent Patients with Schizophrenia.................108
9.5.3.
/
108
9.5.3.1.
...................................................108
9.5.3.2.
Healthcare Resource Utilization...............................................................................108
9.5.3.3.
 
......................................108
9.5.3.4.
CGI-I Score at Endpoint...........................................................................................108
9.5.3.5.
Personal and Social Performance Scale....................................................................108
9.5.4.
Planned Method of Analysis.....................................................................................108
9.5.4.1.
Primary Efficacy Analysis........................................................................................108
9.5.4.2.
Sensitivity Analysis ..................................................................................................109
9.5.4.3.
Subgroup Analysis....................................................................................................109
9.5.4.4.
Key Secondary Analyses ..........................................................................................109
9.5.4.5.
Key Secondary Efficacy Analysis 9.5.2.2-9.5.2.7....................................................109
9.5.4.6.
..................................................................................110
9.6.
Multiple Comparisons and Multiplicity....................................................................110
9.7.
Safety Analysis .........................................................................................................111
9.8.
Tolerability Analysis ................................................................................................112
9.9.
Pharmacokinetic Analysis ........................................................................................113
9.10.
Pharmacodynamic Analysis......................................................................................113

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9.11.
Pharmacokinetic/Pharmacodynamic Analysis..........................................................113
9.12.
Biomarker and Pharmacogenetics Analysis .............................................................113
9.13.
Planned Interim Analysis..........................................................................................113
9.14.
Reporting Deviations from the Statistical Plan ........................................................114
10.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................115
11.
COMPLIANCE STATEMENT................................................................................115
12.
DATA MANAGEMENT AND RECORD KEEPING ............................................115
13.
FINANCING AND INSURANCE...........................................................................116
14.
PUBLICATION POLICY ........................................................................................116
15.
REFERENCES .........................................................................................................117
16.
SUMMARY OF CHANGES....................................................................................120
16.1.
Global Amendment 03 (Dated 19 April 2020).........................................................120
16.2.
Administrative Letter 03 (Dated 09 February 2020)................................................131
16.3.
Global Amendment 02 with Revision 01 (Dated 16 October 2019) ........................133
16.4.
Global Protocol Amendment 02 (Dated 02 September 2019)..................................143
16.5.
Letter of Clarification 02 (27 June 2019) .................................................................165
16.6.
Global Protocol Amendment 01 (Dated 06 December 2018) ..................................167
16.7.
Letter of Clarification 01 (26 June 2018) .................................................................210
16.8.
Local Amendment 01 for Bulgaria (Dated 28 May 2018) .......................................212
16.9.
Protocol with Revision 01 (Dated 15 February 2018)..............................................216
 
.......................................................................................................217
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................219
APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................229
APPENDIX D.
ETHICS ...........................................................................................................231
APPENDIX E.
BIRTH CONTROL METHODS AND PREGNANCY TESTING.................233
APPENDIX F.
LOST TO FOLLOW-UP .................................................................................235
APPENDIX G.
LIST OF PROHIBITED MEDICATIONS .....................................................236
APPENDIX H.
...........................................................................238
APPENDIX I.
...............................................239
APPENDIX J.
PHARMACOGENETIC ASSESSMENTS......................................................240
APPENDIX K.
PRODUCT COMPLAINTS............................................................................241
APPENDIX L.
DATA MANAGEMENT AND RECORD KEEPING....................................243

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APPENDIX M.
PUBLICATION POLICY ..............................................................................246
APPENDIX N.
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 .............247
LIST OF TABLES
Table 1:
 
...................................................................................................................54
Table 2:
TV46000-CNS-30072 (RISE) Study Procedures and Assessments (In-Clinic 
Visits and Telephone Contacts) – Baseline, Double-Blind Maintenance 
Stage (Stage 2), End of Treatment/Early Termination and Follow-Up......................58
Table 3:
Conversion Table Between Oral Risperidone and TV-46000 Doses .........................73
Table 4:
Investigational Medicinal Products Used in the Study...............................................74
Table 5:
Other Medicinal Products Used in the Study .............................................................77
Table 6:
The Relationship of an Adverse Event to the IMP.....................................................88
Table 7:
Clinical Laboratory Tests ...........................................................................................94
Table 8:
Questions for Unblinded Nurses Administering Study Drug to Patients (for 
use of prefilled syringes only) ..................................................................................100
Table 9:
List of Prohibited Medications Affecting Cytochrome P450...................................236
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
averse drug reaction
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
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
CI
confidence interval
CMH
Cochran–Mantel–Haenszel
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
C(t)
concentrations of drug over time [C(t)] reported by time (visit) and treatment

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Abbreviation
Term
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
EOS
end of study
EOT
end of treatment
EPS
extrapyramidal symptoms
EQ-5D-5L
5-Level EuroQol Five Dimensions Questionnaire
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
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
im
intramuscular
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
LAI
long-acting injectable
LOCF
last observation carried forward
LSO
local safety officer
NDA
New Drug Application
NOAEL
no observed adverse effect level
NPRS
Numeric Pain Rating Scale
OTC
over-the-counter

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Abbreviation
Term
PANSS
Positive and Negative Syndrome Scale
PI
prescribing information
PK
pharmacokinetic(s)
PP
per-protocol
PSP
Personal and Social Performance Scale
q1m
every month
q2m
every 2 months
q3m
every 3 months
q4w
every 4 weeks
q8w
every 8 weeks
RNA
ribonucleic acid
RO
receptor occupancy
RSI
reference safety information
SAS
Simpson-Angus Scale
sc
subcutaneous
SCID-5
Structured Clinical Interview for DSM-5
SmPC
Summary of Product Characteristics
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
United States (of America)
US FDA
United States Food and Drug Administration
VC
videoconference
vs
versus

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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 and Travis 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 and Curson 1994, Hughes 2007, Keith and 
Kane 2003, Walburn et al 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 et al 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 is 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, thought disorder), neurocognitive impairments, psychophysiological 
abnormalities, and the presence of structural brain abnormalities (Asarnow et al 1995, Bo and 
Haahr 2016, Rapoport et al 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 and Haahr 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 and Harrison 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.
 
 
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 
 the dose 
 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 and Sharif 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 purpose of the study is to compare the safety and efficacy of different durations of TV-
46000 administered sc versus placebo. 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 et al 2017). Enrollment of adolescents in this study will 
provide data for evaluating the efficacy, safety and tolerability of TV-46000 in this patient 
population.
Refer to the current Investigator’s Brochure (IB) for detailed information on the background, 
pharmaceutical particulars, nonclinical, and clinical experience with TV-46000.
1.2.
Findings from Nonclinical and Clinical Studies
1.2.1.
Nonclinical Studies
The nonclinical pharmacology and toxicology of risperidone have been well established for oral 
and intramuscular (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.

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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 minipigs, 
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 minipigs 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. 
Subsequent clinical investigations 
 have 
demonstrated that this formulation is more suited to a 1-month 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
 
 
 The study found that TV-46000, administered at sub-therapeutic 
 
, was safe and well tolerated when administered as an sc injection to either the posterior 
upper arm or the abdomen.
 
 

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 to evaluate the 
safety, tolerability, and pharmacokinetics of TV-46000 in patients with schizophrenia or 
schizoaffective disorder was also completed. A total of 96 patients with schizophrenia or 
schizoaffective disorder were allocated into 8 sequential cohorts of 12 patients each. Study 
participants were clinically stable patients who are currently on antipsychotic treatment of oral 
risperidone. The study included 5 single-dose cohorts 
 and 2 multiple-dose 
cohorts 
 
. In addition, 
interchangeability of injection site was assessed via administration of a similar dose 
 to 
the abdomen and to the upper arm. 
 
 
 
 
 
 
 
 
 
 
 
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).

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The safety and efficacy of risperidone LAI (RISPERDAL® CONSTA®, Janssen 
Pharmaceuticals) 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 
 risperidone LAI while participating in a 12-week, double-blind, 
placebo-controlled study. The most common adverse drug reactions (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).
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 
 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. 
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 there are only limited data on ADRs 
associated with this formulation. However, the safety profile of the active ingredient, risperidone, 
given in a different long-acting parenteral formulation has been well characterized. The licensed 
risperidone long-acting injection, RIPERDAL CONSTA, 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.
In summary, the benefit and risk assessment of TV-46000 is favorable following review of the 
available data. Additional safety information on TV-46000, including RSI, is presented in the 
TV-46000 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 (im) risperidone was generally well tolerated over the dose range of 
. 
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, 

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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. 
Based on the extensive safety and efficacy database for oral and im risperidone, and preliminary 
findings from the TV-46000 clinical development program thus far, the sponsor anticipates a 
favorable risk-benefit profile for administration of an extended-release suspension of risperidone 
for sc injection in adult patients with schizophrenia. To date, the only new safety signals that 
were identified in the TV-46000 Phase 1 program were some types of injection site reactions 
(see Section 1.2.2.2). They have not significantly impacted TV-46000’s benefit-risk profile nor 
have they presented a significant burden to the patients. 

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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of this 
study is to evaluate the 
efficacy of TV-46000 during 
maintenance treatment in 
adult patients with 
schizophrenia.
The primary efficacy endpoint is time to impending relapse. 
Relapse is defined as 1 or more of the following items:
Clinical Global Impression–Improvement (CGI-I) of ≥5 
(greater than or equal to minimally worse, ie, minimally 
worse, much worse or very much worse), AND
an increase of any of the following individual Positive and 
Negative Syndrome Scale (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
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 increase of ≥4 on the combined score 
of these 4 PANSS items (conceptual disorganization, 
hallucinatory behavior, suspiciousness, and unusual 
thought content) since randomization
hospitalization due to worsening of psychotic symptoms
(including partial hospitalization programs), excluding 
hospitalization for psychosocial reasons
Clinical Global Impression-Severity of Suicidality (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
violent behavior resulting in clinically significant self-injury, 
injury to another person, or property damage
A key secondary objective of 
this study is to evaluate the 
efficacy of TV-46000 during 
maintenance treatment in a 
total population (adults and 
adolescents) and in adolescent 
patients with schizophrenia.
Key secondary endpoints are:
time to impending relapse (as defined under the primary 
objective) in the total population (adults and adolescents) 
impending relapse rate at week 24 
percentage of patients who maintain stability at endpoint 
percentage of patients achieving remission at endpoint 
observed rate of impending relapse at endpoint 
Drug Attitudes Inventory 10-item version (adult patients 
only)
Schizophrenia Quality of Life Scale (SQLS) (adult patients 

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Objectives
Endpoints
only) 
time to impending relapse in adolescent patients with 
schizophrenia
A secondary objective of this 
study is to evaluate the safety 
and tolerability of TV-46000 
in the total population.
The safety variables include adverse events, extrapyramidal 
symptoms (EPS), risk of suicide events, depression symptoms, 
injection pain and other injection site reactions (local 
tolerability), vital signs, laboratory tests, physical examination, 
electrocardiogram (ECG) measurements, body weight, rescue 
medication use, time to all-cause discontinuation, all-cause 
discontinuation rates and discontinuation rates due to adverse 
events (tolerability), and the following rating scales:
Abnormal Involuntary Movement Scale (AIMS)
Simpson-Angus Scale
Barnes Akathisia Rating Scale
Columbia Suicide Severity Rating Scale (C-SSRS)
Calgary Depression Scale for Schizophrenia (CDSS)
CGI-SS
A secondary objective of this 
study is to evaluate the 
pharmacokinetics of oral 
risperidone and TV-46000 
after administration of 
multiple doses in adults, 
adolecsents, and the total 
population.
The pharmacokinetic endpoints are the plasma concentrations 
of risperidone, 9-OH-risperidone, and total active moiety 
(sum of risperidone and 9-OH-risperidone).
Justification of Primary Endpoint
The primary endpoint of the study is time to impending relapse compared with placebo. Time to 
impending relapse is a well-accepted endpoint for the evaluation of efficacy during maintenance 
therapy with antipsychotics.

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2.2.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 double-blind, randomized, relapse prevention study comparing a therapeutic dose of 
TV-46000 sc q1m and q2m with placebo sc (q1m) in a 1:1:1 ratio. 
Patients will undergo screening procedures/assessments within 30 days before the start of 
Stage 1. They should have had a diagnosis of schizophrenia for >1 year (diagnosis must be 
reconfirmed by Structured Clinical Interview for DSM-5 [SCID-5]) and have been generally 
responsive to antipsychotics in the past year based on investigator judgment (and discussions 
with family members, caregivers, or healthcare professionals as applicable). 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.
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. 
Patients can be accompanied by caregivers to visits.
Stage 1: Oral conversion and stabilization stage (12 weeks). Patients not already on oral 
risperidone or injectable risperidone (RISPERDAL CONSTA, Janssen Pharmaceuticals, US PI) 
and on any antipsychotic (other than clozapine), and who can benefit from conversion to oral 
risperidone based on the investigator’s judgement, will be converted to oral risperidone 
(2 to 5 mg/day) to ensure that they tolerate risperidone and that the doses are adequate to treat 
their positive symptoms. Patients who are already on risperidone but can still benefit from the 
study based on the investigator's judgement will also undergo the oral stabilization stage. Open-
label oral risperidone (2 to 5 mg/day) will be used to stabilize patients to the treatments (the dose 
will be based on clinical judgement). 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 dose 
adjustments (Table 1); however, additional visits may be required for dose adjustments. Patients 
will be assessed by 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), and Clinical Global Impression-Severity of Suicidality (CGI-SS). 
Additionally, telephone contacts will take place at weeks -6 and -2, or more frequently if 
required in the judgement of the investigator (see Table 1 for more details). 
 

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
 
 
 
Blood samples for plasma drug concentration will be collected during the in-clinic visits (besides 
screening) and adverse event inquiry will be performed at all visits and telephone 
calls/teleconferences (TCs).
If a patient withdraws from the study prior to the randomization 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.
Stage 2: Double-blind maintenance stage (variable in duration). Stabilized patients (see 
definition above) will be randomized to receive TV-46000 q1m sc injections, TV-46000 q2m sc 
injections, or placebo q1m sc injections in a 1:1:1 ratio. Patients that require a stabilization dose 
below 2 mg/day will not be randomized in the study. Also, as a precautionary measure, 
adolescent patients that will require a stabilization dose of more than 4 mg during the 
stabilization stage will not be randomized.
Patients in the TV-46000 groups will receive a dose of TV-46000 (q1m or q2m) that is 
equivalent to the oral dose on which they were stabilized in Stage 1. The maximal dose 
administered to adult patients will be equivalent to an oral risperidone dose of 5 mg/day, and the 
maximal dose administered to adolescents will be equivalent to 4 mg/day. Patients randomized to 
TV-46000 q1m or placebo sc will receive an sc injection of TV-46000 or placebo, respectively, 
at baseline and every 4 weeks (q4w) thereafter. Patients randomized to TV-46000 q2m will 
receive a TV-46000 injection at baseline and every 8 weeks (q8w) thereafter, and a placebo sc 
injection 4 weeks after baseline and q8w thereafter, to ensure blinding of the doses and durations 
of the TV-46000 injections and the placebo injections.
The study will continue on an outpatient basis (Table 2), and telephone contacts will take place 
weekly between clinic visits. If, in the judgment of the investigator, the patient is likely to 
relapse or pose a danger to himself/herself or others, that patient may be invited for an 
unscheduled visit and/or hospitalized if needed, and treatment with the study drug may be 
discontinued.
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 the 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.
The duration of patient participation in the study will include up to 4 weeks of screening, 
12 weeks of the oral conversion/stabilization stage, and a double-blind maintenance stage. The 
double-blind maintenance stage will be variable in duration, with patients continuing until they 
experience a relapse event; meet 1 or more of the study discontinuation or withdrawal criteria; or 

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remain relapse-free during the double-blind phase until the study is terminated because at least 
90 relapse events are recorded in the study adult population. 
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. Randomized 
patients 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. Patients 
who remain relapse-free when the study is terminated should be invited to perform the End-of-
Treatment visit within 4 weeks of the last injection. Therefore, a patient is considered a study 
completer if he or she experienced impending relapse or remained relapse-free at the time of 
study termination.
Patients will subsequently complete all end-of-study assessments. When the study ends, eligible 
patients may be offered the opportunity to enter the TV46000-CNS-30078 extension study to 
assess the long-term safety and tolerability of extended-release risperidone. This extension study 
is beyond the scope of this protocol, and a separate protocol was issued for it. If patients choose 
to enter the extension study, they will not need to complete the follow-up/exit visits in this study. 
For all other patients (ie, patients who experience a relapse event, meet 1 or more of the study 
discontinuation or withdrawal criteria, or do not consent to join the extension study), there will 
be 2 follow-up/exit visits that will take place at 4 weeks and 8 weeks after the last dosing visit. 
During the follow-up/exit period, patients will be treated according to the investigator’s 
judgement.
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.
The study duration will be approximately 30 months, from Q2 2018 (first patient in) to Q4 2020 
(last patient out). 
During the conduct of this study, an Independent Data Monitoring Committee (IDMC) will 
review accumulating unblinded safety and PK data on a regular basis to ensure the continuing 
safety of the study patients and study conduct issues (see Section 5.10.3). 
For COVID-19 updates, refer to Appendix N.
The study schematic diagram is presented in Figure 1.

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Figure 1:
Overall Study Schematic Diagram

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a Adolescent patients will receive doses equivalent to 2-4 mg/day oral risperidone. Patients that will require a stabilization dose below 2 mg/day will not be 
randomized in the study. 
b With the exception of the screening visit, pharmacokinetic samples will be collected at each in-clinic visit. 
c
 
 
 
d Patients randomized to the TV-46000 q1m or q2m sc groups in Stage 2 will receive TV-46000 sc at doses equivalent to the 2 to 5 mg/day dose of oral 
risperidone on which they were stabilized during Stage 1. Adolescent patients will receive a maximal TV-46000 dose equinvalent to 4 mg/day oral risperidone. 
e When the study ends, eligible patients may be offered the opportunity to enter the TV46000-CNS-30078 extension study to assess the long-term safety and 
tolerability of extended-release risperidone. This extension study is beyond the scope of this protocol and is detailed in a separate protocol. If patients choose to 
enter the extension study, they will not need to complete the follow-up/exit visits in this study. 
f For patients who experience a relapse event, meet 1 or more of the study discontinuation or withdrawal criteria, or do not consent to join the extension study, 
there will be 2 follow-up/exit visits that will take place 4 weeks and 8 weeks after the last dosing visit.
BL = baseline; EoS=end of study; EoT = end of treatment; FU = Follow Up; PK = pharmacokinetics; q1m=every month; q2m=every 2 months; 
sc=subcutaneous; TC – telephone call/teleconference; Wk = week.

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3.2.
Planned Number of Patients and Countries
Approximately 1260 patients will be screened to achieve enrollment of approximately 860 adult 
patients in Stage 1, including approximately 70 adult patients in Bulgaria.
The number of randomized adult patients in Stage 2 is planned to be approximately 520, 
including approximately 55 adult patients in Bulgaria. Details on the definition of evaluable 
patients and determination of the sample size are given in Section 9.1. Adolescent patients will 
only be enrolled in the US; any enrolled adolescents will be in addition to the aforementioned 
total.
The study is planned to be conducted in approximately 80 investigational centers in North 
America and Bulgaria.
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.
 
 
 
 
 
Moreover, the drug class of LAI atypical antipsychotics has not been studied extensively in 
children or adolescents (Lytle et al 2017). Although compliance in children and adolescents 
treated with antipsychotics is substantially higher than in adults, ranging from approximately 
74% to 88% (Pogge et al 2005, Yazdi et al 2008), LAIs may be considered for patients with 
confirmed schizophrenia and with risk factors for medication non-adherence: history of non-
adherence, severe symptoms, comorbid substance use, cognitive impairment, ambivalence or 
negative attitudes towards medication, and poor insight (Ferrin et al 2016). In the Pediatric Study 
 
 
 
 
 
Antipsychotic LAIs are viewed as maintenance therapy in stable patients with schizophrenia, but 
they are not currently approved for treatment of acute symptoms. Thus, the population for this 
study consists of adult and adolescent patients with chronic schizophrenia and excludes patients 
with acute disease. Only patients who have been stabilized on oral therapy with risperidone will 
be randomized into the double-blind maintenance stage of the study.

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3.4.
Stopping Rules for the Study
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (Section 7.1.5.3.1) 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:

new toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment

discontinuation of the development of the investigational medicinal product (IMP)
3.5.
 
For COVID-19 updates, refer to Appendix N.

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Table 1: TV46000-CNS-30072 (RISE) Study Procedures and Assessments (In-Clinic Visits and Telephone Contacts) –
Pre-Treatment Period (Screening and Stage 1)
Study Period
Pre-treatment Period
N/A
Screening
Stage 1: Oral Conversion and Stabilization Stagea
Unscheduled Visit
Visit number
V1
V2
V3b
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 Call e, 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 signs measurementk
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 Period
N/A
Screening
Stage 1: Oral Conversion and Stabilization Stagea
Unscheduled Visit
Visit number
V1
V2
V3b
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 Call e, f
X
X
Urine β-HCG test for women of childbearing 
potential
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-SS
X
X
X
X
X
CGI-In
X
X
X
X
AIMS
X
X
X
X
X
BARS
X
X
X
X
X
SAS
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X 
PSP (in adult patients only)
X
SQLS (in adult patients only)
X
EQ-5D-5L (in adult patients only)
X
CDSS
X
X
X
X
X
Healthcare resource utilization
X
DAI-10 (in adult patients only)
X

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Study Period
Pre-treatment Period
N/A
Screening
Stage 1: Oral Conversion and Stabilization Stagea
Unscheduled Visit
Visit number
V1
V2
V3b
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 Call e, f
X
X
Blood samples for plasma drug concentrationo
X
X
X
X
Oral risperidone dispensing (For qd intake)p
X
X
X
X
Dosage review and adjustment
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 
symptomsq
X
X
a If a patient withdraws from the study prior to the randomization 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. In addition, to reduce patient burden and to avoid unnecessary data collection, the 
investigator will have discretion in determining whether the procedures which are currently marked 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. 
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 contacts that take place 2 weeks after 
visit 4 will be referred to as “visit 4a”).

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f Each contact will include inquiries about injection site pain, suicidal ideation and behavior, 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.
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 CGI-I during Stage 1 will be relative to screening.
o During the in-clinic visits in Stage 1, if possible, the blood samples for PK assessment should be taken within an hour prior to dosing. In any case, the hour of 
the last dose taken prior to collection of the pharmacokinetic sample will be recorded on the CRF.
p 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.
q 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 a psychiatric deterioration as a result of 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; 
EQ-5D-5L=5-Level EuroQol Five Dimensions Questionnaire; ET=early termination; FSH=follicle stimulating hormone; FU=follow-up; HbsAg=hepatitis B 
surface antigen; HIV=human immunodeficiency virus; NPRS=Numeric Pain Rating Scale; PANSS=Positive and Negative Syndrome Scale; PK = 
pharmacokinetics; 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; V = Visit; 
Wk=week.

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Table 2:
TV46000-CNS-30072 (RISE) Study Procedures and Assessments (In-Clinic Visits and Telephone Contacts) –
Baseline, Double-Blind Maintenance Stage (Stage 2), End of Treatment/Early Termination and Follow-Up 
Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention
BL
The 24-week series from Visit 7 to Visit 12c repeats (Visits 13-18c, 19-24c, etc) 
until patient completion, relapse or early termination.
End of 
Treatment 
(EoT)/Early 
Termination 
(ET) Visit
Exitb
Unscheduled 
Visitc
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 
FU1
FU2
As deemed 
necessary by 
the 
investigator
Time point
Procedures and 
assessments 
Day1 Wk 
1-3 
Wk 4
Wk 
5-7
Wk 8
Wk 
9-11
Wk 12 Wk 
13-
15
Wk 
16
Wk 
17-19
Wk 20
Wk 
21-23
Wk 
24
Wk 
25-27
4 Wks 
after last 
dosing 
visit 
8 Wks 
after last 
dosing 
visit 
(EoS)
Allowed time window
±3 days
±3 days
N/A
In-Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Telephone Calld, e
X
X
X
X
X
X
X
Inclusion and exclusion 
criteria
Xf
Clinical laboratory testsg, h
X
X
X
X
X
X
X
Urine drug screen
X
X
Concomitant medication 
inquiry
X
X
X
X
X
X
X
X
X
X
X
Fully physical 
examination, including 
weight
X
X
X
X
Vital signs measurementi
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X
X
X
X
Xk
X
X
Serum β-HCG test for 
women of childbearing 
potential
X
X
X

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Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention
BL
The 24-week series from Visit 7 to Visit 12c repeats (Visits 13-18c, 19-24c, etc) 
until patient completion, relapse or early termination.
End of 
Treatment 
(EoT)/Early 
Termination 
(ET) Visit
Exitb
Unscheduled 
Visitc
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 
FU1
FU2
As deemed 
necessary by 
the 
investigator
Time point
Procedures and 
assessments 
Day1 Wk 
1-3 
Wk 4
Wk 
5-7
Wk 8
Wk 
9-11
Wk 12 Wk 
13-
15
Wk 
16
Wk 
17-19
Wk 20
Wk 
21-23
Wk 
24
Wk 
25-27
4 Wks 
after last 
dosing 
visit 
8 Wks 
after last 
dosing 
visit 
(EoS)
Allowed time window
±3 days
±3 days
N/A
In-Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Telephone Calld, e
X
X
X
X
X
X
X
Urine β-HCG test for 
women of childbearing 
potentiall
X
X
X
X 
X
X
X
X
Inquiry about pregnancy 
status (for women of 
childbearing potential)
X
X
X
X
X
X
X
PANSS
X
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
CGI-SS
X
X
X
X
X
X
X
X
X
X
CGI-Im
X
X
X
X
X
X
X
X
X
AIMS
X
X
X
X
X
X
X
X
X
X
BARS
X
X
X
X
X
X
X
X
X
X
SAS
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
PSP (in adult patients 
only)
X
X
Xn
X
X
X

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Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention
BL
The 24-week series from Visit 7 to Visit 12c repeats (Visits 13-18c, 19-24c, etc) 
until patient completion, relapse or early termination.
End of 
Treatment 
(EoT)/Early 
Termination 
(ET) Visit
Exitb
Unscheduled 
Visitc
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 
FU1
FU2
As deemed 
necessary by 
the 
investigator
Time point
Procedures and 
assessments 
Day1 Wk 
1-3 
Wk 4
Wk 
5-7
Wk 8
Wk 
9-11
Wk 12 Wk 
13-
15
Wk 
16
Wk 
17-19
Wk 20
Wk 
21-23
Wk 
24
Wk 
25-27
4 Wks 
after last 
dosing 
visit 
8 Wks 
after last 
dosing 
visit 
(EoS)
Allowed time window
±3 days
±3 days
N/A
In-Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Telephone Calld, e
X
X
X
X
X
X
X
SQLS (in adult patients 
only)
X
X
Xn
X
X
X
EQ-5D-5L (in adult 
patients only)
X
X
Xn
X
X
X
CDSS
X
X
X
X
X
X
X
X
X
X
Healthcare resource 
utilization
X
Xn
X
X
X
DAI-10 (in adult patients 
only)
X
X
X
Blood sample for 
pharmacogenetic analysis
Xo
Blood sample for 
biomarker analysisp
X
X
X
X
Blood samples for plasma 
drug concentrationq
X
X
X
X
X
X
X
X
X
X
Xr

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Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention
BL
The 24-week series from Visit 7 to Visit 12c repeats (Visits 13-18c, 19-24c, etc) 
until patient completion, relapse or early termination.
End of 
Treatment 
(EoT)/Early 
Termination 
(ET) Visit
Exitb
Unscheduled 
Visitc
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 
FU1
FU2
As deemed 
necessary by 
the 
investigator
Time point
Procedures and 
assessments 
Day1 Wk 
1-3 
Wk 4
Wk 
5-7
Wk 8
Wk 
9-11
Wk 12 Wk 
13-
15
Wk 
16
Wk 
17-19
Wk 20
Wk 
21-23
Wk 
24
Wk 
25-27
4 Wks 
after last 
dosing 
visit 
8 Wks 
after last 
dosing 
visit 
(EoS)
Allowed time window
±3 days
±3 days
N/A
In-Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Telephone Calld, e
X
X
X
X
X
X
X
Blood samples for plasma 
drug concentration 
(Adolescents only)
Xs
Assessment of stability 
Xt
Randomization
X
Placebo sc administrationu
X
X
X
X
X
X
X
Xv
TV-46000 q1m sc 
administrationu
X
X
X
X
X
X
X
Xv
TV-46000 q2m sc 
administrationu, w
X
X
X
X
Xv
Questions to assess ease 
of study drug 
administrationx
X
X 
X
Adverse event inquiry 
(including SAE reporting, 
injection site-related 
events including pain)y
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention
BL
The 24-week series from Visit 7 to Visit 12c repeats (Visits 13-18c, 19-24c, etc) 
until patient completion, relapse or early termination.
End of 
Treatment 
(EoT)/Early 
Termination 
(ET) Visit
Exitb
Unscheduled 
Visitc
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 
FU1
FU2
As deemed 
necessary by 
the 
investigator
Time point
Procedures and 
assessments 
Day1 Wk 
1-3 
Wk 4
Wk 
5-7
Wk 8
Wk 
9-11
Wk 12 Wk 
13-
15
Wk 
16
Wk 
17-19
Wk 20
Wk 
21-23
Wk 
24
Wk 
25-27
4 Wks 
after last 
dosing 
visit 
8 Wks 
after last 
dosing 
visit 
(EoS)
Allowed time window
±3 days
±3 days
N/A
In-Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Telephone Calld, e
X
X
X
X
X
X
X
Inquiry regarding alcohol 
consumption/illicit drug 
use 
X
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 symptomsz
X
X
X
X
X
X
X
a The double-blind maintenance stage will be variable in duration, with patients continuing until they experience a relapse event and complete all end-of-study 
assessments; meet 1 or more of the study discontinuation or withdrawal criteria; or remain relapse-free during the double-blind phase until the study is 
terminated because  at least 90 relapse events are recorded in the study in the ITT analysis set. Patients will continue study visits and assessments as shown in 
the table (ie, the same assessments performed at visits Visits 7 and 8 will be repeated at visits Visits 9 and 10, respectively). However, note that functional 
measures (PSP, SQLS, and EQ-5D-5L) and the healthcare resource utilization will be performed every 12 weeks.
b When the study ends, eligible patients may be offered the opportunity to enter TV46000-CNS-30078, the long-term safety and tolerability extension study. This 
extension study is beyond the scope of this protocol and is detailed in a separate protocol. If the patients choose to enter the extension study, they will not need 
to complete the follow-up/exit visits in this study. All other patients (ie, patients who experience a relapse event, meet 1 or more of the study discontinuation or 
withdrawal criteria, or do not consent to join the extension study), will undergo these 2 follow-up/exit visits. During the follow-up/exit period patients will be 
treated according to the investigator’s judgement. 
c 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 procedures which are currently marked 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 

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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. 
d Telephone contacts 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). 
e Each contact will include inquiries about injection site pain, suicidal ideation and behavior, 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). 
f Patient must meet randomization criteria in addition to other relevant inclusion criteria before randomization.
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 Vital sign measurements will include blood pressure [systolic/diastolic], respiratory rate, tympanic temperature, and pulse.
j 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.
k During the EoT visit, if in the judgment of the investigator the patient will not roll over into the extension study or will not come to one or both of the follow-up 
visits – an ECG should be performed.
l 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 study drug is administered.
m CGI-I during Stage 2 will be relative to the baseline visit.
n As of Visit 9, inclusive, this assessment will be conducted every 12 weeks thereafter (Visits 12, 15, 18, and so on).
o 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.
p Blood 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.
q Blood samples for PK assessment will be taken within an hour prior to dosing.
r 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 the 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.
s Another pharmacokinetic sample will be collected from adolescent patients at a supplementary in-clinic visit at Week 14 (2 Weeks after Visit 9). If it is not 
possible to take the sample at this visit, it may be taken 2 weeks after another in-clinic visit. Two additional samples, 3 weeks and 1 week post-injection, 
respectively, may be taken at the sponsor's discretion.
t Stability is defined as meeting all of the following criteria for at least for 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; Clinical Global Impression of Severity (CGI-S) score ≤4 (moderately ill); 
and CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2.
u Study drug will be administered per the patient’s assigned treatment group.
v Applicable only for EoT visit (ie, not ET). If in the judgment of the investigator, the patient will not roll over into the extension study or will not come to one or 
both of the follow-up visits – a dose of study drug should not be given in this EoT/ET EoT visit.

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w Patients randomized to the TV-46000 q2m group will receive a TV-46000 injection at the baseline visit and q8w thereafter and a placebo sc injection 4 weeks 
after baseline and q8w thereafter to ensure blinding.
x In the event that prefilled syringes become available during the study, this will be completed by the unblinded nurse who administers the study drug to the 
patients following the first 3 injections to each patient.
y Injection 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.
z 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 a psychiatric deterioration as a result of 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; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitudes Inventory 10-item version; ECG = electrocardiography; 
EQ-5D-5L=5-Level EuroQol Five Dimensions Questionnaire; EoS=end of study ;EoT=end of treatment; ET=early termination;FU=follow-up; NPRS=Numeric 
Pain Rating Scale; PANSS=Positive and Negative Syndrome Scale; PSP=Personal and Social Performance Scale; q1m = once monthly; 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; V = Visit; Wk=week.

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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 be enrolledin this study only if they meet all of the following criteria:
a.
The patient has a diagnosis of schizophrenia according to the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for >1 year (diagnosis 
must be reconfirmed by SCID-5) and has had ≥1 episode of relapse in the last 24 
months.
b. The patient has been responsive to an antipsychotic treatment (other than clozapine) 
in the past year based on investigator judgement (and discussions with family 
members, caregivers or healthcare professionals as applicable).
c.
[Revision 1] The patient has provided written informed consent and is competent to 
do so. For adolescent patients, written informed consent has been provided by each 
patient’s parent or legal guardian, and written assent has been provided by 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, tablet ingestion, sc depot 
injection, and discontinuation 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 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.
[Revision 1] The patient is a male or female of any ethnic origin, 13 through 65 years 
of age at screening.
k. [Revision 2] The patient has a body mass index between 18.0 and 38.0 kg/m2, 
inclusive at screening. 

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l.
The patient is in adequate health as determined by medical and psychiatric history, 
medical examination, electrocardiogram (ECG), serum chemistry, hematology, 
urinalysis, and serology.
m. [Revision 1] Women of childbearing potential (see Appendix E) 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 drugs and for the duration of the study and for 120 days 
after the last injection of study drug. Highly effective methods of contraception 
include:

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 and intrauterine hormone-releasing system; these need to be 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. [Revision 1] 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.
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 follow-up procedures and assessments as specified in this 
protocol.
Randomization Criteria:
The following criteria are randomization criteria and must be fulfilled at the baseline visit before 
randomization in addition to other relevant inclusion criteria: 

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p. The patient has not experienced mental or physical deterioration, which prevents 
participation in the study per investigator judgement.
q. The patient has demonstrated good compliance in following protocol requirements 
during Stage 1.

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). 
r.
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 will not be enrolled/randomized in this study if they meet any of the following criteria:
a.
The patient has a current clinically significant DSM-5 diagnosis other than 
schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar 
disorder, delirium, dementia, 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, 
clinically significant tardive dyskinesia, or other medical condition that would expose 
the patient to undue risk.
d. [Revision 1] 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 RNA 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 currently has or has 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.

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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 investigator’s judgement. 
h. The patient has a significant risk of committing suicide based on the patient’s medical 
history or 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 previously participated in a Teva-sponsored clinical study with 
TV-46000.
j.
The patient has a clinically significant deviation from normal in the physical 
examination.
k. The patient has clinically significant findings in biochemistry, hematology, ECG, or 
urinalysis results. 

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 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 the medications prohibited in this protocol.
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 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. 

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Every effort should be made to ensure 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 
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. 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. Alternatively, if the opportunity is available and the patient is eligible, the patient 
may be offered the option to participate in TV46000-CNS-30078, the long-term safety and 
tolerability extension study.
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 case report form 
(CRF); both the adverse events page and the relevant page of the CRF will be completed at that 
time.
The patient will be monitored 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 test IMP or study procedure is made). 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.
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.

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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
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. A serious or intolerable adverse event develops that necessitates discontinuation at the 
discretion of the investigator.
3. The investigator believes 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. A patient requires concomitant medication that may interfere with the 
pharmacokinetics of the study drug.
6. A patient relapses, as defined by the study’s relapse criteria (Section 9.5.1).
7. A 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 ms 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. A patient exhibits an event of possible drug-induced liver injury that requires 
immediate study treatment cessation and is defined as follows:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 times the 
upper limit of normal (ULN)

ALT or AST >5×ULN for more than 2 weeks

ALT or AST >3×ULN and total bilirubin level >2×ULN or international 
normalized ratio >1.5

ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
4.3.3.
Pharmacokinetic Sampling in Case of Patient Withdrawal
Note: Withdrawal under the above criteria (see Section 4.3.2) 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, 

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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 an 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 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
A patient who is randomized but does not complete all treatment periods will not be replaced 
with another eligible patient.
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.
If the patient is rescreened, an informed consent form (ICF) will need to be resigned.
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. 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
Investigational medicinal product is defined as the test IMP (Table 4).
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 
 
 
. 
 
 
 
 
 
 
 
 
 
For COVID-19 updates, refer to Appendix N.
5.1.1.1.
Starting Dose and Dose Levels
In general, TV-46000 will be administered to patients in the abdomen (except as indicated 
below) by sc injection, at intervals of q1m or q2m, at a dose equivalent to oral risperidone 2 to 5 
mg/day on which they were stabilized in Stage 1, per the conversion table below (Table 3). The 
maximal dose administered will be equivalent to an oral risperidone dose of 5 mg/day. Patients 
that require a stabilization dose below 2 mg/day will not be randomized in the study. Also, as a 
precautionary measure, adolescent patients that will require a stabilization dose of more than 4 
mg during the stabilization stage will not be randomized. 
Several investigational centers may be selected by the sponsor (based on the centers’ capabilities, 
sponsor's considerations, and prior clinical experience with injectable medication) for injection 
of study drug into the back of the upper arm, instead of the abdomen, to all or some of the 
enrolled patients at these sites (approximately 20% of the study patient population). 

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Table 3:
Conversion Table Between Oral Risperidone and TV-46000 Doses
Frequency of 
TV-46000 
Administration
Oral Risperidone Doses and Corresponding TV-46000 Doses
2 mg/day
3 mg/day
4 mg/day
5 mg/day (Adults Only)
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 arm and the left. If the chosen site is the abdomen, the injection will be 
administerd in an alternating manner to the right and to the left of the umbilicus. Further details 
will be provided in the dosing manual.
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 study manual.
For COVID-19 updates, refer to Appendix N.

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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 
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The sponsor’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.
For COVID-19 updates, refer to Appendix N.
5.3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
The US FDA requires a placebo-controlled study to demonstrate the efficacy and safety of 
TV-46000 for the maintenance treatment of patients with chronic schizophrenia. While it has 
been demonstrated that regular use of antipsychotics reduces the rate of relapses, treatment 
compliance is poor, which is often related to side effects. It is considered justified to treat 
patients with placebo after they have been stabilized on oral active treatment. Patients who 
experience a relapse will discontinue study drug and may be treated using standard of care.
5.4.
Other Medicinal Products/Non-Investigational Medicinal Products
In the US, oral risperidone for stabilization (Table 5) will be a commercial product supplied by 
the study center. In Bulgaria, oral risperidone for stabilization (Table 5) will be a commercial 
product supplied centrally by the sponsor. The brand name of the oral risperidone supplied will 
be recorded on the source documentation.

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Oral risperidone is to be stored according to the manufacturer’s Summary of Product 
Characteristics (SmPC).
Note that oral risperidone is mandated for use in this study; however, for the purposes of this 
study, it is not considered an IMP.
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 strength(s)/dosage level(s)
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 case the patient is withdrawn from this study, no further treatment is planned by the sponsor 
after the patient completes their participation in this study. Patients will be advised to return to 
their primary physician for additional treatment. Patients may be treated in the meantime per 
investigator judgment and instruction as applicable.
When the study ends, eligible patients may be offered the opportunity to enter the TV46000-
CNS-30078 extension study to assess the long-term safety and tolerability of extended-release 
risperidone. This extension study is beyond the scope of this protocol, and a separate protocol 
was issued for it.
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/exit period. Patient should be 
advised regarding potential risk of drowsiness, dizziness and other side effects of alcohol on 
risperidone treatment.

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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.
5.7.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.8.
 
 
 
 
 
 
 
 
 
 

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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.
5.9.
Randomization and Blinding
Patients will be randomized to receive doses of TV-46000 q1m sc injection, TV-46000 q2m sc 
injection, or placebo q1m sc injection in a 1:1:1 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). The doses of TV-46000 will be equivalent to 2 to 5 mg/day of oral 
risperidone (equivalent to the oral dose on which the patient was stabilized in Stage 1). Patients 
randomized to TV-46000 q1m or placebo sc will receive an sc injection of TV-46000 or placebo, 
respectively, at baseline and q4w thereafter. Patients randomized to TV-46000 q2m will receive 
a TV-46000 injection at baseline and q8w thereafter and a placebo sc injection 4 weeks after 
baseline and q8w thereafter to ensure blinding of the doses and durations of the TV-46000 
injections and the placebo injections.
Patients and investigators will remain blinded to the identity of the treatment administered to 
each patient. Due to the differences between the TV-46000 product and placebo, an unblinded 
nurse, not associated with rating the patient (including assessment of the injection site if needed) 
and independent from the study team, will be required at each site to administer the study drug. 
 
 
 
 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The randomization list will be assigned to the relevant treatment groups 
through a qualified service provider (eg, via the Interactive Response Technology [IRT] system). 
The generation of the randomization list and management of the IRT system will be done by a 
qualified service provider under the oversight of the responsible function at Teva. The 
specifications for randomization will be under the responsibility and oversight of Teva Global 
Statistics.
The sponsor’s clinical personnel (and delegates) involved in the study will be blinded to the 
identity of the IMPs until the database is locked for final analysis, and the IMP assignment is 
known. However, if a prioritized sample analysis is needed, bioanalytical and IDMC clinical 
pharmacology representatives are unblinded.
In the event of an emergency (ie, where knowledge of the study drug assignment is needed to 
make treatment decisions for the patient), the treatment group and dose to which the patient has 
been allocated can be determined by accessing the IRT system. All investigational centers will 

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be provided with details on how to access the 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 pharmacist at each investigational center who will dispense the IMPs will know the IMP 
assignments for each patient. In addition, up to 2 other individuals from each investigational 
center will know the IMP assignments to provide quality assurance and oversight in their 
preparation and administration, as necessary. These individuals will not be involved in conduct 
of any study procedures and assessment of any adverse events and should not discuss the 
medication assignment or appearance with others (except for the unblinded nurse administering 
the medication).
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. At the time of analysis (after the end of study), after receiving 
unblinding request from Teva statistician, the service provider will provide the unblinded IMP 
assignment according to the processes defined in the relevant SOP. 
5.10.2.
Blinding and Unblinding
Pharmacokinetic data will be assessed during the study. Personnel responsible for bioanalysis 
will be provided with the randomization code in order to facilitate the analysis. However, the 
personnel responsible for bioanalysis will not have access to clinical safety and efficacy data and 
will provide unblinded pharmacokinetic concentration data to the unblinded statistician for 
provision to the IDMC members for review, and to a pharmacometrics modeler, independent of 
the study team, for update of the population pharmacokinetic model. In addition, the modeler 
may receive other relevant patient information to update the model (such as demography, certain 
clinical laboratory results, etc). The detailed process of data delivery to the IDMC will be 
described in the IDMC charter. The detailed process of pharmacokinetic analysis during the 
course of the study will be described in the pharmacokinetic analysis plan. The pharmacokinetic
concentrations and modeling results will not be available to the sponsor’s study team until 
unblinding of study. 
For information about personnel who may be aware of IMP assignments (including an unblinded 
nurse and an unblinded pharmacist), see Section 5.9. These individuals will not be involved in 
conduct of any study procedures or assessment of any adverse events.
In case of a serious adverse event, 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 each investigational center via the IRT, 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. The patient's IMP assignment should not be revealed to the sponsor.

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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.
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), the Global Patient Safety and 
Pharmacovigilance (GPSP) team may independently request that the blind code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data.
5.10.3.
Data Monitoring Committee
During the conduct of this study there will be an IDMC that will review accumulating unblinded 
safety and pharmacokinetic data on a regular basis (as detailed in the IDMC charter) to ensure 
the continuing safety of the study patients and any study conduct issues. 
The IDMC will be composed of independent physicians with expertise in the relevant therapeutic 
field and other relevant experts, such as a statistician and a pharmacokinetic specialist. 
The IDMC chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the study. The sponsor will work closely with the committee to 
provide the necessary data for review.
The IDMC will provide recommendations about modifying, stopping, or continuing the study. 
The conduct and specific details regarding the IDMC sessions will be outlined in the IDMC 
charter.
5.11.
 
 
 

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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 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) (Guy 1976a).
The CGI-I will be administered by the investigator/trained rater at all visits during the study 
(except for the screening and baseline visits). 
6.1.2.
Positive and Negative Syndrome Scale (PANSS)
The PANSS (Kay et al 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 by a clinician or trained mental health professional that 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 of 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 et al 2015).
6.2.2.
Quality of Life Scales
6.2.2.1.
Schizophrenia Quality of Life Scale (SQLS)
SQLS will be administered to adult patients only at the time points specified in Table 1 and 
Table 2, and is used to capture quality of life. The 33-item measure yields 3 subscale scores: 

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psychosocial, motivation/energy, and symptoms/side effects (Wilkinson et al 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 and 
de Charro 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 track very closely (r=0.93), and only the 
shorter DAI-10 will be used. 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 et al 1983, Nielsen et al 2012). A positive total score indicates a 
compliant response and a negative 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 et al 2000). The PSPis 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 indicating functioning so poor that intensive 
supervision is required.
6.2.5.
Healthcare Resource Utilization
Healthcare resource utilization will be assessed for both adult and adolescent patients 
approximately every 3 months (at the time points specified in Table 1 and Table 2) for 
hospitalizations, emergency room (ER) visits, and outpatient visits (ie, not including protocol-
mandated outpatient visits). Hospitalizations will be assessed as the percentage of patients with 
hospitalizations over the past 4 weeks, associated length of stay, and the number of 
hospitalizations among patients who were hospitalized. In addition, the percentage of patients 
with ER visits and number of ER visits over the past 4 weeks and the percentage of patients with 
outpatient visits and number of outpatient visits over the past 4 weeks will be evaluated.

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This should be completed by the site investigator/coordinator through patient interviews. and 
where possible, verification against medical records should be performed. The family member or 
caregiver may also need to provide input.
6.2.6.
Clinical Global Impression of Severity 
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 
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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.
A relapse event, defined per one of the criteria listed (see primary endpoint definition in 
Section 2.1), will not be automatically classified as an adverse event unless specifically judged as 
such by the investigator. 
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 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 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 case 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 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 Safety Monitoring Plan.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 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 as follows:
Table 6:
The Relationship of an Adverse Event to the IMP
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 that time 
period from signature of the ICF 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.
A relapse event, defined per one of the criteria listed (see primary endpoint definition in 
Section 2.1), will not be automatically classified as a serious adverse event unless specifically 
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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 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 1 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× the 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 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 SUSAR reporting, the version of the RSI at the time of occurrence of the SUSAR 
applies.

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A serious adverse event that is not included in the Listing of Adverse Reactions in the RSI by its 
specificity, severity, outcome, or frequency is considered an unexpected adverse event.
The sponsor’s 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 team.
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

investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility and reasonable possibility)
Additional information includes:

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event

pertinent laboratory or other diagnostic test data

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
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 team 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.
For double-blind studies, blinding will be maintained for all study personnel except the 
unblinded nurse. Therefore, in case of a SUSAR, only the LSO/CRO will receive the unblinded 
report for regulatory submission; the others will receive a blinded report.
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 
related to IMP

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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 end of 
study, 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 were 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 defect, 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 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 and 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 defect, 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 serious adverse event, as appropriate.
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, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

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
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.
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 of the reference range will be judged by the 
investigator as belonging to 1 of the following categories:

abnormal and not clinically significant

abnormal and clinically significant

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Table 7:
 
 
 
 
For COVID-19 updates, refer to Appendix N.
7.4.1.
 
 
 
Table 7.

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7.5.
Physical Examinations
Full physical examinations, including height (to be obtained at the screening visit only) and 
weight, will be performed at the time points detailed in Table 1 and Table 2. 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; 

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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) 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 
of the reference ranges will be judged by the investigator as belonging to 1 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 at 
all other in-clinic visits. A qualified physician at a central diagnostic center will be interpreting 
the ECG.
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
1 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) 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.
7.8.
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 below as applicable. 

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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/nodules 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 case an adverse event related to an injection site reaction is reported, intensity of injection 
pain will be assessed by patients using an 11-point NPRS (0 [no pain] to 10 mm [worst pain]) 
(Williamson and Hoggart 2005). Pain measurement will be evaluated during visits and telephone 
calls until resolution. The exact timing will be captured in the source documentation. 
7.9.
Assessment of Suicidality
Risperidone is considered to be central nervous system-active. In addition, there is an increased 
risk of suicide attempt 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 

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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 or during this clinical study.
The study population being administered TV-46000 or placebo 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 scale.
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 et al 2011). The interview and rating for the 
C-SSRS will be conducted by a rater specifically trained to rate the scale (per the minimum 
requirements outlined by the scale author), regardless of education level, who has appropriate 
clinical trial experience with C-SSRS administration, after review and approval by the Teva 
clinical project physician or designee. 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 C-SSRS will be administered at screening (baseline/screening version) and all 
post-screening visits (“since last visit” version) during the study, as well as during phone 
contacts (“since last visit” version).
7.9.2.
Clinical Global Impression-Severity of Suicidality
The CGI-SS scale provides an overall clinician-rated assessment of the risk of suicidality 
(Lindenmayer et al 2003). 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 and all visits during the study.
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.

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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 and Angus 
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 et al 1993). This clinician-administered instrument consists of 
9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe). 
7.11.
Other Assessments
 
 
 

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Table 8:
 
 
 
 
 
 

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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.
 
 
 
 
 
 
 
 
 
.
8.4.
Pharmacogenetics
 
 
 
 
 
The final list of genes to be evaluated 
will be determined at the time of analysis to be able to account for the most current research. The 
planned pharmacogenetic analysis and results of other potential genetic factors will be detailed in 
a separate document that will encompass the latest scientific advances related to this evaluation.

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9.
STATISTICS
This section describes the statistical analysis as foreseen at the time of planning the study. 
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).
9.1.
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2.
Analysis Sets
9.2.1.
Enrolled Patients Set
The enrolled patients set will include all patients who have met study eligibility requirements for 
Stage 1 and received oral risperidone. 

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9.2.2.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include adult patients randomized to the double-blind 
maintenance stage (Stage 2), regardless if they have received treatment or not. In the ITT 
analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
The purpose of the primary analyses is to estimate the effect of randomized treatment only, 
omitting any effect of additional treatment that may be administered after discontinuation of the 
randomized treatment. Accordingly, the ITT analysis set complies with while-on-treatment 
strategy1 that will be taken with regard to the intercurrent event of treatment discontinuation, 
with censoring at this intercurrent event. This study estimand will be the difference in time to 
relapse (survival) under the treatment to which the patient was initially randomized until last 
treatment or early termination of all adult patients who were successfully stabilized on oral 
risperidone at a daily dose range of 2 mg to 5 mg.
9.2.3.
Extended Intent-to-Treat Analysis Set 
The extended intent-to-treat (eITT) analysis set will include all patients (adults and adolescents) 
randomized to the double-blind maintenance stage (Stage 2), regardless if they have received 
treatment or not. In the eITT analysis set, treatment will be assigned based on the treatment to 
which patients were randomized, regardless of which treatment they actually received.
9.2.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set will include all patients in the ITT analysis set who have no 
major protocol deviations. In this analysis set, treatment will be assigned based on the treatment 
patients actually received. The PP analysis set will be discussed before unblinding and findings 
will be documented in the study data review document.
9.2.5.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive ≥1 dose of study 
treatment or placebo in the double-blind maintenance stage (Stage 2). In the safety analysis set, 
treatment will be assigned based on the treatment patients actually received, regardless of the 
treatment to which they were randomized, unless otherwise specified.
9.2.6.
Pharmacokinetics Analysis Set
The pharmacokinetics analysis set will include all patients from the safety analysis set who also 
have ≥1 plasma concentration measured.
9.3.
Data Handling Conventions
For all variables, only those observed data from the patients will be used in the statistical 
analyses, ie, there is no plan to estimate missing data, unless otherwise specified. Data from 
                                                
1 ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guidance on statistical 
principles for clinical trials. EMA/CHMP/ICH/436221/2017. European Medicines Agency. 30 August 2017.

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patients who did not relapse will be censored at the last valid relapse assessment date. Detailed 
data imputation rules will be described in the statistical analysis plan.
9.3.1.
Handling Withdrawals and Missing Data
Missing data will not be imputed, unless otherwise specified.
9.4.
Study Population
The eITT analysis set (Section 9.2.3 ) will be used for all study population summaries of the 
double-blind treatment stage unless otherwise specified. Summaries will be presented  by 
treatment group and for all patients. If the number of adolescents permits, summaries will also be 
presented by age subgroup.The primary analysis will be conducted on the ITT analysis set 
(Section 9.2.2), and the eITT analysis set (Section 9.2.3) will be used for analysis of the key 
secondary endpoints unless otherwise specified. The analysis set on which analysis for other 
endpoints will be conducted will be specified on a case-by-case basis. The enrolled patients set 
(Section 9.2.1) will be used for data summaries before the double-blind treatment stage.
9.4.1.
Patient Disposition
Data from patients screened and enrolled in Stage 1; patients who were enrolled in Stage 1 but 
not randomized for the double-blind stage and reason for not randomized; patients who were 
randomized; patients who were randomized but not treated; patients in the ITT patients in the 
eITT, PP, safety, and pharmacokinetics analysis sets; patients who completed the study; and 
patients who withdrew from the study will be summarized using descriptive statistics. Data from 
patients who withdrew from the study will also be summarized by reason for withdrawal using 
descriptive statistics. Adolescent patient disposition may be summarized separately, if 
applicable.
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 the descriptive statistics. For 
continuous variables, descriptive statistics (number [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, the eITT analysis set, and the eITT subset of adolescents will be used for 
the summaries, as applicable. 
9.5.
Efficacy Analysis
9.5.1.
Primary Endpoint
The primary efficacy endpoint is time to impending relapse. Patients meeting any 1 or more of 
the below impending relapse criteria are considered relapsed. Relapse is defined as 1 or more of 
the following items:

CGI-I of ≥5 (greater than or equal to minimally worse, ie, minimally worse, much 
worse or very much worse) AND

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
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

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 increase of ≥4 on the combined score of 
these 4 PANSS items (conceptual disorganization, hallucinatory behavior, 
suspiciousness, and unusual thought content) since randomization

hospitalization due to worsening of psychotic symptoms (including partial 
hospitalization programs), excluding hospitalization for psychosocial reasons

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

violent behavior resulting in clinically significant self-injury, injury to another person, 
or property damage.
Time to impending relapse will be calculated as the earliest date the patient meets ≥1 of the 
impending relapse criteria minus the randomization date plus 1. 
The absolute increase of the combined score of the 4 PANSS items is the sum of the increases of 
those scores (ignoring the decreases).
9.5.2.
Key Secondary Endpoints
The eITT analysis set (Section 9.2.3) will be used for all summaries in this section, unless 
otherwise specified.
For the endpoints that are evaluted only in the adult population, the analysis will be conducted on 
the ITT analysis set.
The key secondary endpoints are listed in Section 2.1 and described in detail below.
9.5.2.1.
Time to Impending Relapse in the eITT Analysis Set
Time to impending relapse using the same definition and primary analysis that is described in 
Section 9.5.1 using the eITT analysis will be employed. 
9.5.2.2.
Impending Relapse Rate at Week 24
This rate will be estimated using the Kaplan-Meier method.
9.5.2.3.
Percentage of Patients Who Maintain Stability at Endpoint 
Stability is defined as meeting all of the following criteria for at least 4 consecutive weeks: 
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. 

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The percentage will be calculated as the number of patients who maintained stability at endpoint 
divided by the number of eITT patients that adhere to treatment for at least 4 weeks or 
experienced relapse in the given treatment group. 
This analysis estimates the treatment effect of randomized treatment on patient's stability once 
the patient adheres to treatment long enough until the last treatment. The use of eITT analysis 
complies with while on treatment estimand and will be comprised of the difference in 
proportions under the treatment to which the patient was initially randomized of all patients who 
were successfully stabilized on oral risperidone at a daily dose range of 2 mg to 5 mg. 
Accordingly, this estimand addresses the clinical question to what extent patients improve their 
chances to maintain stability once they start the treatment if the patient adheres to the treatment 
long enough.
9.5.2.4.
Percentage of Patients Achieving Remission at Endpoint
Positive symptom, negative symptom, and overall symptom remission will be examined and are 
defined by Andreasen et al (2005) including severity and duration criteria. All remission criteria 
can be derived from PANSS items.
For overall symptom remission, the patient must not relapse during the study and in addition, 
over a period of at least 6 months preceding the endpoint, maintain scores of ≤3 on each of the 8 
specific PANSS items: P1 (delusions), G9 (unusual thought content), P3 (hallucinatory 
behavior), P2 (conceptual disorganization), G5 (mannerisms/posturing), N1 (blunted affect), 
N4 (social withdrawal), and N6 (lack of spontaneity). 
The percentage will be calculated as the number of patients who achieved remission at endpoint 
divided by the number of eITT patients that adhere at least 6 months or experienced relapse in 
the given treatment group.
This analysis estimates the treatment effect of randomized treatment on patient's remission once 
the patient adheres to treatment long enough until the last treatment. The use of eITT analysis 
complies with the while on treatment estimand, and will be comprised of the difference in 
proportions under the treatment to which the patient was initially randomized of all patients who 
were successfully stabilized on oral risperidone at a daily dose range of 2 mg to 5 mg. 
Accordingly, this estimand addresses the clinical question to what extent patients improve their 
chances to achieve remission once they start the treatment if the patient adheres to the treatment 
long enough.
9.5.2.5.
Observed Rate of Impending Relapse at Endpoint
Observed rate of impending relapse will be calculated as the number of patients who relapsed by 
endpoint divided by the number of patients in each treatment group.
9.5.2.6.
Drug Attitudes Inventory 10-item Version
The change from baseline to endpoint in total score will be calculated.
9.5.2.7.
Schizophrenia Quality of Life Scale
The change from baseline to endpoint in total score will be calculated.

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9.5.2.8.
Time to Impending Relapse in Adolescent Patients with Schizophrenia
Time to impending relapse using the same definition and primary analysis that was described in 
Section 9.5.1 will be used on the eITT analysis set using adolescent patients alone.
This assessment of time to impending relapse in adolescent patients is pending randomization of 
at least 10 adolescent patients with clinically sufficient exposure.
 
 
9.5.3.1.
 
9.5.3.2.
Healthcare Resource Utilization
The percentage of patients who were hospitalized, number of hospitalizations, and length of 
hospital stay (number of days); percentage of patients who had ER visits and number of ER 
visits; and percentage of patients who had outpatient visits and number of outpatient visits will 
be calculated.
9.5.3.3.
Change in PANSS Total Score from Baseline to Endpoint 
The change from baseline to endpoint in total score will be calculated.
9.5.3.4.
CGI-I Score at Endpoint
CGI-I at endpoint will be analyzed.
9.5.3.5.
Personal and Social Performance Scale
The change from baseline to endpoint in total score will be calculated.
9.5.4.
Planned Method of Analysis
The ITT analysis set (Section 9.2.2) will be used for all efficacy analyses. Summaries will be 
presented by treatment group. Analysis that will be conducted on the eITT analysis set or on the 
adolescent patient subset of the eITT will be described below, as applicable. 
9.5.4.1.
Primary Efficacy Analysis
Time to impending relapse will be calculated as the earliest date the patient meets ≥1 of the 
impending relapse criteria minus the randomization date plus 1. Data from patients who did not 
relapse will be censored at the last valid assessment. Time to impending relapse for TV-46000 
and placebo will be compared using the stratified log-rank test at significance levels described in 
Section 9.6. Hazard ratios and their 2-sided 95% confidence intervals (CIs) for TV-46000 q1m 

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and q2m versus placebo will be analyzed using a Cox proportional hazard model, with treatment 
and stratification variables as the factors, as described in Section 5.9. 
Kaplan-Meier curves will be provided to present impending relapse rate data over time.   
9.5.4.2.
Sensitivity Analysis
A sensitivity analysis will be conducted to assess the impact of large intervals between the 
previous assessment and the assessment at the time the first relapse was observed via the interval 
censoring method. Sensitivity analysis will also be conducted by tipping point analysis that 
imputes time to relapse for dropouts (for reasons suspected to be related to relapse) with 
increasing risk to relapse compared to similar patients in the same treatment group that continue 
treatment. 
The PP analysis set will also be used as supplemental analysis to evaluate the primary efficacy 
variable. Details will be provided in the statistical analysis plan. Senstivity analysis will be 
conducted on the ITT analysis set.
For COVID-19 updates, refer to Appendix N.
9.5.4.3.
Subgroup Analysis
Additional subgroup analysis for the primary endpoint, including region, will be described in the 
statistical analysis plan.
9.5.4.4.
Key Secondary Analyses
The fixed sequential (hierarchical) Strategy (FDA 2017) will be used to control the overall Type-
I statistical error in the study for both primary and secondary efficacy endpoints. The key 
secondary endpoints will be analyzed in a pooled manner for q1m and q2m. The details about the 
Type-I statistical error control for the key secondary endpoints will be discussed in the statistical 
analysis plan.
9.5.4.4.1. Time to Event Key Secondary Analysis 
For the key secondary endpoint discussed in Section 9.5.2.1, time to impending relapse in adult 
and adolescent patients will be assessed similarly to the Primary Efficacy Analysis using the 
eITT Analysis Set (Section 9.2.2). The Cox proportional hazard model will include patient age 
group (if applicable) along with treatment, and the aforementioned stratification variables as the 
factors.
For the key secondary endpoint discussed in Section 9.5.2.8, time to impending relapse in 
adolescent patients will be assessed if the number of randomized patients will be at least 10 with 
clinically sufficient exposure. The method will be similar to the Primary Efficacy Analysis, but 
will use the adolescent patients subset.  Type-I statistical error control will be discussed in 
Multiple Comparisons and Multiplicity.
9.5.4.5.
Key Secondary Efficacy Analysis 9.5.2.2-9.5.2.7 
Impending relapse rate at week 24 will be estimated using the Kaplan-Meier method and 
calculated as 1 minus the proportion of patients free of impending relapse events at week 24. The 
Greenwood formula will be used to calculate standard errors for impending relapse rates at week 

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24, and the pooled standard errors will be used for hypothesis testing using z-statistics, assuming 
that the differences between TV-46000 and placebo follow a normal distribution of large 
samples. 
Two-sided 95% CIs of the differences will also be calculated.
The observed impending relapse rates at endpoint will be compared between groups using the 
Cochran–Mantel–Haenszel (CMH) test adjusting for stratification variables.
The analyses of the proportion of patients who maintain stability at endpoint and the proportion 
of patients achieving remission at endpoint in Stage 2 will be described in the statistical analysis 
plan.
Change from baseline of DAI-10 and SQLS total score, will be analyzed using an analysis of 
covariance (ANCOVA) method, with treatment and stratification variables as factors and 
baseline (score at the end of Stage 1) as a covariate. Additional details regarding the anaysis will 
be documented in the statistical analysis plan.
The eITT analysis set (Section 9.2.3) will be used for all summaries in this section, unless 
otherwise specified.Type-I statistical error control will be discussed in Multiple Comparisons 
and Multiplicity.
 
 
 
 
 
 
 
 
 
 
9.6.
Multiple Comparisons and Multiplicity
, a fixed sequential (hierarchical) testing 
approach will be implemented. If the resulting first p-value of the primary efficacy hypothesis 
test comparing q1m to placebo is found to be significant at 0.05 alpha, then the second primary 
efficacy hypothesis (q2m vs. placebo) will be interpreted inferentially at the same alpha level of 

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0.05. If the first primary hypothesis fails to reach significance no further formal hypothesis 
testing will be performed.
Type-I error will be further controlled for the key secondary endpoints by employing  fixed 
sequential (hierarchical) testing strategy within each endpoints family (primary endpoints and 
key secondary endpoints). Secondary endpoints will be analyzed in a pooled manner for the 
treatment groups if the two primary endpoints are found to be significant. Further details about 
the Type-I statistical error control will be discussed in the statistical analysis plan.
A fixed-sequence (hierarchical) testing procedure will be implemented to control the Type-I 
error rate. The sequence of the secondary endpoints comparisons will be as follows:
1. Time to impending relapse in the eITT analysis set
2. Impending relapse rate at week 24
3. Percentage of patients who maintain stability at endpoint
4. Percentage of patients achieving remission at endpoint
5. Observed rate of impending relapse at endpoint
6. DAI-10 change from baseline to endpoint 
7.
SQLS change from baseline to endpoint
8. Time to impending relapse in adolescent patients with schizophrenia
If the first comparison is found to be significant, then the next comparison of interest will be 
interpreted inferentially at the same alpha level. This process will continue either until all 
comparisons were tested inferentially or until the point at which the resulting 2-sided test is 
insignificant at the same alpha level. 
 
. Any p-
value associated with these comparisons will be considered as nominal p-value and will not be 
used for inference.
 
9.7.
Safety Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.5).
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 test IMP (ie, reasonable 
possibility; see Section 7.1.4) (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 treatment group. Patient listings of serious adverse events and 
adverse events leading to withdrawal will be presented.

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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 (see 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. 
Adjustment to stratification factors may be conducted as appropriate.
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.
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.
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.
Safety data collected in Stage 1 will also be summarized using descriptive statistics in the 
enrolled patients set.
Selected safety data will also be presented by site of injection (abdomen vs arm) and by age 
group (adolescents [ages 13-17] and adults [18 years of age and above]), as applicable.
Separate summaries for adolescent patients may be presented separately for some analyses, as 
applicable, and will be described in the Statistical Analysis Plan.
9.8.
Tolerability Analysis
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 Section 7.8 as applicable. 
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 
of patients who withdrew early due to adverse events, respectively, divided by number of 
patients in each treatment group, and will be presented using descriptive statistics.
Time to all-cause discontinuation will be calculated as the discontinuation date minus the 
randomization date plus 1. Kaplan-Meier curves for the time to discontinuation as a result of all 
causes will be plotted.
Separate summaries for adolescent patients might be presented separately for some analyses, as 
applicable, and will be described in the Statistical Analysis Plan.

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9.9.
 
 
 
 
 
 
 
 
9.11.
Pharmacokinetic/Pharmacodynamic Analysis
 
 
 
 
 
. 
 
 
 
 
9.13.
Planned Interim Analysis
There will be no interim analysis in this study. 

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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 studies 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, 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 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.
Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in 
schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005;62:441-9.
Asarnow R, Brown W, Strandburg R. Children with a schizophrenic disorder: neurobehavioral 
studies. Eur Arch Psychiatry Clin Neurosci. 1995;245:70-9.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 May;154:672-6.
Barnes TR, Curson DA. Long-term depot antipsychotics. A risk-benefit assessment. Drug Saf 
1994;10:464-79.
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.
EAST 6 (Version 6.3) manual, Cytel Statistical Software & Services, Cytel Inc. Volume 10, 
Page 1931, 11Jul2014.
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16:199–208.
FDA. Multiple Endpoints in Clinical Trials. Guidance for Industry. January 2017.
Ferrin M, Gosney H, Marconi A, Rey JM. Using antipsychotic medication for the treatment of 
schizophrenia in children and adolescents. In Rey JM (ed), IACAPAP e-Textbook of Child and 
Adolescent Mental Health. Geneva: International Association for Child and Adolescent 
Psychiatry and Allied Professions 2016.
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-
183.
Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: diagnostic stability and 
predictive validity. Am J Psychiatry 2000;157(10):1652-9. 

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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.
Kane JM, Sanchez R, Perry PP, Jin N, Johnson BR, Forbes RA, et al. Aripiprazole intramuscular 
depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, 
randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2012;73(5):617-24.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr 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. The InterSePT scale 
for suicidal thinking reliability and validity. Schizophr Res. 2003;63(1–2):161–70. 
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):747-750.
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.
Pogge DL, Singer MB, Harvey PD. Rates and predictors of adherence with atypical 
antipsychotic medication: a follow-up study of adolescent inpatients. J Child Adolesc 
Psychopharmacol. 2005;15(6):901-12.
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.

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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;177:42-46.
Williamson A, Hoggart B. Pain: A review of three commonly used pain rating scales. J Clin 
Nurs 2005;14(7):798-804.
Yazdi K, Unterlass G, Kemmler G, et al. Factors influencing adherence in children and 
adolescents treated with antipsychotics or antidepressants. Prim Care Companion J Clin 
Psychiatry 2008;10(2):160-1.

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16.
SUMMARY OF CHANGES
16.1.
Global Amendment 03 (Dated 19 April 2020) 
The primary reason for this amendment is to rescind the previous interim analyses strategy, and 
to perform the final statistical analysis of the study data when at least 90 relapse events are 
observed, without any interim analysis. 
The original assumptions for sample size determination in the initial protocol were as follows:

a placebo effect (namely, median time to impending relapse of 7 months in the placebo 
group) similar to that observed in a similarly-designed study (Kane et al 2012);

a hazard ratio of 1.82 (placebo vs TV-46000 for both dosing regimens);

a randomization ratio of 1:1:1 (q1m:q2m:placebo), with 2 primary hypotheses to be 
tested (q1m vs placebo and q2m vs placebo) at an overall 2-sided alpha of 0.050.
As the study progressed, the preliminary study design assumptions were found to no longer hold  
as the pooled cumulative number of relapse events (across all treatment groups, due to blinding) 
was lower than anticipated, based on the above mentioned median time to relapse and hazard 
ratio. A stronger treatment effect, a longer time to relapse for the placebo group, and an 
increased early termination (ET) rate - either as single factors or in combination - may cause this 
decrease in the rate of observed events. Since Teva personnel and delegates are blinded to the 
treatment assignments, the precise underlying reasons are not known at this time. 
An earlier analysis will permit earlier completion of this double blind, placebo-controlled study 
(TV46000-CNS-30072) and earlier roll-over of patients into the ongoing TV46000-CNS-30078 
safety extension study, in which all patients receive treatment with TV-46000.
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.
In addition to the reasons mentioned above, an earlier completion may be even more important 
now given the COVID-19 challenges.
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Minor editorial changes (typos, punctuation, etc) have been made to the 
protocol (and protocol synopsis, as appropriate).
Table 2 (Study Procedures and Assessments) and  Figure 1 (Overall Study Schematic Diagram) 
have also been revised to reflect the changes described below. 

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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 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 
03, new address following 
relocation of sponsor 
offices.
CLINICAL STUDY PROTOCOL SYNOPSIS
Sample Size Rationale:
Median time to impending relapse was observed to be 7 months 
in the placebo group in a similarly designed study 
(RISPERDAL CONSTA, Janssen Pharmaceuticals,
US PI Kane et al 2012).
Median time to impending relapse was observed to be 7 months 
in the placebo group in a similarly designed study (Kane et al 
2012).
Correction. 
For consistency with 
Section 9.1.
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
...
 
 
 
 
 
 
Clarification and 
simplification.

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...
...
3. STUDY DESIGN
3.1. General Study Design and Study Schematic Diagram
The study will continue on an outpatient basis (Table 1Table 2), 
and telephone contacts will take place
weekly between clinic visits.
The study will continue on an outpatient basis (Table 2), and 
telephone contacts will take place
weekly between clinic visits.
Correction.
The double-blind maintenance stage will be variable in duration, 
with patients continuing until they experience a relapse event; 
meet 1 or more of the study discontinuation or withdrawal 
criteria; or remain relapse-free during the double-blind phase 
until the study is terminated for efficacy due to a successful 
interim analysis or because 207 at least 90 relapse events are 
recorded in the study adult population. 
...
Patients who remain relapse-free when the study is terminated 
for efficacy due to a successful interim analysis or because 207 
relapse events in adults are recorded in the study should be 
invited to perform the End-of-Treatment visit within 4 weeks of 
the last injection.
The double-blind maintenance stage will be variable in duration, 
with patients continuing until they experience a relapse event; 
meet 1 or more of the study discontinuation or withdrawal 
criteria; or remain relapse-free during the double-blind phase 
until the study is terminated because at least 90 relapse events 
are recorded in the study adult population.
...
Patients who remain relapse-free when the study is terminated 
should be invited to perform the End-of-Treatment visit within 4 
weeks of the last injection.
There will be no interim 
analysis for efficacy in this 
study; the final analysis 
will be performed earlier 
due to the low event rate. 
Correction and 
simplification.
The study duration will be approximately 30 months, from Q2 
2018 (first patient in) to Q4 2020 (last patient out). In case of a 
successful interim analysis, the study will be terminated earlier 
(see Section 9.6)  
The study duration will be approximately 30 months, from Q2 
2018 (first patient in) to Q4 2020 (last patient out). 
There will be no interim 
analysis for efficacy in this 
study.
See New wording column
Figure 1 (Overall Study Schematic Diagram) has been revised 
as described below:

Number of randomized patients was updated from 
~417 to ~520;

Number of patients randomized to each treatment arm 
was updated from ~139 to ~173.
Updated enrollment 
projections.

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3.2. Planned Number of Patients and Countries
Approximately 993 1260 patients will be screened to achieve 
enrollment of approximately 695 860 adult patients in Stage 1, 
including approximately 67 70 adult patients in Bulgaria.
The number of randomized adult patients in Stage 2 is planned 
to be approximately 417520, including approximately 40 55
adult patients in Bulgaria. 
Approximately 1260 patients will be screened to achieve 
enrollment of approximately 860 adult patients in Stage 1, 
including approximately 70 adult patients in Bulgaria.
The number of randomized adult patients in Stage 2 is planned 
to be approximately 520, including approximately 55 adult 
patients in Bulgaria. 
Updated enrollment 
projections.
3.4. Stopping Rules for the Study
There are no formal rules for early termination of this study. 
During the conduct of the study, serious adverse events will be 
reviewed (Section 7.1.5.3.1) 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:

new toxicological or pharmacological findings or 
safety issues invalidate the earlier positive benefit-risk 
assessment

discontinuation of the development of the 
investigational medicinal product (IMP)
Two formal interim analyses are planned in this study, when the 
number of events observed in the intent to treat (ITT) analysis 
set reaches 43.5% and 60% of the planned 207 relapse events
(90 and 125 events in adult patients, respectively). An 
Independent Data Monitoring Committee (IDMC) will conduct 
the interim analysis to assess efficacy for all randomized 
patients. Results will need to demonstrate statistically 
significant effects in the primary analysis of the primary 
endpoint (at a significance level of 0.0101) for both risperidone 
treatment groups (q1m and q2m) at any of the interim analyses 
in order to stop the study early for success, as described in 
Section 9.6. The IDMC could recommend to discontinue the 
study for ethical reasons, most notably continued exposure to 
placebo, if efficacy is established.
There are no formal rules for early termination of this study. 
During the conduct of the study, serious adverse events will be 
reviewed (Section 7.1.5.3.1) 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:

new toxicological or pharmacological findings or 
safety issues invalidate the earlier positive benefit-risk 
assessment

discontinuation of the development of the 
investigational medicinal product (IMP)
There will be no interim 
analysis for efficacy in this 
study.

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3.5. Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are 
presented in Table 1 and Table 2.
Study procedures and assessments with their time points are 
presented in Table 1 and Table 2.
Correction.
Table 2: TV46000-CNS-30072 (RISE) Study Procedures and Assessments (In-Clinic Visits and Telephone Contacts) – Baseline, Double-Blind 
Maintenance Stage (Stage 2), End of Treatment/Early Termination and Follow-Up
a. The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; meet 1 
or more of the study discontinuation or withdrawal criteria; or 
remain relapse-free during the double-blind phase until the 
study is terminated for efficacy  due to a successful interim 
analysis or because 207 at least 90 relapse events are recorded 
in the study in the ITT analysis set ...
a. The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; meet 1 
or more of the study discontinuation or withdrawal criteria; or 
remain relapse-free during the double-blind phase until the 
study is terminated because at least 90 relapse events are 
recorded in the study in the ITT analysis set. ...
There will be no interim 
analysis for efficacy in this 
study; the final analysis 
will be performed earlier 
due to the low event rate.
5. TREATMENTS
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. 
At the time of analysis (after the end of study or at each interim 
analysis), after receiving unblinding request from Teva 
statistician, the service provider will provide the unblinded IMP 
assignment according to the processes defined in the relevant 
SOP. The codes will be provided to an independent statistician 
who will perform the interim analyses.
Patient randomization codes will be maintained in a secure 
location at the service provider contracted to generate the codes. 
At the time of analysis (after the end of study), after receiving 
unblinding request from Teva statistician, the service provider 
will provide the unblinded IMP assignment according to the 
processes defined in the relevant SOP. 
There will be no interim 
analysis for efficacy in this 
study.
5.10.3. Data Monitoring Committee
During the conduct of this study there will be an IDMC that will 
review accumulating unblinded safety and pharmacokinetic data 
on a regular basis (as detailed in the IDMC charter) to ensure 
the continuing safety of the study patients and any study 
conduct issues. 
The IDMC will perform up to 2 formal interim analyses for 
efficacy in this study (when the number of events observed 
reaches 43% and 60% of the planned 207 relapse events in the 
ITT analysis set [Section 3.4]). The second interim analysis will 
be performed if at least one of the p values of the 2 primary 
comparisons is above 0.0101 at the first interim analysis. 
During the conduct of this study there will be an IDMC that will 
review accumulating unblinded safety and pharmacokinetic data 
on a regular basis (as detailed in the IDMC charter) to ensure 
the continuing safety of the study patients and any study 
conduct issues. 
The IDMC will be composed of independent physicians with 
expertise in the relevant therapeutic field and other relevant 
experts, such as a statistician and a pharmacokinetic specialist.
... 
There will be no interim 
analysis for efficacy in this 
study.

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The IDMC will be composed of independent physicians with 
expertise in the relevant therapeutic field and other relevant 
experts, such as a statistician and a pharmacokinetic specialist.
... 
5.11. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.4. Study Population
The eITT analysis set (Section 9.2.3) will be used for all study 
population summaries of the double-blind treatment stage 
unless otherwise specified. Summaries will be presented  by 
treatment group and for all patients. If the number of 
adolescents permits, summaries will also be presented by age 
subgroup.The primary analysis will be conducted on the ITT 
analysis set (Section 9.2.2), and the eITT analysis set (Section 
9.2.3) will be used for analysis of the key secondary endpoints 
unless otherwise specified the first key secondary endpoint will 
be conducted on the complete eITT analysis set (Section 9.2.3) 
and the second key secondary will be conducted on the 
adolescent subset of the eITT analysis set, if the number of 
adolescents permits. The analysis set on which analysis for 
other endpoints will be conducted will be specified on a case-
by-case basis. The enrolled patients set (Section 9.2.1) will be 
used for data summaries before the double-blind treatment 
stage.
The eITT analysis set (Section 9.2.3) will be used for all study 
population summaries of the double-blind treatment stage unless 
otherwise specified. Summaries will be presented  by treatment 
group and for all patients. If the number of adolescents permits, 
summaries will also be presented by age subgroup.The primary 
analysis will be conducted on the ITT analysis set (Section 
9.2.2), and the eITT analysis set (Section 9.2.3) will be used for 
analysis of the key secondary endpoints unless otherwise 
specified. The analysis set on which analysis for other endpoints 
will be conducted will be specified on a case-by-case basis. The 
enrolled patients set (Section 9.2.1) will be used for data 
summaries before the double-blind treatment stage.
Correction.

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9.4.2. Demographic and Baseline Characteristics
The ITT analysis set, the eITT analysis set, and the eITT subset 
of adolescents will be used for the summaries, as applicable. 
The ITT analysis set, the eITT analysis set, and the eITT subset 
of adolescents will be used for the summaries, as applicable.
Clarification.
9.5.2. Key Secondary Endpoints
...
The key secondary endpoints are comprised of endpoints that 
correspond to the 2 key secondary objectives described listed in 
Section 2.1 and described in detail below.
...
The key secondary endpoints are listed in Section 2.1 and 
described in detail below.
Correction.
9.5.4. Planned Method of Analysis 
The ITT analysis set (Section 9.2.2) will be used for all efficacy 
analyses. Summaries will be presented by treatment group. 
Analysis that will be conducted on the eITT analysis set or on 
the adolescent patient subset of the eITT will be described 
below, as applicable.
The ITT analysis set (Section 9.2.2) will be used for all efficacy 
analyses. Summaries will be presented by treatment group. 
Analysis that will be conducted on the eITT analysis set or on 
the adolescent patient subset of the eITT will be described 
below, as applicable.
Clarification.
9.5.4.4.1. Time to Event Key Secondary Analysis 
For the key secondary endpoints discussed in Section 
9.5.2.1,time to impending relapse in adult and adolescent 
patients will be assessed similarly to the Primary Efficacy 
Analysis using the eITT Analysis Set (Section 9.2.2).
For the key secondary endpoint discussed in Section 
9.5.2.1,time to impending relapse in adult and adolescent 
patients will be assessed similarly to the Primary Efficacy 
Analysis using the eITT Analysis Set (Section 9.2.2).
Correction of typo.
9.6. Multiple Comparisons and Multiplicity 
There will be up to 2 formal interim analyses when the number 
of events observed reaches 43.5% and 60% of the planned 207 
relapse events (90 and 125 events, respectively) in the ITT 
analysis set. At the first interim analysis, both primary efficacy 
tests will be tested at a 2 sided alpha of 0.0101. If both tests are 
significant at the first interim analysis, the study will be stopped 
early. If only 1 primary efficacy test (or none) is significant at 
the first interim analysis, the study will continue until the 
second interim analysis. If both tests are significant at the 
second interim analysis, the study will be stopped early. If only 
1 primary efficacy test (or none) is significant at this interim 
analysis, the study will continue until 207 relapse events are 
observed.
At the final analysis after 207 at least 90 relapse events, a fixed 
At the final analysis after at least 90 relapse events, a fixed 
sequential (hierarchical) testing approach will be implemented. 
If the resulting first p-value of the primary efficacy hypothesis 
test comparing q1m to placebo is found to be significant at 0.05 
alpha, then the second primary efficacy hypothesis (q2m vs. 
placebo) will be interpreted inferentially at the same alpha level 
of 0.05. If the first primary hypothesis fails to reach significance 
no further formal hypothesis testing will be performed.
...
There will be no interim 
analysis for efficacy in this 
study; the final analysis 
will be performed earlier 
due to the low event rate.

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sequential (hierarchical) testing approach will be implemented. 
If the resulting first p-value of the primary efficacy hypothesis 
test comparing q1m to placebo is found to be significant at 
0.0418 0.05 alpha, then the second primary efficacy hypothesis 
(q2m vs. placebo) will be interpreted inferentially at the same 
alpha level of 0.0418 0.05. If the first primary hypothesis fails 
to reach significance no further formal hypothesis testing will be 
performed.
This procedure will adequately control overall type 1 error for a 
2 sided alpha of 0.05 accounting for the interim analyses. The 
nominal alphas of 0.0101 at each interim analysis and 0.0418 at 
the final analysis were calculated using EAST 6 software, as 
described in the EAST 6 manual (East 6 [Version 6.3] manual, 
2014 ).
...
9.13. Planned Interim Analysis
There will be no interim analysis in this study. 
There will be up to 2 formal interim analyses when the number 
of events observed in the ITT analysis set reaches 43.5% and 
60% of the planned 207 relapse events (90 and 125 events in 
adult patients, respectively). Results will need to demonstrate 
statistically significant effects in the primary analysis of the 
primary endpoint (at a significance level of 0.0101) for both 
risperidone treatment groups (q1m and q2m) at any of the 
interim analyses in order to stop the study early for success as 
described in  Section 9.6. If success criteria was not met [ie, if 
only 1 primary efficacy test (or none) is significant] at the first 
interim analysis (at 90 relapse events), the study will continue to 
the second interim analysis (at 125 relapse events). If only 1 
primary efficacy test (or none) is significant at this interim 
analysis, (ie, if none of the interim analyses demonstrate 
success), the study will continue until 207 relapse events are 
reached.
An IDMC will conduct the interim analyses to assess efficacy 
for all randomized patients. An IDMC charter will be developed 
for the interim analyses. Procedures will be taken to ensure the 
There will be no interim analysis in this study. 
Deleted since text is no 
longer relevant; no interim 
analysis for efficacy will 
be performed. 
The IDMC is described in 
Section 5.10.3. of the 
protocol.

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integrity of the study follows the IDMC charter. The IDMC 
could recommend to discontinue the study for ethical reasons, 
most notably continued exposure to placebo, if efficacy is 
established.
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
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: 
Per Administrative Letter 
03, updated to reflect 
change of responsibilities 
at Teva. 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
Note in Section g Stage 2: Early Termination (ET) 
Visit/End-of-Treatment Visit (EoT):
Note: The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; meet 1 
or more of the study discontinuation or withdrawal criteria; or 
remain relapse-free at the time of study termination during the 
double blind phase until the study is terminated for efficacy due 
to a successful interim analysis or because 207 relapse events 
are recorded in the study in the ITT analysis set.
Note in Section g Stage 2: Early Termination (ET) 
Visit/End-of-Treatment Visit (EoT):
Note: The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; meet 1 
or more of the study discontinuation or withdrawal criteria; or 
remain relapse-free at the time of study termination. 
There will be no interim 
analysis for efficacy in this 
study; the final analysis 
will be performed earlier 
due to the low event rate.
Note in Section c Stage 2: Relapse Prevention (Visit 6a, 
Week 1±3 days; Visit 6b, Week 2±3 days; and Visit 6c, Week 
3±3 days [Telephone Contacts]) (Visit 7a, Week 5±3 days; 
Visit 7b, Week 6±3 days; and Visit 7c, Week 7±3 days 
[Telephone Contacts], 8a-8c, 9a-9c, etc.)
Note: Telephone contacts will occur weekly between in-clinic 
visits during the double-blind maintenance stage (Stage 2) (see 
Table 1 Table 2).
Note in Section c Stage 2: Relapse Prevention (Visit 6a, 
Week 1±3 days; Visit 6b, Week 2±3 days; and Visit 6c, Week 
3±3 days [Telephone Contacts]) (Visit 7a, Week 5±3 days; 
Visit 7b, Week 6±3 days; and Visit 7c, Week 7±3 days 
[Telephone Contacts], 8a-8c, 9a-9c, etc.)
Note: Telephone contacts will occur weekly between in-clinic 
visits during the double-blind maintenance stage (Stage 2) (see
Table 2).
Correction.
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 
...
In addition to those listed above, medications that may be 
expected to significantly interfere with the metabolism or 
Clarification due to 
COVID-19 pandemic.

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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.
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.
 
 
 
 
 
 
 
 
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.
Updated 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; 7.4. Clinical Laboratory Tests; 7.6. Vital Signs; 7.7. Electrocardiography; Section 8.1. Pharmacokinetic Assessment; 
Section 9.5.4.2. Sensitivity 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 03 (Dated 09 February 2020)

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16.3.
Global Amendment 02 with Revision 01 (Dated 16 October 2019) 
The primary reason for this revision of Global Amendment 02 is to reorganize the statistical 
analyses with the introduction of the fixed sequential (hierarchy) method to control the Type-I 
error for the primary analyses in the final analysis and a reconsideration and hierarchy of the key 
secondary endpoints. 
A comparison table showing the changes from Global Amendment 02 to Global Amendment 02 
with Revision 01 with is provided below. Previous text is presented in the column titled 
"Original text with changes shown", and the revised or new text is presented in the column titled 
"new wording." Revised or new text is shown in bold italics and deleted text is shown in strike-
through. 
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and are considered significant by the Teva Authorized Representative.
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the 
subjects in this clinical study or the scientific value of the clinical study.
Also, to adhere with current Teva standards, some formatting and editing changes have been 
made.

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TITLE PAGE (Other sections affected by this change: Header, Investigator Agreement; Coordinating Investigator Agreement)
Clinical Study Protocol with Amendment 02 with Revision 
01
Clinical Study Protocol  Amendment 02 with Revision 01
To denote the new global 
amendment with revision 
AMENDMENT HISTORY
The protocol for Study TV46000-CNS-30072 (original protocol 
dated 14 December 2017) has been amended and reissued as 
follows:
Global 
Amendment 02 
with Revision 01
16 October 
2019
(649 patients 
enrolled to 
date)
Global 
Amendment 02
02 September 
2019
(584 patients 
enrolled to date)
Letter of 
Clarification 02
27 June 2019
Global 
Amendment 01
06 December 
2018
(184 patients 
enrolled to date)
…
…
The Summary of Changes to the Protocol includes the 
corresponding reason/justification for each change and is 
provided in Section 16.
The protocol for Study TV46000-CNS-30072 (original protocol 
dated 14 December 2017) has been amended and reissued as 
follows:
Global 
Amendment 02 
with Revision 01
16 October 
2019
(649 patients 
enrolled to date)
Global 
Amendment 02
02 September 
2019
(584 patients 
enrolled to date)
Letter of 
Clarification 02
27 June 2019
Global 
Amendment 01
06 December 
2018
(184 patients 
enrolled to date)
…
…
The Summary of Changes to the Protocol includes the 
corresponding reason/justification for each change and is 
provided in Section 16.
This page was updated 
with the details of the 
documents issued since the 
last amendment
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1.Primary and Secondary Study Objectives and Endpoints (Other sections affected by this change: Clinical Study Protocol Synopsis)  
The A key secondary objective of this study is to evaluate the 
efficacy of TV-46000 during maintenance treatment in a total 
population (adults and adolescents) and in adolescent patients 
with schizophrenia.
A key secondary objective of this study is to evaluate the 
efficacy of TV-46000 during maintenance treatment in a total 
population (adults and adolescents) and in adolescent patients 
with schizophrenia.
Correction   
The kKey secondary endpoints are:
1
time to impending relapse (as defined under the 
Key secondary endpoints are:

time to impending relapse (as defined under the 
Revision and 
reorgarnization to the 

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primary objective) in the total population (adults and 
adolescents), and
impending relapse rate at week 24  
percentage of patients who maintain stability at 
endpoint
percentage of patients achieving remission at 
endpoint
observed rate of impending relapse at endpoint
Drug Attitudes Inventory 10-item version (adult 
patients only)
Schizophrenia Quality of Life Scale (SQLS) (adult 
patients only)
2
time to impending relapse in adolescent patients with 
schizophrenia.
NOTE: The assessment of time to impending relapse in 
adolescent patients is pending randomization of at least 10 
adolescent patients with clinically sufficient exposure.
primary objective) in the total population (adults and 
adolescents)

impending relapse rate at week 24  

percentage of patients who maintain stability at 
endpoint

percentage of patients achieving remission at endpoint

observed rate of impending relapse at endpoint 

Drug Attitudes Inventory 10-item version (adult 
patients only)

Schizophrenia Quality of Life Scale (SQLS) (adult 
patients only)

time to impending relapse in adolescent patients with 
schizophrenia
secondary endpoints 
A secondary objective of this study is to evaluate the specific 
efficacy parameters of TV 46000 in the total population beyond 
the measures of the primary objective.
Not applicable 
Correction due to moving 
the endpoints up to key 
secondary endpoints
Secondary efficacy endpoints are as follows:

impending relapse rate at week 24

observed rate of impending relapse at endpoint

percentage of patients who maintain stability at endpoint 
(Section 9.5.3.3)
percentage of patients achieving remission at endpoint (Section 
9.5.3.4) 
Not applicable 
Correction (now included 
under the key secondary 
endpoints ) 
The following quality of life and healthcare resource utilization 
measures will be assessed:

Schizophrenia Quality of Life scale (adult patients only)  

5-Level EuroQol Five Dimensions Questionnaire (adult 
patients only)

Drug Attitudes Inventory 10 item version (adult patients 
only)
...
The following quality of life and healthcare resource utilization 
measures will be assessed:

5-Level EuroQol Five Dimensions Questionnaire (adult 
patients only)
...
Correction (now included 
under the key secondary 
endpoints )

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9.5. EFFICACY ANALYSIS 
9.5.2. Key Secondary Endpoints 
The key secondary endpoints are:
1 time to impending relapse (as defined under the 
primary objective) in the eITT analysis set, and
2 time to impending relapse in adolescent patients with 
schizophrenia.
NOTE: The assessment of time to impending relapse in 
adolescent patients is pending randomization of at least 10 
adolescent patients with clinically sufficient exposure.
The eITT analysis set (Section 9.2.3) will be used for all 
summaries in this section, unless otherwise specified.
For the endpoints that are evaluted only in the adult population, 
the analysis will be conducted on the ITT analysis set.
The key secondary endpoints are comprised of endpoints that 
correspond to the 2 key secondary objectives described in
The eITT analysis set (Section 9.2.3) will be used for all 
summaries in this section, unless otherwise specified.
For the endpoints that are evaluted only in the adult population, 
the analysis will be conducted on the ITT analysis set.
The key secondary endpoints are comprised of endpoints that 
correspond to the 2 key secondary objectives described in 
Section 2.1.
Revision and 
reorganization to the 
section 9.5.2. The section 
numbers will be updated 
accordingly.  

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Reason/Justification for 
change
Section 2.1.
9.5.2.1. Time to Impending Relapse in the eITT Analyses Set 
Not applicable 
Time to impending relapse using the same definition and 
primary analysis that is described in section 9.5.1 using the eITT 
analysis will be employed. 
New section added, 
included in the key 
secondary endpoints 
9.5.2.2 Impending Relapse Rate at Week 24 
This rate will be estimated using the Kaplan-Meier method
This rate will be estimated using the Kaplan-Meier method
Reorganization of the 
section (now included 
under the key secondary 
endpoints)
9.5.2.3. Percentage of Patients Who Maintain Stability at Endpoint 
The percentage will be calculated as the number of patients who 
maintained stability at endpoint divided by the number of eITT
patients that adhere to treatment for at least 4 weeks or 
experienced relapse in the given treatment group.
This analysis estimates the treatment effect of randomized 
treatment on patient's stability once the patient adheres to 
treatment long enough until the last treatment. The use of 
eITT analysis complies with while on treatment estimand and 
will be comprised of the difference in proportions under the 
treatment to which the patient was initially randomized of all 
patients who were successfully stabilized on oral risperidone at 
a daily dose range of 2 mg to 5 mg. Accordingly, this estimand 
addresses the clinical question to what extent patients improve 
their chances to maintain stability once they start the 
treatment if the patient adheres to the treatment long enough.
The percentage will be calculated as the number of patients who 
maintained stability at endpoint divided by the number of eITT 
patients that adhere to treatment for at least 4 weeks or 
experienced relapse in the given treatment group. 
This analysis estimates the treatment effect of randomized 
treatment on patient's stability once the patient adheres to  
treatment long enough until the last treatment. The use of eITT 
analysis complies with while on treatment estimand and will be 
comprised of the difference in proportions under the treatment 
to which the patient was initially randomized of all patients who 
were successfully stabilized on oral risperidone at a daily dose 
range of 2 mg to 5 mg. Accordingly, this estimand addresses the 
clinical question to what extent patients improve their chances 
to maintain stability once they start the treatment if the patient 
adheres to the treatment long enough.
Revision and 
reorganization to the 
section 
9.5.2.4. Percentage of Patients Achieving Remission at Endpoint 
For overall symptom remission, the patient must not relapse 
during the study and in addition, over a period of at least 
6 months preceding the endpoint, maintain scores of ≤3 on each 
of the 8 specific PANSS items: P1 (delusions), G9 (unusual 
thought content), P3 (hallucinatory behavior), P2 (conceptual 
disorganization), G5 (mannerisms/posturing), N1 (blunted 
affect), N4 (social withdrawal), and N6 (lack of spontaneity). 
For overall symptom remission, the patient must not relapse 
during the study and in addition, over a period of at least 
6 months preceding the endpoint, maintain scores of ≤3 on each 
of the 8 specific PANSS items: P1 (delusions), G9 (unusual 
thought content), P3 (hallucinatory behavior), P2 (conceptual 
disorganization), G5 (mannerisms/posturing), N1 (blunted 
affect), N4 (social withdrawal), and N6 (lack of spontaneity). 
Revision and 
reorganization of the 
section

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Reason/Justification for 
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The percentage will be calculated as the number of patients 
who achieved remission at endpoint divided by the number of 
eITT patients that adhere at least 6 months or experienced 
relapse in the given treatment group.
This analysis estimates the treatment effect of randomized 
treatment on patient's remission  once the patient adheres to 
treatment long enough until the last treatment. The use of 
eITT analysis complies with the while on treatment estimand, 
and will be comprised of the difference in proportions under 
the treatment to which the patient was initially randomized of 
all patients who were successfully stabilized on oral 
risperidone at a daily dose range of 2 mg to 5 mg. Accordingly, 
this estimand addresses the clinical question to what extent 
patients improve their chances to achieve remission once they 
start the treatment if the patient adheres to the treatment long 
enough.
The analysis will be detailed in the statistical analysis plan.
The percentage will be calculated as the number of patients who 
achieved remission at endpoint divided by the number of eITT 
patients that adhere at least 6 months or experienced relapse in 
the given treatment group.
This analysis estimates the treatment effect of randomized 
treatment on patient's remission  once the patient adheres to 
treatment long enough until the last treatment. The use of eITT 
analysis complies with the while on treatment estimand, and 
will be comprised of the difference in proportions under the 
treatment to which the patient was initially randomized of all 
patients who were successfully stabilized on oral risperidone at 
a daily dose range of 2 mg to 5 mg. Accordingly, this estimand 
addresses the clinical question to what extent patients improve 
their chances to achieve remission once they start the treatment 
if the patient adheres to the treatment long enough.
9.5.2.5. Observed Rate of  Impending Relapse at Endpoint 
Observed rate of impending relapse will be calculated as the 
number of patients who relapsed by endpoint divided by the 
number of patients in each treatment group.
Observed rate of impending relapse will be calculated as the 
number of patients who relapsed by endpoint divided by the 
number of patients in each treatment group.
Reorganization of the 
section (now included 
under the key secondary 
endpoints)
9.5.2.6. Drug Attitudes Inventory 10-item Version
The change from baseline to endpoint in total score will be 
calculated
The change from baseline to endpoint in total score will be 
calculated
Reorganization of the 
section (now included 
under the key secondary 
endpoints)
9.5.2.7.Schizophrenia Quality of Life Scale 
The change from baseline to endpoint in total score will be 
calculated
The change from baseline to endpoint in total score will be 
calculated
Reorganization of the 
section (now included 
under the key secondary 
endpoints)

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change
9.5.2.8. Time to Impending Relapse in aAdolescent Patients with Schizophrenia 
Not applicable 
Time to impending relapse using the same definition and 
primary analysis that was described in section 9.5.1 will be used 
on the eITT analysis set using adolescent patients alone.
This assessment of time to impending relapse in adolescent 
patients is pending randomization of at least 10 adolescent 
patients with clinically sufficient exposure.
New section added, 
included in the key 
secondary endpoints
9.5.4.2. Sensitivity Analyses 
The PP analysis set will also be used as supplemental analysis 
to evaluate the primary efficacy variable. Details will be 
provided in the statistical analysis plan. Senstivity analysis will 
be conducted on the ITT analysis set.
The PP analysis set will also be used as supplemental analysis to 
evaluate the primary efficacy variable. Details will be provided 
in the statistical analysis plan. Senstivity analysis will be 
conducted on the ITT analysis set.
Clarification to the 
sensitivity analyses 
9.5.4.4. Key Secondary Analyses 
The fixed sequential (hierarchical) Strategy (FDA 2017) will 
be used to control the overall Type-I statstical error in the 
study for both primary and secondary efficacy endpoints. The 
key secondary endpoints will be analyzed in a pooled manner 
for q1m and q2m.The details about the Type-I statistical error
control for the key secondary endpoints will be discussed in 
the statistical analysis plan.
The fixed sequential (hierarchical) Strategy (FDA 2017) will be 
used to control the overall Type-I statstical error in the study for 
both primary and secondary efficacy endpoints. The key 
secondary endpoints will be analyzed in a pooled manner for 
q1m and q2m.The details about the Type-I statistical error 
control for the key secondary endpoints will be discussed in the 
statistical analysis plan.
New text added 
9.5.4.4.1. Time to Event Key Secondary Analyses 
Time to Event Key Secondary Analyses 1
Time to Event Key Secondary Analyses
Correction to the title 
For the key secondary endpoints discussed in Section 
9.5.2.1,Ttime to impending relapse in adult and adolescent 
patients will be assessed similarly to the Primary Efficacy 
Analysis using the eITT Analysis Set (Section 9.2.2). The Cox 
proportional hazard model will include patient age group (if 
applicable) along with treatment, and the aforementioned 
stratification variables as the factors. The details about the Type 
I statistical error control will be discussed in Section 9.6.
For the key secondary endpoint discussed in Section 
9.5.2.8,Ttime to impending relapse in adolescent patients will 
be assessed if the number of randomized patients will be at least 
10 with clinically sufficient exposure. The method will be 
similar to the Primary Efficacy Analysis, but will use the 
For the key secondary endpoints discussed in Section 9.5.2.1, 
time to impending relapse in adult and adolescent patients will 
be assessed similarly to the Primary Efficacy Analysis using the 
eITT Analysis Set (Section 9.2.2). The Cox proportional hazard 
model will include patient age group (if applicable) along with 
treatment, and the aforementioned stratification variables as the 
factors.
For the key secondary endpoint discussed in Section 9.5.2.8, 
time to impending relapse in adolescent patients will be 
assessed if the number of randomized patients will be at least 10 
with clinically sufficient exposure. The method will be similar 
to the Primary Efficacy Analysis, but will use the adolescent 
patients subset. Type-I statistical error control will be discussed 
Clarification to the key 
secondary analysis 

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change
adolescent patients subset. The details about the Type I 
statistical error control will be discussed in Section 9.6.
Multiple Comparisons and Multiplicity.
in Multiple Comparisons and Multiplicity.
9.5.4.5. Key Secondary Efficacy Analysis 9.5.2.2-9.5.2.7
Key Secondary Efficacy Analysis 9.5.2.2-9.5.2.7
Key Secondary Efficacy Analysis 9.5.2.2-9.5.2.7
Correction to the title
Impending relapse rate at week 24 will be estimated using the 
Kaplan-Meier method and calculated as 1 minus the proportion 
of patients free of impending relapse events at week 24. The 
Greenwood formula will be used to calculate standard errors for 
impending relapse rates at week 24, and the pooled standard 
errors will be used for hypothesis testing using z-statistics, 
assuming that the differences between TV-46000 and placebo 
follow a normal distribution of large samples. The tests will be 
conducted at a nominal 2 sided alpha of 0.05.
Impending relapse rate at week 24 will be estimated using the 
Kaplan-Meier method and calculated as 1 minus the proportion 
of patients free of impending relapse events at week 24. The 
Greenwood formula will be used to calculate standard errors for 
impending relapse rates at week 24, and the pooled standard 
errors will be used for hypothesis testing using z-statistics, 
assuming that the differences between TV-46000 and placebo 
follow a normal distribution of large samples.
Change due to the 
implementation of the 
hierarchy 
Change from baseline of DAI-10 and SQLS total score, will be 
analyzed using an analysis of covariance (ANCOVA) method, 
with treatment and stratification variables as factors and 
baseline (score at the end of Stage 1) as a covariate. 
Additional details regarding the analysis will be documented 
in the statistical analysis plan.
Change from baseline of DAI-10 and SQLS total score, will be 
analyzed using an analysis of covariance (ANCOVA) method, 
with treatment and stratification variables as factors and 
baseline (score at the end of Stage 1) as a covariate. Additional 
details regarding the analysis will be documented in the 
statistical analysis plan. 
New text added 
The eITT analysis set (Section 9.2.3) will be used for all 
summaries in this section, unless otherwise specified. Type-I 
statistical error control will be discussed in Multiple 
Comparisons and Multiplicity.
The eITT analysis set (Section 9.2.3) will be used for all 
summaries in this section, unless otherwise specified. Type- I 
statistical error control will be discussed in Multiple 
Comparisons and Multiplicity.
Change added 
 
 
 
 
 
 
9.6 Multiple Comparisons and Multiplicity 
If both tests are significant at the first interim analysis, the study 
will be stopped early. If only 1 primary efficacy test (or none) is 
significant at the first interim analysis, the study will continue 
until the second interim analysis. If both tests are significant at 
the second interim analysis, the study will be stopped early
…
If both tests are significant at the first interim analysis, the study 
will be stopped early. If only 1 primary efficacy test (or none) is 
significant at the first interim analysis, the study will continue 
until the second interim analysis. If both tests are significant at 
the second interim analysis, the study will be stopped early
…
Clarifiication and 
correction to the multiple 
Comparisons and 
Multiplicity methodology 
for the primary analyses

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At the final analysis after 207 events, a fixed sequential 
(hierarchical) testing approach will be implemented . If the 
resulting first p-value of the  both primary efficacy tests
hypothesis test comparing q1m to placebo will be conducted 
with 2 sided is found to be significant at alphas of 0.0418 
alpha, then the second primary efficacy hypothesis (q2m vs. 
placebo) will be interpreted inferentially at the same alpha 
level of 0.0418 if 1 primary efficacy test is not significant at a 
2 sided alpha of 0.0418, the other will be tested at a 2 sided 
alpha of 0.0418 divided by 2. If the first primary hypothesis 
fails to reach significance no further formal hypothesis testing  
will be performed.
This procedure will adequately control overall Type-I error for 
a 2-sided alpha of 0.05 accounting for the interim analyses. 
The nominal alphas of 0.0101 at each interim analysis and 
0.0418 at the final analysis were calculated using EAST 6 
software, as described in the EAST 6 manual  (East 6 [Version 
6.3] manual, 2014).
Type-I error will be further controlled for the 2 key secondary 
endpoints by employing the fixed sequential (hierarchical)
testing strategy within each endpoints family (primary 
endpoints and key secondary endpoints)approach, Secondary 
endpoints #1 will be analyzed in a pooled manner  only in case 
the 2 for  the  treatment groups if the two primary endpoints 
are found to be primary efficacy endpoints have significant. p
values less than or equal to alpha of 0.0418. In that case, key 
secondary endpoint #1 will be tested for the 2 dosing regimens 
using the same approach. Namely, tests for the 2 dosing 
regimens will be conducted with 2 sided alphas of 0.0418; if 
one of the comparisons for the key secondary endpoint #1 is not 
significant at a 2 sided alpha of 0.0418, the other will be tested 
at a 2 sided alpha of 0.0418 divided by 2. Further details about 
the Type-I statistical error control will be discussed in the
statistical analysis plan.
A fixed-sequence (hierarchical) testing procedure will be 
implemented to control the Type-I error rate. The sequence of 
the secondary endpoints comparisons will be as follows If 
secondary endpoint #1 is successful on both dosing regimens 
At the final analysis after 207 events, a fixed sequential 
(hierarchical) testing approach will be implemented. If the 
resulting first p-value of the primary efficacy hypothesis test 
comparing q1m to placebo is found to be significant at 0.0418 
alpha, then the second primary efficacy hypothesis (q2m vs. 
placebo) will be interpreted inferentially at the same alpha level
of 0.0418. If the first primary hypothesis fails to reach 
significance no further formal hypothesis testing will be 
performed.
This procedure will adequately control overall Type-I error for a 
2-sided alpha of 0.05 accounting for the interim analyses. The 
nominal alphas of 0.0101 at each interim analysis and 0.0418 at 
the final analysis were calculated using EAST 6 software, as 
described in the EAST 6 manual (East 6 [Version 6.3] manual, 
2014).
Type-I error will be further controlled for the key secondary 
endpoints by employing fixed sequential (hierarchical) testing 
strategy within each endpoints family (primary endpoints and 
key secondary endpoints). Secondary endpoints will be analyzed 
in a pooled manner for the treatment groups if the two primary 
endpoints found to be significant. Further details about the 
Type-I statistical error control will be discussed in the statistical 
analysis plan. 
A fixed-sequence (hierarchical) testing procedure will be 
implemented to control the Type-I error rate. The sequence of 
the secondary endpoints comparisons will be as follows: 
1.
Time to impending relapse in the eITT analysis set
2.
Impending relapse rate at week 24
3.
Percentage of patients who maintain stability at 
endpoint
4.
Percentage of patients achieving remission at endpoint
5.
Observed rate of impending relapse at endpoint
6.
DAI-10 change from baseline to endpoint
7.
SQLS change from baseline to endpoint
8.
Time to impending relapse in adolescent patients with 
schizophrenia
If the first comparison is found to be significant, then the next 
comparison of interest will be interpreted inferentially at the 

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against placebo, and there are at least 10 adolescent patients in 
the study with clinically sufficient exposure, then the 2 dosing 
regimens in the adolescent study population will be tested 
against placebo in the same way as described for the primary 
efficacy endpoint and key secondary endpoint #1.
1.
Time to impending relapse in the eITT analysis set
2.
Impending relapse rate at week 24
3.
Percentage of patients who maintain stability at 
endpoint
4.
Percentage of patients achieving remission at 
endpoint
5.
Observed rate of impending relapse at endpoint
6.
DAI-10 change from baseline to endpoint
7.
SQLS change from baseline to endpoint
8.
Time to impending relapse in adolescent patients with 
schizophrenia
If the first comparison is found to be significant, then the next 
comparison of interest will be interpreted inferentially at the 
same alpha level. This process will continue either until all 
comparisons were tested  inferentially or until the point at 
which the resulting 2-sided is insignificant at the same alpha 
level.
 
ny p-value associated with these 
comparisons will be considered as nominal p-value and will 
not be used for inference.
There will be no multiplicity control for all other exploratory
efficacy endpoints (secondary or exploratory), which will be 
tested at a nominal 5% level.
same alpha level. This process will continue either until all 
comparisons were tested  inferentially or until the point at which 
the resulting 2-sided is insignificant at the same alpha level
 
 
ny p-value associated with these comparisons will be 
considered as nominal p-value and will not be used for 
inference.
There will be no multiplicity control for all other exploratory 
efficacy endpoints , which will be tested at a nominal 5% level.
REFERENCES
Not applicable 
FDA, Multiple Endpoints in Clinical Trials. Guidance for 
Industry. DRAFT GUIDANCE. January 2017
Reference added

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16.4.
Global Protocol Amendment 02 (Dated 02 September 2019) 
The primary reason for this global amendment is to revise the number of relapse events at which 
the formal, pre-specified interim analysis will be conducted. In addition to the originally-
planned, single interim analysis that was to be conducted when 125 relapse events were 
observed, the Sponsor now plans to also conduct an earlier interim analysis when 90 relapse 
events are reached. Since the study's initiation, the rate of observed relapse events (pooled across 
all treatment groups due to blinding) is lower than expected. This may be due to a longer median 
time to relapse than assumed for the placebo group, or a higher hazard ratio than assumed during 
the study planning. An earlier analysis, if successful, will allow the Sponsor to stop this double-
blind, placebo-controlled study and roll the patients over earlier into the long term TV46000-
CNS-30078 extension study (in which all patients receive treatment with TV-46000) without 
affecting the statistical power of the study, while maintaining control of the type-I error. Patients 
randomized to the q1m or q2m treatment arms in the RISE study will continue on their assigned 
treatment regimen in the extension study, and patients randomized to the placebo arm in the 
RISE study will be re-randomized in a 1:1 manner to the q1m or q2m treatment arms in the 
extension study. 
These changes to the statistical methodology are unlikely to affect the safety (physical or mental 
integrity) or rights of the patients in this clinical Phase 3 study, the secondary endpoints of the 
study or the study’s scientific value, since the focus on the impending time to relapse as the 
primary endpoint is maintained, as well as the originally-planned time points for the interim and 
final analysis, and the overall control of type-I error using the same principles and methodology 
originally used for the study. Moreover, from an ethical perspective, adding an earlier interim 
analysis will enable patients on placebo to receive effective treatment earlier, if the treatment is 
found to be effective.The technical details of the planned statistical analysis of the study data will 
be provided in the Statistical Analysis Plan.
Further clarifications and changes related to study conduct were also implemented in this 
amendment. These include (but are not limited to) prolongation of study duration (although in 
case of a successful interim analysis, the study will be terminated earlier), change of inclusion 
criterion k to omit the BMI percentile limitation, updates to the planned number of enrolled 
patients per updated projections, clarification of procedures to be performed during unscheduled 
visits (per Clarification Letter 02 dated 27 June 2019) and clarification regarding highly effective 
birth control methods (see Appendix E) and some administrative details (see Appendix A). 
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and are not considered significant by the Teva Authorized Representative. The 
study schema (Figure 1), Table 1 (Screening and Stage 1), Table 2 (Stage 2 and Follow-Up) and 
the corresponding footnotes,  have been revised to reflect the changes described below.
A comparison table showing the changes from Global Amendment 01 to Global Amendment 02 
is provided below. Previous text is presented in the column titled "Original text with changes 
shown", and the revised or new text is presented in the column titled "new wording." Revised or 
new text is shown in bold italics and deleted text is shown in strike-through. 
Also, to adhere with current Teva standards, some formatting and editing changes have been 
made.

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Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for change
TITLE PAGE (Other sections affected by this change: Investigator Agreement; Coordinating Investigator Agreement)
Clinical Study Protocol with Amendment 01 02
Clinical Study Protocol with Amendment 02
To denote the new global 
amendment.
AMENDMENT HISTORY
AMENDMENT HISTORY
The protocol for Study TV46000-CNS-30072 (original 
protocol dated 14 December 2017) has been amended and 
reissued as follows:
Global 
Amendment 02
02 September 
2019
(584 patients 
enrolled to 
date)
Letter of 
Clarification 02
27 June 2019
Global 
Amendment 01
06 December 
2018
(184 patients 
enrolled to date)
…
…
The Summary of Changes to the Protocol includes the 
corresponding reason/justification for each change and is 
provided in Section 16.
AMENDMENT HISTORY
The protocol for Study TV46000-CNS-30072 (original 
protocol dated 14 December 2017) has been amended 
and reissued as follows:
Global 
Amendment 02
02 September 
2019
(584 patients 
enrolled to date)
Letter of 
Clarification 02
27 June 2019
Global 
Amendment 01
06 December 
2018
(184 patients 
enrolled to date)
…
…
The Summary of Changes to the Protocol includes the 
corresponding reason/justification for each change and 
is provided in Section 16.
This page was updated with the 
details of the documents issued 
since the last amendment.
SPONSOR PROTOCOL APPROVAL
Sponsor’s Authorized Representative
Vice President 
Therapeutic Area Head, Neurology and Psychiatry, 
Specialty Clinical Development
Sponsor’s Authorized Representative
 
Vice President 
Therapeutic Area Head, Neurology and Psychiatry, 
Specialty Clinical Development
This reflects a change in 
responsibilities at Teva.
1. INTRODUCTION AND BACKGROUND INFORMATION
1.2.2.1 Clinical Pharmacology Studies
A Phase 1 single and multiple ascending dose study 
(TV46000-SAD-10055) to evaluate the safety, tolerability, and 
A Phase 1 single and multiple ascending dose study 
(TV46000-SAD-10055) to evaluate the safety, 
Text updated to reflect completion 
of the 10055 study and final results 

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pharmacokinetics of TV-46000 in patients with schizophrenia 
or schizoaffective disorder is ongoing was also completed.
…
A preliminary The comparison of different sites of injection of 
a single 
 sc dose administered in the abdomen versus 
the upper arm, suggests indicated that there are no clinically
therapeutically relevant differences in exposure and that 
either the abdomen or upper arm could be used for sc 
injection without significantly altering the controlled-release 
drug delivery of risperidone. 
tolerability, and pharmacokinetics of TV-46000 in 
patients with schizophrenia or schizoaffective disorder 
was also completed.
…
The comparison of different sites of injection of a 
single 
 sc dose administered in the abdomen 
versus the upper arm indicated that there are no 
therapeutically relevant differences in exposure and that 
either the abdomen or upper arm could be used for sc 
injection without significantly altering the controlled-
release drug delivery of risperidone.
(CSR issued 21 December 2018).
3.
STUDY DESIGN
3.1. General Study Design and Study Schematic Diagram
… 
The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event; meet 1 or more of the study discontinuation or 
withdrawal criteria; or remain relapse-free during the double-
blind phase until the study is terminated for efficacy at the due 
to a successful interim analysis or because 207 relapse events 
are recorded in the study adult population.
…
Patients who remain relapse-free when the study is terminated 
for efficacy at the due to a successful interim analysis or 
because 207 relapse events in adults are recorded in the study 
should be invited to perform the End-of-Treatment visit within 
4 weeks of the last injection.
…
Patients will subsequently complete all end-of-study 
assessments. When the study ends, eligible patients may be 
offered the opportunity to enter an the TV46000-CNS-30078
extension study to assess the long-term safety and tolerability 
of extended-release risperidone. This extension study is beyond 
the scope of this protocol., A and a separate protocol will was
issued for the extension study as applicable it.
…
The study duration will be approximately 1830 months, from 
… 
The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience 
a relapse event; meet 1 or more of the study 
discontinuation or withdrawal criteria; or remain 
relapse-free during the double-blind phase until the 
study is terminated for efficacy due to a successful 
interim analysis or because 207 relapse events are 
recorded in the study adult population.
…
Patients who remain relapse-free when the study is 
terminated for efficacydue to a successful interim 
analysis or because 207 relapse events in adults are 
recorded in the study should be invited to perform the 
End-of-Treatment visit within 4 weeks of the last 
injection.
…
Patients will subsequently complete all end-of-study 
assessments. When the study ends, eligible patients 
may be offered the opportunity to enter the TV46000-
CNS-30078 extension study to assess the long-term 
safety and tolerability of extended-release risperidone. 
This extension study is beyond the scope of this 
protocol, and a separate protocol was issued for it.
Clarification following the addition 
of an earlier interim analysis.
Updated to the expected duration of 
the full study (207 relapse events) 
per the current projections.
The number of the safety extension 
study was added.

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Q2 2018 (first patient in) to Q4 20192020 (last patient out). In 
case of a successful interim analysis, the study will be 
terminated earlier (see Section 9.6).  
…
…
The study duration will be approximately 30 months, 
from Q2 2018 (first patient in) to Q4 2020 (last patient 
out). In case of a successful interim analysis, the study 
will be terminated earlier (see Section 9.6)  
…
The number of the safety extension 
study was added to the study 
schema.
e When the study ends, eligible patients may be offered the 
opportunity to enter an the TV46000-CNS-30078 extension 
study to assess the long-term safety and tolerability of 
extended-release risperidone. This extension study is beyond 
the scope of this protocol and will be is detailed in a separate 
protocol as applicable. If patients choose to enter the extension 
study, they will not need to complete the follow-up/exit visits 
in this study. 
e When the study ends, eligible patients may be offered 
the opportunity to enter the TV46000-CNS-30078
extension study to assess the long-term safety and 
tolerability of extended-release risperidone. This 
extension study is beyond the scope of this protocol and 
is detailed in a separate protocol. If patients choose to 
enter the extension study, they will not need to 
complete the follow-up/exit visits in this study.
The protocol for the 30078 
extension study was issued, and its 
number was therefore implemented.
3.2. Planned Number of Patients and Countries
Approximately 795993 patients will be screened to achieve 
enrollment of approximately 596695 adult patients in Stage 1, 
including approximately 5767adult patients in Bulgaria.
Approximately 993 patients will be screened to achieve 
enrollment of approximately 695 adult patients in Stage 
1, including approximately 67 adult patients in 
Bulgaria.
Corrected per updated enrollment 
projections and screen failure rate.

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3.4. Stopping Rules for the Study 
One Two formal interim analysis analyses will be conducted
are planned in this study, when the number of events observed 
in the intent-to-treat (ITT) analysis set (reaches 43.5% and
60% of the planned 207 relapse events (90 and 125 events in 
adult patients, respectively). An Independent Data Monitoring 
Committee (IDMC) will conduct the interim analysis to assess 
efficacy for all randomized patients. Results will need to 
demonstrate statistically significant effects in the primary 
analysis of the primary endpoint (at a significance level of 
0.0101) for both risperidone treatment groups (q1m and q2m), 
at any of the interim analyses in order to stop the study early 
for success, as described in Section 9.6. The IDMC could 
recommend to discontinue the study for ethical reasons, most 
notably continued exposure to placebo, if efficacy is 
established.
Two formal interim analyses are planned in this study, 
when the number of events observed in the intent-to-
treat (ITT) analysis set reaches 43.5% and 60% of the 
planned 207 relapse events (90 and 125 events in adult 
patients, respectively). An Independent Data 
Monitoring Committee (IDMC) will conduct the 
interim analysis to assess efficacy for all randomized 
patients. Results will need to demonstrate statistically 
significant effects in the primary analysis of the 
primary endpoint (at a significance level of 0.0101) for 
both risperidone treatment groups (q1m and q2m) at 
any of the interim analyses in order to stop the study 
early for success, as described in Section 9.6. The 
IDMC could recommend to discontinue the study for 
ethical reasons, most notably continued exposure to 
placebo, if efficacy is established.
Revised due to the addition of 
another, earlier interim analysis.
3.5. Schedule of Study Procedures and Assessments
Table 1:
d. 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 procedures which are 
currently marked 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.
d. 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 procedures which are currently marked 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. 
Clarification regarding procedures 
to be performed during unscheduled 
visits, per Letter of Clarification 02.
q. The specific questions asked will be at the discretion of the 
investigator. This A list of suggested questions are detailed in 
the study manual will be provided to the investigator. 
q. 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 
Corrected since there is no study 
manual; the list was provided to the 
investigators and is also available 

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Psychiatric adverse events or suspicion of a psychiatric 
deterioration as a result of 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. 
or suspicion of a psychiatric deterioration as a result of 
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.
vis the study portal.
Table 2:
a. The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; meet 
1 or more of the study discontinuation or withdrawal criteria; 
or remain relapse-free during the double-blind phase until the 
study is terminated for efficacy at the due to a successful 
interim analysis or because 207 relapse events are recorded in 
the study in the ITT analysis set.
…
a. The double-blind maintenance stage will be variable 
in duration, with patients continuing until they 
experience a relapse event and complete all end-of-
study assessments; meet 1 or more of the study 
discontinuation or withdrawal criteria; or remain 
relapse-free during the double-blind phase until the 
study is terminated for efficacy  due to a successful 
interim analysis or because 207 relapse events are 
recorded in the study in the ITT analysis set.
...
Revised due to the addition of 
another, earlier interim analysis.
b. When the study ends, eligible patients may be offered the 
opportunity to enter aTV46000-CNS-30078, the long-term 
safety and tolerability extension study. This extension study 
is beyond the scope of this protocol and is detailed in a 
separate protocol. If the patients choose to enter the 
extension study, they will not need to complete the follow-
up/exit visits in this study. All other patients (ie, patients who 
experience a relapse event, meet 1 or more of the study 
discontinuation or withdrawal criteria, or do not consent to 
join the extension study), will undergo these 2 follow-up/exit 
visits. During the follow-up/exit period patients will be 
treated according to the investigator’s judgement. 
b. When the study ends, eligible patients may be 
offered the opportunity to enter TV46000-CNS-30078, 
the long-term safety and tolerability extension study. 
This extension study is beyond the scope of this 
protocol and is detailed in a separate protocol. If the 
patients choose to enter the extension study, they will 
not need to complete the follow-up/exit visits in this 
study. All other patients (ie, patients who experience a 
relapse event, meet 1 or more of the study 
discontinuation or withdrawal criteria, or do not 
consent to join the extension study), will undergo these 
2 follow-up/exit visits. During the follow-up/exit period 
patients will be treated according to the investigator’s 
judgement.
Name of the extension study added.
c. 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 procedures which are 
currently marked 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 
c. 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 procedures which are currently marked 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 
Clarification regarding procedures 
to be performed during unscheduled 
visits, per Letter of Clarification 02.

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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. 
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. 
p. Blood 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.
p. Blood 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.
Clarification.
z. The specific questions asked will be at the discretion of the 
investigator. This A list of suggested questions are detailed in 
the study manual. will be provided to the investigator
Psychiatric adverse events or suspicion of a psychiatric 
deterioration as a result of 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.
z. 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 a psychiatric deterioration as a 
result of 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.
Corrected since there is no study 
manual; the list was provided to the 
investigators and is also available 
vis the study portal.
4. SELECTION AND WITHDRAWAL OF PATIENTS
4.1. Patient Inclusion Criteria
k. [Revision 12] The patient has a body mass index between 
18.0 and 38.0 kg/m2, inclusive at screening. For adolescent 
patients, the BMI should be at least in the 50th percentile for 
age and gender and must not exceed 38.0 kg/m2.
k. [Revision 2] The patient has a body mass index 
between 18.0 and 38.0 kg/m2, inclusive at screening. 
This limitation was removed to 
encourage enrollment of otherwise 
eligible adolescents.
4.3.1.General Withdrawal Criteria
…
Patients should be treated with standard of care after 
withdrawal from or termination of the study as appropriate. 
Alternatively, if the opportunity is available and the patient is 
eligible, the patient may be offered the option to participate in 
a TV46000-CNS-30078, the long-term safety and tolerability 
extension study.
…
…
Patients should be treated with standard of care after 
withdrawal from or termination of the study as 
appropriate. Alternatively, if the opportunity is 
available and the patient is eligible, the patient may be 
offered the option to participate in TV46000-CNS-
30078, the long-term safety and tolerability extension 
study.
…
Name of the extension study added.

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5. TREATMENTS
5.1.2. Placebo Investigational Medicinal Product
TV-46000 placebo is available as an extended-release 
 
 
 
 
 
 
 
 
 
Correction; wording on PFS added 
for consistency with the packaging 
description in the Table of 
Investigational Medicinal Products 
Used in the Study. 
Table 4: Investigational Medicinal Products Used in the Study
 
 
 
 
 
 
Clarification;
 dose 
should also be marked as Adults 
Only, since this dose is comparable 
to 5 mg oral risperidone for the TV-
46000 q1m product.
Correction; 
 dose has 
been marked as Adults Only for 
consistency with the protocol 
synopsis.
5.5. Treatment After the End of the Study
…
When the study ends, eligible patients may be offered the 
opportunity to enter an the TV46000-CNS-30078 extension 
study to assess the long-term safety and tolerability of 
extended-release risperidone. This extension study is beyond 
the scope of this protocol. A, and a separate protocol will was
issued for the extension study as applicable it.
…
When the study ends, eligible patients may be offered 
the opportunity to enter the TV46000-CNS-30078 
extension study to assess the long-term safety and 
tolerability of extended-release risperidone. This 
extension study is beyond the scope of this protocol, 
and a separate protocol was issued for it.
Name of the extension study added.
5.7. Prior and Concomitant Medication or Therapy

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…
In general, aAntidepressants, antipsychotics (other than study 
drug), and mood stabilizers will not be permitted as 
concomitant medications. However, some antidepressants and 
mood 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. No 
dose changes or new administrations of these drugs will be 
permitted during the study. If these are required as rescue 
medications, this should lead to a consideration of 
discontinuation from the study due to exacerbation or relapse.
…
In general, antidepressants, antipsychotics (other than 
study drug), and mood stabilizers will not be permitted 
as concomitant medications. However, some 
antidepressants and mood 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. No dose 
changes or new administrations of these drugs will be 
permitted during the study. If these are required as 
rescue medications, this should lead to a consideration 
of discontinuation from the study due to exacerbation 
or relapse.
Clarification that exceptions are 
allowed for some antidepressants 
under the conditions listed.
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. At the time of analysis (after the end of study or at each 
interim analysis), after receiving unblinding request from Teva 
statistician, the service provider will provide the unblinded 
IMP assignment according to the processes defined in the 
relevant SOP. The codes will be provided to an independent 
statistician who will perform an the interim analysis analyses. 
Patient randomization codes will be maintained in a 
secure location at the service provider contracted to 
generate the codes. At the time of analysis (after the 
end of study or at each interim analysis), after receiving 
unblinding request from Teva statistician, the service 
provider will provide the unblinded IMP assignment 
according to the processes defined in the relevant SOP. 
The codes will be provided to an independent 
statistician who will perform the interim analyses.
Clarification.
5.10.3. Data Monitoring Committee
…
The IDMC will perform 1 up to 2 formal interim analysis
analyses of for efficacy in this study (when the number of
events observed reaches 43.5% and 60% of the planned 207 
relapse events in the ITT analysis set [Section 3.4]). The 
second interim analysis will be performed if at least one of 
the p-values of the 2 primary comparisons is above 0.0101 at 
the first interim analysis. 
…
…
The IDMC will perform up to 2 formal interim analyses 
for efficacy in this study (when the number of events 
observed reaches 43.5% and 60% of the planned 207 
relapse events in the ITT analysis set [Section 3.4]). 
The second interim analysis will be performed if at 
least one of the p-values of the 2 primary comparisons 
is above 0.0101 at the first interim analysis. 
…
Revised due to the addition of 
another, earlier interim analysis.
8. ASSESSMENT OF PHARMACOKINETICS/PHARMACODYNAMICS/BIOMARKERS/PHARMACOGENOMICS
8.3. 
 
 

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with a known or hypothesized role in schizophrenia or 
response to antipsychotic medications, unless the patient 
declines testing or local regulations prohibit testing.
biomarkers with a known or hypothesized role in 
schizophrenia or response to antipsychotic medications, 
unless the patient declines testing or local regulations 
prohibit testing.
9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.

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used, the p-value for the other comparison (the significant 
comparison), should be significant at a 2-sided alpha/2 level.
Assuming the above, a total of 207 relapse events will need to 
be observed during Stage 2 of the study forin the ITT analysis 
set (adult patients) in the 3 treatment groups (combined) in 
order to have a statistical power or approximately attain 90% 
power (East 6 [Version 6.3] manual, 2014). The sample size 
rationale is based on the adult patients. There is no estimation 
of the sample size in the adolescent population, and their 
number is not known at this time.
Assuming an accrual time of 6 months and a maximal 
treatment duration during the double-blind stage of 
approximately 13 months, approximately 139 adult patients 
will need to be randomized to each treatment group for a total 
of 417 adult patients randomized. Assuming that 30% 40% of 
the patients enrolled in Stage 1 will not be randomized to the 
double-blind phase (Stage 2), a total of 596 approximately 695
adult patients will need to be enrolled into Stage 1. As an 
event-driven study, depending on the actual recruitment rate 
and percentage of patients who are enrolled in Stage 1 and are 
randomized to Stage 2, it may be possible to randomize more 
than 417 adult patients, as long as Stage 2 of the study ends 
due to a successful interim analysis or when the number of 
relapse events in the ITT analysis set reaches 207.
Assuming an accrual time of 6 months and a maximal 
treatment duration during the double-blind stage of 
approximately 13 months, approximately 139 adult 
patients will need to be randomized to each treatment 
group for a total of 417 adult patients randomized. 
Assuming that 40% of the patients enrolled in Stage 1 
will not be randomized to the double-blind phase (Stage 
2), a total of approximately 695 adult patients will need 
to be enrolled into Stage 1. As an event-driven study, 
depending on the actual recruitment rate and percentage 
of patients who are enrolled in Stage 1 and are 
randomized to Stage 2, it may be possible to randomize 
more than 417 adult patients, as long as Stage 2 of the 
study ends due to a successful interim analysis or when 
the number of relapse events in the ITT analysis set 
reaches 207.
9.2.2. Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include adult patients 
randomized to the double-blind maintenance stage (Stage 2), 
regardless if they have received treatment or not. In the ITT 
analysis set, treatment will be assigned based on the treatment 
to which patients were randomized, regardless of which 
treatment they actually received.
The purpose of the primary analyses is to estimate the effect 
of randomized treatment only, omitting any effect of 
additional treatment that may be administered after 
discontinuation of the randomized treatment. Accordingly, 
the ITT analysis set complies with while-on-treatment 
strategy1 that will be taken with regard to the intercurrent 
The intent-to-treat (ITT) analysis set will include adult 
patients randomized to the double-blind maintenance 
stage (Stage 2), regardless if they have received 
treatment or not. In the ITT analysis set, treatment will 
be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they 
actually received.
The purpose of the primary analyses is to estimate the 
effect of randomized treatment only, omitting any 
effect of additional treatment that may be administered 
after discontinuation of the randomized treatment. 
Accordingly, the ITT analysis set complies with while-
Per ICH guidance the description of 
the estimand was included for 
clarification and elaboration of the 
previous ITT definition. 
The citation of the guidance was 
added as a footnote.

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event of treatment discontinuation, with censoring at this 
intercurrent event. This study estimand will be the difference 
in time to relapse (survival) under the treatment to which the 
patient was initially randomized until last treatment or early 
termination of all adult patients who were successfully 
stabilized on oral risperidone at a daily dose range of 2 mg to 
5 mg.
1 ICH E9 (R1) addendum on estimands and sensitivity 
analysis in clinical trials to the guidance on statistical 
principles for clinical trials. EMA/CHMP/ICH/436221/2017. 
European Medicines Agency. 30 August 2017
on-treatment strategy1 that will be taken with regard to 
the intercurrent event of treatment discontinuation, with 
censoring at this intercurrent event. This study estimand 
will be the difference in time to relapse (survival) under 
the treatment to which the patient was initially 
randomized until last treatment or early termination of 
all adult patients who were successfully stabilized on 
oral risperidone at a daily dose range of 2 mg to 5 mg.
1 ICH E9 (R1) addendum on estimands and sensitivity 
analysis in clinical trials to the guidance on statistical 
principles for clinical trials. 
EMA/CHMP/ICH/436221/2017. European Medicines 
Agency. 30 August 2017
9.4. Study Population
The eITT analysis set (Section 9.3) (Section 9.2.3) will be used 
for all study population summaries of the double-blind 
treatment stage unless otherwise specified. Summaries will be 
presented by treatment group and for all patients. If the 
number of adolescents permits, summaries will also be 
presented by age subgroup. The primary analysis will be 
conducted on the ITT analysis set (Section 9.2.2), the first key 
secondary endpoint will be conducted on the complete eITT 
analysis set (Section 9.2.3) and the second key secondary will 
be conducted on the adolescent subset of the eITT analysis set, 
if the number of adolescents permits. The analysis set on 
which analysis for other end points endpoints will be 
conducted will be specified on a case-by-case basis. The 
enrolled patients set (Section 9.2.1) will be used for data 
summaries before the double-blind treatment stage.
The eITT analysis set (Section 9.2.3) will be used for 
all study population summaries of the double-blind 
treatment stage unless otherwise specified. Summaries 
will be presented by treatment group and for all 
patients. If the number of adolescents permits, 
summaries will also be presented by age subgroup. The 
primary analysis will be conducted on the ITT analysis 
set (Section 9.2.2), the first key secondary endpoint will 
be conducted on the complete eITT analysis set 
(Section 9.2.3) and the second key secondary will be 
conducted on the adolescent subset of the eITT analysis 
set, if the number of adolescents permits. The analysis 
set on which analysis for other endpoints will be 
conducted will be specified on a case-by-case basis. 
The enrolled patients set (Section 9.2.1) will be used 
for data summaries before the double-blind treatment 
stage.
Correction of cross-link to correct 
sub-section.
Clarification regarding data analysis 
and presentation.
9.5.1. Primary Endpoint
…
Time to impending relapse will be calculated as the earliest 
date the patient meets ≥1 of the impending relapse criteria 
minus the randomization date plus 1. 
…
Time to impending relapse will be calculated as the 
earliest date the patient meets ≥1 of the impending 
relapse criteria minus the randomization date plus 1. 
Clarification regarding the absolute 
increase of the combined score 
defined in the primary endpoint.

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The absolute increase of the combined score of the 4 PANSS 
items is the sum of the increases of those scores (ignoring the 
decreases).
The absolute increase of the combined score of the 4 
PANSS items is the sum of the increases of those 
scores (ignoring the decreases).
9.5.5.2. Sensitivity Analysis
A sensitivity analysis will be conducted to assess the impact of 
large intervals between the previous assessment and the 
assessment when at the time the first relapse was observed via 
the interval censoring method. Sensitivity analysis will also be 
conducted by classifying dropouts tipping point analysis that 
imputes time to relapse for dropouts (for reasons other than
suspected to be related to relapse) as relapse events instead of 
censoring with increasing risk to relapse, compared to similar 
patients in the same treatment group that continue treatment. 
The PP analysis set will also be used to assessevaluate the 
primary efficacy variable. Details will be provided in the 
statistical analysis plan. Senstivity analysis will be conducted 
on the ITT analysis set.
A sensitivity analysis will be conducted to assess the 
impact of large intervals between the previous 
assessment and the assessment at the time the first 
relapse was observed via the interval censoring method. 
Sensitivity analysis will also be conducted by tipping 
point analysis that imputes time to relapse for dropouts 
(for reasons suspected to be related to relapse) with 
increasing risk to relapse, compared to similar patients 
in the same treatment group that continue treatment. 
The PP analysis set will also be used to evaluate the 
primary efficacy variable. Details will be provided in 
the statistical analysis plan. Senstivity analysis will be 
conducted on the ITT analysis set.
Correction of the former 
methodology; the current 
methodology is tipping point 
analysis.
Correction in terminology.
9.6. Multiple Comparisons and Multiplicity
There will be 1 up to 2 formal interim analysis analyses when 
the number of events observed reaches 43.5% and 60% of the 
planned 207 relapse events (90 and 125 events, respectively) in 
the ITT analysis set. At this the first interim analysis, both 
primary efficacy tests will be tested at a 2-sided alpha of 
0.0101. If both tests are significant at the first interim analysis, 
the study maywill be stopped. If only 1 primary efficacy test 
(or none) is significant at the first interim analysis, the study 
will continue until the second interim analysis. If both tests 
are significant at the second interim analysis, the study will 
be stopped. If only 1 primary efficacy test (or none) is 
significant at this interim analysis, the study will continue
until 207 required number of relapse events are observed
At the final analysis, both primary efficacy tests will be 
conducted with 2-sided alphas of 0.0464 0.0418; if 1 primary 
efficacy test is not significant at a 2-sided alpha of 0.0464
0.0418, the other will be tested at a 2-sided alpha of 0.0464
0.0418 divided by 2.
This procedure will adequately control overall type 1 error for 
a 2-sided alpha of 0.05. The nominal alphas of 0.0101 at the
There will be up to 2 formal interim analyses when the 
number of events observed reaches 43.5% and 60% of 
the planned 207 relapse events (90 and 125 events, 
respectively) in the ITT analysis set. At the first interim 
analysis, both primary efficacy tests will be tested at a 
2-sided alpha of 0.0101. If both tests are significant at 
the first interim analysis, the study will be stopped. If 
only 1 primary efficacy test (or none) is significant at 
the first interim analysis, the study will continue until 
the second interim analysis. If both tests are significant 
at the second interim analysis, the study will be 
stopped. If only 1 primary efficacy test (or none) is 
significant at this interim analysis, the study will 
continue until 207 relapse events are observed 
At the final analysis, both primary efficacy tests will be 
conducted with 2-sided alphas of 0.0418; if 1 primary 
efficacy test is not significant at a 2-sided alpha of 
0.0418, the other will be tested at a 2-sided alpha of 
0.0418 divided by 2. 
This procedure will adequately control overall type 1 
Clarification following addition of a 
2nd interim analysis.

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each interim analysis and 0.0464 0.0418 at the final analysis 
were calculated using EAST 6 software as described in the 
EAST 6 manual (East 6 [Version 6.3] manual, 2014).
Type-I error will be further controlled for the 2 key secondary 
endpoints by employing the hierarchical approach. Secondary 
endpoint #1 will be analyzed only in case the 2 primary
efficacy endpoints have p-values less than or equal to alpha of 
0.0464 0.0418. In that case, key secondary endpoint #1 will be 
tested for the 2 dosing regimens using the same approach. 
Namely, tests for the 2 dosing regimens will be conducted with 
2-sided alphas of 0.0464 0.0418; if one of the comparisons for 
the key secondary endpoint #1 is not significant at a 2-sided 
alpha of 0.0464 0.0418, the other will be tested at a 2-sided 
alpha of 0.0464 0.0418 divided by 2.
…
error for a 2-sided alpha of 0.05. The nominal alphas of 
0.0101 at each interim analysis and 0.0418 at the final 
analysis were calculated using EAST 6 software as 
described in the EAST 6 manual (East 6 [Version 6.3] 
manual, 2014).
Type-I error will be further controlled for the 2 key 
secondary endpoints by employing the hierarchical 
approach. Secondary endpoint #1 will be analyzed only 
in case the 2 primary efficacy endpoints have p-values 
less than or equal to alpha of 0.0418. In that case, key 
secondary endpoint #1 will be tested for the 2 dosing 
regimens using the same approach. Namely, tests for 
the 2 dosing regimens will be conducted with 2-sided 
alphas of 0.0418; if one of the comparisons for the key 
secondary endpoint #1 is not significant at a 2-sided 
alpha of 0.0418, the other will be tested at a 2-sided 
alpha of 0.0418 divided by 2. 
…
9.7. Safety Analysis
Safety assessments and time points are provided in Table 1 and 
Table 2.
Safety assessments and time points are provided in 
Table 1 and Table 2.
Correction; addition of cross-link to 
other Table of Assessments.
9.13. Planned Interim Analysis
There will be 1 up to 2 formal interim analysis analyses when 
the number of events observed in the ITT analysis set reaches 
43.5% and 60% of the planned 207 relapse events (90 and 125 
events in adult patients, respectively).
Results will need to demonstrate statistically significant 
effects in the primary analysis of the primary endpoint (at a 
significance level of 0.0101) for both risperidone treatment 
groups (q1m and q2m) at any of the interim analyses in order 
to stop the study early for success as described in  Section
9.5.5.2 9.6. If success criteria was not met [ie, if only 1 
primary efficacy test (or none) is significant] at the first 
interim analysis (at 90 relapse events), the study will continue 
to the second interim analysis (at 125 relapse events). If only 
1 primary efficacy test (or none) is significant at this interim 
analysis, (ie, if none of the interim analyses demonstrate 
There will be up to 2 formal interim analyses when the 
number of events observed in the ITT analysis set 
reaches 43.5% and 60% of the planned 207 relapse 
events (90 and 125 events in adult patients, 
respectively).
Results will need to demonstrate statistically significant 
effects in the primary analysis of the primary endpoint 
(at a significance level of 0.0101) for both risperidone 
treatment groups (q1m and q2m) at any of the interim 
analyses in order to stop the study early for success as 
described in  Section 9.6. If success criteria was not met 
[ie, if only 1 primary efficacy test (or none) is 
significant] at the first interim analysis (at 90 relapse 
events), the study will continue to the second interim 
analysis (at 125 relapse events). If only 1 primary 
Revised due to the addition of 
another, earlier interim analysis.
Re-organization of section text for 
clarification.
Correction of cross-link to correct 
section of protocol.

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success), the study will continue until 207 relapse events are 
reached.
An IDMC will conduct the interim analysis analyses to assess 
efficacy for all randomized patients. An IDMC charter will be 
developed for the interim analyses. Procedures will be taken to 
ensure the integrity of the study that follows the IDMC charter. 
Results will need to demonstrate statistically significant effects 
in the primary analysis of the primary endpoint (at a 
significance level of 0.0101for both risperidone treatment 
groups (q1m and q2m) ) as described in Section 9.5.5.2. The 
IDMC could recommend to discontinue the study for ethical 
reasons, most notably continued exposure to placebo, if 
efficacy is established.
efficacy test (or none) is significant at this interim 
analysis, (ie, if none of the interim analyses 
demonstrate success), the study will continue until 207 
relapse events are reached.
An IDMC will conduct the interim analyses to assess 
efficacy for all randomized patients. An IDMC charter 
will be developed for the interim analyses. Procedures 
will be taken to ensure the integrity of the study follows 
the IDMC charter. The IDMC could recommend to 
discontinue the study for ethical reasons, most notably 
continued exposure to placebo, if efficacy is 
established.
APPENDIX A . CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
Vice President, Therapeutic Area Head, 
Neurology and Psychiatry 
Specialty Clinical Development 
Teva Branded Pharmaceutical Products R&D, Inc.
Tel:
Email: 
Sponsor’s Authorized Representative
Vice President, Therapeutic Area Head, 
Neurology and Psychiatry 
Specialty Clinical Development 
Teva Branded Pharmaceutical Products R&D, Inc.
Tel:
Email: 
This reflects a change in 
responsibilities at Teva.
Sponsor’s Medical Expert/Contact Point designated by the 
Sponsor for Further Information on the Study
Senior Director, Global Clinical Development, 
Neuropsychiatry
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: 
Eran Harary was appointed as the 
Therapeutic Area Head, thus the 
title change as above. He remains 
the Sponsor's medical expert for the 
study.
Medical Monitors
For US:
 
Medical Director
ICON PLC  
For US:
 
Medical Director
ICON PLC  
Addition of the contact details for 
the medical monitor for Bulgaria.

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Mobile: 
 
Email: 
For Bulgaria:
 
Medical Director
ICON PLC  
Mobile: +
 
Email: 
Mobile: 
 
Email: 
For Bulgaria:
 
Medical Director
ICON PLC  
Mobile: 
 
Email: 
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
b. Stage 1: Oral Conversion and Stabilization (Telephone Contacts [Visit 4a, Week -6±3 days and Visit 5a, Week -2±3 days]) (Other sections affected by 
this change: c. Stage 2: Relapse Prevention [Telephone Contacts]).
...

brief set of clinical questions to detect psychotic 
symptoms – the specific questions asked will be at the 
discretion of the investigator. A list of suggested 
questions will be provided to the investigator.
...

brief set of clinical questions to detect 
psychotic symptoms – the specific questions 
asked will be at the discretion of the 
investigator. A list of suggested questions will 
be provided to the investigator.
Added for clarity and consistency 
with corresponding footnote 
inTable 1 and Table 2.
Procedures During Double-blind Maintenance Stage Administration of Investigational Medicinal Product (Baseline [Visit 6, Day 1 ±3 days]) (Other 
sections affected by this change: g. Early Termination (ET) Visit/End-of-Treatment Visit (EoT); Follow-up/ Exit Period
...

blood sample for pharmacogenetic analysis, unless 
the patient declines testing or local regulations 
prohibit testing.
...

blood sample for pharmacogenetic analysis, 
unless the patient declines testing or local 
regulations prohibit testing.
Added for clarity and consistency 
with corresponding footnotes  in 
Table 2 and other protocol sections.

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
blood sample for biomarker analysis, unless the 
patient declines testing or local regulations prohibit 
testing.
---

blood sample for biomarker analysis, unless 
the patient declines testing or local regulations 
prohibit testing.
...
g. Stage 2: Early Termination (ET) Visit/End-of-Treatment Visit (EoT)
Note: The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; meet 
1 or more of the study discontinuation or withdrawal criteria; 
or remain relapse-free during the double-blind phase until the 
study is terminated for efficacy at the due to a successful 
interim analysis or because 207 relapse events are recorded in 
the study in the ITT analysis set. 
Note: The double-blind maintenance stage will be 
variable in duration, with patients continuing until they 
experience a relapse event and complete all end-of-
study assessments; meet 1 or more of the study 
discontinuation or withdrawal criteria; or remain 
relapse-free during the double-blind phase until the 
study is terminated for efficacy due to a successful 
interim analysis or because 207 relapse events are 
recorded in the study in the ITT analysis set. 
Revised due to the addition of 
another, earlier interim analysis.
Follow-up/Exit Period (Follow-up Visit 1 [4 weeks after last dosing visit] and Follow-up Visit 2 [8 weeks after the last dosing visit, End-of-Study (EoS) 
Visit])
Note: Eligible patients who choose to enter the long term 
TV46000-CNS-30078 extension study will not need to 
complete the follow-up/exit visits in this study. 
Note: Eligible patients who choose to enter the long 
term TV46000-CNS-30078 extension study will not 
need to complete the follow-up/exit visits in this study. 
Name of the extension study added.
Unscheduled Visits
…
Procedures performed during unscheduled visits will include 
the following:

concomitant medication review;

inquiry about changes in use of alcohol and illicit 
drugs

vital sign measurements

adverse event inquiry (including serious adverse event 
reporting, injection site-related
events including pain)

C-SSRS ("Since Last Visit" version) (if visit 
scheduled to assess psychiatric adverse
events)

PANSS and review of relapse criteria
Other procedures may be performed at the discretion of the 
investigator.
In addition, to reduce patient burden and to avoid 
…
Procedures performed during unscheduled visits will 
include the following:

concomitant medication review;

inquiry about changes in use of alcohol and 
illicit drugs

vital sign measurements

adverse event inquiry (including serious 
adverse event reporting, injection site-related
events including pain)

C-SSRS ("Since Last Visit" version) (if visit 
scheduled to assess psychiatric adverse
events)

PANSS and review of relapse criteria
Other procedures may be performed at the discretion of 
the investigator.
In addition, to reduce patient burden and to avoid 
Clarification regarding procedures 
to be performed during unscheduled 
visits, per Letter of Clarification 02.

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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.
…
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.
…
APPENDIX E. BIRTH CONTROL METHODS AND PREGNANCY TESTING
…
Postmenopausal women are defined as:

1 year postmenopausal (no menses for 12 months 
without an alternative medical cause plus an increased 
concentration of follicle stimulating hormone [FSH] 
of more than 35 U/L) in women not using hormonal 
contraception or hormonal replacement therapy
…
Description of different birth control methods
Description of Hhighly 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:

Combined estrogen and progestogen hormonal 
contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation; these should 
be initiated at least 7 days (for IMPs without 
suspected teratogenicity/genotoxicity) and 1 month 
…
Postmenopausal women are defined as:

1 year postmenopausal (no menses for 
12 months without an alternative medical 
cause plus an increased concentration of 
follicle stimulating hormone [FSH] of more 
than 35 U/L) in women not using hormonal 
contraception or hormonal replacement 
therapy
…
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. Such methods include 
the following:

Combined estrogen and progestogen hormonal 
contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation; these 
Only highly effective birth control 
methods should be used in this 
study. Therefore, unnecessary 
information was deleted.
The information provided in this 
appendix was aligned with that in 
the 30078 protocol for consistency 
and in line with the Clinical Trials 
Facilitation Group (CTFG) 
document "Recommendation 
related to contraception and 
pregnancy testing in clinical trials" 
(Final Version, 2014-09-15).
The paragraphs on pregnancy tests 
in women of childbearing potential 
were deleted since the time points 
for pregnancy testing are defined in 
the protocol.

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(for IMPs potentially teratogenic/genotoxic) before 
the first dose of IMP.

Progestogen-only hormonal contraception (oral, 
injectable, 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 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.

Periodic abstinence (eg, calendar, ovulation, 
symptothermal, 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, MHRA).
Acceptable birth control methods:
Acceptable birth control methods that result in a failure rate of 
more than 1% per year include: progestogen only oral 
hormonal contraception for which the inhibition of ovulation is 
not the primary mode of action; male or female condom with 
or without spermicide; cap, diaphragm, or sponge with 
spermicide. The combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double barrier 
methods) are also considered acceptable but not highly 
effective methods of birth control.
Unacceptable birth control methods:
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, 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 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.

Periodic abstinence (eg, calendar, ovulation, 
symptothermal, 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, MHRA).
Male contraception
Male patients must always use a condom.
…
Pregnant female partners of male study 

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Periodic abstinence (calendar, symptothermal, post ovulation 
methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhea method are not acceptable methods 
of contraception. Female condom and male condom should not 
be used together.
Male contraception
Male patients must always use a condom, except in cases of no 
genotoxicity; or no demonstrated or suspected human 
teratogenicity/fetotoxicity.
…
Contraception for female partners of male study 
participants:
Female partners (who are not pregnant) of male study 
participants must use contraception for non pregnant women of 
childbearing potential until the end of relevant systemic 
exposure in case of IMPs with genotoxicity or IMPs with no 
genotoxicity but demonstrated or suspected human 
teratogenicity/fetotoxicity.
Pregnancy tests in women of childbearing potential:
1.Conduct monthly pregnancy testing from first dose of IMP 
until last dose of IMP and additional 30 days in case the IMP 
does not have a marketing authorization and has suspected 
human teratogenicity/genotoxicity/fetotoxicity. Conduct 
monthly pregnancy testing and in case the IMP has a marketing 
authorization, if the IMP has a demonstrated or suspected 
human teratogenicity/genotoxicity/fetotoxicity according to 
Risk Safety Information. Shorter testing intervals are to be 
considered depending on drug dosing schedule.
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.
For IMPs with unlikely risk of human 
teratogenicity/fetotoxicity, additional pregnancy testing is 
participants:
Male study participants must use condoms during 
intercourse if their female partners are pregnant.

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generally not necessary. This refers to IMPs for which 
assessment of the completed necessary nonclinical studies does 
not indicate teratogenicity/fetotoxicity in early pregnancy and 
human data are not available or do not contradict these findings 
or there is already sufficient evidence for lack of risk based on 
human data.
Pregnant female partners of male study participants:
Male study participants must use condoms during intercourse if 
their female partners are pregnant.
 
 
 
 
.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
All blood tubes will be labeled with the patient code number. If 
required by local regulations, following DNA extraction from 
the pharmacogenetic blood sample, the DNA sample will be 
labeled with a new code (ie, double coding).
All blood tubes will be labeled with the patient code 
number.
Correction; text relevant to PGx 
samples deleted from here and 
moved to Appendix J.
APPENDIX J. PHARMACOGENETIC ASSESSMENTS
A blood sample (6 mL) for pharmacogenetic assessment will 
be collected from all patients who signed the informed consent 
for pharmacogenetic assessments at the time point detailed in 
Table 2, unless the patient declines testing or local 
regulations prohibit testing. All blood tubes will be labeled 
with the patient code number. If required by local 
regulations, following DNA extraction from the 
pharmacogenetic blood sample, the DNA sample will be 
A blood sample (6 mL) for pharmacogenetic 
assessment will be collected from all patients who 
signed the informed consent for pharmacogenetic 
assessments at the time point detailed in Table 2, unless 
the patient declines testing or local regulations prohibit 
testing. All blood tubes will be labeled with the patient 
code number. If required by local regulations, 
following DNA extraction from the pharmacogenetic 
Added for clarity and consistency 
with corresponding footnote in 
Table 2 and Section 8.4.
Correction; relevant text moved 
here from Appendix I.

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Reason/Justification for change
labeled with a new code (ie, double coding). Genetic 
variability in the metabolizer gene, cytochrome P450 2D6 
(CYP2D6), will be evaluated for an association with drug 
concentrations of TV-46000 and oral risperidone.
blood sample, the DNA sample will be labeled with a 
new code (ie, double coding). Genetic variability in the 
metabolizer gene, cytochrome P450 2D6 (CYP2D6), 
will be evaluated for an association with drug 
concentrations of TV-46000 and oral risperidone.

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16.5.
Letter of Clarification 02 (27 June 2019)

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16.6.
Global Protocol Amendment 01 (Dated 06 December 2018) 
The primary reason for this global amendment is to allow adolescent patients (aged 13-17 years) 
to enroll in this clinical study and receive treatment with TV-46000, following regulatory 
interactions with FDA. To this end, assent to study procedures was introduced, some inclusion 
criteria were modified and 2 new key secondary endpoints for data analysis were added. 
Clarifications regarding risperidone dosing and assessment of certain scales relevant to 
adolescent patients were also added.
Further clarifications and changes related to study conduct were also implemented in this 
amendment. These include (but are not limited to) splitting the Table of Assessments into 2 
separate tables (1 for each stage of the study) for clarity. The end-of-study (EoS)/Early 
Termination (ET) visit is now depicted as a separate visit, and the repeating 24-week visit 
window (ie, Visit 7-12c, 13-18c, etc) is depicted to better detail the assessments performed at the 
various visits. Other examples include: a urine pregnancy test was added to the baseline visit, 
specifying which scales will only be performed in adult patients, and up to 3 additional 
pharmacokinetic samples will be collected from adolescents. 
In addition, the country-specific items introduced in the Local Amendment 01 for Bulgaria 
(dated 28 May 2018) and in the Clarification Letter (dated 26 June 2018) were implemented as 
applicable.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and are considered significant by the Teva Authorized Representative.
Table 1 (Screening and Stage 1), Table 2 (Stage 2 and Follow-Up), the Overall Study Schematic 
Diagram, and the corresponding footnotes,  have been revised to reflect changes described 
below.
A comparison table showing the changes from the Protocol with Revision 01 to Amendment 01 
is provided below. Previous text is presented in the column titled "Original text with changes 
shown", and the revised or new text is presented in the column titled "new wording." Revised or 
new text is shown in bold italics and deletions are shown in strike-through. 
Throughout the protocol, cross-references to both Table 1 and Table 2  were created for certain 
procedures and assessments as applicable. If this was the only change made to the section text, it
is not depicted in the comparison table.
Also, in order to adhere with current Teva standards, some formatting and editing changes have 
been made.

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Reason/Justification for change
TITLE PAGE (Other sections affected by this change: Investigator Agreement; Coordinating Investigator Agreement)
Clinical Study Protocol with Amendment 01
Clinical Study Protocol with Amendment 01
To denote the global amendment.
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy, Safety, and 
Tolerability of Risperidone Extended-Release Injectable 
Suspension (TV-46000) for Subcutaneous Use as 
Maintenance Treatment in Adult and Adolescent Patients 
with Schizophrenia
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy, Safety, and 
Tolerability of Risperidone Extended-Release Injectable 
Suspension (TV-46000) for Subcutaneous Use as 
Maintenance Treatment in Adult and Adolescent Patients 
with Schizophrenia
To reflect the introduction of the 
possibility to enroll adolescent 
patients in the study.
A Randomized, Double-Blind, Placebo-Controlled Study on 
Efficacy, Safety, and Tolerability of TV-46000 in Adults and
Adolescents with Schizophrenia
A Randomized, Double-Blind, Placebo-Controlled Study 
on Efficacy, Safety, and Tolerability of TV-46000 in 
Adults and Adolescents with Schizophrenia
To reflect the introduction of the 
possibility to enroll adolescent 
patients in the study.
[Not applicable]
(The RISE Study – The RIsperidone Subcutaneous 
Extended-release Study)
Addition of study name to protocol.
EudraCT number: Not applicable 2018-001619-65
EudraCT number: 2018-001619-65
Number added for study conduct in 
EU.
PREFACE
This Clinical Study Protocol with Revision 01 includes 
updates to the original protocol dated 14
December 2017.
[Deleted]
Preface deleted and moved to 
Section 16.4 as part of Summary 
Changes to protocol.
AMENDMENT HISTORY
[Not applicable]
AMENDMENT HISTORY
The protocol for Study TV46000-CNS-30072 (original 
protocol dated 14 December 2017) has been amended and 
reissued as follows:
Global Amendment 
01
06 December 2018
(184 patients enrolled to date)
Letter of 
Clarification 01
26 June 2018
This page was added in the 
amendment for tracking history.

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Reason/Justification for change
Local 
Amendment 01 for 
Bulgaria
28 May 2018
(6 patients enrolled to date)
Protocol with 
Revision 01
15 February 2018
(0 patients enrolled to date)
The Summary of Changes to the Protocol includes the 
corresponding reason/justification for each change and is 
provided in Section 16.
LIST OF ABBREVIATIONS
[Not applicable]
FSH = Follicle stimulating hormone
Newly-added abbreviation.
[Not applicable]
SmPC = Summary of Product Characteristics
Newly-added abbreviation.
1. INTRODUCTION AND BACKGROUND INFORMATION
1.1 Introduction
[Not applicable]
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 is 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, thought disorder), 
neurocognitive impairments, psychophysiological 
abnormalities, and the presence of structural brain 
abnormalities (Asarnow et al 1995, Bo and Haahr 2016, 
Rapoport et al 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 
and Haahr 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 
New text regarding schizophrenia in 
the pediatric population.
Literature references added to 
reference list.

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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 
and Harrison 2011).
The purpose of the study is to compare the safety and 
efficacy of different durations of TV-46000 administered sc 
versus placebo. 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 et al 2017). Enrollment of 
adolescents in this study will provide data for evaluating the 
efficacy, safety and tolerability of TV-46000 in this patient 
population.
The purpose of the study is to compare the safety and 
efficacy of different durations of TV-46000 administered 
sc versus placebo. 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 et al 2017). Enrollment 
of adolescents in this study will provide data for evaluating 
the efficacy, safety and tolerability of TV-46000 in this 
patient population.
Added justification for inclusion of 
adolescents in the study.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Primary and Secondary Study Objectives and Endpoints
[Not applicable]
The key secondary objective of this study is to evaluate 
the efficacy of TV-46000 during maintenance treatment in 
a total population (adults and adolescents)  and in 
adolescent patients with schizophrenia.
The key secondary endpoints are:
1. time to impending relapse (as defined under the primary 
objective) in the total population (adults and adolescents),
and
2. time to impending relapse in adolescent patients with 
schizophrenia.
NOTE: The assessment of time to impending relapse in 
adolescent patients is pending randomization of at least 10 
adolescent patients with clinically sufficient exposure.
Pursuant to inclusion of adolescent 
patients in the study, a secondary 
objective and two key secondary 
endpoints were added for analysis 
of study data.
A secondary objective of this study is to evaluate the 
specific efficacy parameters of TV-46000 in the total 
population beyond the measures of the primary objective.
A secondary objective of this study is to evaluate the 
specific efficacy parameters of TV-46000 in the total 
population beyond the measures of the primary objective.
Clarification. 
A secondary objective of this study is to evaluate the safety 
and tolerability of TV-46000 in the total population.
A secondary objective of this study is to evaluate the 
safety and tolerability of TV-46000 in the total population.
Clarification.

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A secondary objective of this study is to evaluate the 
pharmacokinetics of oral risperidone and TV-46000 after 
administration of multiple doses in adults, adolescents, and 
the total population.
A secondary objective of this study is to evaluate the 
pharmacokinetics of oral risperidone and TV-46000 after 
administration of multiple doses in adults, adolescents, and 
the total population.
Clarification.
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
 
 
 
 
 
 
 
 
 
 

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3.
STUDY DESIGN
3.1. General Study Design and Study Schematic Diagram
Patients will provide informed consent or assent, as 
applicable, at the screening visit.
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. 
Patients can be accompanied by caregivers to visits.
Open-label oral risperidone (2 to 5 mg/day) will be used to 
stabilize patients to the treatments (the dose will be based on 
clinical judgement). Adolescent patients will receive a 
maximal dose of 4 mg/day.
If a patient withdraws from the study prior to the 
randomization 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.
Patients will provide informed consent or assent, as 
applicable, at the screening visit.
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. 
Patients can be accompanied by caregivers to visits.
Open-label oral risperidone (2 to 5 mg/day) will be used to 
stabilize patients to the treatments (the dose will be based 
on clinical judgement). Adolescent patients will receive a 
maximal dose of 4 mg/day.
If a patient withdraws from the study prior to the 
randomization 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.
Newly-added text pertaining to 
study conduct for adolescents: 
provision of assent, mandatory
caregiver presence, maximal dose 
received.
Clarification regarding other aspects 
of study conduct.
Definition of study completers 
added.
Sentence on unscheduled PK 
samples revised throughout the 
document to clarify that 
unscheduled PK samples do not 
need to be collected during Stage 1, 
and this is relevant only for Stage 2. 
The word "potential" was removed 
from the safety extension study,

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Stage 2: Double-blind maintenance stage (variable in 
duration). Stabilized patients (see definition above) will be 
randomized to receive TV-46000 q1m sc injections, TV-
46000 q2m sc injections, or placebo q1m sc injections in a 
1:1:1 ratio. Patients that require a stabilization dose below 2 
mg/day will not be randomized in the study. Also, as a 
precautionary measure, adolescent patients that will require 
a stabilization dose of more than 4 mg during the 
stabilization stage will not be randomized.
The maximal dose administered to adult patients will be 
equivalent to an oral risperidone dose of 5 mg/day, and the 
maximal dose administered to adolescents will be equivalent 
to 4 mg/day.
During Stage 2, Uunscheduled 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 the 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.
The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event; meet 1 or more of the study discontinuation or 
withdrawal criteria; or remain relapse-free during the double-
blind phase until the study is terminated for efficacy at the 
interim analysis or because 207 relapse events are recorded in 
the ITT analysis set.
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. 
Randomized patients who relapse or meet 1 or more of the 
withdrawal criteria should be invited to perform the Early 
Stage 2: Double-blind maintenance stage (variable in 
duration). Stabilized patients (see definition above) will be 
randomized to receive TV-46000 q1m sc injections, TV-
46000 q2m sc injections, or placebo q1m sc injections in a 
1:1:1 ratio. Patients that require a stabilization dose below 
2 mg/day will not be randomized in the study. Also, as a 
precautionary measure, adolescent patients that will require 
a stabilization dose of more than 4 mg during the 
stabilization stage will not be randomized.
The maximal dose administered to adult patients will be 
equivalent to an oral risperidone dose of 5 mg/day, and the
maximal dose administered to adolescents will be 
equivalent to 4 mg/day.
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 the 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
The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event; meet 1 or more of the study discontinuation 
or withdrawal criteria; or remain relapse-free during the 
double-blind phase until the study is terminated for 
efficacy at the interim analysis or because 207 relapse 
events are recorded in the ITT analysis set. 
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.
Randomized patients who relapse or meet 1 or more of the 
since preparations for it have begun.

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Termination (ET) visit as soon as possible, within 4 weeks 
of the last injection. Therefore, a patient is considered a 
study completer if he or she experienced impending relapse 
or remained relapse-free at the time of study termination.
This potential extension study is beyond the scope of this 
protocol.
withdrawal criteria should be invited to perform the Early 
Termination (ET) visit as soon as possible, within 4 weeks 
of the last injection. Therefore, a patient is considered a 
study completer if he or she experienced impending relapse 
or remained relapse-free at the time of study termination.
This extension study is beyond the scope of this protocol.
Figure 1: Overall Study Schematic Diagram
a Adolescent patients will receive doses equivalent to 2-4 
mg/day oral risperidone. Patients that will require a 
stabilization dose below 2 mg/day will not be randomized 
in the study. 
b With the exception of the screening visit, 
pharmacokinetic samples will be collected at each in-clinic 
visit. 
c Another pharmacokinetic sample will be collected at 
Week 14 (2 weeks after Visit 9) from adolescent patients 
only. It is highly preferable to collect the sample at Week 
14. However, if this is not possible, it may be collected 2 
Schema and footnotes revised to 
reflect dosing and pharmacokinetic 
sampling in the adolescent patient 
population.
The word "potential" was removed 
from the safety extension study, 
since preparations for it have begun.

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a Adolescent patients will receive doses equivalent to 2-4 
mg/day oral risperidone. Patients that will require a 
stabilization dose below 2 mg/day will not be randomized in 
the study. 
b With the exception of the screening visit, pharmacokinetic 
samples will be collected at each in-clinic visit. 
c  Another pharmacokinetic sample will be collected at 
Week 14 (2 weeks after Visit 9) from adolescent patients 
only. 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 (3 
weeks and 1 week post-injection, respectively) at the 
sponsor's discretion. 
d Patients randomized to the TV-46000 q1m or q2m sc 
groups in Stage 2 will receive TV-46000 sc at doses 
equivalent to the 2 to 5 mg/day dose of oral risperidone on 
which they were stabilized during Stage 1. Adolescent 
patients will receive a maximal TV-46000 dose equinvalent 
to 4 mg/day oral risperidone. 
e When the study ends, eligible patients may be offered the 
opportunity to enter an extension study to assess the long-
weeks after another in-clinic visit. Up to 2 additional 
samples may also be collected from adolescent patients (3 
weeks and 1 week post-injection, respectively) at the 
sponsor's discretion. 
d Patients randomized to the TV-46000 q1m or q2m sc 
groups in Stage 2 will receive TV-46000 sc at doses 
equivalent to the 2 to 5 mg/day dose of oral risperidone on 
which they were stabilized during Stage 1. Adolescent 
patients will receive a maximal TV-46000 dose 
equinvalent to 4 mg/day oral risperidone. 
e When the study ends, eligible patients may be offered the 
opportunity to enter an extension study to assess the long-
term safety and tolerability. This extension study is beyond 
the scope of this protocol and will be detailed in a separate 
protocol as applicable. If patients choose to enter the 
extension study, they will not need to complete the follow-
up/exit visits in this study. 
f For patients who experience a relapse event, meet 1 or 
more of the study discontinuation or withdrawal criteria, or 
do not consent to join the extension study, there will be 
2 follow-up/exit visits that will take place 4 weeks and 8 
weeks after the last dosing visit.

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term safety and tolerability. This extension study is beyond 
the scope of this protocol and will be detailed in a separate 
protocol as applicable. If patients choose to enter the 
extension study, they will not need to complete the follow-
up/exit visits in this study. 
f For patients who experience a relapse event, meet 1 or more 
of the study discontinuation or withdrawal criteria, or do not 
consent to join the extension study, there will be 2 follow-
up/exit visits that will take place 4 weeks and 8 weeks after 
the last dosing visit.
3.2. Planned Number of Patients and Countries
Approximately 795 patients will be screened to achieve 
enrollment of approximately 596 patients in Stage 1, 
including approximately 57 patients in Bulgaria.
The number of randomized patients in Stage 2 is planned to 
be approximately 417, including approximately 40 patients 
in Bulgaria. Details on the definition of evaluable patients 
and determination of the sample size are given in Section 9.1. 
The study is planned to be conducted in approximately 80
investigational centers in North America and possibly other 
regions as well Bulgaria.
Approximately 795 patients will be screened to achieve 
enrollment of approximately 596 patients in Stage 1, 
including approximately 57 patients in Bulgaria.
The number of randomized patients in Stage 2 is planned 
to be approximately 417, including approximately 40 
patients in Bulgaria. Details on the definition of evaluable 
patients and determination of the sample size are given in 
Section 9.1. 
The study is planned to be conducted in approximately 80
investigational centers in North America and Bulgaria.
Information added regarding study 
projection in Bulgaria.
3.3. Justification for Study Design and Selection of Population
[Not applicable] 
Moreover, the drug class of LAI atypical antipsychotics 
has not been studied extensively in children or adolescents 
(Lytle et al 2017). Although compliance in children and 
adolescents treated with antipsychotics is substantially 
higher than in adults, ranging from approximately 74% to 
88% (Pogge et al 2005, Yazdi et al 2008), LAIs may be 
considered for patients with confirmed schizophrenia and 
with risk factors for medication non-adherence: history of 
non-adherence, severe symptoms, comorbid substance use, 
cognitive impairment, ambivalence or negative attitudes 
towards medication, and poor insight (Ferrin et al 2016). In 
the Pediatric Study Plan submitted to FDA, a partial waiver 
was proposed for patients 0 to 12 years of age, since 
New text describing the justification 
of adolescent enrollment in the 
study.

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necessary studies in this age group would be impossible or 
highly impracticable, and the inclusion of adolescent 
patients (13-17 years of age) in this Phase 3 program was 
proposed.  The Agency concurred with these proposals. 
Non-clinical studies with TV-46000 in young and mature 
animals did not identify a particular concern for treatment 
of the targeted adolescent population aged 13 and above.
Antipsychotic LAIs are viewed as maintenance therapy in 
stable patients with schizophrenia, but they are not currently 
approved for treatment of acute symptoms. Thus, the 
population for this study consists of adult and adolescent
patients with chronic schizophrenia and excludes patients 
with acute disease. Only patients who have been stabilized on 
oral therapy with risperidone will be randomized into the 
double-blind maintenance stage of the study.
Antipsychotic LAIs are viewed as maintenance therapy in 
stable patients with schizophrenia, but they are not 
currently approved for treatment of acute symptoms. Thus, 
the population for this study consists of adult and 
adolescent patients with chronic schizophrenia and 
excludes patients with acute disease. Only patients who 
have been stabilized on oral therapy with risperidone will 
be randomized into the double-blind maintenance stage of 
the study.
Revision due to the option of 
adolescent enrollment in the study.
3.4. Stopping Rules for the Study
One formal interim analysis will be conducted, when the 
number of events observed in the intent-to-treat (ITT) 
analysis set reaches 60% of the planned 207 relapse events
(125 events in adult patients).
One formal interim analysis will be conducted, when the 
number of events observed in the intent-to-treat (ITT) 
analysis set reaches 60% of the planned 207 relapse events
(125 events in adult patients).
Clarification.
3.5. Schedule of Study Procedures and Assessments
TV46000-CNS-30072 Study Procedures and Assessments
This was previously Table 1; both stages of the study were 
depicted.
The table was split into 2 separate tables: Table 1 (In-
Clinic Visits and Telephone Contacts) for the pre-treatment 
period (Stage 1), and Table 2 for the double-blind, 
maintenance stage (Stage 2).
The rows corresponding to each stage are included in the 
relevant table. Footnotes which are relevant to both are 
included under each table.
Only newly-added or revised rows and footnotes are 
denoted in this summary of changes.
For further clarity, especially the 
assessments which are conducted at 
repeating time points.
General Revisions to Table 1 (Stage 1):
Revisions to Table 1 (Stage 1):
Assent must be obtained from 
adolescent patients.

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Informed consent (and assent, as applicable)
[Not applicable]
[Not applicable]
Adverse event inquiry (including SAE reporting, injection 
site related events including pain) 
Informed consent (and assent, as applicable)
FSH test added aseparate procedure at screening for 
women without menses for the past 12 months.
Addition of (adults patients only) to some assessments and 
procedures.
Adverse event inquiry (including SAE reporting)
Clarification regarding FSH testing.
Clarification in which patients these 
assessments should be performed.
Revised since there are no injections 
during Stage 1.
[Not applicable]
a If a patient withdraws from the study prior to the 
randomization 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.
m
The FSH test will only be performed for women with 
no menses for 12 months in order to confirm 
postmenopausal status.
o During the in-clinic visits in Stage 1, if possible, the 
blood samples for PK assessment should be taken within 
an hour prior to dosing. In any case, the hour of the last 
dose taken prior to collection of the pharmacokinetic 
sample will be recorded on the CRF.
Newly-added footnotes to Table 1.
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 contacts that 
take place 1, 2, and 3 weeks after visit 6 4 will be referred to 
as “visit 6a 4a” “visit 6b,” and “visit 6c,” respectively).
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 contacts that take place 2 weeks after visit 4 will 
be referred to as “visit 4a”).
Footnote revised for applicability to 
Stage 1 of study.
At screening and baseline, measurements will be done in 
At screening, measurements will be done in triplicate. The 
Footnote revised for applicability to 

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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.
mean of the 3 measurements will be used to determine 
study eligibility. 
Stage 1 of study.
General Revisions to Table 2 (Stage 2):
During Stage 2, Uunscheduled 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 the 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.
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 the 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.
Revised to clarify that unscheduled 
PK samples do not need to be 
collected during Stage 1, and this is 
relevant only for Stage 2.
[Not applicable]
In Table 2, an “X” was added to denote a urine β-HCG test 
will be performed at the baseline visit, in addition to the 
serum β-HCG.
For consistency with Section 
7.4.2.2. which states that a urine test 
will be performed prior to every 
study drug administration, and since 
the serum result may not be 
available that day prior to dosing.
l. Urine β HCG (dipstick) will be performed at all visits 
where study drug is administered (prior to study drug 
administration). A negative result must be obtained before 
study study drug is administered done prior to each study 
drug administration, except screening and baseline, where 
serum β HCG tests are performed.
l. 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 study drug is administered.
Clarification regarding urine 
pregnancy testing during Stage 2.
n. This assessment will be performed every 12 weeks. As of 
Visit 9, inclusive, this assessment will be conducted every 12 
weeks thereafter (Visits 12, 15, 18, and so on).
n. As of Visit 9, inclusive, this assessment will be 
conducted every 12 weeks thereafter (Visits 12, 15, 18, and 
so on).
Footnote revised and elaborated for 
clarification regarding timing of 
certain assessments during Stage 2.
p. Blood for biomarker analyses will be collected as follows: 
6 mL for serum, 6 mL for plasma, and 6.5 2.5 mL for 
PAXgene RNA.
p. Blood for biomarker analyses will be collected as 
follows: 6 mL for serum, 6 mL for plasma, and 2.5 mL for 
PAXgene RNA.
Correction per laboratory manual.
[Not applicable]
s. Another pharmacokinetic sample will be collected from 
adolescent patients at a supplementary in-clinic visit at 
Week 14 (2 Weeks after Visit 9). If it is not possible to 
take the sample at this visit, it may be taken 2 weeks after 
another in-clinic visit. Two additional samples, 3 weeks 
New footnote regarding 
pharmacokinetic sampling in 
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and 1 week post-injection, respectively, may be taken at 
the sponsor's discretion.
4. SELECTION AND WITHDRAWAL OF PATIENTS
4.1. Patient Inclusion Criteria
c. [Revision 1] The patient has provided written informed 
consent and is competent to do so. For adolescent patients, 
written informed consent has been provided by each 
patient’s parent or legal guardian, and written assent has 
been provided by each patient. 
c. [Revision 1] The patient has provided written informed 
consent and is competent to do so. For adolescent patients, 
written informed consent has been provided by each 
patient’s parent or legal guardian, and written assent has 
been provided by each patient.
Criterion revised to allow 
enrollment of adolescent patients in 
the study.
j. [Revision 1] The patient is a male or female of any ethnic 
origin, 18 13 through 65 years of age at screening.
j. [Revision 1] The patient is a male or female of any ethnic 
origin, 13 through 65 years of age at screening.
Criterion revised to allow 
enrollment of adolescent patients in 
the study per regulatory input.
k. [Revision 1] The patient has a body mass index between 
18.0 and 38.0 kg/m2, inclusive, at screening. For adolescent 
patients, the BMI should be at least in the 50th percentile 
for age and gender and must not exceed 38.0 kg/m2.
k. [Revision 1] The patient has a body mass index between 
18.0 and 38.0 kg/m2, inclusive, at screening. For 
adolescent patients, the BMI should be at least in the 
50th percentile for age and gender and must not exceed 
38.0 kg/m2.
Criterion revised to allow 
enrollment of adolescent patients in 
the study.
m. [Revision 1] Women of childbearing potential (see 
Appendix E) 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 drugs and for the duration of the 
study and for 120 days after the last injection of study drug.
m. [Revision 1] Women of childbearing potential (see 
Appendix E) 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 drugs and for the duration of the 
study and for 120 days after the last injection of study 
drug.
Criterion revised to allow 
enrollment of adolescent patients in 
the study.
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 (see Appendix E) 
must use condoms even if surgically sterile. In addition, male 
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 (see Appendix E) must use condoms even if 
Clarification following enrollment 
option of adolescent patients in the 
study.

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patients may not donate sperm for the duration of the study 
and for 120 days after taking the study drug.
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.
4.2. Patient Exclusion Criteria
d. [Revision 1] 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 RNA 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.
d. [Revision 1] 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 RNA 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.
Clarification regarding patient 
enrollment in case of positive 
hepatitis C serology result.
k. The patient has clinically significant findings in 
biochemistry, hematology, ECG, or urinalysis results. 

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 and 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. 
k. The patient has clinically significant findings in 
biochemistry, hematology, ECG, or urinalysis results. 

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.
To clarify that discussion should 
take place in case of QTcF 
prolongation at either time point.
4.3.3. Pharmacokinetic Sampling in Case of Patient Withdrawal
Note: Withdrawal under the above criteria (see Section 
4.3.2.) 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.
Note: Withdrawal under the above criteria (see Section 
4.3.2.) 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.
Correction of typos in text.
5.
TREATMENTS
5.1.1.1 Starting Dose and Dose Levels
In general, TV-46000 will be administered to the adult 
patients in the abdomen  (except as indicated below) by sc 
injection, at intervals of q1m or q2m, at a dose equivalent to 
oral risperidone 2 to 5 mg/day on which they were stabilized 
In general, TV-46000 will be administered to patients in 
the abdomen  (except as indicated below) by sc injection, 
at intervals of q1m or q2m, at a dose equivalent to oral 
risperidone 2 to 5 mg/day on which they were stabilized in 
Clarifications regarding 
administration of TV-46000.

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in Stage 1, per the conversion table below (Table 3). The 
maximal dose administered will be equivalent to an oral 
risperidone dose of 5 mg/day. Patients that require a 
stabilization dose below 2 mg/day will not be randomized in 
the study. Also, as a precautionary measure, adolescent 
patients that will require a stabilization dose of more than 4 
mg during the stabilization stage will not be randomized. 
Several investigational centers may be pre selected by the 
sponsor (based on the centers’ capabilities, sponsor's 
considerations, and prior clinical experience with injectable 
medication) for injection of study drug in the back of the 
upper arm, instead of the abdomen, to all or some of the
enrolled patients at these sites (approximately 20% of the 
study patient population). 
Stage 1, per the conversion table below (Table 3). The 
maximal dose administered will be equivalent to an oral 
risperidone dose of 5 mg/day. Patients that require a 
stabilization dose below 2 mg/day will not be randomized 
in the study. Also, as a precautionary measure, adolescent 
patients that will require a stabilization dose of more than 4 
mg during the stabilization stage will not be randomized. 
Several investigational centers may be selected by the 
sponsor (based on the centers’ capabilities, sponsor's 
considerations, and prior clinical experience with injectable 
medication) for injection of study drug in the back of the 
upper arm, instead of the abdomen, to all or some of the 
enrolled patients at these sites (approximately 20% of the 
study patient population).
To allow for greater flexibility.
5.1.2. Placebo Investigational Medicinal Product
 
 
 
.
5.2.1. Storage and Security
The investigator or designee must confirm appropriate 
temperature conditions have been maintained for all IMPs
medicinal products received, and any discrepancies must be 
reported and resolved before their use of the IMPs.
…
Oral risperidone is to be stored and securely locked according 
to the storage conditions specified in the package insert 
(RISPERIDONE tablets, Teva Pharmaceuticals, US PI).
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.
…
 
 
 
Since it is not considered an IMP, 
the sentence on oral risperidone 
storage was moved to Section 5.4.
5.2.3.
Accountability
Used and partially used IMP (test or placebo) will
be destroyed by the study center. Unused IMP (test or 
placebo) will be Unused IMP (test or placebo) All test or 
placebo IMP supplies (used, partially-used, and unused)
will be returned to the sponsor or its designee according to 
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.
Clarification that all IMP will be 
returned to the sponsor.
Correction of text duplication.

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Reason/Justification for change
local and national regulations and the site's standard operating 
procedures (SOPs), following written authorization from the 
sponsor.
5.3. Justification for Dose of Test Investigational Medicinal Product
…
Based on the pharmacokinetic performance and the safety 
profile of TV-46000 in Study TV46000-SAD-10055 and the 
population pharmacokinetic model-derived simulations, it is 
expected that TV-46000 provides sufficient coverage 
throughout 28 and 56 days in 4 doses
 
equivalent 
to 2-, 3-, 4-, and 5-mg oral risperidone based on total active 
moiety (Table 3). Adolescent patients will receive a maximal 
dose of TV-46000 equivalent to 4 mg oral risperidone.
…
Based on the pharmacokinetic performance and the safety 
profile of TV-46000 in Study TV46000-SAD-10055 and 
the population pharmacokinetic model-derived simulations, 
it is expected that TV-46000 provides sufficient coverage 
throughout 28 and 56 days in 4 doses
 
) 
equivalent to 2-, 3-, 4-, and 5-mg oral risperidone based on 
total active moiety (Table 3). Adolescent patients will 
receive a maximal dose of TV-46000 equivalent to 4 mg 
oral risperidone.
Clarification regarding maximal 
dose of TV-46000 for adolescents.
5.4. Other Medicinal Products/Non-Investigational Medicinal Products
In the US, Ooral risperidone tablets for stabilization (Table 
4) will be a commercial product supplied by the study center. 
In Bulgaria, oral risperidone for stabilization (Table 4) will 
be a commercial product supplied centrally by the sponsor.
The brand name of the oral risperidone supplied will be 
recorded on the source documentation. Oral risperidone is to 
be stored and securely locked according to the storage 
conditions specified in the package insert (RISPERIDONE 
tablets, Teva Pharmaceuticals, US PI) manufacturer’s 
Summary of Product Characteristics (SmPC). 
In the US, oral risperidone for stabilization (Table 4) will 
be a commercial product supplied by the study center. In 
Bulgaria, oral risperidone for stabilization (Table 4) will be 
a commercial product supplied centrally by the sponsor. 
The brand name of the oral risperidone supplied will be 
recorded on the source documentation. Oral risperidone is 
to be stored according to the manufacturer’s Summary of 
Product Characteristics (SmPC). 
Correction for consistency with 
Table 4; all forms of oral 
risperidone are allowed. 
Clarification regarding oral 
risperidone sourcing.
Since it is not considered an IMP, 
the sentence on oral risperidone 
storage was moved from Section 
5.2.1 to this section and revised to 
encompass storage conditions for all 
forms of oral risperidone.
5.5 Treatment After the End of the Study
When the study ends, eligible patients may be offered the 
opportunity to enter an extension study to assess the long-
term safety and tolerability of extended-release risperidone. 
This potential extension study is beyond the scope of this 
protocol. A separate protocol will issued for the extension 
study as applicable.
When the study ends, eligible patients may be offered the 
opportunity to enter an extension study to assess the long-
term safety and tolerability of extended-release risperidone. 
This extension study is beyond the scope of this protocol. 
A separate protocol will issued for the extension study as 
applicable.
Preparations for the feasibility and 
conduct of the extension study have 
begun. 

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5.7. Prior and Concomitant Medication or Therapy
Enrolled patients not already on oral risperidone or 
injectable risperidone (RISPERDAL CONSTA, Janssen 
Pharmaceuticals, US PI) and on any antipsychotic (other 
than clozapine), will be converted to oral risperidone during 
Stage 1 of the study. The patients should start taking their 
oral risperidone beginning from Visit 2. However, they will 
be allowed to receive their down-titrated other antipsychotic 
medication together with a low dose of risperidone for the 
purpose of conversion only, and for as short a duration as 
possible. The previous antipsychotic must be completely 
stopped within four weeks of visit 2. It is highly preferable 
that the patients be transitioned to oral risperidone during 
the allowed screening period after eligibility has been 
established. 
… 
The following medications will be prohibited during this 
study:

antipsychotics other than the study treatments
o
Except during the conversion and 
stabilization stage (Stage 1), and only if 
required for conversion from the previous 
antipsychotics to oral risperidone.
…Allowed rescue medications will include zolpidem or 
diphenhydramine for insomnia; benztropine, trihexyphenidyl, 
or diphenhydramine for EPS; and propranolol and 
benzodiazepines for akathisia. In addition, use of lorazepam 
(up to 6 mg/day) is permitted on an as needed basis for 
indications other than akathisia (anxiety etc.). Use in this 
context must be limited to no more than 72 consecutive 
hours, and lorazepam should not be taken within 8 hours of 
rating scale assessment.
Enrolled patients not already on oral risperidone or 
injectable risperidone (RISPERDAL CONSTA, Janssen 
Pharmaceuticals, US PI) and on any antipsychotic (other 
than clozapine), will be converted to oral risperidone 
during Stage 1 of the study. The patients should start 
taking their oral risperidone beginning from Visit 2. 
However, they will be allowed to receive their down-
titrated other antipsychotic medication together with a low 
dose of risperidone for the purpose of conversion only, and 
for as short a duration as possible. The previous 
antipsychotic must be completely stopped within four 
weeks of visit 2. It is highly preferable that the patients be 
transitioned to oral risperidone during the allowed 
screening period after eligibility has been established. 
The following medications will be prohibited during this 
study:

antipsychotics other than the study treatments
o
Except during the conversion and 
stabilization stage (Stage 1), and only if 
required for conversion from the 
previous antipsychotics to oral 
risperidone.
…
Allowed rescue medications will include zolpidem or 
diphenhydramine for insomnia; benztropine, 
trihexyphenidyl, or diphenhydramine for EPS; and 
propranolol and benzodiazepines for akathisia. In addition, 
use of lorazepam (up to 6 mg/day) is permitted on an as 
needed basis for indications other than akathisia (anxiety 
etc.). Use in this context must be limited to no more than 
72 consecutive hours, and lorazepam should not be taken 
within 8 hours of rating scale assessment.
Clarification regarding conversion 
of patients to oral risperidone and 
benzodiazepine use.
Additional clarification regarding 
use of lorazepam.
5.8. Procedures for Monitoring Patient Compliance
In Stage 1, A patient with total compliance of less than 80% 
A patient with total compliance of less than 80% in Stage 1 
Compliance will be measured for 

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in Stage 1(measured on Visits 2, 3, 4, and 5) will be 
considered noncompliant. 
will be considered noncompliant.
the overall stabilization period. 
5.9. Randomization and Blinding
In the event of an emergency (ie, where knowledge of the 
study drug assignment is needed to make treatment decisions 
for the patient), the treatment group and dose to which the 
patient has been allocated can be determined by accessing the 
IRT system. All investigational centers will be provided with 
details on how to access the system for code breaking at the 
start of the study. The medical monitor or equivalent should 
be consulted before unblinding, whenever possible. 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.
In the event of an emergency (ie, where knowledge of the 
study drug assignment is needed to make treatment 
decisions for the patient), the treatment group and dose to 
which the patient has been allocated can be determined by 
accessing the IRT system. All investigational centers will 
be provided with details on how to access the 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.
Clarification per updated sponsor 
template to enhance patient safety 
and ensure that the patient’s needs 
are first addressed.
5.10.2 Blinding and Unblinding
In case of a serious adverse event, 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 
each investigational center via the IRT, both via telephone 
and internet. If possible, the sponsor should be notified of the 
event before breaking of the code. If this is not possible, the 
sponsor should be notified immediately afterwards, and the 
patient’s IMP assignment should not be given. Breaking of 
the randomization treatment code can always be performed 
by the investigational centers investigator without prior 
approval by the sponsor; however, the sponsor should be 
notified following the breaking of the treatment code. The 
patient's IMP assignment should not be revealed to the 
sponsor.
In case of a serious adverse event, 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 each investigational center via the IRT, 
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. 
The patient's IMP assignment should not be revealed to the 
sponsor.
Clarification per updated sponsor 
template to enhance patient safety 
and ensure that the patient’s needs 
are first addressed. 
5.10.3. Data Monitoring Committee
The IDMC will perform 1 formal interim analysis of efficacy 
The IDMC will perform 1 formal interim analysis of 
Clarification.

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Reason/Justification for change
in this study (when the number of events observed reaches 
60% of the planned 207 relapse events in the ITT analysis 
set [Section 3.4] 3.4). 
efficacy in this study (when the number of events observed 
reaches 60% of the planned 207 relapse events in the ITT 
analysis set [Section 3.4]).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. ASSESSMENT OF EFFICACY
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 is used to capture 
quality of life.
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 is used to capture 
quality of life.
Clarification in which patient 
population this scale will be 
assessed.
Cross-link created to new table of 
assessments.
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 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.
Clarification in which patient 
population this scale will be 
assessed.
Cross-link created to new table of 
assessments.
6.2.3. Drug Attitudes Inventory 10-item Version (DAI-10)

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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.
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.
Clarification in which patient 
population this scale will be 
assessed.
Cross-link created to new table of 
assessments.
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 et al 2000). The scale 
consists of 100 items The PSP is a 100-point single-item 
rating scale, divided into 10 equal intervals. 
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 et al 2000). The PSP 
is a 100-point single-item rating scale, divided into 10 
equal intervals.
Clarification in which patient 
population this scale will be 
assessed.
Cross-link created to new table of 
assessments.
Correction of PSP scale description.
6.2.5. Healthcare Resource Utilization
Healthcare resource utilization will be assessed for both adult 
and adolescent patients approximately every 3 months (at the 
time points specified in Table 1 and Table 2 ) for 
hospitalizations, emergency room (ER) visits, and outpatient 
visits (ie, not including protocol-mandated outpatient visits).
Healthcare resource utilization will be assessed for both 
adult and adolescent patients approximately every 3 
months (at the time points specified in Table 1 and Table 
2) for hospitalizations, emergency room (ER) visits, and 
outpatient visits (ie, not including protocol-mandated 
outpatient visits).
Clarificatin in which patient 
population this scale will be 
assessed.
Cross-link created to new table of 
assessments.
7. ASSESSMENT OF SAFETY
7.4. Clinical Laboratory Tests
Table 6 7 Header: Hematology and coagulation
Table 7 Header: Hematology 
Correction; coagulation samples are 
not collected in this study.
7.4.1. Serum Chemistry, Hematology and Urinalysis
Clinical laboratory tests (serum chemistry, hematology and 
coagulation, and urinalysis) will be performed at the time 
points detailed in Table 1 and Table 2. 
Clinical laboratory tests (serum chemistry, hematology, 
and urinalysis) will be performed at the time points 
detailed in Table 1 and Table 2.
Correction; coagulation samples are 
not collected in this study.
7.4.2.2. Human Chorionic Gonadotropin Tests
A FSH test will be performed at the screening visit for any 
female who has been without menses for at least 12 months 
to confirm post-menopausal status. Women may be allowed 
A FSH test will be performed at the screening visit for any 
female who has been without menses for at least 12 months 
to confirm post-menopausal status. Women may be 
Clarification for whom the FSH test 
should be performed. 

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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 at screening, baseline, and 
the follow-up/exit visits (see Table 1 and Table 2). At 
baseline, both a serum and a urine β-HCG test will be 
performed. 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 
prior to study drug administration.
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 at screening, baseline, and 
the follow-up/exit visits (see Table 1 and Table 2). At 
baseline, both a serum and a urine β-HCG test will be 
performed. 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 
prior to study drug administration.
At the baseline visit, both types of 
pregnancy tests will be performed 
since the serum result may not be 
available that day prior to dosing.
Clarification that a negative result 
must be obtained before study drug 
is administered.
7.4.2.3. Urine Drug Screen
A urine drug screen will be performed at the time points 
specified in Table 1 and Table 2. The urine drug screen 
detects the presence of drugs of abuse, including 
amphetamine, barbiturates, benzodiazepines, cocaine, 
opiates, and tetrahydrocannabinol.
Substance use disorder is exclusionary and will preclude the 
patient from enrollment/randomization. However, if per the 
investigator’s judgment, a patient does not meet the criteria 
for substance use disorder, a A positive result for any of the 
above drugs or their metabolites, without medical 
explanation, will preclude the patient from 
randomization/enrollment or continued participation in the 
study. be discussed on a case-by-case basis between the site, 
the Medical Monitor and the sponsor to determine the 
patient’s eligibility, based on the information available. The 
patients should be advised that use of these substances should 
be avoided during the study.
A urine drug screen will be performed at the time points 
specified in Table 1and Table 2. The urine drug screen 
detects the presence of drugs of abuse, including 
amphetamine, barbiturates, benzodiazepines, cocaine, 
opiates, and tetrahydrocannabinol.
Substance use disorder is exclusionary and will preclude 
the patient from enrollment/randomization. However, if per 
the investigator’s judgment, a patient does not meet the 
criteria for substance use disorder, a positive result for any 
of the above drugs or their metabolites, without medical 
explanation, will be discussed on a case-by-case basis 
between the site, the Medical Monitor and the sponsor to 
determine the patient’s eligibility, based on the information 
available. The patients should be advised that use of these 
substances should be avoided during the study.
Clarification regarding a positive 
urine drug screen result due to the 
high prevlalence of recreational and 
medical use of various substances in 
this patient population.
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 et al 2011). The interview 
and rating for the C-SSRS is will be conductedcompleted by 
The C-SSRS is a semi structured interview that captures 
the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors (Posner et al 2011). The interview 
and rating for the C-SSRS will be rater specifically trained 
Corrected per Clarification Letter 01 
(June2018). Any rater who meets 
the scale author’s requirements may 
conduct the rating following 

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a licensed clinician rater specifically trained to rate the scale 
(per the minimum requirements outlined by the scale 
author), regardless of education level, who has appropriate 
clinical trial experience with C-SSRS administration 
specifically trained to rate the scale, after review and 
approval by the Teva clinical project physician or designee. 
to rate the scale (per the minimum requirements outlined 
by the scale author), regardless of education level, who has 
appropriate clinical trial experience with C-SSRS 
administration, after review and approval by the Teva 
clinical project physician or designee. 
approval from the Sponsor or 
designee.
8. ASSESSMENT OF PHARMACOKINETICS/PHARMACODYNAMICS/BIOMARKERS/PHARMACOGENOMICS
8.1. Pharmacokinetic Assessment
Blood samples will be collected from all patients for 
quantitation of the plasma concentrations of risperidone, 9-
OH-risperidone, and total active moiety (sum of risperidone 
and 9-OHrisperidone) at weeks -12, -10, -8, and -4 in Stage 1, 
at baseline, q4w in Stage 2, and at the follow-up/exit visits.
In case the patient is on a twice-daily (bid) oral risperidone 
dosing regimen, the patient can take the first out of the 2 
daily oral doses at the clinic with a PK assessment taken 
within an hour prior to dosing, and the second dose can be 
taken at home in the afternoon/evening, per the patient’s 
convenience at approximately the same hour every day.
During Stage 2 of the study, blood samples for PK 
assessment will be taken within an hour prior to sc dose 
administration.
Another pharmacokinetic sample will be collected from 
adolescent patients only at Week 14 (2 weeks after Visit 9 
[Week 12]), approximately after steady state is reached. 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, respectively) at the sponsor's discretion. 
This may be considered, for example, if few adolescent 
patients will be enrolled. 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, 
Blood samples will be collected from all patients for 
quantitation of the plasma concentrations of risperidone, 9-
OH-risperidone, and total active moiety (sum of 
risperidone and 9-OHrisperidone) at weeks -12, -10, -8, 
and -4 in Stage 1, at baseline, q4w in Stage 2, and at the 
follow-up/exit visits.
In case the patient is on a twice-daily (bid) oral risperidone 
dosing regimen, the patient can take the first out of the 2 
daily oral doses at the clinic with a PK assessment taken 
within an hour prior to dosing, and the second dose can be 
taken at home in the afternoon/evening, per the patient’s 
convenience at approximately the same hour every day.
During Stage 2 of the study, blood samples for PK 
assessment will be taken within an hour prior to sc dose 
administration.
Another pharmacokinetic sample will be collected from 
adolescent patients only at Week 14 (2 weeks after Visit 9 
[Week 12]), approximately after steady state is reached. 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, respectively) at the sponsor's 
discretion. This may be considered, for example, if few 
adolescent patients will be enrolled. The additional 
samples, if taken following another in-clinic visit, will be 
collected at the same intervals. If more than 1 additional 
Clarification regarding oral 
risperidone dosing and collection of 
pharmacokinetic samples during 
Stage 1 of the study.
New text describing collection of 
additional pharmacokinetic samples 
from adolescents to further 
characterize the PK profile in this 
patient population.
Clarification that unscheduled 
pharmacokinetic samples are 
relevant for Stage 2 of the study.

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1 sample can be taken 3 weeks after Visit X and another can 
be taken 1 week after Visit Y). 
Thus, up to 3 additional pharmacokinetic samples may be 
taken from adolescent patients at supplementary in-clinic 
visits (without dosing) at varying time intervals following sc 
dose administration.
…
During Stage 2, uUnscheduled 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 the 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.
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).
Thus, up to 3 additional pharmacokinetic samples may be 
taken from adolescent patients at supplementary in-clinic 
visits (without dosing) at varying time intervals following 
sc dose administration.
…
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 the 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.
9. STATISTICS
9.1. Sample Size and Power Considerations
Median time to impending relapse was observed to be 
7 months in the placebo group in a similarly designed study 
(Kane et al 2012). Assuming a similar placebo effect in this 
study, as well as a hazard ratio of 1.82 (placebo vs TV-
46000), at a 2-sided alpha of 0.0250.05, and randomization 
ratio of 1:1:1 (q1m:q2m:placebo), a total of 207 relapse 
events will need to be observed during Stage 2 of the study 
for the the ITT analysis set (adult patients) in the 3 treatment 
groups (combined) to have a statistical power of 
approximately 90% (East 6 [Version 6.3] manual, 2014). The 
sample size rationale is based on the adult patients. There is 
no estimation of the sample size in the adolescent 
population, and their number is not known at this time.
Assuming an accrual time of 6 months and a maximal 
treatment duration during the double-blind stage of 
approximately 13 months, approximately 139 adult patients 
will need to be randomized to each treatment group for a total 
of 417 adult patients randomized. Assuming that 30% of the 
patients enrolled in Stage 1 will not be randomized to the 
Median time to impending relapse was observed to be 
7 months in the placebo group in a similarly designed 
study (Kane et al 2012). Assuming a similar placebo effect 
in this study, as well as a hazard ratio of 1.82 (placebo vs 
TV-46000), at a 2-sided alpha of 0.05, and randomization 
ratio of 1:1:1 (q1m:q2m:placebo), a total of 207 relapse 
events will need to be observed during Stage 2 of the study 
for the ITT analysis set (adult patients) in the 3 treatment 
groups (combined) to have a statistical power of 
approximately 90% (East 6 [Version 6.3] manual, 2014). 
The sample size rationale is based on the adult patients. 
There is no estimation of the sample size in the adolescent 
population, and their number is not known at this time.
Assuming an accrual time of 6 months and a maximal 
treatment duration during the double-blind stage of 
approximately 13 months, approximately 139 adult 
patients will need to be randomized to each treatment 
group for a total of 417 adult patients randomized. 
Assuming that 30% of the patients enrolled in Stage 1 will 
Correction of typo.
Additional details provided 
regarding the expected sample size 
in the adult and adolescent 
populations.

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double-blind phase (Stage 2), a total of 596 adult patients 
will need to be enrolled into Stage 1. As an event-driven 
study, depending on the actual recruitment rate and 
percentage of patients who are enrolled in Stage 1 and are 
randomized to Stage 2, it may be possible to randomize more 
than 417 adult patients, as long as Stage 2 of the study ends 
when the number of relapse events in the ITT analysis set
reaches 207.
not be randomized to the double-blind phase (Stage 2), a 
total of 596 adult patients will need to be enrolled into 
Stage 1. As an event-driven study, depending on the actual 
recruitment rate and percentage of patients who are 
enrolled in Stage 1 and are randomized to Stage 2, it may 
be possible to randomize more than 417 adult patients, as 
long as Stage 2 of the study ends when the number of 
relapse events in the ITT analysis set reaches 207.
9.2.2. Intent-toTreat Analysis Set
The intent-to-treat (ITT) analysis set will include all adult 
patients randomized during the double-blind maintenance 
stage (Stage 2), regardless if they have received treatment or 
not. In the ITT analysis set, treatment will be assigned based 
on the treatment to which patients were randomized, 
regardless of which treatment they actually received.
The intent-to-treat (ITT) analysis set will include adult
patients randomized during the double-blind maintenance 
stage (Stage 2), regardless if they have received treatment 
or not. In the ITT analysis set, treatment will be assigned 
based on the treatment to which patients were randomized, 
regardless of which treatment they actually received.
Clarification; the ITT analysis set is 
defined for adult patients only.
9.2.3. Extended Intent-toTreat Analysis Set
[Not applicable]
The extended intent-to-treat (eITT) analysis set will 
include all patients (adults and adolescents) randomized to 
the double-blind maintenance stage (Stage 2), regardless if 
they have received treatment or not. In the ITT analysis set, 
treatment will be assigned based on the treatment to which 
patients were randomized, regardless of which treatment 
they actually received.
Newly-created sub-section and  text 
to define this analysis set due to the 
option of adolescent enrollment.
9.4. Study Population
The eITT analysis set (Section 9.2) will be used for all study 
population summaries of the double-blind treatment stage 
unless otherwise specified. Summaries will be presented by
treatment group and for all patients. The primary analysis 
will be conducted on the ITT analysis set, the first key 
secondary endpoint will be conducted on the complete eITT 
analysis set and the second key secondary endpoint will be 
conducted on the adolescent subsetof the eITT analysis set.
The analysis set on which analysis for other end-points will 
be conducted will be specified on a case-by-case basis. The 
The eITT analysis set (Section 9.2) will be used for all 
study population summaries of the double-blind treatment 
stage unless otherwise specified. Summaries will be 
presented by treatment group and for all patients. The 
primary analysis will be conducted on the ITT analysis set, 
the first key secondary endpoint will be conducted on the 
complete eITT analysis set and the second key secondary 
endpoint will be conducted on the adolescent subset of the 
eITT analysis set. The analysis set on which analysis for 
other end-points will be conducted will be specified on a 
case-by-case basis. The enrolled patients set will be used 
Clarification regarding the 
endpoints and corresponding 
analysis sets with the newly-
introduced option of adolescent 
enrollment.

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enrolled patients set will be used for data summaries
before the double-blind treatment stage.
for data summaries before the double-blind treatment 
stage.
9.4.1. Patient Disposition
Data from patients screened and enrolled in Stage 1; patients 
who were enrolled in Stage 1 but not randomized for the 
double-blind stage and reason for not randomized; patients 
who were randomized; patients who were randomized but not 
treated; patients in the ITT, patients in the eITT, PP, safety, 
and pharmacokinetics analysis sets; patients who completed 
the study; and patients who withdrew from the study will be 
summarized using descriptive statistics. Data from patients 
who withdrew from the study will also be summarized by 
reason for withdrawal using descriptive statistics. Adolescent 
patient disposition may be summarized separately, if 
applicable.
Data from patients screened and enrolled in Stage 1; 
patients who were enrolled in Stage 1 but not randomized 
for the double-blind stage and reason for not randomized; 
patients who were randomized; patients who were 
randomized but not treated; patients in the ITT, patients in 
the eITT, PP, safety, and pharmacokinetics analysis sets; 
patients who completed the study; and patients who 
withdrew from the study will be summarized using 
descriptive statistics. Data from patients who withdrew 
from the study will also be summarized by reason for 
withdrawal using descriptive statistics. Adolescent patient 
disposition may be summarized separately, if applicable.
Clarification regarding analysis sets 
used.
9.4.2. Demographic and Baseline Characteristics
Treatment groups will be compared for all continuous 
variables, using an analysis of variance (ANOVA) with 
treatment group and investigational center as factors. The 
categorical variables of patient sex and race will be 
summarized using the descriptive statistics for each variable
category. Missing categories will be presented if necessary. 
Treatment groups will be compared for all categorical 
variables using a Pearson's chi-squared test (or Fisher's exact 
test if cell sizes are too small).
The ITT analysis set, the eITT analysis set, and the eITT 
subset of adolescents will be used for the summaries. 
The ITT analysis set, the eITT analysis set, as well as the 
eITT subset of adolescents will be used for the summaries. 
The analysis methods will be 
detailed in the Statistical Analysis 
Plan.
New text to clarify subsets used in 
the analysis.
9.5.1. Primary Endpoint
…
-
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 
..
-
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 
Correction of typos for consistency 
with other protocol sections.

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increase of > ≥4 on the combined score of these 
4 PANSS items (conceptual disorganization, 
hallucinatory behavior, suspiciousness, and unusual 
thought content) since randomization
absolute increase of ≥4 on the combined score of 
these 4 PANSS items (conceptual disorganization, 
hallucinatory behavior, suspiciousness, and 
unusual thought content) since randomization
9.5.2. Key Secondary Endpoints
[Not applicable]
The key secondary endpoints are:
1. time to impending relapse (as defined under the primary 
objective) in the eITT analysis set), and
2. time to impending relapse in adolescent patients with 
schizophrenia.
NOTE: The assessment of time to impending relapse in 
adolescent patients is pending randomization of at least 10 
adolescent patients with clinically sufficient exposure.
Newly-added sub-section defining 
the introduced key secondary 
endpoints.
9.5.3. Secondary Endpoints
[Not applicable]
The eITT analysis set (Section 9.2) will be used for all 
summaries in this section, unless otherwise specified.
For the endpoints that are evaluted only in the adult 
population, the analysis will be conducted on the ITT 
analysis set. 
[Previously Section 9.5.2.] 
New text to clarify subsets used in 
the analysis.
 
 
 
 
 
9.5.4.2. 5-Level EuroQol Five Dimensions Questionnaire
The change from baseline to endpoint in total score will be 
calculated.The change from baseline to each visit and to 
endpoint in each of the EQ-5D-5L domains will be 
calculated.
The change from baseline to each visit and to endpoint in 
each of the EQ-5D-5L domains will be calculated.
Correction since there is no "total 
score" in this scale.
9.5.4.6. CGI-I Score at Endpoint

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The change from baseline to endpoint in total score will be 
calculated. CGI-I at endpoint will be analyzed.
CGI-I at endpoint will be analyzed.
Correction since there is no "total 
score" in this scale.
9.5.5. Planned Method of Analysis
The ITT analysis set (Section 9.2.2) will be used for all 
efficacy analyses. Summaries will be presented by treatment 
group. Analysis that will be conducted on the eITT analysis 
set or on the adolescent patient subset of the eITT will be 
described below.
The ITT analysis set (Section 9.2.2) will be used for all 
efficacy analyses. Summaries will be presented by 
treatment group. Analysis that will be conducted on the 
eITT analysis set or on the adolescent patient subset of the 
eITT will be described below.
Re-numbering of section (instead of  
9.5.4).
Clarification.
9.5.5.2. Sensitivity Analysis
A sensitivity analysis will be conducted to assess the impact 
of large intervals between the previous assessment and the 
assessment when the first relapse was observed via the 
interval censoring method. If the interval is ≥1.5 times the 
protocol planned assessment interval length, then the patient 
will be censored at the previous assessment visit. Sensitivity 
analysis will also be conducted by classifying dropouts (for 
reasons other than relapse) as relapse events instead of 
censoring. The PP analysis set will also be used to assess the 
primary efficacy variable. A sensitivity analysis to assess the 
impact of dropouts (for reasons other than relapse) will be 
conducted as well. Details will be provided in the statistical 
analysis plan. Senstivity analysis will be conducted on the 
ITT analysis set.
A sensitivity analysis will be conducted to assess the 
impact of large intervals between the previous assessment 
and the assessment when the first relapse was observed. 
Sensitivity analysis will also be conducted by classifying 
dropouts (for reasons other than relapse) as relapse events 
instead of censoring. The PP analysis set will also be used 
to assess the primary efficacy variable. Details will be 
provided in the statistical analysis plan. Senstivity analysis 
will be conducted on the ITT analysis set.
Section number changed from 
9.5.4.2. due to addition of key 
secondary enpoints.
Introduction of the interval 
censoring method instead of the 
previous description of method of 
sensitivity to the large inter 
assessment intervals.
Deletion of redundant reference to 
dropout sensitivity analysis 
(mentioned 2 sentences before).
Clarification regarding patient 
subset analyzed.
9.5.5.3. Subgroup Analysis
Additional sSubgroup analysis for the primary endpoint, 
including region, will be described in the statistical analysis 
plan.
Additional subgroup analysis for the primary endpoint, 
including region, will be described in the statistical 
analysis plan.
Clarification.
9.5.5.4. Key Secondary Analyses 
[Not applicable[]
9.5.5.4.1. Key Secondary Analysis 1
Time to impending relapse in adult and adolescent patients 
will be assessed similarly to the Primary Efficacy Analysis 
using the eITT Analysis Set (Section 9.2.2.). The Cox 
proportional hazard model will include patient age group 
New sub-section describing the 
analysis of the newly-introduced 
key secondary endpoints.

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(if applicable) along with treatment, and the 
aforementioned stratification variables as the factors. The 
details about the Type I statistical error control will be 
discussed in Section 9.6.
9.5.5.4.1. Key Secondary Analysis 1
Time to impending relapse in adolescent patients will be 
assessed if the number of randomized patients will be at 
least 10 with clinically sufficient exposure. The method 
will be similar to the Primary Efficacy Analysis, but will 
use the adolescent patients subset. The details about the 
Type I statistical error control will be discussed in 
Section 9.6.
9.5.5.5. Secondary Efficacy Analysis
[Not applicable]
The eITT analysis set (Section 9.2) will be used for all 
summaries in this section, unless otherwise specified.
[Previously Section 9.5.4.4] 
Information added regarding the 
analysis set to be used.
9.5.5.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
[Previously Section 9.5.4.5] 
 
 
9.6. Multiple Comparisons and Multiplicity

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There will be 1 interim analysis when the number of events 
observed reaches 60% of the planned 207 relapse events (125 
events) in the ITT analysis set. At this interim analysis, both 
primary efficacy tests will be tested at a 2-sided alpha of 
0.0101. If both tests are significant at the interim analysis, the 
study may be stopped. If only 1 primary efficacy test (or 
none) is significant at the interim analysis, the study will 
continue until the required number of relapse events are 
observed.
…
Type-I error will be further controlled for the 2 key 
secondary endpoints by employing the hierarchical 
approach. Secondary endpoint #1 will be analyzed only in 
case the2 primary efficacy endpoints have p-value less than 
or equal to alpha of 0.0464. In that case, key secondary 
endpoint #1 will be tested for the 2 dosing regimens using 
the same approach. Namely, tests for the 2 dosing regimens 
will be conducted with 2-sided alphas of 0.0464; if one of 
the comparisons for the key secondary endpoint #1 is not 
significant at a 2-sided alpha of 0.0464, the other will be 
tested at 2-sided alpha of 0.0464 divided by 2. 
If secondary endpoint #1 is successful on both dosing 
regimens against placebo, and there are at least 10 
adolescent patients in the study with clinically sufficient 
exposure, then the 2 dosing regimens in the adolescent 
study population will be tested against placebo in the same 
way as described for the primary efficacy endpoint and key 
secondary endpoint #1. 
There will be 1 interim analysis when the number of events 
observed reaches 60% of the planned 207 relapse events 
(125 events) in the ITT analysis set. At this interim 
analysis, both primary efficacy tests will be tested at a 2-
sided alpha of 0.0101. If both tests are significant at the 
interim analysis, the study
may be stopped. If only 1 primary efficacy test (or none) is 
significant at the interim analysis, the
study will continue until the required number of relapse 
events are observed.
…
Type-I error will be further controlled for the 2 key 
secondary endpoints by employing the hierarchical 
approach. Secondary endpoint #1 will be analyzed only in 
case the2 primary efficacy endpoints have p-value less than 
or equal to alpha of 0.0464. In that case, key secondary 
endpoint #1 will be tested for the 2 dosing regimens using 
the same approach. Namely, tests for the 2 dosing regimens 
will be conducted with 2-sided alphas of 0.0464; if one of 
the comparisons for the key secondary endpoint #1 is not 
significant at a 2-sided alpha of 0.0464, the other will be 
tested at 2-sided alpha of 0.0464 divided by 2. 
If secondary endpoint #1 is successful on both dosing 
regimens against placebo, and there are at least 10 
adolescent patients in the study with clinically sufficient 
exposure, then the 2 dosing regimens in the adolescent 
study population will be tested against placebo in the same 
way as described for the primary efficacy endpoint and key 
secondary endpoint #1.
Clarification.
Details regarding Type I error 
control for the newly-introduced 
key secondary endpoints are 
provided.
9.7. Safety Analysis
Allowed rescue medications will include zolpidem or 
diphenhydramine for insomnia; benztropine, trihexyphenidyl, 
or diphenhydramine for EPS; and propranolol and 
benzodiazepines for akathisia. Descriptive statistics for 
Descriptive statistics for allowed rescue medications (see 
Section 5.75.7) will be presented by treatment group.
Safety outcomes, including changes from baseline in EPS 
scale scores (BARS, AIMS, and SAS) and CDSS during 
Details of the rescue medication 
were deleted since not relvant here. 
Cross-reference to concomitant 
medication section was created for 

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allowed rescue medications (see 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 and/or ANCOVA, with
treatment and stratification variables as factors and baseline 
as a covariate (LOCF will be used) by treatment group.
Adjustment to stratification factors may be conducted as 
appropriate.
…
Selected safety data will also be presented by site of injection 
(abdomen vs arm) and by age group (adolescents [ages 13-
17] and adults [18 years of age and above]), as applicable.
Separate summaries for adolescent patients may be 
presented separately for some analyses, as applicable and 
will be described in the Statistical Analysis Plan.
Stage 2, will be presented using descriptive statistics by 
treatment group. Adjustment to stratification factors may 
be conducted as appropriate.
…
Selected safety data will also be presented by site of 
injection (abdomen vs arm) and by age group (adolescents 
[ages 13-17] and adults [18 years of age and above]), as 
applicable.
Separate summaries for adolescent patients may be 
presented separately for some analyses, as applicable and 
will be described in the Statistical Analysis Plan.
clarity.
The safety analysis method(s) will 
be detailed in the Statistical 
Analysis Plan.
Newly-introduced text regarding 
adolescent data.
9.8. Tolerability Analysis
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 of patients who withdrew early due to adverse 
events, respectively, divided by number of patients in each 
treatment group, and will be analyzed presented using 
descriptive statistics.
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 of patients who withdrew early due to 
adverse events, respectively, divided by number of patients 
in each treatment group, and will be presented using 
descriptive statistics.
Correction.
[Not applicable]
Separate summaries for adolescent patients may be 
presented separately for some analyses, as applicable and 
will be described in the Statistical Analysis Plan.
Newly-introduced text regarding 
adolescent data. 
9.9. Pharmacokinetic Analysis
All concentration data will be summarized by age subset 
(adult, adolescent), treatment (q1m, q2m or oral), dose and 
All concentration data will be summarized by age subset 
(adult, adolescent), treatment (q1m, q2m or oral), dose and 
Clarifications regarding the 
pharmacokinetic modeling and 

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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-OH-risperidone, and total active moiety (sum 
of risperidone and 9-OH-risperidone).
Additional pharmacokinetic parameters may be determined if 
data permits (see Section 2.2). 
In addition, the pharmacokinetics of TV-46000 (and if data 
permits, also of oral risperidone) will be evaluated using a 
population pharmacokinetics approach.
 
 
 
 
Importantly, pharmacokinetic concentration analysis and 
population pharmacokinetics analysis independent 
pharmacokinetic modeling and population-based modeling 
analysis will take place during the study conduct, while 
maintaining the blind, as will be described in the 
pharmacokinetics analysis plan.
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-OH-risperidone, and 
total active moiety (sum of risperidone and 
9-OH-risperidone).
Additional pharmacokinetic parameters may be determined 
if data permit (see Section 2.2). 
In addition, the pharmacokinetics of TV-46000 (and if data 
permit, also of oral risperidone) will be evaluated using a 
population pharmacokinetics approach. 
 
 
 
 
 
Importantly, independent pharmacokinetic modeling and 
population-based modeling analysis will take place during 
the study conduct, while maintaining the blind, as will be 
described in the pharmacokinetics analysis plan.
analysis.
9.13. Planned Interim Analysis
There will be 1 formal interim analysis when the number of 
events observed in the ITT analysis set reaches 60% of the 
planned 207 relapse events (125 events in adult patients).
There will be 1 formal interim analysis when the number 
of events observed in the ITT analysis set reaches 60% of 
the planned 207 relapse events (125 events in adult 
patients).
Clarification.
15. REFERENCES
[Not applicable] 
Asarnow R, Brown W, Strandburg R. Children with a 
schizophrenic disorder: neurobehavioral studies. Eur Arch 
Psychiatry Clin Neurosci. 1995;245:70-9.
Bo S, Haahr UH. Early-onset psychosis and child and 
adolescent schizophrenia. Scandinavian J Child Adolescent 
Psychiatry and Psychology 2016;4(1):1-3.
Ferrin M, Gosney H, Marconi A, Rey JM. Using 
Newly-added references on 
diagnostics and treatment of 
schizophrenia in the pediatric 
patient population.

Placebo-Controlled Study – Schizophrenia
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Reason/Justification for change
antipsychotic medication for the treatment of schizophrenia 
in children and adolescents. In Rey JM (ed), IACAPAP e-
Textbook of Child and Adolescent Mental Health. Geneva: 
International Association for Child and Adolescent 
Psychiatry and Allied Professions 2016.
Hollis C. Adult outcomes of child- and adolescent-onset 
schizophrenia: diagnostic stability and predictive validity. 
Am J Psychiatry 2000;157(10):1652-9. 
Lytle S, McVoy M, Sajatovic M. Long-acting injectable 
antipsychotics in children and adolescents. J Child Adolesc 
Psychopharmacol. 2017;27(1): 2-9. 
Pogge DL, Singer MB, Harvey PD. Rates and predictors of 
adherence with atypical antipsychotic medication: a 
follow-up study of adolescent inpatients. J Child Adolesc 
Psychopharmacol. 2005;15(6):901-12.
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.
Weinberger D, Harrison PJ (Eds.) Schizophrenia. 3rd ed. 
Hoboken, NJ: Wiley-Blackwell; 2011. 
Yazdi K, Unterlass G, Kemmler G, et al. Factors 
influencing adherence in children and adolescents treated 
with antipsychotics or antidepressants. Prim Care 
Companion J Clin Psychiatry 2008;10(2):160-1.
Lindenmayer JP, Czobor P, Alphs L, Nathan AM, Anand R, 
Islam Z. et al. The InterSePT scale for suicidal thinking 
reliability and validity. Schizophr Res. 2003;63(1–2):161–
170. 1 9.
Lindenmayer JP, Czobor P, Alphs L, Nathan AM, Anand 
R, Islam Z. et al. The InterSePT scale for suicidal thinking 
reliability and validity. Schizophr Res. 2003;63(1–2):161–
70. 
Correction; the reference appears on 
pg 161-170 of the journal.  
APPENDIX A . CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Legal Representative of the Sponsor in the European 
Union
Senior Director, Head of European Regulatory Affairs 
Legal Representative of the Sponsor in the European 
Union
This reflects a change in 
responsibilities at Teva; introduced 
in Local Am 01 for Bulgaria.

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Graf-Arco-Str. 3 
89079 Ulm
Germany
Tel.: +
E mail: 
Graf-Arco-Str.3
89079 Ulm
Germany
Telephone: 
E-mail: 
[Not applicable]
Medical Monitor:
 
Medical Director
ICON PLC  
Mobile: +
 
Addition of the medical monitor 
contact details to the protocol.
Electronic Data Capture:
Medidata Solutions Worldwide
350 Hudson Street
New York, NY 10014
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
United States
Electronic Data Capture:
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
United States
Correction. The service is sub-
contracted to and managed by 
ICON.
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
Procedures for Screening (Visit 1, Week -16+4 weeks)
…

functional measures (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

Calgary Depression Scale for Schizophrenia (CDSS) 

healthcare resource utilization – for all patients
Procedures for Screening (Visit 1, Week -16+4 weeks)
…

functional measures (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

Calgary Depression Scale for Schizophrenia (CDSS) 

healthcare resource utilization – for all patients
Clarification regarding which 
patient population(s) will be 
analyzed for the quality of life and 
healthcare resource utilization 
endpoints.
This change affects the other sub-
sections in this appendix in which 
these scales are mentioned.

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
Drug Attitudes Inventory 10-item version (DAI-10) – for 
adult patients only
…

Drug Attitudes Inventory 10-item version (DAI-10) –
for adult patients only
…
Procedures During Double-blind Maintenance Stage 
Administration of Investigational Medicinal Product 
(Baseline [Visit 6, Day 1 ±3 days])
…

12-lead electrocardiography (in triplicate)

serum β-HCG tests (for women of childbearing potential)

urine β-HCG tests (for women of childbearing 
potential)

PANSS 

CGI-S 
…

questions to assess ease of study drug administration – to 
be performed only in the event that prefilled syringes 
become available during the study (assessed during 3 in-
clinic visits for each patient)
…
Procedures During Double-blind Maintenance Stage 
Administration of Investigational Medicinal Product 
(Baseline [Visit 6, Day 1 ±3 days])
…

12-lead electrocardiography (in triplicate)

serum β-HCG tests (for women of childbearing 
potential)

urine β-HCG tests (for women of childbearing 
potential)

PANSS 

CGI-S 
…

questions to assess ease of study drug administration –
to be performed only in the event that prefilled 
syringes become available during the study (assessed 
during 3 in-clinic visits for each patient)
…
Addition of urine pregnancy test at 
the baseline visit.
Clarification regarding which 
patient population(s) will be 
analyzed for the quality of life and 
healthcare resource utilization 
endpoints.
Clarification; assessment of ease of 
study drug administration will only 
be performed for the first 3 visits for 
each patient after introduction of the 
PFS. 
o
This change is also 
relevant for sub-section d 
(Visit 7) and sub-section e 
(Visit 8)
d. Stage 2: Relapse Prevention (Visit 7, Week 4±3 days)

questions to assess ease of study drug administration – to 
be performed only in the event that prefilled syringes 
become available during the study (assessed during 3 
in-clinic visits for each patient)
d. Stage 2: Relapse Prevention (Visit 7, Week 4±3 days)

questions to assess ease of study drug administration –
to be performed only in the event that prefilled 
syringes become available during the study 
(assessed during 3 in-clinic visits for each patient)
Clarification 
[Not applicable]
f. Stage 2: Relapse Prevention (Visit 9, Week 12±3 days)
The following procedures and assessments will be 
performed at visit 9:

inquiry of concomitant medication

vital sign measurement

urine β-HCG test (for women of childbearing potential)
Newly-introduced text outlining 
Visit 9 procedures due to the time 
points for quality of life and 
healthcare utilization scales. 

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Reason/Justification for change

PANSS

CGI-I 

CGI-S

CGI-SS

AIMS 

BARS 

SAS

C-SSRS

PSP - and every 12 weeks thereafter (for adult 
patients only)

SQLS - and every 12 weeks thereafter (for adult 
patients only)

EQ-5D-5L - and every 12 weeks thereafter (for adult 
patients only)

CDSS 

healthcare resource utilization - and every 12 weeks 
thereafter (for all patients)

blood samples for plasma drug concentration - will be 
taken within an hour prior to dosing 

TV-46000 q1m/placebo administration – for patients 
randomized to those treatment groups

questions to assess ease of study drug administration –
to be performed only in the event that prefilled 
syringes become available during the study (assessed 
during 3 in-clinic visits for each patient)

adverse event inquiry (including serious adverse event 
reporting, injection site-related events including pain)

inquiry about alchohol consumption and illicit drug 
use since previous visit
NOTE: Patients will continue study visits and assessments as 
detailed above (ie, the same assessments performed at visits 7 
and 8 will be repeated at visits 9 and 10, respectively). 
NOTE: Patients will continue study visits and assessments 
as detailed above (ie, the same assessments performed at 
visits 7 and 8 will be repeated at visits 9 and 10, 
Clarification regarding the 
repetition of the in-clinic visits 
(detailed in Table 2).

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However, note that functional measures (PSP, SQLS, and 
EQ-5D-5L) and the healthcare resource utilization will be 
performed every 12 weeks as of Visit 9, inclusive.
Thus, the 24 week series from Visit 7 to Visit 12c (Visits 13-
18c, Visits 19-24c, etc) repeats until patient completion of 
the study, relapse or early termination.
Another pharmacokinetic sample will be collected from 
adolescent patients only 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, 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 
one additional sample is taken, they do not need to be 
collected after the same injection (ie, one sample can be 
taken 3 weeks after Visit X and another can be taken 1 week 
after visit Y). 
respectively). However, note that functional measures 
(PSP, SQLS, and EQ-5D-5L) and the healthcare resource 
utilization will be performed every 12 weeks. 
Thus, the 24 week series from Visit 7 to Visit 12c (Visits 
13-18c, Visits 19-24c, etc) repeats until patient 
completion of the study, relapse or early termination.
Another pharmacokinetic sample will be collected from 
adolescent patients only 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, 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 one additional sample is taken, they 
do not need to be collected after the same injection (ie, one 
sample can be taken 3 weeks after Visit X and another can 
be taken 1 week after visit Y). 
Newly-added text detailing the 
additional PK sampling in 
adolescents.
Stage 2: Relapse Prevention (Visit 9, Week 12±3 days) 
(or Early Termination (ET) Visit/End-of-Treatment Visit 
(EoT))
The following procedures and assessments will be performed 
at visit 9 or at the ET/EoT visit:

urine drug screen – will be performed if this is the 
patient’s ET/EoT visit

inquiry of concomitant medication

full physical examination, including weight – will be 
performed if this is the patient’s ET/EoT visit

vital sign measurement

urine β-HCG test (for women of childbearing potential)

PANSS 

CGI-S
Stage 2: Early Termination (ET) Visit/End-of-
Treatment Visit (EoT)
The following procedures and assessments will be 
performed at the ET/EoT visit:

urine drug screen 

inquiry of concomitant medication

full physical examination, including weight 

vital sign measurement

urine β-HCG test (for women of childbearing 
potential)

PANSS 

CGI-S

CGI-I 

CGI-SS
The ET/EoT visit is now depicted as 
a separate visit, and therefore the 
clarifying comments are redundant.
Clarification regarding the number 
of events at the end of the study.
Clarification regarding performance 
of an ECG at this visit.

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
CGI-I 

CGI-SS

AIMS 

BARS 

SAS

C-SSRS

PSP - will be performed if this is the patient’s ET/EoT 
visit for adult patients only

SQLS - will be performed if this is the patient’s ET/ 
EoT visit - for adult patients only

EQ-5D-5L - will be performed if this is the patient’s 
ET/EoT visit - for adult patients only

CDSS 

healthcare resource utilization – and every 12 weeks 
thereafter (will also be performed if this is the 
patient’s ET/EoT visit) - for all patients 

DAI-10 – will be performed if this is the patient’s 
ET/EoT visit for adult patients only

blood sample for biomarker analysis – will be performed 
if this is the patient’s ET/ EoT visit

blood samples for plasma drug concentration - will be 
taken within an hour prior to dosing 

TV-46000 q1m/placebo administration – for patients 
randomized to those treatment groups study drug 
administration (for patients randomized to all treatment 
groups).

questions to assess ease of study drug administration – to 
be performed only in the event that prefilled syringes 
become available (in total if this is one of the 3 visits in 
which it is assessed)

adverse event inquiry (including serious adverse event 
reporting, injection site-related events including pain)

inquiry about alchohol consumption and illicit drug use 

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 – for all patients

DAI-10 - for adult patients only

blood sample for biomarker analysis 

blood samples for plasma drug concentration - will be 
taken within an hour prior to dosing 

study drug administration (for patients randomized to 
all treatment groups).

questions to assess ease of study drug administration –
to be performed only in the event that prefilled 
syringes become available (if this is one of the 3 
visits in which it is assessed)

adverse event inquiry (including serious adverse event 
reporting, injection site-related events including pain)

inquiry about alchohol consumption and illicit drug 
use since previous visit
Note: The double-blind maintenance stage will be variable 
in duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; 
meet 1 or more of the study discontinuation or withdrawal 
criteria; or remain relapse-free during the double-blind 
phase until the study is terminated for efficacy at the 
interim analysis or because 207 relapse events are recorded 
in the study in the ITT analysis set. 
Note: If per the investigator's judgement, the patient is at 

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since previous visit
Note: The double-blind maintenance stage will be variable in 
duration, with patients continuing until they experience a 
relapse event and complete all end-of-study assessments; 
meet 1 or more of the study discontinuation or withdrawal 
criteria; or remain relapse-free during the double-blind phase 
until the study is terminated for efficacy at the interim 
analysis or because 207 relapse events are recorded in the 
study in the ITT analysis set. 
Note: If per the investigator's judgement, the patient is at 
risk of not appearing to 1 or both of the follow-up visits, the 
investigator may also complete the unscheduled visit form 
and perform an ECG.
risk of not appearing to 1 or both of the follow-up visits, 
the investigator may also complete the unscheduled visit 
form and perform an ECG.
Unscheduled Visits
During Stage 2, Uunscheduled 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 the 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.
Unscheduled Visits
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 the 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.
Clarification; relevant only to Stage 
2 of study.
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 
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, 
Verbiage regarding assent was 
added following the introduction of 
the possibility to enroll adolescent 
patients in the study.

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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.
…
For adolescent patients, a personally signed and dated 
informed consent form 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.
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.
…
For adolescent patients, a personally signed and dated 
informed consent form 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.
APPENDIX G. LIST OF PROHIBITED MEDICATIONS
…
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
o
Except during the conversion and 
stabilization stage (Stage 1), and only if 
required for conversion from the previous 
antipsychotics to oral risperidone

dopamine reuptake inhibitors or prescription 
psychostimulants within 30 days prior to first oral 
risperidone dose
…
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
o
Except during the conversion and 
stabilization stage (Stage 1), and only if 
required for conversion from the 
previous antipsychotics to oral 
risperidone

dopamine reuptake inhibitors or prescription 
psychostimulants within 30 days prior to first oral 
Clarification regarding use of 
antipsychotics during Stage 1 of the 
study; for consistency with Section 
5.7.

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
opiates or opiate-containing analgesics within 14 days 
prior to first oral risperidone dose medications
risperidone dose

opiates or opiate-containing analgesics within 14 days 
prior to first oral risperidone dose medications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.

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Pharmacogen
etics
6
1d
6
Virology
9
1
9
Total
37.553.5
4045
217297
(309 for 
adolescents)
a Serum pregnancy test to be performed for women of 
childbearing potential only.
b Up to 3 additional samples will be collected from 
adolescent patients.
bc Biomarker blood samples will be collected as follows: 6 
mL each for plasma and serum, and 6.5 2.5 mL for RNA 
(PAXgene).
d 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.
Pharmacogene
tics
6
1d
6
Virology
9
1
9
Total
53.5
45
297
(309 for 
adolescen
ts)
a Serum pregnancy test to be performed for women of 
childbearing potential only.
b Up to 3 additional samples will be collected from 
adolescent patients.
c Biomarker blood samples will be collected as follows: 6 
mL each for plasma and serum, and 2.5 mL for RNA 
(PAXgene).
d 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 for pharmacogenetic assessments at the time point 
detailed in Table 1 Table 2. Genetic variability in the 
metabolizer gene, cytochrome P450 2D6 (CYP2D6), will be
evaluated for an association with drug concentrations of TV-
46000 and oral risperidone. 
A blood sample (6 mL) for pharmacogenetic assessment 
will be collected from all patients who signed the informed 
consent for pharmacogenetic assessments at the time point 
detailed in Table 2. Genetic variability in the metabolizer 
gene, cytochrome P450 2D6 (CYP2D6), will be evaluated 
for an association with drug concentrations of TV-46000 
and oral risperidone. 
Table of Assessments has been 
divided into 2 to reflect Stage 1 and 
Stage 2; therefore, the cross-link 
was corrected to appropriate table.

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16.7.
Letter of Clarification 01 (26 June 2018)

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16.8.
Local Amendment 01 for Bulgaria (Dated 28 May 2018)
The primary reason for this local amendment is to allow inclusion of Bulgarian investigational 
centers and patients in this study. The amended protocol was submitted as part of the Clinical 
Trial Authorization (CTA) Application in Bulgaria.
To adhere with local regulations, the European Union Drug Regulating Authorities Clinical 
Trials (EudraCT) number  has been added to the protocol.  A few additional revisions have been 
made to clarify various aspects of the planned study conduct in this country.
The revisions listed below have been made to the protocol and protocol synopsis, as appropriate, 
and are considered non-substantial and administrative by the Teva Authorized Representative.
A comparison table showing the changes from the Protocol with Revision 01 to the Local 
Amendment 01 for Bulgaria is provided below. Previous text with changes indicated is presented 
in the column titled “Original text with changes shown,” and the final text is presented in the 
column titled "New wording". Revised or new text is shown in bold italics and deletions are 
shown with strike-throughs.

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Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for change
TITLE PAGE (Other sections affected by this change: Investigator Agreement; Coordinating Investigator Agreement)
Clinical Study Protocol with Revision Local Am 01for 
Bulgaria
Clinical Study Protocol with Local Am 01for 
Bulgaria
To denote the country-specific local 
amendment.
EudraCT number: Not applicable 2018-001619-65
EudraCT number: 2018-001619-65
Number added for study conduct in 
EU.
AMENDMENT HISTORY
[Not applicable]
AMENDMENT HISTORY
The protocol for Study TV46000-CNS-30072 (original 
protocol dated 14 December 2017) has been amended 
and reissued as follows:
Local 
Amendment 01 
for Bulgaria
28 May 2018
(6 patients 
enrolled to date)
Protocol with 
Revision 01
15 February 
2018
(0 patients 
enrolled to date)
The Summary of Changes to the Protocol includes the 
corresponding reason/justification for each change and 
is provided in Section 16.
This page was added in the 
amendment for tracking history.
LIST OF ABBREVIATIONS
[Not applicable]
SmPC = Summary of Product Characteristics
Newly-added abbreviation.
3.
STUDY DESIGN
3.2. Planned Number of Patients and Countries
Approximately 795 patients will be screened to achieve 
enrollment of approximately 596 patients in Stage 1, including 
approximately 57 patients in Bulgaria.
The number of randomized patients in Stage 2 is planned to be 
approximately 417, including approximately 40 patients in 
Approximately 795 patients will be screened to achieve 
enrollment of approximately 596 patients in Stage 1, 
including approximately 57 patients in Bulgaria.
The number of randomized patients in Stage 2 is 
planned to be approximately 417, including 
Information added regarding study 
projection in Bulgaria.

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Reason/Justification for change
Bulgaria. Details on the definition of evaluable patients and 
determination of the sample size are given in Section 9.1. 
The study is planned to be conducted in approximately 80
investigational centers in North America and possibly other 
regions (eg, Bulgaria) as well.
approximately 40 patients in Bulgaria. Details on the 
definition of evaluable patients and determination of 
the sample size are given in Section 9.1. 
The study is planned to be conducted in approximately 
80 investigational centers in North America and 
possibly other regions (eg, Bulgaria) as well.
5.
TREATMENTS
5.2.1. Storage and Security
The investigator or designee must confirm appropriate 
temperature conditions have been maintained for all IMPs
medicinal products received, and any discrepancies must be 
reported and resolved before their use of the IMPs.
…
Oral risperidone is to be stored and securely locked according 
to the storage conditions specified in the package insert 
(RISPERIDONE tablets, Teva Pharmaceuticals, US PI).
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.
…
 
 
 
Since it is not considered an IMP, 
the sentence on oral risperidone 
storage was moved to Section 5.4.
5.2.3.
Accountability
Used and partially used IMP (test or placebo) will be destroyed 
by the study center. Unused and partially used IMP (test or 
placebo) will be Unused IMP (test or placebo) 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.
Unused and partially used IMP (test or placebo) 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.
Clarification that the IMP will be 
returned to the sponsor.
Correction of text duplication.
5.4.  Other Medicinal Products/Non-Investigational Medicinal Products
Oral risperidone tablets for stabilization (Table 4) will be a 
commercial product supplied centrally by the study center the 
sponsor. The brand name of the oral risperidone supplied will 
be recorded on the source documentation. Oral risperidone is 
to be stored and securely locked according to the storage 
conditions specified in the package insert (RISPERIDONE 
tablets, Teva Pharmaceuticals, US PI) manufacturer’s 
Summary of Product Characteristics (SmPC). 
Oral risperidone for stabilization (Table 4) will be a 
commercial product supplied centrally by the sponsor. 
The brand name of the oral risperidone supplied will be 
recorded on the source documentation. Oral risperidone 
is to be stored according to the manufacturer’s 
Summary of Product Characteristics (SmPC). 
Correction for consistency with 
Table 4; all forms of oral 
risperidone are allowed. 
In Bulgaria, oral risperidone will be 
sourced by the sponsor.
Since it is not considered an IMP, 
the sentence on oral risperidone 
storage was moved from Section 
5.2.1 to this section and revised to 
encompass storage conditions for all 

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Reason/Justification for change
forms of oral risperidone.
9. STATISTICS
9.5.1. Primary Endpoint
…
-
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 
increase of > ≥4 on the combined score of these 
4 PANSS items (conceptual disorganization, 
hallucinatory behavior, suspiciousness, and unusual 
thought content) since randomization
..
-
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 increase of ≥4 
on the combined score of these 4 PANSS 
items (conceptual disorganization, 
hallucinatory behavior, suspiciousness, and 
unusual thought content) since randomization
Correction of typos for consistency 
with other protocol sections.
APPENDIX A . CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Legal Representative of the Sponsor in the European 
Union
 
 Merckle GmbH
Graf-Arco-Str. 3 
89079 Ulm
Germany
Tel.
E mail: 
Legal Representative of the Sponsor in the 
European Union
Merckle GmbH
Graf-Arco-Str.3
89079 Ulm
Germany
Telephone: 
E-mail: 
This reflects a change in 
responsibilities at Teva.

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16.9.
Protocol with Revision 01 (Dated 15 February 2018)
The Clinical Study Protocol with Revision 01 includes updates to the original protocol dated 14 
December 2017. 

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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
Vice President, Therapeutic Area Head, 
Neurology and Psychiatry 
Specialty Clinical Development 
Teva Branded Pharmaceutical Products R&D, Inc.
Tel
Cell: 
Legal Representative of the Sponsor in the European 
Union
Merckle GmbH
Graf-Arco-Str.3
89079 Ulm
Germany
Telephone
E-mail: 
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: 
Study Principal Investigator
Professor of Psychiatry, Neurology and 
Neuroscience; Chairman, Donald and Barbara 
Zucker School of Medicine at Hofstra/Northwell
Tel: 
Email: 
Medical Monitors
For US:
 
Medical Director
ICON PLC  
Mobile:
 
For Bulgaria:
) 
Medical Director
ICON PLC  
Mobile:
 
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.
Director, Safety Physician
Global Patient Safety and Pharmacovigilance 
Teva Pharmaceutical Industries, 

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Contract Research Organization
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
United States
Central Clinical Laboratory
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
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
Electronic Data Capture
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
United States
Central Electrocardiogram Evaluation
eResearch Technology, Inc
1818 Market Street #1000
Philadelphia, PA, 19103
United States
Interactive Response Technology
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
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)
The screening visit (visit 1) will take place not more than 4 weeks before Stage 1 (visits 2, 3, 
4, and 5). The following procedures will be performed at visit 1:

obtain written informed consent 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 

review prior medication history

review inclusion and exclusion criteria

clinical laboratory tests (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 electrocardiography (in triplicate)

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)

functional measures (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

Calgary Depression Scale for Schizophrenia (CDSS) 

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
healthcare resource utilization – for all patients

Drug Attitudes Inventory 10-item version (DAI-10) – for adult patients only

inquiry about adverse events (including serious adverse event reporting)

inquiry about alchohol consumption and illicit drug use
2. Procedures Before Administration of Investigational Medicinal Product 
(Stage 1: Oral Conversion and Stabilization Stage)
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 measurement

urine β-HCG test (for women of childbearing potential)

PANSS 

Clinical Global Impression–Improvement (CGI-I) 

Clinical Global Impression of Severity (CGI-S)

CGI-SS

AIMS 

BARS  

SAS

C-SSRS

CDSS 

blood samples for plasma drug concentration - will be taken within an hour prior to 
dosing

oral risperidone dispensing (for qd intake)

inquiry about adverse events (including serious adverse event reporting)

dosage review and adjustment

inquiry about alchohol consumption and illicit drug use since previous visit
b. Stage 1: Oral Conversion and Stabilization (Telephone Contacts [Visit 4a, 
Week -6±3 days and Visit 5a, Week -2±3 days])

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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 alchohol 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. A list of suggested questions will be 
provided to the investigator.
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:

review inclusion and exclusion criteria (including randomization-specific criteria)

clinical laboratory tests (serum chemistry, hematology, and urinalysis)

urine drug screen

inquiry of concomitant medication

full physical examination (including weight)

vital sign measurement

12-lead electrocardiography (in triplicate)

serum β-HCG tests (for women of childbearing potential)

urine β-HCG tests (for women of childbearing potential)

PANSS 

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

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
DAI-10  – for adult patients only

blood sample for pharmacogenetic analysis, unless the patient declines testing or local 
regulations prohibit testing.

blood sample for biomarker analysis, unless the patient declines testing or local 
regulations prohibit testing.

assessment of stability (based on the defined criteria)

randomization 

blood samples for plasma drug concentration - will be taken within an hour prior to 
dosing 

TV-46000 every month (q1m)/placebo administration – for patients randomized to 
those treatment groups

TV-46000 every 2 months (q2m) administration – for patients randomized to that 
treatment group

questions to assess ease of study drug administration – to be performed only in the 
event that prefilled syringes become available during the study (assessed during 
3 in-clinic visits for each patient).

inquiry about adverse events (including serious adverse event reporting, injection 
site-related events including pain)

inquiry about alchohol consumption and illicit drug use since previous visit
Procedures During Double-blind Maintenance Stage Administration of Investigational 
Medicinal Product (Stage 2: Relapse Prevention)
c.
Stage 2: Relapse Prevention (Visit 6a, Week 1±3 days; Visit 6b, Week 2±3 days; 
and Visit 6c, Week 3±3 days [Telephone Contacts]) (Visit 7a, Week 5±3 days; 
Visit 7b, Week 6±3 days; and Visit 7c, Week 7±3 days [Telephone Contacts], 8a-
8c, 9a-9c, etc.)
Note: Telephone contacts 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 visits 6a, 6b, and 6c 
(telephone contacts) and the other 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, injection site-related 
events including pain)

inquiry about alchohol consumption and illicit drug use since previous visit

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
brief set of clinical questions to detect psychotic symptoms – 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 as a result of the 
telephone contact will trigger an invitation to the patient to an unscheduled visit where 
psychiatric scales will be administered to rule out an impending relapse at the discretion of 
the investigator.
d. Stage 2: Relapse Prevention (Visit 7, Week 4±3 days)
The following procedures and assessments will be performed at visit 7:

inquiry of concomitant medication

vital sign measurement

urine β-HCG test (for women of childbearing potential)

PANSS 

CGI-I 

CGI-S

CGI-SS

AIMS 

BARS 

SAS

C-SSRS

CDSS 

blood samples for plasma drug concentration - will be taken within an hour prior to 
dosing 

 
 
 
 

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
vital sign measurement

12-lead electrocardiography

urine β-HCG test (for women of childbearing potential)

PANSS

CGI-I 

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 

blood samples for plasma drug concentration - will be taken within an hour prior to 
dosing 

TV-46000 q1m/placebo administration – for patients randomized to those treatment 
groups

TV-46000 q2m administration – for patients randomized to that treatment group

questions to assess ease of study drug administration – to be performed only in the 
event that prefilled syringes become available during the study (assessed during 
3 in-clinic visits for each patient)

adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

inquiry about alchohol consumption and illicit drug use since previous visit
f.
Stage 2: Relapse Prevention (Visit 9, Week 12±3 days)
The following procedures and assessments will be performed at visit 9:

inquiry of concomitant medication

vital sign measurement

urine β-HCG test (for women of childbearing potential)

PANSS

CGI-I 

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
CGI-S

CGI-SS

AIMS 

BARS 

SAS

C-SSRS

PSP - and every 12 weeks thereafter (for adult patients only)

SQLS - and every 12 weeks thereafter (for adult patients only)

EQ-5D-5L - and every 12 weeks thereafter (for adult patients only)

CDSS 

healthcare resource utilization - and every 12 weeks thereafter

blood samples for plasma drug concentration - will be taken within an hour prior to 
dosing 

TV-46000 q1m/placebo administration – for patients randomized to those treatment 
groups

questions to assess ease of study drug administration – to be performed only in the 
event that prefilled syringes become available during the study (assessed during 
3 in-clinic visits for each patient)

adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

inquiry about alchohol consumption and illicit drug use since previous visit
NOTE: Patients will continue study visits and assessments as detailed above (ie, the same 
assessments performed at visits 7 and 8 will be repeated at visits 9 and 10, respectively). 
However, note that functional measures (PSP, SQLS, and EQ-5D-5L) and the healthcare 
resource utilization will be performed every 12 weeks after visit 9. 
Thus, the 24 week series from Visit 7 to Visit 12c (Visits 13-18c, Visits 19-24c, etc) repeats until 
patient completion of the study, relapse or early termination.
Another pharmacokinetic sample will be collected from adolescent patients only 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, 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). 
g. Stage 2: Early Termination (ET) Visit/End-of-Treatment Visit (EoT)

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The following procedures and assessments will be performed at the ET/EoT visit:

urine drug screen 

inquiry of concomitant medication

full physical examination, including weight 

vital sign measurement

urine β-HCG test (for women of childbearing potential)

PANSS 

CGI-S

CGI-I 

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 sample for biomarker analysis, unless the patient declines testing or local 
regulations prohibit testing. 

blood samples for plasma drug concentration - will be taken within an hour prior to 
dosing 

study drug administration (for patients randomized to all treatment groups) - This is 
applicable only for the EoT visit, not the ET visit.

questions to assess ease of study drug administration – to be performed only in the 
event that prefilled syringes become available ( if this is 1 of the 3 visits in which 
it is assessed)

adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

inquiry about alchohol consumption and illicit drug use since previous visit

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Note: The double-blind maintenance stage will be variable in duration, with patients continuing 
until they experience a relapse event and complete all end-of-study assessments; meet 1 or more 
of the study discontinuation or withdrawal criteria; or remain relapse-free  at the time of study 
termination. 
Note: If per the investigator's judgement, the patient is at risk of not appearing to 1 or both of the 
follow-up visits, the investigator may also complete the unscheduled visit form and perform an 
ECG.
Follow-up/Exit Period (Follow-up Visit 1 [4 weeks after last dosing visit] and Follow-up 
Visit 2 [8 weeks after the last dosing visit, End-of-Study (EoS) Visit])
The following procedures and assessments will be performed at follow-up visit 1 and 
follow-up visit 2:

clinical laboratory tests (serum chemistry, hematology, and urinalysis)

inquiry of concomitant medication

full physical examination (including weight)

vital sign measurement

12-lead electrocardiography

serum β-HCG tests (for women of childbearing potential)

PANSS

CGI-I 

CGI-S

CGI-SS

AIMS 

BARS 

SAS

C-SSRS

PSP - at Follow-up Visit 2 only

SQLS - at Follow-up Visit 2 only

EQ-5D-5L - at Follow-up Visit 2 only

CDSS 

healthcare resource utilization - at Follow-up Visit 2 only

DAI-10 - at Follow-up Visit 2 only

blood sample for biomarker analysis, unless the patient declines testing or local 
regulations prohibit testing.

blood samples for plasma drug concentration

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
adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

inquiry about alchohol consumption and illicit drug use since previous visit
Note: Eligible patients who choose to enter the long term TV46000-CNS-30078 extension study 
will not need to complete the follow-up/exit visits in this study. 
Unscheduled Visits
An unscheduled visit may be performed at any time during the study as deemed necessary by the 
investigator (eg, in case of psychiatric adverse events or suspicion of a 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:

concomitant medication review; 

inquiry about changes in use of alcohol and illicit drugs

vital sign measurements

adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

C-SSRS ("Since Last Visit" version) (if visit scheduled to assess psychiatric adverse 
events)

PANSS and review of relapse criteria
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 the 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.
Protocol Deviations
A protocol deviation is defined as any change, divergence, or departure from the study design or 
procedures defined in the protocol. Important protocol deviations are a subset of protocol 
deviations that might significantly affect the completeness, accuracy, and/or reliability of the 
study data or that might significantly affect a subject's rights, safety, or well-being. For example, 
important protocol deviations might include enrolling subjects in violation of key eligibility 
criteria designed to ensure a specific subject population or failing to collect data necessary to 
interpret primary endpoints, as these may compromise the scientific value of the trial. All 
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 
discontinue 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. A noncompliant patient may continue 
taking the study treatment only if this does not jeopardize the patient’s safety. The sponsor will 
assess each protocol deviation and decide whether any of these noncompliances should be 
reported to the Regulatory Authority as a serious breach of Good Clinical Practice (GCP) and the 
protocol.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If the 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 protocol deviation. A deviation from the eligibility criteria will always result in 
study drug discontinuation in case the patient has not been dosed. In case a patient who was 
wrongly randomized has already started taking the study drug, a risk/benefit evaluation has to 
take place, and a strong clinical justification must be provided in case the patient is not 
withdrawn from the study drug. 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 

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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.
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 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 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 (CRFs 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 informed consent form 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 product (IMPs) as well as non-IMPs, eg, background therapy, and the measures to be 
followed should be based on the medicinal product with 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 P4504A inducers. In case 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:

1 year postmenopausal (no menses for 12 months without an alternative medical 
cause plus an increased concentration of follicle stimulating hormone [FSH] 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. Such methods include the following:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 

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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, 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 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.

Periodic abstinence (eg, calendar, ovulation, symptothermal, 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, MHRA).
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.
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 record.

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 drugs that are either strong/moderate inhibitors of cytochrome P450 (CYP) 2D6 
or strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) are presented below:
Table 9:
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.
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 new administrations will be permitted during the study).
CYP2D6=cytochrome P450 2D6; CYP3A4=cytochrome P450 3A4; P-gp=P-glycoprotein.

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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 the previous antipsychotics 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 medications
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 J.
PHARMACOGENETIC ASSESSMENTS
A blood sample (6 mL) for pharmacogenetic assessment will be collected from all patients who 
signed the informed consent for pharmacogenetic assessments at the time point detailed in 
Table 2, unless the patient declines testing or local regulations prohibit testing. All blood tubes 
will be labeled with the patient code number. If required by local regulations, following DNA 
extraction from the pharmacogenetic blood sample, the DNA sample will be labeled with a new 
code (ie, double coding).
 
 
 
. The candidate 
genes may be related to pharmacokinetics, safety features, drug mechanism of action, 
schizophrenia, or related diseases. The final list of genes that will be investigated will be selected 
at a later stage before the analysis to allow for updating with the latest scientific evidence. 
Genetic analysis could also include sequencing of the whole genome, if warranted. 
The planned pharmacogenetic analysis and results of other potential genetic factors will be 
detailed in a separate document.
Pharmacogenetic assessment will be performed only for investigations related to schizophrenia, 
related diseases, or various aspects of understanding response to the test drug or related drugs 
(other antipsychotics). 
Details on processes for collection and shipment of these samples can be found in the procedural 
manual.

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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:

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

excessive force to inject
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)

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
product was taken or used according to protocol (yes/no)

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.
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.
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 of the protocol, 
respectively).
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, 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, 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. 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, electronic patient-reported outcome [ePRO] 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 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:

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, 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 the 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 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 countries/sites.
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 Coronavirus disease 2019 [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 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;
 
 
Section 5.2.3 Accountability  
Any
 IMP transported for home administration will be returned to the clinic to maintain 
accountability. Used syringes 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 
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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 9.5.4.2. Sensitivity Analysis
Sensitivity and supplementary analyses will be conducted to evaluate the impact of the change to 
remote monitoring (VC visits) and the impact of the COVID-19 pandemic on the impending 
relapse and rating scales. The analysis will include subgroup analysis (eg, pre, during and post 
COVID-19 pandemic outbreak, where each patient will be classified into one of the levels), a 
multivariate model (eg, Cox model with time dependent covariate for COVID-19), and/or 
imputation methodology for patients' attrition due to the COVID-19 pandemic, as appropriate 
and if data permit. Details of the supplementary and sensitivity analyses will be presented in the 
statistical analysis plan or addendum thereof, following a blinded review meeting prior to 
database lock.
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
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 

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an increased public health risk, in accordance with IRB approval.  Details are provided in the 
monitoring plan. 
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.”