A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study With an Open-Label, Long-Term Safety Phase to Evaluate the Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release Injectable Suspension (TV-44749) for Subcutaneous Use as Treatment of Adult Patients With Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Teva Branded Pharmaceutical Products R&D LLC

 
 
Clinical Study Protocol 
 
 
A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study with an Open-Label, Long-Term Safety Phase to 
Evaluate the Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release 
Injectable Suspension (TV-44749) for Subcutaneous Use as Treatment of Adult 
Patients with Schizophrenia 
 
 
Study Number TV44749-CNS-30096 
 
 
NCT05693935 
 
 
Protocol with Amendment 01 Approval Date: 15 February 2024 

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
1 
 
  
Clinical Study Protocol with Amendment 01 
Study Number TV44749-CNS-30096 
A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study with an Open-Label, Long-Term Safety Phase to Evaluate the 
Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release Injectable 
Suspension (TV-44749) for Subcutaneous Use as Treatment of Adult Patients with 
Schizophrenia 
Brief Title: A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label, 
Long-Term Safety Phase to Evaluate the Efficacy and Safety of TV-44749 in Adults with 
Schizophrenia 
Lay Title: A Study to Test if TV-44749 is Effective in Relieving Schizophrenia 
(The SOLARIS Study - Subcutaneous OLAnzapine Extended-Release Injection Study) 
Efficacy and Safety Study (Phase 3) 
IND number: 128851; 
NDA number: N/A;  BLA number: N/A; EudraCT number: 
2022-001865-11 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
 
Protocol Version Date: 15 February 2024 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States of America 
 
Sponsor’s Authorized Representative 
 
 
Teva Pharmaceutical Industries Ltd. 
 
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 of Technical Requirements for 
Pharmaceuticals for Human Use (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; the protocol; and the sponsor’s Standard Operating Procedures (SOPs). 
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Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
2 
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 (Teva) and/or its affiliates. The recipient agrees that no information 
contained herein may be published or disclosed without written approval from Teva and/or affiliates. 
©2024 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 
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Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
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INVESTIGATOR AGREEMENT  
Clinical Study Protocol with Amendment 01  
Version Date: 15 February 2024 
IND number: 128851; 
NDA number: N/A; BLA number: N/A; EudraCT number: 
2022-001865-11 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
 
A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study with an Open-Label, Long-Term Safety Phase to Evaluate the 
Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release Injectable 
Suspension (TV-44749) for Subcutaneous Use as Treatment of Adult Patients with 
Schizophrenia 
Principal Investigator:   
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
I have read the protocol with Amendment 01 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice 
regulations as well as all other national and international laws and regulations. 
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Clinical Study Protocol with Amendment 01 
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Principal Investigator 
 
Signature 
Date 
Executed signature pages are maintained within the Investigator Site File and 
the Trial Master File  
 
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Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
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SPONSOR PROTOCOL APPROVAL 
Sponsor’s Authorized 
Representative 
 
 
 
 
Teva Pharmaceutical Industries 
Ltd. 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
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COORDINATING INVESTIGATOR AGREEMENT  
Clinical Study Protocol with Amendment 01  
Version Date: 15 February 2024 
IND number: 128851; 
NDA number: N/A; BLA number: N/A; EudraCT number: 
2022-001865-11 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study with an Open-Label, Long-Term Safety Phase to Evaluate the 
Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release Injectable 
Suspension (TV-44749) for Subcutaneous Use as Treatment of Adult Patients with 
Schizophrenia 
I have read the protocol with Amendment 01 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national and local legal and regulatory requirements and applicable regulations and guidelines. 
I 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 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: 
 
 
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Study TV44749-CNS-30096 
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Coordinating Investigator 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
 
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PROTOCOL AMENDMENT DETAILS  
Document History 
Administrative Letter 05 
05 September 2023 
Administrative Letter 04 
31 July 2023 
Administrative Letter 03 
21 March 2023 
Administrative Letter 02 
15 February 2023 
Administrative Letter 01 
27 November 2022 
Original Protocol 
01 September 2022 
Current Amendment 01 15 February 2024 
As of 29 January 2024, 675 participants have been randomized to the trial. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary reason for this amendment is to describe the course of action for Period 2 
participants following the completion of the Period 1 efficacy analyses and the top line results 
availability. This amendment also provides clarity to assessments and processes in several 
sections and incorporates all changes from 5 prior administrative letters (see Appendix N for 
details). 
All major changes to the protocol body are listed in the table below and are reflected in the 
synopsis, as applicable. Minor editorial changes (eg, typos, punctuation) have been made to the 
protocol (and protocol synopsis, as appropriate). 
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Section Number and Name 
Description of Change 
Brief Rationale 
1.2. Study Scheme 
Updated timeframe of the 
revealing of treatment 
assignment  
(Administrative Letter 04) 
To provide clarification 
1.3. Schedule of Study Procedures and 
Assessments:  
Table 1. Study Procedures and Assessments 
for Period 1 
Table 2. Study Procedures and Assessments 
for Period 2 
4.1. General Study Design and Study 
Schematic Diagram:  
Period 2 (up to 48 weeks) 
6.9. Randomization and Blinding 
6.9.2. Blinding Procedures 
1.3 Schedule of Study Procedures and 
Assessments: 
Table 1. Study Procedures and Assessments 
for Period 1 
Table 2. Study Procedures and Assessments 
for Period 2 
Table 3. Study Procedures and Assessments 
for a Potential Post-injection 
Delirium/Sedation Syndrome Event 
Added option of urine drug 
screen in certain cases 
(Administrative Letter 02) 
To provide clarification 
4.1. General Study Design and Study 
Schematic Diagram:  
Procedures for Potential Post-injection 
Delirium/Sedation Syndrome 
6.11. Total Blood Volume 
8.10. Post-injection Delirium/Sedation 
Syndrome Monitoring 
1.3 Schedule of Study Procedures and 
Assessments: 
Table 1. Study Procedures and Assessments 
for Period 1 
Table 2. Study Procedures and Assessments 
for Period 2 
Updated end of treatment 
(EOT) and follow-up (FU) 
allowed visit windows 
(Administrative Letter 03) 
To provide clarification 
4.1. General Study Design and Study 
Schematic Diagram: 
Period 2 (up to 48 weeks) 
Early Termination and Follow-up Period 
1.3 Schedule of Study Procedures and 
Assessments:  
Table 1. Study Procedures and Assessments 
for Period 1, footnotes f and k 
Table 2. Study Procedures and Assessments 
for Period 2, footnotes a and f 
Updated footnote text 
To correct inconsistences and 
provide clarification 
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Section Number and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Study Procedures and 
Assessments: 
Table 1. Study Procedures and Assessments 
for Period 1, footnote a 
Updated the allowed duration 
of the screening period under 
special circumstances 
(Administrative Letter 03) 
To provide clarification 
4.1, General Study Design and Study 
Schematic Diagram: 
Screening (up to 8 days Prior to 
Randomization to Period 1) 
APPENDIX B. STUDY PROCEDURES 
AND ASSESSMENTS BY VISIT: 
Procedures for Screening/Visit 1 (Day -8, 
Weeks -2 to -1) 
1.3 Schedule of Study Procedures and 
Assessments: 
Table 1. Study Procedures and Assessments 
for Period 1, footnote dd  
Update the Readiness for 
Discharge Questionnaire 
(RDQ) rater qualifications 
(Administrative Letter 03) 
To provide clarification 
4.1 General Study Design and Study 
Schematic Diagram: 
Period 1 (8 weeks) 
1.3 Schedule of Study Procedures and 
Assessments:  
Table 1. Study Procedures and Assessments 
for Period 1 
Table 2. Study Procedures and Assessments 
for Period 2 
Updated Injection site 
reactions to injection site 
findings (local tolerability 
assessments) 
(Administrative Letter 04) 
To provide clarification 
6.9.1. Procedures and Assessments to be 
Performed Before and After Randomization 
into Period 2 at Visit 11 (Week 8) 
8. ASSESSMENT OF SAFETY 
8.8. Assessment of Local Tolerability and 
Pain 
8.8. Assessment of Local Tolerability and 
Pain:  
Table 10. Assessment of Local Tolerability 
(Injection Site Findings and Pain), Title 
APPENDIX B. STUDY PROCEDURES 
AND ASSESSMENTS BY VISIT 
1.3. Schedule of Study Procedures and 
Assessments:  
Table 1. Study Procedures and Assessments 
for Period 1, footnote h 
Updated safety laboratory 
tests during visit 3 
(Administrative Letter 04) 
To provide clarification 
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Section Number and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Study Procedures and 
Assessments:  
Table 2. Study Procedures and Assessments 
for Period 2 
Updated the timing of 
assessments before and after 
randomization at visit 11 
(Administrative Letter 04) 
To provide clarification 
4.1. General Study Design and Study 
Schematic Diagram: 
Period 2 (up to 48 weeks) 
2.1.3 Olanzapine for Subcutaneous Use 
(TV-44749) 
Updated description of TV-
44749 as a combination 
product 
(Administrative Letter 04) 
To provide clarification 
6.1.1. Test Investigational Medicinal 
Product 
3.2.2. Other Efficacy Estimand 
Added text regarding 
estimand for key secondary 
endpoints 
To align with final statistical 
analysis plan 
4.1 General Study Design and Study 
Schematic Diagram: 
Screening (up to 8 days Prior to 
Randomization to Period 1) 
Updated Positive and 
Negative Syndrome Scale 
(PANSS) 
 
requirement and analysis 
(Administrative Letter 03) 
To provide clarification 
5.1. Patient Inclusion Criteria, criterion b 
7.1.1. Positive and Negative Syndrome 
Scale 
APPENDIX D. ETHICS: 
Informed Consent 
4.1. General Study Design and Study 
Schematic Diagram: 
Screening (up to 8 days Prior to 
Randomization to Period 1) 
Updated timing of providing 
informed consent by the 
caregiver 
(Administrative Letter 04) 
To provide clarification 
5.1. Patient Inclusion Criteria, criterion h 
4.1. General Study Design and Study 
Schematic Diagram 
Added text for dose 
adjustment following 
outcome of primary endpoint 
analysis 
To describe the course of action 
following the outcome of primary 
efficacy analysis 
6.9.4 Treatment of Study Participants 
Following Period 1 Efficacy Topline 
Results Availability 
5.1. Patient Inclusion Criteria, criterion a 
Updated age limit 
(Administrative Letter 01) 
To correct an error and provide 
clarification. 
5.2. Patient Exclusion Criteria, criteria n 
and w 
Updated exclusion criteria 
language 
(Administrative Letter 01, 
Administrative Letter 03) 
To correct an error and provide 
clarification 
6.1.1 Test Investigational Medicinal 
Product 
Updated text to indicate the 
injection will be rotated 
between quadrants. 
To provide additional clarification 
and align with the pharmacy 
manual 
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Section Number and Name 
Description of Change 
Brief Rationale 
6.1.2. Placebo Investigational Medicinal 
Product 
Updated description of TV-
44749 placebo as a 
combination product 
To provide clarification 
6.2. Preparation, Handling, Labeling, 
Storage, and Accountability for 
Investigational Medicinal Products 
6.7. Prior and Concomitant Medication or 
Therapy 
Added non-pharmacological 
treatment and updated 
allowed concomitant 
medications 
(Administrative Letter 01) 
To provide clarification 
Updated text regarding 
allowed antidepressants 
To provide clarification 
6.7.1.2. Antidepressants and Mood 
Stabilizers: 
Period 2 
Updated text to indicate that 
only antidepressants 
approved according to the 
study protocol are allowed to 
be used during the study 
(Administrative Letter 05) 
To provide clarification 
6.9 Randomization and Blinding 
Updated text for blinding and 
unblinding 
To provide clarification 
6.9.3 Discontinuation of the Placebo 
Treatment Group 
6.10.2. Blinding and Unblinding 
Updated timing of unblinding 
of prolactin levels during the 
study 
(Administrative Letter 01) 
To provide clarification 
Added a back-up process to 
unblind a patient in case of 
internet connection issues 
(Administrative Letter 01) 
To provide clarification 
6.11. Total Blood Volume 
Updated text for total blood 
volume 
(Administrative Letter 01, 
Administrative Letter 04) 
To correct an error and to provide 
clarification 
7.1.1. Positive and Negative Syndrome 
Scale 
Updated the data sources for 
PANSS, including informant 
data recording 
(Administrative Letter 04) 
To provide clarification 
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Section Number and Name 
Description of Change 
Brief Rationale 
8.1.1. Definition of an Adverse Event 
Updated assessment of 
adverse events related to 
device 
(Administrative Letter 04) 
To provide clarification 
8.1.2. Recording and Reporting of Adverse 
Events 
8.1.4. Relationship of an Adverse Event to 
the Investigational Medicinal Product 
8.1.4. Relationship of an Adverse Event to 
the Investigational Medicinal Product: 
Table 8. The Relationship of an Adverse 
Event to the Investigational Medicinal 
Product and/or Device 
8.1.5.1. Definition of a Serious Adverse 
Event 
10.7. Safety Analysis 
11. QUALITY CONTROL AND 
QUALITY ASSURANCE 
APPENDIX I. PRODUCT COMPLAINTS 
8.4 Clinical Laboratory Tests 
Added text for clinical 
laboratory tests during Visit 3 
To provide clarification 
8.4. Clinical Laboratory Tests: 
Table 9. Clinical Laboratory Tests 
Updated source of 
glomerular filtration rate 
calculation in footnote a 
(Administrative Letter 01) 
To correct an error 
Removed unneeded clinical 
laboratory tests 
(Administrative Letter 01, 
Administrative Letter 03) 
To correct an error 
8.7. Electrocardiography 
Updated interpretation of 
ECGs to assess patient 
eligibility for enrollment 
(Administrative Letter 04) 
To provide clarification 
8.8.1. Procedures for Injection Site Pus-
Containing Lesion (Abscess, Infection, or 
Inflammation), Ulceration, Necrosis, or 
Atrophy 
Added text regarding the 
follow-up questionnaire 
(Administrative Letter 05) 
To provide clarification 
8.9. Assessment of Suicidality 
Updated the C-SSRS rater 
qualifications 
(Administrative Letter 03) 
To provide clarification 
9.1. Pharmacokinetic Assessment 
 
 
(Administrative Letter 03) 
To provide clarification 
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Section Number and Name 
Description of Change 
Brief Rationale 
9.3. Assessment of Exploratory Biomarkers 
 
 
 
(Administrative Letter 01) 
To provide clarification 
10.2.4 Per Protocol Analysis Set 
Deleted section 
To align with final statistical 
analysis plan 
Throughout 
Minor editorial and 
document formatting 
revisions 
Minor; therefore, have not been 
summarized 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................6 
PROTOCOL AMENDMENT DETAILS ........................................................................................8 
LIST OF ABBREVIATIONS ........................................................................................................24 
1. 
PROTOCOL SUMMARY ..........................................................................................27 
1.1. 
Synopsis ......................................................................................................................27 
1.2. 
Study Scheme .............................................................................................................29 
1.3. 
Schedule of Study Procedures and Assessments ........................................................30 
2. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................51 
2.1. 
Introduction .................................................................................................................51 
2.1.1. 
Schizophrenia .............................................................................................................51 
2.1.2. 
Olanzapine for Oral and Intramuscular Use ...............................................................52 
2.1.2.1. 
Immediate-Release Olanzapine Formulations ............................................................52 
2.1.2.2. 
Extended-Release Olanzapine Formulations ..............................................................52 
2.1.3. 
Olanzapine for Subcutaneous Use (TV-44749) ..........................................................53 
2.2. 
Findings from Nonclinical and Clinical Studies .........................................................53 
2.2.1. 
Nonclinical Studies .....................................................................................................53 
2.2.2. 
Clinical Studies ...........................................................................................................55 
2.2.2.1. 
Clinical Pharmacology Studies ...................................................................................55 
2.2.2.2. 
Clinical Efficacy and Safety Studies ..........................................................................59 
2.3. 
Known and Potential Benefits and Risks to Patients ..................................................60 
2.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................60 
2.3.2. 
Known and Potential Benefits and Risks of Other Treatment ....................................61 
2.3.3. 
Overall Benefit and Risk Assessment for This Study ................................................61 
3. 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS ....................................63 
3.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................63 
3.1.1. 
Justification of Primary Endpoint ...............................................................................63 
3.2. 
Estimand .....................................................................................................................64 
3.2.1. 
Primary Estimand .......................................................................................................64 
3.2.2. 
Other Efficacy Estimand .............................................................................................65 
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3.2.3. 
Safety and Tolerability Estimand ...............................................................................66 
3.3. 
Exploratory Objectives and Endpoints .......................................................................66 
4. 
STUDY DESIGN .......................................................................................................68 
4.1. 
General Study Design and Study Schematic Diagram ...............................................68 
4.2. 
Planned Number of Patients and Countries ................................................................74 
4.3. 
Justification for Study Design and Selection of Population .......................................74 
4.3.1. 
Study Duration ............................................................................................................75 
4.3.2. 
Patient Selection .........................................................................................................75 
4.4. 
Stopping Rules for the Study ......................................................................................76 
4.5. 
Schedule of Study Procedures and Assessments ........................................................76 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................77 
5.1. 
Patient Inclusion Criteria ............................................................................................77 
5.2. 
Patient Exclusion Criteria ...........................................................................................79 
5.3. 
Eligibility Criteria for Period 2 ...................................................................................81 
5.4. 
Withdrawal Criteria and Assessments/Procedures for the Patient .............................82 
5.5. 
Replacement of Patients .............................................................................................83 
5.6. 
Rescreening .................................................................................................................84 
5.7. 
Screening Failure ........................................................................................................84 
6. 
TREATMENTS ..........................................................................................................85 
6.1. 
Investigational Medicinal Products Used in the Study ...............................................85 
6.1.1. 
Test Investigational Medicinal Product ......................................................................85 
6.1.1.1. 
Dosing Groups ............................................................................................................85 
6.1.1.2. 
Dose Adjustment ........................................................................................................85 
6.1.2. 
Placebo Investigational Medicinal Product ................................................................85 
6.1.3. 
Other Components ......................................................................................................86 
6.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................86 
6.2.1. 
Storage and Security ...................................................................................................87 
6.2.2. 
Labeling ......................................................................................................................87 
6.2.3. 
Accountability .............................................................................................................87 
6.3. 
Justification for Investigational Medicinal Products ..................................................88 
6.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................88 
6.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................88 
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6.4. 
Other Medicinal Products/Auxiliary Medicinal Products ..........................................89 
6.5. 
Treatment after the End of the Study ..........................................................................89 
6.6. 
Restrictions .................................................................................................................89 
6.6.1. 
Activity .......................................................................................................................89 
6.6.2. 
Fasting.........................................................................................................................89 
6.6.3. 
Specific Food and Beverages ......................................................................................90 
6.6.4. 
Blood Donation ...........................................................................................................90 
6.6.5. 
Cigarette/Tobacco Use ................................................................................................90 
6.7. 
Prior and Concomitant Medication or Therapy ..........................................................90 
6.7.1. 
Allowed Concomitant Medications ............................................................................91 
6.7.1.1. 
Rescue Medications ....................................................................................................91 
6.7.1.2. 
Antidepressants and Mood Stabilizers ........................................................................92 
6.8. 
Procedures for Monitoring Patient Compliance .........................................................92 
6.9. 
Randomization and Blinding ......................................................................................92 
6.9.1. 
Procedures and Assessments to be Performed Before and After 
Randomization into Period 2 at Visit 11 (Week 8) .....................................................93 
6.9.2. 
Blinding Procedures ....................................................................................................94 
6.9.3. 
Discontinuation of the Placebo Treatment Group ......................................................95 
6.9.4. 
Treatment of Study Participants Following the Outcome of Primary Efficacy 
Analysis Availability ..................................................................................................95 
6.10. 
Maintenance of Randomization and Blinding ............................................................96 
6.10.1. 
Maintenance of Randomization ..................................................................................96 
6.10.2. 
Blinding and Unblinding ............................................................................................96 
6.10.3. 
Independent Data Monitoring Committee ..................................................................97 
6.11. 
Total Blood Volume ...................................................................................................97 
7. 
ASSESSMENT OF EFFICACY ................................................................................98 
7.1. 
Assessments of Efficacy .............................................................................................98 
7.1.1. 
Positive and Negative Syndrome Scale ......................................................................98 
7.1.2. 
Clinical Global Impression–Improvement .................................................................98 
7.1.3. 
Clinical Global Impression–Severity of Illness Scale ................................................98 
7.1.4. 
Patient Global Impression-Improvement ....................................................................99 
7.1.5. 
Personal and Social Performance Scale ......................................................................99 
7.2. 
Other Assessment .......................................................................................................99 
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7.2.1. 
Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-
CT) ..............................................................................................................................99 
7.2.2. 
Quality of Life Scales .................................................................................................99 
7.2.2.1. 
Schizophrenia Quality of Life Scale ...........................................................................99 
7.2.2.2. 
 .....................................................99 
8. 
ASSESSMENT OF SAFETY ...................................................................................101 
8.1. 
Adverse Events .........................................................................................................101 
8.1.1. 
Definition of an Adverse Event ................................................................................101 
8.1.2. 
Recording and Reporting of Adverse Events ...........................................................102 
8.1.3. 
Severity of an Adverse Event ...................................................................................102 
8.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product ...........103 
8.1.5. 
Serious Adverse Events ............................................................................................103 
8.1.5.1. 
Definition of a Serious Adverse Event .....................................................................104 
8.1.5.2. 
Expectedness .............................................................................................................104 
8.1.6. 
Reporting a Serious Adverse Event ..........................................................................105 
8.1.6.1. 
Investigator Responsibility .......................................................................................105 
8.1.6.2. 
Sponsor Responsibility .............................................................................................106 
8.1.7. 
Protocol-Defined Adverse Events of Special Interest ..............................................107 
8.1.7.1. 
Protocol-Defined Adverse Events of Special Interest that Require Reporting 
to the Sponsor’s Global Patient Safety and Pharmacovigilance ...............................107 
8.1.7.2. 
Protocol-Defined Adverse Events of Special Interest that Do Not Require 
Reporting to the Sponsor’s Global Patient Safety and Pharmacovigilance ..............107 
8.1.8. 
Protocol Deviations Because of an Adverse Event ..................................................107 
8.2. 
Pregnancy .................................................................................................................107 
8.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products ...................................................................................................108 
8.4. 
Clinical Laboratory Tests .........................................................................................109 
8.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis ..................................111 
8.4.2. 
Other Clinical Laboratory Tests ...............................................................................112 
8.4.2.1. 
Human Chorionic Gonadotropin and Follicle-Stimulating Hormone Tests .............112 
8.4.2.2. 
Urine Drug Screen ....................................................................................................112 
8.4.2.3. 
Prolactin ....................................................................................................................112 
8.5. 
Physical Examinations ..............................................................................................113 
8.6. 
Vital Signs ................................................................................................................113 
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8.7. 
Electrocardiography ..................................................................................................113 
8.8. 
Assessment of Local Tolerability and Pain ..............................................................114 
8.8.1. 
Procedures for Injection Site Pus-Containing Lesion (Abscess, Infection, or 
Inflammation), Ulceration, Necrosis, or Atrophy .....................................................115 
8.9. 
Assessment of Suicidality .........................................................................................116 
8.10. 
Post-injection Delirium/Sedation Syndrome Monitoring .........................................116 
8.11. 
Other Safety Assessments .........................................................................................117 
8.11.1. 
Abnormal Involuntary Movement Scale ..................................................................117 
8.11.2. 
Barnes Akathisia Rating Scale..................................................................................118 
8.11.3. 
Simpson-Angus Scale ...............................................................................................118 
8.11.4. 
Calgary Depression Scale for Schizophrenia ...........................................................118 
9. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/BIOMARKERS/ PHARMACOGENETICS ...............119 
9.1. 
Pharmacokinetic Assessment ....................................................................................119 
9.2. 
Pharmacodynamic Assessment .................................................................................119 
9.3. 
Assessment of Exploratory Biomarkers ...................................................................119 
9.4. 
Pharmacogenetics .....................................................................................................121 
9.5. 
 ....................................................121 
10. 
STATISTICS ............................................................................................................122 
10.1. 
Sample Size and Power Considerations ...................................................................122 
10.2. 
Analysis Sets .............................................................................................................123 
10.2.1. 
Full Analysis Set .......................................................................................................123 
10.2.2. 
Efficacy Analysis Set ................................................................................................123 
10.2.3. 
Safety Analysis Set ...................................................................................................123 
10.2.4. 
Pharmacokinetic Analysis Set ..................................................................................123 
10.3. 
Data Handling Conventions ......................................................................................123 
10.3.1. 
Handling Withdrawals and Missing Data .................................................................123 
10.4. 
Study Population .......................................................................................................123 
10.4.1. 
Patient Disposition ....................................................................................................124 
10.4.2. 
Demographic and Baseline Characteristics ..............................................................124 
10.5. 
Efficacy Analysis ......................................................................................................124 
10.5.1. 
Primary Estimand .....................................................................................................124 
10.5.2. 
Primary Endpoint ......................................................................................................124 
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10.5.3. 
Other Estimands ........................................................................................................124 
10.5.4. 
Secondary Endpoints ................................................................................................124 
10.5.5. 
Exploratory Endpoints ..............................................................................................124 
10.5.6. 
Planned Method of Analysis .....................................................................................124 
10.5.6.1. 
Primary Efficacy Analysis ........................................................................................124 
10.5.6.2. 
Sensitivity Analysis ..................................................................................................125 
10.5.6.3. 
Supplementary Analysis ...........................................................................................125 
10.5.6.4. 
Key Secondary Efficacy Analysis ............................................................................126 
10.5.6.5. 
Secondary Efficacy Analysis ....................................................................................126 
10.5.6.6. 
Other Efficacy Analysis ............................................................................................126 
10.6. 
Multiple Comparisons and Multiplicity....................................................................126 
10.7. 
Safety Analysis .........................................................................................................127 
10.8. 
Tolerability Analysis ................................................................................................127 
10.9. 
Pharmacokinetic, Population Pharmacokinetic, Pharmacodynamic, and 
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................128 
10.10. 
Biomarker and Pharmacogenetic Analysis ...............................................................128 
10.11. 
 ........................................................................................129 
10.12. 
Planned Interim Analysis ..........................................................................................129 
10.13. 
Reporting Deviations from the Statistical Plan ........................................................129 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................130 
12. 
COMPLIANCE STATEMENT ................................................................................131 
13. 
DATA MANAGEMENT AND RECORD-KEEPING ............................................132 
14. 
FINANCING AND INSURANCE ...........................................................................133 
15. 
PUBLICATION POLICY ........................................................................................134 
16. 
REFERENCES .........................................................................................................135 
APPENDIX A. INDEPENDENT DATA MONITORING COMMITTEE ..............................139 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................140 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ..............................152 
APPENDIX D. ETHICS ...........................................................................................................154 
APPENDIX E. BIRTH CONTROL METHODS .....................................................................156 
APPENDIX F. LOST TO FOLLOW-UP .................................................................................157 
APPENDIX G. LIST OF DISALLOWED MEDICATIONS ...................................................158 
APPENDIX H. PHARMACOGENETIC ASSESSMENTS .....................................................159 
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APPENDIX I. PRODUCT COMPLAINTS .............................................................................160 
APPENDIX J. DATA MANAGEMENT AND RECORD KEEPING.....................................163 
APPENDIX K. PUBLICATION POLICY ...............................................................................167 
APPENDIX L. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 
OUTBREAKS ..........................................................................................................168 
APPENDIX M. LIST OF SCALES ..........................................................................................171 
APPENDIX N. PRIOR PROTOCOL AMENDMENTS AND ADMINISTRATIVE 
LETTERS .................................................................................................................173 
Administrative Letter 05 Dated 05 Sep 2023 ..............................................................................173 
Administrative Letter 04 Dated 31 Jul 2023 ................................................................................176 
Administrative Letter 03 Dated 21 Mar 2023 ..............................................................................188 
Administrative Letter 02 Dated 15 Feb 2023 ..............................................................................196 
Administrative Letter 01 Dated 27 Nov 2022..............................................................................199 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments for Period 1 ........................................................30 
Table 2: 
Study Procedures and Assessments for Period 2 ........................................................40 
Table 3: 
Study Procedures and Assessments for a Potential Post-injection 
Delirium/Sedation Syndrome Event ...........................................................................50 
Table 4: 
Classification of Intercurrent Events ..........................................................................64 
Table 5: 
Conversion Between Oral Olanzapine and TV-44749 Doses ....................................85 
Table 6: 
Investigational Medicinal Products Used in the Study ...............................................86 
Table 7: 
Other Medicinal Products Used in the Study .............................................................89 
Table 8: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product and/or Device ..............................................................................................103 
Table 9: 
Clinical Laboratory Tests .........................................................................................111 
Table 10: Assessment of Local Tolerability (Injection Site Findings and Pain) ......................115 
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LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................29 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Term 
β-HCG 
Beta-human chorionic gonadotropin 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCtau 
area under the plasma drug concentration-time curve over dosing interval 
BARS 
Barnes Akathisia Rating Scale 
C-SSRS 
Columbia Suicide Severity Rating Scale 
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-Severity 
Cmax 
maximum observed drug concentration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CRO 
contract research organization 
CSR 
clinical study report 
CYP 
cytochrome P450 
 
 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition  
ECG 
electrocardiogram 
EOT 
end-of-treatment 
 
 
EU 
European Union 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FU 
follow-up (period) 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
HIV 
human immunodeficiency virus 
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Abbreviation 
Term 
IB 
Investigator’s Brochure 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
im 
intramuscular 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
LAI 
long-acting injectable 
LSO 
local safety officer 
MAR 
missing at random 
MM 
medical monitor 
MMRM 
mixed-model repeated measures 
MNAR 
missing not at random 
n 
number 
NCA 
noncompartmental analysis 
OLAI 
olanzapine long-acting injection 
PANSS 
Positive and Negative Syndrome Scale 
PDAESI 
protocol-defined adverse event of special interest 
PDSS 
Post-injection Delirium/Sedation Syndrome 
PFS 
prefilled syringe 
PGI-I 
Patient Global Impression-Improvement 
PP 
per-protocol 
PSP 
Personal and Social Performance Scale 
q1m 
once monthly 
RDQ 
Readiness for Discharge Questionnaire 
RNA 
ribonucleic acid 
RSI 
reference safety information 
RTSM 
Randomization and Trial Supply Management 
SAS 
Simpson-Angus Scale 
sc 
subcutaneous 
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Abbreviation 
Term 
SCID-5-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SQLS 
Schizophrenia Quality of Life Scale 
SUSAR 
suspected unexpected serious adverse reaction 
TC 
Teleconference 
ULN 
upper limit of normal 
US 
United States (of America) 
USPI  
United States Prescribing Information 
VC 
videoconference 
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1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis  
Protocol Title: A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study with an Open-Label, Long-Term Safety Phase to Evaluate the 
Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release Injectable Suspension 
(TV-44749) for Subcutaneous Use as Treatment of Adult Patients with Schizophrenia 
Brief Title: A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label, 
Long-Term Safety Phase to Evaluate the Efficacy and Safety of TV-44749 in Adults with 
Schizophrenia 
Rationale: Schizophrenia is a severely debilitating psychotic disorder characterized by positive 
and negative symptoms and a worldwide lifetime morbidity risk of approximately 1%. For most 
patients, the disease follows a chronic course requiring long-term treatment with antipsychotic 
agents. Noncompliance and nonadherence to long-term oral medication regimens are the most 
significant therapeutic issues in treating schizophrenia and related disorders, resulting in many of 
these patients suffering frequent relapses or exacerbations and not experiencing the full benefit 
of antipsychotic drug therapy. Extended-release injectable antipsychotic agents may increase 
adherence in patients with schizophrenia. Currently, oral, long-acting intramuscular (im), and 
rapid-acting im formulations of olanzapine are approved for the treatments of adults affected by 
schizophrenia. A new formulation of olanzapine as an extended-release injectable suspension 
(TV-44749) for subcutaneous (sc) use is intended for the treatment of schizophrenia. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
The primary objective is to evaluate 
the efficacy of TV-44749 in adult 
patients with schizophrenia. 
The change from baseline to week 8 in the Positive and Negative 
Syndrome Scale (PANSS) total score 
A key secondary objective is to 
further evaluate the efficacy of 
TV-44749 based on additional 
parameters in adult patients with 
schizophrenia. 
Change in Clinical Global Impression-Severity (CGI-S) scale score 
from baseline to week 8; Change in Personal and Social Performance 
Scale (PSP) score from baseline to week 8 
A secondary objective is to evaluate 
the safety and tolerability of TV-44749 
in adult patients with schizophrenia. 
The safety and tolerability endpoints will include, where appropriate, 
the following: adverse events (including serious adverse events, 
extrapyramidal symptoms, injection pain and other injection site 
reactions [local tolerability]), vital signs (blood pressure, pulse and 
orthostatic changes, and temperature), body weight, laboratory tests, 
electrocardiogram, concomitant 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, Simpson-Angus Scale, 
Barnes Akathisia Rating Scale, Columbia Suicide Severity Rating 
Scale, and Calgary Depression Scale for Schizophrenia. 
A secondary objective of this study is 
to evaluate the efficacy of TV-44749 
Change in total PANSS score from baseline to weeks 1, 2, and 4; 
Change in Clinical Global Impression-Improvement scale score from 
baseline to weeks 4 and 8; Change in CGI-S scale score from baseline 
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Objectives 
Endpoints 
from baseline to endpoint in Period 1 in 
adult patients with schizophrenia. 
to weeks 1, 2, and 4; Change in Patient Global Impression-
Improvement (PGI-I) scale score from baseline to week 8; Change in 
PGI-I scale score from baseline to weeks 2 and 4; Change in 
Schizophrenia Quality of Life Scale score from baseline to weeks 4 
and 8; Change in PSP score from baseline to week 4 
Exploratory objectives and endpoints will be assessed as well. 
Overall Design: This is a Phase 3, multinational, multicenter, randomized, double-blind, 
parallel-group, placebo-controlled study with an open-label, long-term safety phase to evaluate 
the efficacy, safety, and tolerability of olanzapine for extended-release injectable suspension for 
sc use as treatment of adult patients with schizophrenia. Patients with exacerbation of 
schizophrenia that started ≤8 weeks prior to screening and who would benefit from psychiatric 
hospitalization or continued hospitalization for symptoms of schizophrenia may be included. The 
study will be composed of 2 periods: Period 1 (the double-blind, placebo-controlled, efficacy and 
safety period) and Period 2 (open-label safety period). For each patient, the duration of Period 1 
will be 8 weeks, and the duration of Period 2 will be up to 48 weeks. Screening is up to 8 days 
prior to randomization. In Period 1, patients will be randomized to one of 3 TV-44749 treatment 
groups (318 mg once monthly [q1m], 425 mg q1m, or 531 mg q1m) or a placebo group q1m in a 
1:1:1:1 ratio. In order to maintain the blind in Period 1, all patients will be randomized again 
between Period 1 and Period 2; patients who were previously assigned to the active treatment 
groups will retain their Period 1 treatment assignment for Period 2, and patients who were 
previously assigned to the placebo group will be randomized to one of the active treatment 
groups in a 1:1:1 ratio for Period 2. The end-of-treatment and follow-up visits will be at 4 and 8 
weeks after the last dose of investigational medicinal product administration, respectively. 
Study Intervention and Intervention Form: The purpose of this study is to assess the efficacy, 
safety, and tolerability of olanzapine extended-release injectable suspension for sc use compared 
with placebo in patients with schizophrenia. Total study duration is up to 61 weeks, and 
treatment duration is up to 56 weeks, with weekly visits during the first 8 weeks and then 
monthly in-clinic visits with weekly calls during the remainder of the treatment period. 
Number of Participants: Approximately 
 patients will be screened to achieve approximately 
640 randomized patients. 
Intervention Groups and Duration: The screening period includes treatment with 
2 consecutive daily doses of oral olanzapine to establish tolerability (for patients who were not 
previously treated with oral olanzapine in the past year) prior to randomization into Period 1. 
During Period 1 (8 weeks), patients will receive 2 monthly sc injections of TV-44749 (318 mg, 
425 mg, or 531 mg) or placebo. During Period 2 (up to 48 weeks), all patients will receive up to 
12 monthly injections of TV-44749.  
Data Monitoring: An independent data monitoring committee (IDMC) will review accumulated 
unblinded safety, pharmacokinetic, and efficacy data on a regular basis, as detailed in the IDMC 
charter, to evaluate the safety of the product for the purpose of ensuring the continuing safety of 
the study patients and overseeing study conduct issues, as applicable.
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1.2. 
Study Scheme  
Figure 1: 
Overall Study Schematic Diagram  
 
a Patients entering the study who have not previously received oral olanzapine will receive 2 oral doses of olanzapine for 2 consecutive days during the screening 
period (the second dose should be administered at least 24 hours prior to randomization) to assess patient tolerability (oral olanzapine 10 mg/day or higher [but 
not exceeding 20 mg/day] per investigator decision). Patients who received olanzapine within the last year will not be required to receive the 2 doses of oral 
treatment. The investigator will verify the previous use, tolerability, and duration of olanzapine treatment to assure prior tolerability. 
b In order to maintain the blind in Period 1, all patients will be randomized again between Period 1 and Period 2; patients who were previously assigned to the 
active treatment groups will retain their Period 1 treatment assignment (the re-randomization of patients in the TV-44749 groups is being done only to maintain 
blinding of Period 1, and de facto is a deterministic assignment and not randomization), and patients who were previously assigned to the placebo group will be 
randomized to one of the active treatment groups in a 1:1:1 ratio. Revealing of the treatment assignment in Period 2 will be performed only after completion 
and reporting of the relevant study procedures related to assessment of efficacy and safety endpoints in Period 1 (Section 6.9.1), on a patient-by-patient basis. 
The revealing of the Period 2 treatment assignment will be performed after week 8 (visit 11) by the authorized site staff according to a process predefined in the 
relevant study plans, provided that all requirements stipulated in this process were met. Therefore, the dosing at week 8, although assigned to Period 2, will be 
handled in a blinded manner by all parties, similarly to the dosing in Period 1. The sites are encouraged to complete the revealing of the treatment assignment 
procedure before IMP administration in week 12 (visit 12). 
q1m=once monthly; R=randomization. 
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1.3. 
Schedule of Study Procedures and Assessments  
Study procedures and assessments with their time points are presented Table 1 (Period 1) and Table 2 (Period 2). Detailed descriptions 
of each method of procedures and assessments are provided in Section 7 (efficacy assessments), Section 8 (safety assessments), and 
Section 9 (pharmacokinetic and other assessments). Study procedures and assessments by visit are listed in Appendix B. 
Table 1: 
Study Procedures and Assessments for Period 1  
Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
Informed 
consent 
X 
 
 
 
Inclusion and 
exclusion criteria 
X 
X 
 
 
 
Medical and 
psychiatric 
history 
(including the 
number of 
relapse episodes 
and years post 
diagnosis) 
X 
 
 
 
SCID-5-CT 
X 
 
 
 
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Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
Prior medication 
and treatment 
history 
X 
 
 
 
Clinical 
laboratory tests 
(serum 
chemistry, 
hematology, 
coagulation, and 
urinalysis)h      
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Virology and 
thyroid testsi      
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
FSH testj      
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Xk      
 
 
 
 
 
Administration 
of oral 
olanzapinel      
X 
 
 
 
Urine drug 
screen 
X 
X 
X 
X 
X 
X 
 
X 
Physical 
examination, 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
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Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
including height 
and weightm      
12-lead ECGn      
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
measuremento      
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum β-HCG 
test for women 
of childbearing 
potential 
X 
 
X 
 
Urine β-HCG 
test for women 
of childbearing 
potentialp      
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
PANSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-Iq      
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
AIMS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BARS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PSP 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
SQLS  
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
  
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
CDSS 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
PGI-I  
 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
r      
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abdominal fat 
measurement 
(waist-to-hip 
ratio) 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples 
for plasma 
concentration of 
IMPs      
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples 
for plasma 
concentration of 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
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Placebo-Controlled Study–Schizophrenia 
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34 
Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
IMP at 2.5 to 
3 hours postdose 
Blood samples 
for biomarker 
analysist      
X 
X 
X 
X 
Xu 
 
Blood samples 
for 
pharmacogenetic
sv      
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
inquiry 
(including 
serious adverse 
event reporting 
and injection site 
related events 
[including 
pain])w      
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Injection site 
findings and pain 
assessmentx      
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Inquiry 
regarding 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
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35 
Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
alcohol 
consumption/illic
it drug usey      
Cigarette use 
assessmentz      
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
IMP 
administrationaa 
bb      
X 
X 
Xcc 
 
 
 
Site 
confinementd 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
RDQ –discharge 
from site 
confinementdd      
 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
Outpatient 
period of the 
studyee d      
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication 
inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
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36 
Study period 
Screeninga   
Double-blind treatment period (acute treatment phase; Period 1) 
Early 
terminationb 
End of 
treatmentb 
Follow-
upb 
Unscheduled 
visitc 
Short-
term 
leaved 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11e     
ET 
EOT 
FU 
Day 
Day -8 
Day
 1 
Day 
2 
Day
 8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Allowed time 
window 
Up to 8 
days prior 
to day 1 
N/A 
N/A 
±3 days for dosing visits; ±2 days for all non-dosing 
visitsf      
N/A 
±1 week 
–1/+2 
weeks 
N/A 
Upon 
patient 
return 
to the 
site 
Weekg      
Wk -2 
to -1 
Wk 
0 
BL 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
N/A 
4 weeks 
after last 
dose 
8 weeks 
after 
last 
dose 
Per 
investigator 
decision 
N/A 
Review of 
eligibility 
(stability) criteria 
 
 
 
 
 
 
 
 
 
 
Xff      
 
 
 
 
 
a In the event that a patient meets all study inclusion criteria and does not meet any of the study exclusion criteria, but results of screening blood and urine 
samples taken within the 8-day screening period are not available by day 8 of screening, the screening period may be extended by 2 days (until day 10 of 
screening) to allow the receipt of the results to confirm patients’ eligibility. In case results are not available by day 10, the patient will be considered a screening 
failure and may be considered for rescreening. In addition, the screening period may be extended by 2 days (until day 10 of screening), in exceptional cases, 
due to special conditions (eg, extreme weather) after receiving approval from the medical monitor (MM) or sponsor. In case the site faces a delay in obtaining 
the central laboratory results for the clinical laboratory tests performed during screening that are needed to determine eligibility, additional screening blood 
samples (specifically those with delayed results) may be collected as soon as possible and analyzed in a local laboratory to allow study eligibility determination 
within the 8-day screening window. Refer to Section 8.4 for more details. 
b Randomized patients who meet 1 or more of the study discontinuation or withdrawal criteria (Section 5.4) should be invited to perform the ET visit as soon as 
possible. An EOT visit will be conducted at 4 weeks after the last dose of IMP (±1 week), and a FU visit for safety evaluation will be conducted at 8 weeks 
(-1/+2 weeks) after the last dose of IMP. Since TV-44749 is an LAI, additional antipsychotic treatment is not required for 4 weeks following the last dosing visit 
(unless clinically indicated), whereas during the subsequent 4 weeks (FU period), patients may be treated for schizophrenia according to the investigator’s 
judgment. 
c Other procedures may be performed according to the discretion of the investigator. However, in order to reduce patient burden and to avoid unnecessary data 
collection, the investigator will have discretion in determining whether all unscheduled visit procedures should be performed during the unscheduled visit in the 
event that (i) the unscheduled visit is one of multiple in-clinic visits that are deemed necessary in close proximity (ie, 2 or more visits within 1 week) or (ii) the 
visit is for administrative purposes (eg, reconsenting) or technical reasons (eg, repeat laboratory sample collection for reasons unrelated to an adverse event) 
and not due to a change in the patient’s medical status per clinical judgment. 
d All patients will be hospitalized upon study entry (screening) and will remain hospitalized during the screening period and for the first 4 weeks after 
randomization (until the second IMP administration). After the second injection, patients may be discharged if all discharge criteria are met and if, in the 
opinion of the investigator, discharge is appropriate. During the hospitalization period (ie, before the patient is discharged), a short-term leave from the site may 
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37 
be allowed if requested by the patient. Patient’s eligibility for such leave will be determined by the investigator clinical judgment, in accordance with the study 
conduct and with the patient’s best interest. During the leave, the patient will be escorted by a caregiver or another individual per investigator approval. The 
patient will return to the site on the same calendar day. In exceptional cases, an overnight stay outside the site may be approved by the investigator. Upon return 
to the site, after any period of leave, the patient will undergo a urine drug screen, an abbreviated physical examination (including weight), and a concomitant 
medication and alcohol consumption/illicit drug use inquiry. The results of these assessments, along with the date and time of site leave and return, will be 
captured in a dedicated case report form. 
e Visit 11 (week 8) assessments are included in both Table 1 and Table 2 for completeness; however, they need to be performed only once prior to randomization 
to Period 2 (refer to footnote “k” for a list of procedures and assessments that must be performed prior to randomization). 
f A window of ±3 days will be allowed around the scheduled visit dates for dosing visits; a window of ±2 days will be allowed for all non-dosing visits (during 
the inpatient period, every effort will be made to maintain the assessments on the scheduled dates). Visit dates should be calculated from the date of previous 
IMP administration. In exceptional cases, per the discretion of the investigator and with permission from the MM or sponsor, dosing visits may take place up to 
5 days before the scheduled visit date (and recorded accordingly). 
g Days/weeks shown are nominal; visit dates should be calculated from date of previous IMP administration. 
h Clinical laboratory tests (including serum chemistry, hematology, coagulation, and urinalysis) may also be performed at any time if clinically indicated. 
Coagulation laboratory tests are performed at screening only. Glomerular filtration rate will be calculated at screening only. At baseline (visit 2; week 0), 
visit 11 (week 8), and at the EOT visit, clinical laboratory tests will also include hemoglobin A1C. Patients must fast for at least 8 hours prior to baseline (visit 
2; week 0), visit 11 (week 8), and the EOT visit (and preferably the ET visit). At screening (prior to intake of oral olanzapine, where relevant), baseline (visit 2; 
week 0 [prior to IMP administration]), visit 11 (week 8 [prior to IMP administration]), and at the EOT visit, clinical laboratory tests will also include prolactin. 
Additionally, toxicological blood test should be collected as soon as a potential PDSS event is suspected. In cases where performing toxicological blood test is 
not feasible due to a lack of suitable analytical facilities, a urine drug screen may be performed instead. In case visit 3 safety laboratory blood samples cannot 
be shipped to the central laboratory on the same day, the samples may be processed in the local clinical laboratory instead. If needed, an additional set of safety 
laboratory tests may be collected for that purpose. In case visit 3 occurs over the weekend and the local safety laboratory tests cannot be processed on the 
collection day, visit 3 safety laboratory samples will be collected up to 2 days after the visit 3 nominal date and sent to the central laboratory. 
i Includes HIV, HBsAg, hepatitis C antibody, TSH, T3, and T4. Virology (HIV, HBsAg, and hepatitis C antibody) is only performed at screening. 
j The FSH test will only be performed for women with no menses for 12 months prior to screening in order to confirm postmenopausal status. 
k In order to maintain the blind in Period 1, all patients will be randomized again between Period 1 and Period 2; patients who were previously assigned to the 
active treatment groups will retain their Period 1 treatment assignment (the re-randomization of patients in the TV-44749 groups is being done only to maintain 
blinding of Period 1, and de facto is a deterministic assignment and not randomization), and patients who were previously assigned to the placebo group will be 
randomized to one of the active treatment groups in a 1:1:1 ratio. Revealing of the treatment assignment in Period 2 will be performed only after completion 
and reporting of the relevant study procedures related to assessment of efficacy and safety endpoints in Period 1, on a patient-by-patient basis. Procedures and 
assessments that need to be performed prior to randomization into Period 2 at visit 11 (week 8) include clinical laboratory tests, thyroid tests, physical 
examination, ECG, vital signs, urine β-HCG, PANSS, CGI-S, CGI-I, AIMS, BARS, SAS, C-SSRS, PSP, CDSS, PGI-I, blood samples for plasma concentration 
of IMP, AE inquiry, injection site findings and pain assessment of last injection, inquiry regarding alcohol consumption/illicit drug use, and concomitant 
medication inquiry. Procedures and assessments that need to be performed after randomization into Period 2 at visit 11 (week 8) include IMP administration 
and blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose, pain 30 minutes after injection and pain and injection site findings 3 hours after 
injection. Remaining procedures and assessments at visit 11 (week 8) may be performed either before or after randomization. The revealing of the Period 2 
treatment assignment will be performed after week 8 (visit 11) by the authorized site staff according to a process predefined in the relevant study plans, 
provided that all requirements stipulated in this process were met. Therefore, the dosing at week 8, although assigned to Period 2, will be handled in a blinded 
manner by all parties, similarly to the dosing in Period 1. The sites are encouraged to complete the revealing of the treatment assignment procedure before IMP 
administration in week 12 (visit 12). 
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38 
l Patients will receive 2 consecutive treatments with oral olanzapine (oral olanzapine 10 mg/day or higher [but not exceeding 20 mg/day] per investigator 
decision) at an interval of 24 hours apart to assess patient tolerability. The second dose should be given at least 24 hours prior to randomization. The PANSS 
and CGI-S should be completed prior to oral olanzapine administration. Patients who received olanzapine within the last year will not be required to receive the 
2 doses of oral treatment. The investigator will verify the previous use, tolerability, and duration of olanzapine treatment to assure prior tolerability.  
m Height will be measured at the screening visit only. Weight does not need to be measured at visit 3 (day 2), since it will be measured at visit 2 (day 1). Full 
physical examination will be conducted at screening visit and unscheduled visits only; the rest of the visits will include an abbreviated physical examination 
(including weight). 
n At screening and baseline, measurements will be done in triplicate (approximately 5 minutes apart). Single measurements will be performed at all other in-
clinic visits where ECG recordings are taken. 
o Vital signs (blood pressure [systolic/diastolic], pulse and orthostatic changes, respiratory rate, and temperature) should be measured at each in-clinic visit pre-
injection. Before blood pressure and pulse are measured, the patient must rest in a supine or semi-erect position for at least 5 minutes; measurements should be 
taken again after standing for approximately 2 minutes. 
 
 Vital signs should also be measured in the event of an injection site 
pus-containing lesion (abscess, infection, or inflammation), ulceration, or necrosis. 
p Urine β-HCG (dipstick) test: a negative result must be obtained prior to administration of IMP, as applicable (if a borderline result is obtained on a urine test, a 
serum test should be performed and a negative result obtained prior to IMP administration). 
q CGI-I during Period 1 will be relative to the CGI-S score at the baseline visit. 
r This assessment is optional and applicable in the US only for patients who sign a dedicated ICF for participation in this assessment. This assessment will be 
performed only after the PANSS, CGI-S, PSP, PGI-I, CGI-I, and SQLS are complete (as applicable). 
s When collected at dosing visits, blood samples for plasma drug concentration determination will be collected prior to TV-44749 dosing (ie, trough levels). It is 
recommended that at non-dosing visits, blood samples should be collected at approximately the same time of day as the IMP administration at the previous 
visit. 
 
 Unscheduled 
pharmacokinetic samples may also be collected after any serious adverse event and patient withdrawal. Every effort should be made to obtain the additional 
pharmacokinetic sample at the closest time possible to the occurrence of the serious adverse event.  
t Biomarker samples (6 mL serum, 6 mL plasma, and 2.5 mL PAXgene RNA) will be collected prior to IMP administration. Additionally, patients who develop 
metabolic syndrome (Section 9.3) after starting IMP will have an additional biomarker sample collected at the following visit that contains a blood draw. 
 
 
 
 
u Additional biomarker samples will be collected (where local regulations allow, unless the patient declines to provide consent) from patients with injection site 
reactions that require an unscheduled visit, ie, pus-containing lesion (abscess, infection, or inflammation), ulceration, necrosis, or atrophy or severe injection 
site reaction (and for 2 consecutive visits after the event is identified).  
v A blood sample for pharmacogenetic analysis will be collected at baseline or any visit thereafter. Participation in this sampling is optional for patients and also 
depends on local regulations. Patients willing to participate in pharmacogenetic sampling will sign a separate ICF for this purpose. 
w In case an adverse event associated with an ISR is reported, pain may be assessed periodically using a numeric pain rating scale until resolution. 
x Pain will be assessed 30 minutes after the completion of each IMP administration; pain and injection site findings will be assessed 3 hours after the completion 
of each IMP administration. Allowed time windows for these local tolerability assessments are ±15 minutes. In Period 1, injection site findings and pain will 
also be assessed weekly. The site of the preceding IMP injection will be assessed on the day of the following IMP administration prior to IMP administration 
VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
39 
and at the EOT visit. No time windows are specified for these assessments. In addition, telephone call visits in Period 2 will include inquiries about injection 
site findings and pain. 
y This inquiry is only required for outpatients (except for at the screening and baseline visits), as well as for patients who are given short-term leave during their 
inpatient period. 
z Data on cigarette use will be collected using the question, “How many packs of cigarettes did you smoke over the past 7 days?” at the time points specified in 
the table of assessment. 
aa At visits 2 and 7, the PANSS, C-SSRS, CGI-S, and CGI-I (visit 7 [week 4] only) scales should be completed prior to IMP administration; all other scales and 
questionnaires may be completed either prior to IMP administration or after. Any assessments performed after IMP administration must be completed on the 
day of IMP administration. 
bb Following IMP administration, patients will remain in the clinic for at least 3 hours for observation. 
cc First treatment in Period 2. IMP administration will be performed after all visit procedures and assessments have been completed, and after randomization into 
Period 2. 
dd Please refer to the discharge criteria (Section 4.1). The RDQ should be completed by a qualified health care professional (HCP) who has a thorough knowledge 
of the patient's clinical condition, and has been following them throughout the duration of the hospitalization. 
ee Patients will return to the CU on an outpatient basis for scheduled assessments.  
ff In order to enter Period 2, the patient should meet the following eligibility criteria: 1) patient has completed Period 1, 2) patient is considered sufficiently 
clinically stable per the investigator’s judgment, and 3) patient is an outpatient (ie, met RDQ criteria and was discharged prior to Period 2). Note: Patients who 
do not meet RDQ criteria, but in the opinion of the investigator show sufficient clinical stabilization for transition to Period 2 and may benefit from 
continuation of participation in the study, may continue to Period 2 as inpatients for up to an additional 8 weeks. For such patients, RDQ can be assessed 
periodically according to investigator discretion; if RDQ criteria are not met by the end of the additional 8-week hospitalization period (week 16), then the 
patient will be discontinued from study treatment and will be asked to complete ET and FU visits. 
β-HCG=beta-human chorionic gonadotropin; AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; 
BL=baseline; CDSS=Calgary Depression Scale for Schizophrenia; CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-
Severity; C-SSRS=Columbia Suicide Severity Rating Scale; CU=Clinical Unit; ECG=electrocardiogram; EOT=end-of-treatment; 
 
; ET=early termination; FSH=follicle-stimulating hormone; FU=follow-up; HBsAg=hepatitis B surface antigen; HIV=human 
immunodeficiency virus; ICF=informed consent form; IMP=investigational medicinal product; ISR=injection site reaction; LAI=long-acting injectable; 
MM=medical monitor; N/A=not applicable; PANSS=Positive and Negative Syndrome Scale; PDSS=Post-injection Delirium/Sedation Syndrome; PGI-
I=Patient Global Impression-Improvement; PSP=Personal and Social Performance Scale; RDQ=Readiness for Discharge Questionnaire; RNA=ribonucleic 
acid; SAS=Simpson-Angus Scale; SCID-5-CT=Structured Clinical Interview for DSM-5, Clinical Trials Version; SQLS=Schizophrenia Quality of Life Scale; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; US=United States; V=visit; Wk=week 
VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
40 
Table 2: 
Study Procedures and Assessments for Period 2  
Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Review of 
eligibility 
(stability) 
criteria 
Xj      
 
 
 
Randomizatio
n 
Xk      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory 
testsl (serum 
chemistry, 
hematology, 
and urinalysis)  
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Thyroid testm     
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Urine drug 
screen 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
41 
Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
medication 
inquiry 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
Physical 
examination, 
including 
weightn      
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Abdominal fat 
measurement 
(waist-to-hip 
ratio) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Vital signs 
measuremento   
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
12-lead ECGp     
X 
X 
X 
X 
 
X 
X 
X 
 
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Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum β-HCG 
test for women 
of 
childbearing 
potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urine β-HCG 
test for women 
of 
childbearing 
potentialq      
X 
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 
X 
 
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Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
X 
X 
X 
X 
X 
X 
X 
 
 
 
CGI-Ir      
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
AIMS 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
BARS 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
SAS 
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  
X 
X 
X 
 
X 
X 
X 
 
SQLS  
X 
 
X 
X 
 
X 
X 
X 
 
  
X 
 
X 
X 
 
X 
X 
X 
 
CDSS 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
PGI-I 
X 
 
X 
X 
 
 
 
 
s      
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
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Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
X 
X 
X 
X 
X 
X 
X 
 
 
 
Blood samples 
for biomarker 
analysist      
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Xu 
 
Blood samples 
for plasma 
concentration 
of IMPv      
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Blood samples 
for plasma 
concentration 
of IMP at 2.5 
to 3 hours 
postdose 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
IMP 
administration
w x      
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
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Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse 
events inquiry 
(including 
serious 
adverse event 
reporting and 
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 
 
Injection site 
findings and 
pain 
assessmentz      
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
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Study period 
Safety period (long-term safety phase; Period 2 [up to 48 weeks])a      
Follow-
upb 
ETa 
Unschedule
d visitc 
Short-
term 
leaved 
Visit number 
The series from visit 12 to visit 17c repeats until EOT or ET 
(visit 22c being the last visit prior to EOT) 
EOTb 
FU 
ET 
V11 V11a 
11b 
11ce    
V12 
V12
a 
12b 
12ce 
V13 
V13
a 
13b 
13c 
V14 
V14
a 
14b 
14c 
V15 
V15
a 
15b 
15c 
V16 
V16
a 
16b 
16c 
V17 V17a 
17b 
17c 
V18-
22c 
Allowed time 
window 
±3 daysf      
±1 
week 
-1/+2 
weeks 
N/A 
N/A 
Upon 
patient 
return to 
the site 
Weekg      
Wk 
8 
(Day 
57) 
Wk 
9-11 
Wk 
12 
Wk 
13-
15 
Wk 
16 
Wk 
17-
19 
Wk 
20 
Wk 
21-
23 
Wk 
24 
Wk 
25-
27 
Wk 
28 
Wk 
29-
31 
Wk 
32 
Wk 
33-35 
See 
footn
ote a 
4 wks 
after 
last 
dose 
8 wks 
after 
last 
dose 
N/A 
Per 
investigator 
decision 
N/A 
In-clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone 
callh i      
X 
X 
X 
X 
X 
X 
X 
 
 
 
Inquiry 
regarding 
alcohol 
consumption/ 
illicit drug 
useaa       
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Cigarette use 
assessmentbb      
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Brief set of 
clinical 
questions to 
detect 
psychotic 
symptomscc      
X 
X 
X 
X 
X 
X 
X 
 
 
 
a The open-label safety period in Period 2 will be up to 48 weeks, with patients continuing until the end of Period 2 or until they meet 1 or more of the study 
discontinuation or withdrawal criteria. Randomized patients who meet 1 or more of the study discontinuation or withdrawal criteria (Section 5.4) should be 
invited to perform the ET visit as soon as possible. The series from visit 12 to visit 17c repeats until EOT (visit 22c being the last visit prior to EOT) or ET (ie, 
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visit 18 should be identical to visit 12, visit 19 should be identical to visit 13, visit 20 should be identical to visit 14, visit 21 should be identical to visit 15, and 
visit 22 should be identical to visit 16). 
b An EOT visit will be conducted at 4 weeks after the last dose of IMP (ie, 4 weeks [±1 week] after visit 22 if the patient completes the entire Period 2 or earlier 
if the patient early terminates or the sponsor stops the study), and a FU visit for safety evaluation will be conducted at 8 weeks (-1/+2 weeks) after the last dose 
of IMP. Since TV-44749 is an LAI, additional antipsychotic treatment is not required for 4 weeks following the last dosing visit (unless clinically indicated), 
whereas during the subsequent 4 weeks (FU period), patients may be treated for schizophrenia according to the investigator’s judgment. 
c Other procedures may be performed according to the discretion of the investigator. However, in order to reduce patient burden and to avoid unnecessary data 
collection, the investigator will have discretion in determining whether all unscheduled visit procedures should be performed during the unscheduled visit in the 
event that (i) the unscheduled visit is one of multiple in-clinic visits that are deemed necessary in close proximity (ie, 2 or more visits within 1 week) or (ii) the 
visit is for administrative purposes (eg, reconsenting) or technical reasons (eg, repeat laboratory sample collection for reasons unrelated to an adverse event) 
and not due to a change in the patient’s medical status per clinical judgment.  
d For any patients who are inpatients at the beginning period 2, during the hospitalization period (ie, before the patient is discharged), a short-term leave from the 
site may be allowed if requested by the patient. Patient’s eligibility for such leave will be determined by the investigator clinical judgment, in accordance with 
the study conduct and with the patient’s best interest. During the leave, the patient will be escorted by a caregiver or another individual per investigator 
approval. The patient will return to the site on the same calendar day. In exceptional cases, an overnight stay outside the site may be approved by the 
investigator. Upon return to the site, after any period of leave, the patient will undergo a urine drug screen, an abbreviated physical examination (including 
weight), and a concomitant medication and alcohol consumption/illicit drug use inquiry. The results of these assessments, along with the date and time of site 
leave and return, will be captured in a dedicated case report form. 
e For patients who are inpatients (for up to the first 8 weeks of Period 2), in-clinic visits will take place instead of phone visits, using the same assessments 
specified for the phone visits. 
f A window of ±3 days will be allowed around the scheduled visit dates for dosing and non-dosing visits during Period 2; visits; for any patients who are 
inpatients at the beginning of Period 2, every effort will be made to maintain the assessments on the scheduled dates during the inpatient period. Visit dates 
should be calculated from the date of previous IMP administration. In exceptional cases, per the discretion of the investigator and with permission from the 
MM or sponsor, dosing visits may take place up to 5 days before the scheduled visit date (and recorded accordingly). 
g Weeks shown are nominal; visit dates should be calculated from date of previous IMP administration. 
h Telephone contacts (or other comparable form of remote communication) will occur weekly between clinic visits. These contacts will be referred to by the 
previous visit number and a letter (eg, the telephone contacts that take place 1, 2, and 3 weeks after visit 11 [week 8] will be referred to as “visit 11a,” “visit 
11b,” and “visit 11c,” respectively).  
i Each telephone contact will include inquiries about injection site pain, suicidal ideation and behavior (C-SSRS), adverse events, alcohol consumption, and 
pregnancy status (for women of childbearing potential). Patients will also be asked a brief set of clinical questions in order to detect psychotic symptoms (see 
row and corresponding footnote for “brief set of clinical questions to detect psychotic symptoms” in the table). 
j In order to enter Period 2, the patient should meet the following eligibility criteria: 1) patient has completed period 1, 2) patient is considered sufficiently 
clinically stable per the investigator’s judgment, and 3) patient is an outpatient (ie, met RDQ criteria and was discharged prior to Period 2). Note: Patients who 
do not meet RDQ criteria, but in the opinion of the investigator show sufficient clinical stabilization for transition to Period 2 and may benefit from 
continuation of participation in the study, may continue to Period 2 as inpatients for up to an additional 8 weeks. For such patients, RDQ can be assessed 
periodically according to investigator discretion; if RDQ criteria are not met by the end of the additional 8-week hospitalization period (week 16), then the 
patient will be discontinued from study treatment and will be asked to complete ET and FU visits. 
k In order to maintain the blind in Period 1, all patients will be randomized again between Period 1 and Period 2; patients who were previously assigned to the 
active treatment groups will retain their Period 1 treatment assignment (the re-randomization of patients in the TV-44749 groups is being done only to maintain 
blinding of Period 1, and de facto is a deterministic assignment and not randomization), and patients who were previously assigned to the placebo group will be 
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randomized to one of the active treatment groups in a 1:1:1 ratio. Revealing of the treatment assignment in Period 2 will be performed only after completion 
and reporting of the relevant study procedures related to assessment of efficacy and safety endpoints in Period 1, on a patient-by-patient basis. Procedures and 
assessments that need to be performed prior to randomization into Period 2 at visit 11 (week 8) include clinical laboratory tests, thyroid tests, physical 
examination, ECG, vital signs, urine β-HCG, PANSS, CGI-S, CGI-I, AIMS, BARS, SAS, C-SSRS, PSP, CDSS, PGI-I, blood samples for plasma concentration 
of IMP, AE inquiry, injection site findings and pain assessment of last injection, inquiry regarding alcohol consumption/illicit drug use, and concomitant 
medication inquiry. Procedures and assessments that need to be performed after randomization into Period 2 at visit 11 (week 8) include IMP administration 
and blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose. Remaining procedures and assessments at visit 11 (week 8) may be performed 
either before or after randomization. The revealing of the Period 2 treatment assignment will be performed after week 8 (visit 11) by the authorized site staff 
according to a process predefined in the relevant study plans, provided that all requirements stipulated in this process were met. Therefore, the dosing at week 
8, although assigned to Period 2, will be handled in a blinded manner by all parties, similarly to the dosing in Period 1. The sites are encouraged to complete the 
revealing of the treatment assignment procedure before IMP administration in week 12 (visit 12). 
l Clinical laboratory tests (including serum chemistry, hematology, coagulation, and urinalysis) may also be performed at any time if clinically indicated. At 
visit 11 (week 8), visit 14 (week 20), visit 17 (week 32), visit 20 (week 44), and at the EOT visit, clinical laboratory tests will also include hemoglobin A1C. 
Patients must fast for at least 8 hours prior to visit 11 (week 8) and the EOT visit (and preferably the ET visit). At visit 11 (week 8 [prior to IMP 
administration]), visit 14 (week 20 [prior to IMP administration]), and at the EOT visit, clinical laboratory tests will also include prolactin. Additionally, 
toxicological blood test should be collected as soon as a potential PDSS event is suspected. In cases where performing toxicological blood test is not feasible 
due to a lack of suitable analytical facilities, a urine drug screen may be performed instead. 
m Includes TSH, T3, and T4. 
n Full physical examination will be conducted at unscheduled visits only; the rest of the visits will include an abbreviated physical examination (including 
weight). 
o Vital signs (blood pressure [systolic/diastolic], pulse and orthostatic changes, respiratory rate, and temperature) should be measured at each in-clinic visit pre-
injection. Before blood pressure and pulse are measured, the patient must rest in a supine or semi-erect position for at least 5 minutes; measurements should be 
taken again after standing for approximately 2 minutes. 
 
 Vital signs should also be measured in the event of an injection site 
pus-containing lesion (abscess, infection, or inflammation), ulceration, or necrosis. 
p Single measurements will be performed at all in-clinic visits where ECG recordings are taken. 
q Urine β-HCG (dipstick) test: a negative result must be obtained prior to administration of IMP, as applicable (if a borderline result is obtained on a urine test, a 
serum test should be performed and a negative result obtained prior to IMP administration). 
r CGI-I during Period 2 will be relative to the CGI-S score at the baseline visit (visit 2 in Period 1). 
s This assessment is optional and applicable in the US only for patients who sign a dedicated ICF for participation in this assessment. This assessment will be 
performed only after the PANSS, CGI-S, PSP, PGI-I, CGI-I, and SQLS are complete (as applicable). 
t Biomarker samples (6 mL serum, 6 mL plasma, and 2.5 mL PAXgene RNA) will be collected prior to IMP administration. Additionally, patients who develop 
metabolic syndrome (Section 9.3) after starting IMP will have an additional biomarker sample collected at the following visit that contains a blood draw.
 
 
 
 
u Additional biomarker samples will be collected (where local regulations allow, unless the patient declines to provide consent) from patients with injection site 
reactions that require an unscheduled visit, ie, pus-containing lesion (abscess, infection, or inflammation), ulceration, necrosis, or atrophy or severe injection 
site reaction (and for 2 consecutive visits after the event is identified). 
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v Blood samples for plasma drug concentration determination will be collected prior to TV-44749 dosing (ie, trough levels). 
 
 
 Unscheduled pharmacokinetic samples may also be collected 
after any serious adverse event and patient withdrawal. Every effort should be made to obtain the additional pharmacokinetic sample at the closest time 
possible to the occurrence of the serious adverse event. 
w The PANSS, C-SSRS, CGI-S, and CGI-I scales should be completed prior to IMP administration; all other scales and questionnaires may be completed either 
prior to IMP administration or after (except for visit 11 [week 8], where all assessments must be completed as detailed in Section 6.9.1 and footnote “k” of 
Table 1 and Table 2). Any assessments performed after IMP administration must be completed on the day of IMP administration. 
x Following IMP administration, patients will remain in the clinic for at least 3 hours for observation. During Period 2, the investigator may perform dose 
adjustments of TV-44749 (to one of the doses offered in the protocol) from visit 12 (week 12) and onward, based on clinical judgment. Dose adjustment will be 
documented in the CRF. 
y In case an adverse event associated with an ISR is reported, pain may be assessed periodically using a numeric pain rating scale until resolution. 
z Pain will be assessed 30 minutes after the completion of each IMP administration; pain and injection site findings will be assessed 3 hours after the completion 
of each IMP administration. Allowed time windows for these local tolerability assessments are ±15 minutes. In Period 2, injection site findings and pain will 
also be assessed monthly. The site of the preceding IMP injection will be assessed on the day of the following IMP administration prior to IMP administration 
and at the EOT visit. No time windows are specified for these assessments. In addition, telephone call visits in Period 2 will include inquiries about injection 
site findings and pain.  
aa This inquiry is only required for outpatients (as well as for any patients who are inpatients at the beginning of Period 2 and who are given short-term leave 
during their inpatient period). 
bb Data on cigarette use will be collected using the question, “How many packs of cigarettes did you smoke over the past 7 days?” at the time points specified in 
the table of assessment. 
cc 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; AE=adverse event; 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-Severity; CRF=case 
report form; C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end-of-treatment; 
 
; ET=early termination; FU=follow-up; ICF=informed consent form; IMP=investigational medicinal product; ISR=injection site 
reaction; LAI=long-acting injectable; MM=medical monitor; N/A=not applicable; PANSS=Positive and Negative Syndrome Scale; PDSS=Post-injection 
Delirium/Sedation Syndrome; PGI-I=Patient Global Impression-Improvement; PSP=Personal and Social Performance Scale; RDQ=Readiness for Discharge 
Questionnaire; RNA=ribonucleic acid; SAS=Simpson-Angus Scale; SQLS=Schizophrenia Quality of Life Scale; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid stimulating hormone; US=United States; V=visit; Wk=week 
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Table 3: 
Study Procedures and Assessments for a Potential Post-injection Delirium/Sedation Syndrome Event  
 
      
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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2. 
INTRODUCTION AND BACKGROUND INFORMATION  
2.1. 
Introduction  
2.1.1. 
Schizophrenia  
Schizophrenia is a severely debilitating psychotic disorder characterized by positive symptoms 
(eg, delusions, hallucinations, and grossly disorganized behavior) and negative symptoms (eg, 
affective flattening, alogia, and avolition) (Kahn et al 2015, New York State Office of Mental 
Health 2018, Stefan et al 2002). 
The worldwide lifetime morbidity risk of the disorder is approximately 1% across diverse 
geographic, cultural, and socioeconomic 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 (CATIE) study, 
74% of patients discontinued their drug within 18 months either due to poor tolerability, lack of 
efficacy, patient choice (ie, nonadherence/study withdrawal), or for investigator reasons 
(Lieberman et al 2005). Even among those who do not explicitly discontinue drug therapy, 
nonadherence to long-term oral medication regimens is one of the most significant therapeutic 
issues in the therapy of schizophrenia and related disorders (Kane et al 2013). 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 (Carbon and Correll 2014), often 
in the context of psychiatric emergency (Rainer 2008).  
Thus, long-acting injectable (LAI) antipsychotic agents may increase adherence in patients with 
schizophrenia (Barnes and Curson 1994, Hughes 2008, Keith and Kane 2003, Walburn et al 
2001) and have been shown to significantly reduce relapse and rehospitalization as well as 
improve many clinically relevant outcomes significantly more than oral antipsychotics in 
randomized trials, cohort studies, and mirror-image studies (Kishimoto et al 2021). 
The critical importance of optimal adherence with prescribed antipsychotic regimens has been 
repeatedly and convincingly demonstrated in patients with schizophrenia (Kane et al 2013). 
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). 
Note: the terms “long-acting” and “extended-release” are used interchangeably within this 
document. 
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2.1.2. 
Olanzapine for Oral and Intramuscular Use  
Olanzapine is a well characterized and commonly prescribed second-generation antipsychotic 
drug available as oral and intramuscular (im) formulations and has not yet been approved for use 
as a subcutaneous (sc) injection.  
Oral formulations (Section 2.1.2.1) are approved for the treatment of adults and adolescents 
affected by schizophrenia. The long-acting im depot preparation containing olanzapine pamoate 
(Section 2.1.2.2) is approved for the treatment of adults affected by schizophrenia, while a 
rapid-acting im formulation of olanzapine (Section 2.1.2.1) is approved for the treatment of 
adults with acute agitation associated with schizophrenia. 
2.1.2.1. 
Immediate-Release Olanzapine Formulations  
Olanzapine is currently marketed in the United States (US) as ZYPREXA® tablets (2.5, 5, 7.5, 
10, 15, and 20 mg); ZYPREXA® INTRAMUSCULAR for rapid-acting injection (10 mg/mL) 
and as ZYPREXA® ZYDIS® orally disintegrating tablets (5, 10, 15, and 20 mg) (ZYPREXA 
United States Prescribing Information [USPI] 2021). 
2.1.2.2. 
Extended-Release Olanzapine Formulations  
ZYPREXA® RELPREVV™, an extended-release olanzapine pamoate powder and diluent for 
suspension, is administered by deep im gluteal injection. Before use, the powder for injection is 
suspended in a viscous, aqueous vehicle containing croscarmellose sodium, mannitol, 
polysorbate 80, water, as well as hydrochloric acid and sodium hydroxide for pH adjustment 
(ZYPREXA RELPREVV USPI 2021). ZYPREXA RELPREVV should be administered im 
either every 2 weeks (150, 210, and 300 mg) or every 4 weeks (300 and 405 mg), depending on 
the target oral olanzapine dose (10, 15, or 20 mg/day). ZYPREXA RELPREVV is currently 
approved and marketed in the US for the treatment of schizophrenia; however, it is only 
available through a restricted distribution program.  
ZYPREXA RELPREVV must be administered in a registered healthcare facility (such as a 
hospital, clinic, residential treatment center, or community healthcare center) with ready access 
to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare 
professional must continuously observe the patient at the healthcare facility for at least 3 hours 
and must confirm that the patient is alert, oriented, and absent of any signs and symptoms of 
Post-injection Delirium/Sedation Syndrome (PDSS), as a consequence of the route of 
administration, prior to being released. All patients must be accompanied to their destination 
upon leaving the facility. For the remainder of the day, patients should not drive or operate heavy 
machinery and should be advised to be vigilant for symptoms of PDSS and be able to obtain 
medical assistance if needed. If PDSS is suspected, close medical supervision and monitoring 
should be instituted in a facility capable of resuscitation. If parenteral benzodiazepines are 
required for patient management during an event of PDSS, careful evaluation of clinical status 
for excessive sedation and cardiorespiratory depression is recommended. 
Because of the precautions required for safe use of ZYPREXA RELPREVV, the product is 
rarely used in routine clinical practice. As a consequence, the options available to psychiatrists 
for clinical management of schizophrenia are curtailed.  
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2.1.3. 
Olanzapine for Subcutaneous Use (TV-44749)  
The sponsor is developing a new formulation of olanzapine as an extended-release injectable 
suspension for sc use that will deliver therapeutic levels of olanzapine over a 1-month interval to 
patients with schizophrenia.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of olanzapine for 
extended-release injectable suspension (TV-44749) for sc use in adult patients with 
schizophrenia. 
2.2. 
Findings from Nonclinical and Clinical Studies  
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Investigator’s Brochure (IB). 
The systemic and local safety of olanzapine has been well characterized in nonclinical and 
clinical studies, both for oral and im routes of administration (ZYPREXA USPI 2021). 
ZYPADHERA® (European Union [EU]; Summary of Product Characteristics [SmPC] 2022), 
which is identical to ZYPREXA RELPREVV, was also used to support the nonclinical 
development of TV-44749. 
2.2.1. 
Nonclinical Studies  
 
 
 
 
 
 
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2.2.2. 
Clinical Studies  
2.2.2.1. 
Clinical Pharmacology Studies  
 
 
 
 
 
 
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2.2.2.1.1. Pharmacokinetics of TV-44749 Single-Dose Cohorts  
 
 
 
 
 
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2.2.2.1.2. Pharmacokinetics of TV-44749 Multiple-Dose Cohorts  
 
 
 
 
 
  
2.2.2.1.3. TV-44749 Comparability to Oral Olanzapine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2.2.1.4. Olanzapine Pharmacokinetics After Oral Administration  
ZYPREXA olanzapine tablets and ZYPREXA ZYDIS olanzapine orally disintegrating tablets 
are intended for oral use only. A ZYPREXA tablet contains olanzapine equivalent to 2.5, 5, 7.5, 
10, 15, or 20 mg. A ZYPREXA ZYDIS orally disintegrating tablet contains olanzapine 
equivalent to 5, 10, 15, or 20 mg. 
2.2.2.1.4.1. Single Oral Dose  
The pharmacokinetics of olanzapine are linear and dose proportional within the approved dosage 
range (Callaghan et al 1999). In clinical studies in healthy subjects, olanzapine peak 
concentrations were reached in approximately 6 hours following an oral dose. Its mean half-life 
in healthy individuals was 30 hours, ranging from 21 to 54 hours (5th to 95th percentile). The 
mean apparent plasma clearance was 25 L/h, ranging from 12 to 47 L/h (5th to 95th percentile). 
Smokers and men had a higher clearance of olanzapine than women and nonsmokers.  
2.2.2.1.4.2. Multiple Oral Doses  
The pharmacokinetic profile of olanzapine after multiple doses follows linear principles 
(ie, plasma concentrations after multiple doses can be linearly related to dose and can be 
predicted from single dose Cmax and AUC parameters) (Callaghan et al 1999). Once-daily 
administration of olanzapine leads to steady-state concentrations in approximately 1 week. The 
steady-state Cmax of olanzapine was approximately 2-fold higher than after single doses. The 
pharmacokinetics of olanzapine at steady state were consistent with those generated in single 
dose studies. 
A population pharmacokinetic model involving data from 1711 patients with schizophrenia 
receiving olanzapine daily for up to 6 weeks in Phase 2 and 3 studies characterized 655 patients 
in a low-clearance group (38%) and 1056 patients in a high-clearance group (Callaghan et al 
1999). In both populations, olanzapine clearance was lower in women than in men (by about 
25%). The typical apparent clearance values in these groups differed by approximately 2-fold. 
Smoking and gender were identified as important factors contributing to clearance only in the 
high-clearance group. In the high-clearance group, nonsmokers had a lower clearance. Smoking 
and gender were also important factors for the volume of distribution across the entire 
population.  
2.2.2.1.5. Olanzapine Pharmacokinetics Following Intramuscular Injection of 
Long-Acting Preparation of Olanzapine  
ZYPREXA RELPREVV (olanzapine [pamoate] long-acting injection; OLAI) is provided as 
powder for suspension for im use only in vials containing 210, 300, and 405 mg. Dose linear 
exposure for ZYPREXA RELPREVV aligns with the corresponding exposure for an oral dose of 
olanzapine. Olanzapine presents a linear pharmacokinetic profile over the clinical dosing range 
(an overview is provided in Heres et al 2014). In clinical studies, olanzapine concentrations were 
observed immediately upon injection. Peak concentrations most often occurred at 2 to 4 days 
after injection. Upon multiple dosing, olanzapine concentrations increase gradually, taking 
approximately 3 months to reach steady-state conditions. Despite this slower time to reach 
steady-state conditions (compared to oral), data indicated that therapeutic concentrations were 
available within hours of the first OLAI. Half-life was approximately 30 days, controlled by the 
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slow rate of im absorption, while the 30-hour half-life of oral olanzapine is elimination rate 
based.  
OLAI dosages of 150 mg every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks in 
patients with schizophrenia stabilized on daily oral olanzapine (10, 15, or 20 mg/day), produced 
average (10th to 90th percentile) steady-state plasma olanzapine concentrations (5 to 41, 8 to 51, 
and 7 to 73 ng/mL, respectively) that were similar to those for oral olanzapine at dosages of 10, 
15, and 20 mg/day (13 to 48, 21 to 63, and 21 to 85 ng/mL, respectively) (Kane et al 2010).  
2.2.2.2. 
Clinical Efficacy and Safety Studies  
Several safety concerns have been identified in the adult clinical studies programs for 
olanzapine. The most commonly observed adverse reactions associated with the use of oral 
olanzapine in patients with schizophrenia (incidence of 5% or greater, rounded to the nearest 
percent) and not observed at an equivalent incidence among placebo-treated patients (olanzapine 
incidence at least twice that for placebo) in 6-week, placebo-controlled trials were dizziness 
(11%), constipation (9%), personality disorder (8%), weight gain (6%), and postural hypotension 
and akathisia (5% each) (ZYPREXA USPI 2021). In 3- and 4-week placebo-controlled trials in 
patients with bipolar I disorder (manic or mixed episodes), the most commonly observed adverse 
reactions associated with the use of oral olanzapine (adverse event incidence of 5% or greater, 
rounded to the nearest percent) and not observed at an equivalent incidence among 
placebo-treated patients (olanzapine incidence at least twice that for placebo) were somnolence 
(35%), dry mouth (22%), dizziness (18%), asthenia (15%), constipation and dyspepsia (11% 
each), and increased appetite and tremor (6% each). 
There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among im 
olanzapine for injection-treated patients and not observed at an equivalent incidence among 
placebo-treated patients (olanzapine incidence at least twice that for placebo) during the 
placebo-controlled premarketing studies. The incidence of somnolence during the 24-hour im 
treatment period in clinical studies in agitated patients with schizophrenia or bipolar I mania was 
6% for im olanzapine for injection and 3% for placebo (ZYPREXA USPI 2021).  
A dose group difference has been observed for fatigue, dizziness, weight gain, and prolactin 
elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 
20 (N=200), and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or 
schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 
6.6%) was observed with significant differences between 10 versus 40 mg/day and 20 versus 
40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) 
was observed with significant differences between 20 versus 40 mg. Dose group differences 
were also noted for weight gain and prolactin elevation. 
Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients 
experienced treatment-emergent injection-related adverse reactions (injection site pain, buttock 
pain, injection site mass, induration, injection site induration) in the placebo-controlled database. 
The most frequently occurring treatment-emergent adverse reaction was injection site pain 
(2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated) (ZYPREXA RELPREVV USPI 
2021). 
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PDSS has been characterized by signs of delirium and/or excessive sedation following deep im 
injection with OLAI (Detke et al 2010). The symptomatology is consistent with olanzapine 
overdose (eg, sedation, confusion, slurred speech, altered gait, or unconsciousness), although no 
clinically significant decreases in vital signs are observed.  
In the clinical development of im OLAI, 30 cases (in 29 patients) of PDSS were identified 
(Detke et al 2010). Symptom onset ranged from immediate to 3 to 5 hours post-injection, with a 
median onset time of 25 minutes post-injection. All patients recovered within 1.5 to 72 hours 
after onset. PDSS could be readily identified based on symptom presentation, progression, and 
temporal relationship to the injection. Olanzapine overdose resulted in excessive sedation (which 
can include coma) and/or delirium.  
All 30 cases described by (Detke et al 2010) presented with at least 1 symptom related to either 
delirium or sedation, with 83% of cases resulting in both delirium- and sedation-related 
symptoms. Delirium-related adverse events, such as disorientation, confusion, ataxia, and 
dysarthria, were reported in 97% of events. Sedation-related adverse events, defined as 
somnolence, sedation, or other change in level of consciousness, were reported in 87% of the 
events. Initial symptoms (ie, symptoms first noted by the patient, investigator, or other witness at 
the onset of the event) included delirium-related symptoms (47% of cases) and sedation-related 
symptoms (40% of cases). However, in another 40% of cases, the first symptoms noted did not 
include signs of sedation or delirium but were instead related to general malaise or other 
symptoms such as extrapyramidal symptoms, agitation, anxiety, or irritability. In those cases, the 
delirium or sedation developed subsequent to the initial symptoms. 
Incapacitation was found in 21 cases, defined as the presence of clinically significant 
disorientation, ataxia, or sedation such that the patient would not have been able to seek 
assistance on his own (Detke et al 2010). 
Plasma drug levels after im olanzapine pamoate injection typically result in a slowly increasing 
plasma concentration profile that does not show any initial rapid release or “dose dumping” 
effect (McDonnell et al 2010). Instead, the slow depot release of ZYPREXA RELPREVV 
maintains the olanzapine concentration within the expected therapeutic range. Injections that 
result in a PDSS event demonstrated higher olanzapine concentrations in the plasma exceeding 
100 ng/mL and in some cases reaching >600 ng/mL at the first hours post-injection. These 
plasma levels are significantly higher than the expected therapeutic range of olanzapine of 5 to 
73 ng/mL. Olanzapine concentrations gradually return to the therapeutic range over the 
following 24 to 72 hours (McDonnell et al 2010). Resolution of the clinical symptoms of an 
event is concordant with the return of plasma olanzapine concentrations to therapeutic levels. 
2.3. 
Known and Potential Benefits and Risks to Patients  
2.3.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)  
Olanzapine is a well characterized and commonly prescribed second-generation antipsychotic 
drug available as oral and im formulations. Oral formulations (Section 2.1.2.1) are approved for 
the treatment of adults and adolescents affected by schizophrenia. The long-acting im depot 
preparation containing olanzapine pamoate (Section 2.1.2.2) is approved for the treatment of 
adults affected by schizophrenia, while a rapid-acting im formulation of olanzapine 
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(Section 2.1.2.1) is approved for the treatment of adults with acute agitation associated with 
schizophrenia. 
Data from Study TV44749-SAD-10154, including pharmacokinetics, safety, and tolerability 
associated with TV-44749, ie, olanzapine for extended-release injectable suspension (for sc use), 
are available. To date, the sponsor has evaluated TV-44749 safety data from 71 patients and 30 
healthy subjects at doses of 70 to 566 mg and 6 healthy subjects treated with TV-44749 vehicle. 
The safety profile emerging from these data is consistent with that seen with other olanzapine 
formulations (Section 2.2.2.2), with the exception of the identification of ISRs. None of these 
were identified as serious events, and they have not significantly impacted TV-44749’s benefit-
risk profile. 
 
 The current ZYPREXA label 
contains warning language describing an association with hyperglycemia, diabetes mellitus, 
weight gain, and lipid elevations. The label also contains the standard boxed warning regarding 
increased risk of mortality in elderly patients with dementia-related psychosis. 
Furthermore, it has been proposed that the rapid and significant increases in plasma 
concentration leading to an olanzapine overdose and PDSS with ZYPREXA RELPREVV arise 
from vessel injury during the im injection process. Vessel injury could result in blood contact, 
causing rapid dissolution due to the marked increase in solubility of olanzapine pamoate in 
plasma compared to the intended im environment, and ultimately lead to an olanzapine overdose 
(Heres et al 2014). 
 
 
 
 
No 
suspected PDSS event occurred in Study TV44749-SAD-10154. 
Additional information regarding benefits and risks to patients may be found in the IB. 
In summary, the benefit and risk assessment for TV-44749 is favorable following review of the 
outlined data. 
2.3.2. 
Known and Potential Benefits and Risks of Other Treatment  
Information regarding benefits and risks to patients of oral olanzapine used in this study during 
the screening period may be found in the prescribing information for oral olanzapine 
(ZYPREXA USPI 2021). 
2.3.3. 
Overall Benefit and Risk Assessment for This Study  
 
 
 
 
 
 
 
 
 
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The study design, inclusion/exclusion criteria, and procedures have been developed in a manner 
to protect patient safety. Management of study activities during coronavirus disease 2019 
(COVID-19) outbreaks is detailed in Appendix L. 
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3. 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
3.1. 
Primary and Secondary Study Objectives and Endpoints  
The primary and secondary study objectives and endpoints are: 
Objectives  
Endpoints 
The primary objective is to evaluate the 
efficacy of TV-44749 in adult patients with 
schizophrenia. 
The primary efficacy endpoint is as follows: 
• 
The change from baseline to week 8 in the Positive and 
Negative Syndrome Scale (PANSS) total score. 
A key secondary objective is to further 
evaluate the efficacy of TV-44749 based on 
additional parameters in adult patients with 
schizophrenia. 
The key secondary efficacy endpoints are as follows: 
• 
Change in Clinical Global Impression-Severity (CGI-S) 
scale score from baseline to week 8 
• 
Change in Personal and Social Performance Scale (PSP) 
score from baseline to week 8 
A secondary objective is to evaluate the 
safety and tolerability of TV-44749 in adult 
patients with schizophrenia. 
The safety and tolerability endpoints will include, where 
appropriate, the following: adverse events (including serious 
adverse events, extrapyramidal symptoms, injection pain and 
other injection site reactions [local tolerability]), vital signs 
(blood pressure, pulse and orthostatic changes, and 
temperature), body weight, laboratory tests, electrocardiogram 
(ECG), concomitant 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) 
A secondary objective of this study is to 
evaluate the efficacy of TV-44749 from 
baseline to endpoints in Period 1 in adult 
patients with schizophrenia. 
• 
Change in total PANSS score from baseline to weeks 1, 
2, and 4 
• 
Change in Clinical Global Impression-Improvement 
(CGI-I) scale score from baseline to weeks 4 and 8 
• 
Change in CGI-S scale score from baseline to weeks 1, 2, 
and 4 
• 
Change in Patient Global Impression-Improvement 
(PGI-I) scale score from baseline to week 8 
• 
Change in PGI-I scale score from baseline to weeks 2 and 
4 
• 
Change in Schizophrenia Quality of Life Scale (SQLS) 
score from baseline to weeks 4 and 8 
• 
Change in PSP score from baseline to week 4 
3.1.1. 
Justification of Primary Endpoint  
The primary efficacy endpoint of the study is the change from baseline to week 8 in the PANSS 
total score. The PANSS is a well-characterized, standardized measurement technique used for 
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rating presence and severity of positive and negative symptoms in patients with schizophrenia 
and is widely used in the research of antipsychotic treatment. 
The 30-item PANSS instrument measures the severity of positive symptoms (7 items), negative 
symptoms (7 items), and general psychopathology symptoms (16 items) and is the most widely 
used measure of symptom severity in schizophrenia drug trials. PANSS has high internal validity 
and reliability and excellent sensitivity to change in both short‐ and long‐term trials 
(Gopalakrishnan et al 2021, Curson et al 1986, Wyatt et al 1999). 
PANSS will be administered by the investigator/trained rater who will evaluate a patient’s 
current severity level of each symptom (item).  
3.2. 
Estimand  
3.2.1. 
Primary Estimand  
For the primary efficacy objective, the following estimand attributes will be employed: 
a. Treatment: the treatment of low, medium, or high dose of TV-44749 compared to 
placebo, separately, will be evaluated according to the randomization assignment at 
Period 1. 
b. Population: all randomized adult patients who have a confirmed diagnosis of 
schizophrenia, present with acute exacerbation of disease, and are eligible for 
olanzapine treatment. 
c. Endpoint: change from baseline to week 8 in the PANSS total score while (as if) 
patients did not withdraw from randomized treatment or use prohibited antipsychotic 
medications. 
d. Population-level summary: Rubin’s rule-derived least squares means of the 
difference in the change from baseline to week 8 between treatment groups according 
to the randomization assignment, regardless of the treatment actually received. 
Any data collected after the intercurrent event (ICE) of taking prohibited antipsychotic 
medications or early termination (ET) due to insufficient clinical response (lack of efficacy) will 
be regarded as patients not reaching the optimal treatment effect (ie, missing not at random 
[MNAR]). ICE of early discontinuation for other reasons will be regarded as if the patient fully 
complied and completed the study (assuming missing at random [MAR]); see Table 4 for further 
details on the classification and handling of ICEs. This complies with the hypothetical approach. 
Table 4: 
Classification of Intercurrent Events  
Intercurrent Event  
Strategy 
Analysis 
Early discontinuation due to: 
Lack of efficacy 
Prohibited antipsychotic 
Disease progression 
Hypothetical  
Measurements after ICE will be 
imputed using reference-based 
imputation (assuming MNAR) 
Self-administered prohibited 
antipsychotics 
Suicide 
Hypothetical 
Measurements after ICE will be 
imputed using reference-based 
imputation (assuming MNAR) 
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Table 4: 
Classification of Intercurrent Events (Continued) 
Intercurrent Event  
Strategy 
Analysis 
Early discontinuation due to other 
reasons (including due to adverse 
event) 
Hypothetical 
Measurements after ICE will be 
imputed based on randomized 
treatment group (assuming MAR) 
Allowed concomitant medications 
Adverse event that did not lead to 
discontinuation  
Use of prohibited medications that 
are not antipsychotic 
Injection site reaction 
Out of window safety assessments 
Treatment policy 
Measurements after ICE will be 
included in analysis 
ICE=intercurrent event; MAR=missing at random; MNAR=missing not at random. 
For ICEs that were not foreseen at the time of writing the protocol and that require the use of the 
hypothetical strategy, classification as MAR/MNAR will be done in a blinded manner on a case-
by-case basis prior to database lock for efficacy and will be documented in a dedicated 
document. Also, the classification above will be revisited in a blinded manner before database 
lock for efficacy and will be documented in the same document. 
The purpose of this estimand is to evaluate the efficacy of TV-44749 when patients adhere to 
treatment, while patients who used any prohibited antipsychotic medications or withdrew from 
the study due to disease progression or lack of efficacy are regarded from that withdrawal time 
point as behaving like patients randomized to the placebo arm. This also applies to the “other 
efficacy estimand” (Section 3.2.2).  
3.2.2. 
Other Efficacy Estimand  
This efficacy estimand will be used for the key secondary endpoints based on the CGI-S and PSP 
scores. Attributes “a” and “b” will be implemented in the same manner as planned for the 
primary efficacy estimand. 
a. Treatment: the treatment of low, medium, or high dose of TV-44749 compared to 
placebo, separately, will be evaluated according to the randomization assignment at 
Period 1. 
b. Population: all randomized adult patients who have a confirmed diagnosis of 
schizophrenia, present with acute exacerbation of disease, and are eligible for 
olanzapine treatment. 
c. Endpoint: change from baseline to week 8 in the CGI-S and PSP scores as if patients 
did not withdraw from randomized treatment or use prohibited antipsychotic 
medications. 
d. Population-level summary: details are described in the statistics section. 
See “Primary and Secondary Objectives and Endpoints” table above; the endpoint will be 
evaluated while (as if) patients are on treatment and did not use prohibited antipsychotic 
medications. Any data collected after the ICE of taking prohibited antipsychotic medications or 
ET due to insufficient clinical response (lack of efficacy) will be regarded as patients not 
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reaching the optimal treatment effect (ie, MNAR). ICE of early discontinuation for other reasons 
will be regarded as if the patient fully complied and completed the study (assuming MAR); see 
Table 4 for further details on the classification and handling of ICEs. This complies with the 
hypothetical approach. 
3.2.3. 
Safety and Tolerability Estimand  
For safety and tolerability objectives, the following estimand attributes will be employed: 
a. Treatment: the treatment of low, medium, or high dose of TV-44749 and placebo, 
separately, will be evaluated according to treatment actually received.  
b. Population: all randomized adult patients who have a confirmed diagnosis of 
schizophrenia, present with acute exacerbation of disease at randomization and 
received at least 1 administration of study drug (as per Safety Analysis Set; see 
Section 10.2.3). 
c. Endpoint: see table of “Primary and Secondary Objectives and Endpoints” above; 
the endpoints will be evaluated without regard to any ICE. 
d. Population-level summary: details are described in the statistics section. 
3.3. 
Exploratory Objectives and Endpoints  
Exploratory objectives are: 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. 
STUDY DESIGN  
4.1. 
General Study Design and Study Schematic Diagram  
This is a Phase 3, multinational, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study with an open-label, long-term safety phase to evaluate the efficacy, 
safety, and tolerability of olanzapine for extended-release injectable suspension (TV-44749) for 
sc use as treatment of adult patients with schizophrenia. 
The study will be composed of 2 periods (Figure 1): Period 1 (the double-blind, 
placebo-controlled, efficacy and safety period [acute treatment phase]) and Period 2 (open-label 
safety period [long-term safety phase]). For each patient, the duration of Period 1 will be 8 
weeks, and the duration of Period 2 will be up to 48 weeks. 
Patients will be randomized to the 8-week efficacy and safety period (acute treatment phase; 
Period 1) to 1 of 3 active treatment groups (low [318 mg q1m], medium [425 mg q1m], or high 
dose [531 mg q1m]) or the placebo group in a 1:1:1:1 ratio.  
Period 2 will be open-label and will not include a placebo group. Period 1 will remain blinded to 
the Sponsor, the site staff, and the study participants until database lock for Period 1. In order to 
maintain the blind in Period 1, all patients will be randomized again between Period 1 and Period 
2; patients who were previously assigned to the active treatment groups will retain their Period 1 
treatment assignment (the re-randomization of patients in the TV-44749 groups is being done 
only to maintain blinding of Period 1, and de facto is a deterministic assignment and not 
randomization), and patients who were previously assigned to the placebo group will be 
randomized to one of the active treatment groups in a 1:1:1 ratio. Revealing of the treatment 
assignment in Period 2 will be performed only after completion and reporting of the relevant 
study procedures related to assessment of efficacy and safety endpoints in Period 1 
(Section 6.9.1), on a patient-by-patient basis. The revealing of the Period 2 treatment assignment 
will be performed after week 8 (visit 11) by the authorized site staff according to a process 
predefined in the relevant study plans, provided that all requirements stipulated in this process 
were met. Therefore, the dosing at week 8, although assigned to Period 2, will be handled in a 
blinded manner by all parties, similarly to the dosing in Period 1. The sites are encouraged to 
complete the revealing of the treatment assignment procedure before IMP administration in 
week 12 (visit 12). 
During the conduct of this study, an Independent Data Monitoring Committee (IDMC) will 
review accumulated unblinded safety, pharmacokinetic, and efficacy data on a regular basis, as 
detailed in the IDMC charter, to evaluate the safety of the product for the purpose of ensuring the 
continuing safety of the study patients and overseeing study conduct issues, as applicable. 
Once all patients completed Period 1, and Period 2 is ongoing, an analysis of the full efficacy 
data will be performed.  
Refer to Section 6.7.1 for a description of allowed concomitant medications (including rescue 
medications [Section 6.7.1.1] and antidepressants and/or mood stabilizers [Section 6.7.1.2]). 
Screening (up to 8 days Prior to Randomization to Period 1): 
Patients will undergo screening procedures and assessments up to 8 days prior to randomization 
to Period 1. Patients will provide informed consent at the screening visit before any study-related 
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procedures are performed. Patients will be asked to consent to share their information with a 
vendor that will verify that they are not currently participating or have not recently participated 
in another clinical study, unless prohibited by local requirements. 
 
 
 
 
 
 
 
 
Patients with exacerbation that started ≤8 weeks prior to screening (the investigator should 
confirm the exacerbation based on the patient’s medical records and/or based on anamnesis) and 
who would benefit from psychiatric hospitalization or continued hospitalization for symptoms of 
schizophrenia may be included in this study. 
The patient’s total Positive and Negative Syndrome Scale (PANSS) score should be between 80 
and 120, inclusive, at screening with a score ≥4 on at least 2 of the following 4 items of the 
PANSS positive subscale: hallucinatory behavior, delusions, conceptual disorganization, or 
suspiciousness/persecution. 
Patients must have an identified responsible person (referred to as the caregiver) who has agreed 
to provide information about the patient’s location, condition, and overall status during 
outpatient portions of the study during Period 1. The site personnel must identify the caregiver at 
the screening visit and consider the caregiver a reliable contact person. The caregiver must have 
regular contact with the patient (defined as direct contact not fewer than 3 times per week), with 
the expectation that this frequency of contact would continue throughout the outpatient portion 
of Period 1 (it is also advised during the rest of the study, including Period 2 and the FU period). 
The patient’s caregiver will be asked to sign a caregiver ICF during the screening period. 
Patients who are not already in an inpatient setting will be hospitalized during the screening 
period (see details pertaining to hospitalization duration and discharge criteria in the description 
of “Period 1” below). 
Patients will taper off their prior oral antipsychotic medications at rates per the investigator’s 
discretion. The tapering-off process should be completed prior to randomization. 
Patients entering the study who have not previously received oral olanzapine will receive 2 oral 
doses of olanzapine for 2 consecutive days during the screening period (the second dose should 
be administered at least 24 hours prior to randomization) to assess patient tolerability (oral 
olanzapine 10 mg/day or higher [but not exceeding 20 mg/day] per investigator decision). The 
PANSS and Clinical Global Impression-Severity (CGI-S) should be completed prior to oral 
olanzapine administration. 
Patients who received olanzapine within the last year will not be required to receive the 2 doses 
of oral treatment. The investigator will verify the previous use, tolerability, and duration of 
olanzapine treatment to assure prior tolerability. 
In the event that a patient meets all study inclusion criteria and does not meet any of the study 
exclusion criteria, but results of screening blood and urine samples taken within the 8-day 
screening period are not available by day 8 of screening, the screening period may be extended 
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by 2 days (until day 10 of screening) to allow the receipt of the results to confirm patients’ 
eligibility. In case results are not available by day 10, the patient will be considered a screening 
failure and may be considered for rescreening. In addition, the screening period may be extended 
by 2 days (until day 10 of screening), in exceptional cases, due to special conditions (eg, extreme 
weather) after receiving approval from the MM or sponsor. 
Period 1 (8 weeks):  
Period 1 is an 8-week double-blind, placebo-controlled, efficacy and safety period (acute 
treatment phase). 
Randomized patients should have a PANSS total score between 80 and 120, inclusive, at 
baseline (prior to randomization) with a score ≥4 on at least 2 of the following 4 items of the 
PANSS positive subscale: hallucinatory behavior, delusions, conceptual disorganization, or 
suspiciousness/persecution. 
Patients demonstrating a reduction in the total PANSS score of ≥20% between screening and the 
baseline (randomization) visit will not be eligible for randomization into the study. 
Randomized patients will be treated with sc injections of TV-44749 (low [318 mg q1m], medium 
[425 mg q1m], or high dose [531 mg q1m]) or placebo at visit 2 (week 0) and visit 7 (week 4). 
At visits 2 and 7, the PANSS, Columbia Suicide Severity Rating Scale (C-SSRS), CGI-S, and 
Clinical Global Impression-Improvement (CGI-I; visit 7 [week 4] only) scales should be 
completed prior to investigational medicinal product (IMP) administration; all other scales and 
questionnaires may be completed either prior to IMP administration or after. Any assessments 
performed after IMP administration must be completed on the day of IMP administration. 
Prior to screening, patients can be either outpatients or inpatients. All patients will be 
hospitalized upon study entry (screening) and will remain hospitalized during the screening 
period and for the first 4 weeks after randomization (until the second IMP administration). After 
the second injection, patients may be discharged if all discharge criteria are met and if, in the 
opinion of the investigator, discharge is appropriate. During the hospitalization period (ie, before 
the patient is discharged), a short-term leave from the site may be allowed if requested by the 
patient. Patient’s eligibility for such leave will be determined by the investigator clinical 
judgment, in accordance with the study conduct and with the patient’s best interest. During the 
leave, the patient will be escorted by a caregiver or another individual per investigator approval. 
The patient will return to the site on the same calendar day. In exceptional cases, an overnight 
stay outside the site may be approved by the investigator. Upon return to the site, after any 
period of leave, the patient will undergo a urine drug screen, an abbreviated physical 
examination (including weight), and a concomitant medication and alcohol consumption/illicit 
drug use inquiry. The results of these assessments, along with the date and time of site leave and 
return, will be captured in a dedicated case report form (CRF). 
The Readiness for Discharge Questionnaire (RDQ) will be used to assess a patient’s readiness 
for discharge (Potkin et al 2005) and should be completed by a qualified health care professional 
(HCP) who has a thorough knowledge of the patient's clinical condition, and has been following 
them throughout the duration of the hospitalization. The RDQ consists of 6 items, as presented 
below. 
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Discharge Criteria (RDQ): 
1. The patient is not actively suicidal or homicidal. 
2. The patient has adequate control over aggression and impulsivity. 
3. The patient has the ability to carry out basic activities of daily living such as bathing, 
dressing, climbing stairs, eating, etc. 
4. The patient has the ability to take medicine independently (from the hospital/medical 
staff). 
5. The patient’s delusions and hallucinations do not significantly interfere with functioning. 
6. The patient has a CGI-S score of ≤4. 
Once discharge criteria are met, and in the opinion of the investigator discharge is appropriate, 
the patient can be discharged to a suitable supervised environment or to the responsibility of the 
patient’s caregiver.  
If the patient no longer has a caregiver or lacks a supervised environment, the patient can also be 
discharged if the patient has stable housing (ie, a permanent address or a tenancy agreement) and 
the site can provide frequent monitoring via telephone contact. If the patient is discharged before 
week 8, the patient will return to the clinic for weekly visits from the time of discharge and until 
the end of Period 1. If discharge criteria are not met, the patient will remain in the clinic. Patients 
may remain as inpatients for the full duration of Period 1 if they do not meet the discharge 
criteria. 
If at any point after discharge during Period 1 the patient no longer has a caregiver (including if 
the caregiver has resigned or excluded himself/herself from the responsibility), lacks a 
supervised environment, or lacks stable housing and the site cannot provide frequent monitoring 
via telephone contact, the patient may be discontinued from study treatment and will be asked to 
complete ET and FU visits. 
An unscheduled visit may be performed at any time per investigator decision. Each unscheduled 
visit should include clinical laboratory tests, a full physical examination (including weight), 
abdominal fat measurement (waist-to-hip ratio), inquiry regarding alcohol consumption/illicit 
drug use, vital signs measurements, PANSS, CGI-S, CGI-I, C-SSRS, Calgary Depression Scale 
for Schizophrenia (CDSS), blood samples for plasma concentration of IMP, adverse event and 
concomitant medication inquiries (Table 1), and any other procedures according to the discretion 
of the investigator. However, in order to reduce patient burden and to avoid unnecessary data 
collection, the investigator will have discretion in determining whether all unscheduled visit 
procedures (Table 1) should be performed during the unscheduled visit in the event that (i) the 
unscheduled visit is one of multiple in-clinic visits that are deemed necessary in close proximity 
(ie, 2 or more visits within 1 week) or (ii) the visit is for administrative purposes 
(eg, reconsenting) or technical reasons (eg, repeat laboratory sample collection for reasons 
unrelated to an adverse event) and not due to a change in the patient’s medical status per clinical 
judgment. 
For the entire duration of Period 1 (including the inpatient and outpatient setting), a window of 
±3 days will be allowed around the scheduled visit dates for dosing visits; a window of ±2 days 
will be allowed for non-dosing visits (during the inpatient period, every effort will be made to 
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maintain the assessments on the scheduled dates). Visit dates should be calculated from the date 
of previous IMP administration. In exceptional cases, per the discretion of the investigator and 
with permission from the medical monitor (MM) or sponsor, dosing visits may take place up to 
5 days before the scheduled visit date (and recorded accordingly). 
Period 2 (up to 48 weeks): 
Following completion of Period 1 (8 weeks), eligible patients will continue to Period 2, the 
safety period (long-term safety phase; up to 48 weeks). During this period, patients will receive 
monthly sc injections of TV-44749. 
In order to enter Period 2, the patient should meet the following eligibility criteria: 
1. Patient has completed Period 1. 
2. Patient is considered sufficiently clinically stable per the investigator’s judgment. 
3. Patient is an outpatient (ie, met RDQ criteria and was discharged prior to Period 2). 
Note: Patients who do not meet RDQ criteria, but in the opinion of the investigator show 
sufficient clinical stabilization for transition to Period 2 and may benefit from 
continuation of participation in the study, may continue to Period 2 as inpatients for up to 
an additional 8 weeks. For such patients, RDQ can be assessed periodically according to 
investigator discretion; if RDQ criteria are not met by the end of the additional 8-week 
hospitalization period (week 16), then the patient will be discontinued from study 
treatment and will be asked to complete ET and FU visits. 
Visit 11 (week 8) will be the last visit of Period 1 and the first visit in Period 2. In order to 
maintain the blind in Period 1, all patients will be randomized again between Period 1 and 
Period 2; patients who were previously assigned to the active treatment groups will retain their 
Period 1 treatment assignment (the re-randomization of patients in the TV-44749 groups is being 
done only to maintain blinding of Period 1, and de facto is a deterministic assignment and not 
randomization), and patients who were previously assigned to the placebo group will be 
randomized to one of the active treatment groups in a 1:1:1 ratio. The treatment with TV-44749 
at this visit will be assigned to Period 2 and will be performed according to the re-randomization 
treatment assignment. Scales and questionnaires and other assessments will be completed only 
once. Revealing of the treatment assignment in Period 2 will be performed only after completion 
and reporting of the relevant study procedures related to assessment of efficacy and safety 
endpoints in Period 1 (Section 6.9.1), on a patient-by-patient basis. The revealing of the Period 2 
treatment assignment will be performed after week 8 (visit 11) by the authorized site staff 
according to a process predefined in the relevant study plans, provided that all requirements 
stipulated in this process were met. Therefore, the dosing at week 8, although assigned to Period 
2, will be handled in a blinded manner by all parties, similarly to the dosing in Period 1. The sites 
are encouraged to complete the revealing of the treatment assignment procedure before IMP 
administration in week 12 (visit 12). 
The study will continue on an outpatient basis (or inpatient basis for patients who remain 
hospitalized for up to an additional 8 weeks), and telephone contacts (or other comparable form 
of remote communication) will take place weekly between the monthly in-clinic visits. If, in the 
judgment of the investigator, the patient is likely to experience an exacerbation or pose a danger 
to himself/herself or others, that patient should be invited for an unscheduled visit (as described 
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under “Period 1” above, per assessments specified in Table 2) and/or hospitalized if needed, and 
the patient should be treated per the investigator’s judgment. If treatment with disallowed 
medications is required, including antipsychotics other than TV-44749, the patient will be 
discontinued from study treatment and will be asked to complete ET and FU visits. 
The PANSS, C-SSRS, CGI-S, and CGI-I scales should be completed prior to IMP 
administration; all other scales and questionnaires may be completed either prior to IMP 
administration or after (except for visit 11 [week 8], where all assessments must be completed as 
detailed in Section 6.9.1 and footnote “k” of Table 1 and Table 2). Any assessments performed 
after IMP administration must be completed on the day of IMP administration. 
For the entire duration of Period 2 (including any phone visits), a window of ±3 days will be 
allowed around the scheduled visit dates for dosing visits and for non-dosing visits; for any 
patients who are inpatients at the beginning of Period 2, every effort will be made to maintain the 
assessments on the scheduled dates during the inpatient period. Visit dates should be calculated 
from the date of previous IMP administration. In exceptional cases, per the discretion of the 
investigator and with permission from the MM or sponsor, dosing visits may take place up to 5 
days before the scheduled visit date (and recorded accordingly). 
Patients entering Period 2 will be treated for up to 48 weeks. An end-of-treatment (EOT) visit 
will be completed 4 weeks after the patient’s last injection. The time window for the EOT visit is 
±1 week. 
Dose Adjustment: 
During Period 2, the investigator may perform dose adjustments of TV-44749 (to one of the 
doses offered in the protocol) from visit 12 (week 12) and onward, based on clinical judgment. 
Dose adjustment will be documented in the CRF. 
Detailed procedures regarding dose adjustments will be provided in the pharmacy manual and in 
any other study plans as applicable. 
Section 6.9.4 provides details for dose adjustment following outcome of primary endpoint 
analysis. 
Procedures for Potential Post-injection Delirium/Sedation Syndrome 
 
 
 
 
 
 
 
 
 
 
 
  
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Early Termination and Follow-up Period 
Randomized patients who meet 1 or more of the study discontinuation or withdrawal criteria 
(Section 5.4) should be invited to perform the ET visit as soon as possible. An EOT visit will be 
conducted at 4 weeks after the last dose of IMP, and a FU visit for safety evaluation will be 
conducted at 8 weeks after the last dose of IMP. The time window for the EOT visit is ±1 week, 
and the time window for the FU visit is -1/+2 weeks. Since TV-44749 is an LAI, additional 
antipsychotic treatment is not required for 4 weeks following the last dosing visit (unless 
clinically indicated), whereas during the subsequent 4 weeks (FU period), patients may be 
treated for schizophrenia according to the investigator’s judgment. In case the ET visit is 
conducted during the time window of the EOT visit, the ET and EOT visits may be conducted on 
the same day (ie, the visits will be combined, and all assessments listed in the Study Procedures 
and Assessments tables [Table 1 or Table 2] for the ET and EOT visits must be performed). 
Patients who discontinue study treatment should be encouraged to complete the remaining visits 
until completion of the study (ie, ET, EOT, and FU visits). 
In case the sponsor decides to stop the study, active randomized patients will be asked to 
complete the EOT visit 4 weeks after the last dose of IMP and a FU visit 8 weeks after the last 
dose of IMP. The time window for the EOT visit is ±1 week, and the time window for the FU 
visit is -1/+2 weeks. 
The total duration of patient participation in the study will include up to 8 days of screening, 
during which oral olanzapine will be administered for 2 consecutive days (to establish 
tolerability), 8 weeks of treatment with TV-44749 or placebo (Period 1 [acute treatment phase]), 
up to 48 weeks of treatment with TV-44749 (Period 2 [long-term safety phase]), and 4 weeks of 
FU. 
The end of study is defined as the last visit of the last patient. 
The study duration will be from Q4 2022 (first patient screened) to Q2 2025 (last patient last 
visit). 
The study schematic diagram is presented in Figure 1.  
4.2. 
Planned Number of Patients and Countries  
Approximately 
 patients will be screened to achieve approximately 640 randomized patients. 
Following the primary efficacy estimand, all randomized patients will be evaluable for efficacy 
analysis in this study. Details on definition of evaluable patients and sample size are given in 
Section 10. 
The study is planned to be conducted in the US, Bulgaria, 
, Romania, 
, Turkey, and 
possibly other countries, in approximately 100 investigational centers. The study is expected to 
start in Q4 2022 and last until approximately Q2 2025. 
4.3. 
Justification for Study Design and Selection of Population  
Schizophrenia is a lifelong illness with evolving symptoms that can fluctuate in severity over 
time. A major goal in designing treatments for schizophrenia is to effectively stabilize 
symptoms, keep them stable over the long term, and maintain an acceptable safety profile. The 
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present study is designed to assess the ability of TV-44749 to stabilize symptoms in a patient 
population with unstable symptomology experiencing an acute exacerbation of schizophrenia. 
The study will evaluate the efficacy of TV-44749 on psychiatric symptoms, relative to placebo. 
It will also assess the safety and tolerability of TV-44749 in patients with schizophrenia over a 
treatment period of 56 weeks. 
Refer to Section 6.3 for the justification of the IMP dose and the use of placebo IMP and to 
Section 3.1.1 for the justification of the primary endpoint. 
4.3.1. 
Study Duration  
Registration trials for drugs indicated for schizophrenia, in patients experiencing an acute 
symptom exacerbation, are typically randomized, double‐blind, placebo‐controlled studies, 6 to 
8 weeks in duration. This is because thus far, for second-generation antipsychotics, a reasonable 
stability of effect is often observed (as well as some effect on negative symptoms) only after 
6 weeks of treatment (Gopalakrishnan et al 2021). 
In case of LAIs, the selection of the timing for the primary endpoint should take into 
consideration the dosing interval of the LAI under investigation as well as the anticipated onset 
of therapeutic effect. For instance, the confirmatory efficacy trial for the recently approved LAI 
risperidone product PERSERIS® (Indivior Inc.) used mean change from baseline to week 8 in the 
PANSS total score as the primary efficacy endpoint, aligned with the q1m administration 
regimen of the investigational product (Nasser et al 2016). 
Similarly, as TV-44749 is an LAI intended for q1m administration, this study is designed as a 
randomized, double-blind, placebo-controlled study in patients with acute exacerbation of 
schizophrenia, comparing 3 dose strengths of TV-44749 q1m with placebo q1m with a primary 
endpoint of change from baseline to week 8 in the PANSS total score, with a long-term safety 
period. 
Shorter study duration (eg, 4 weeks) could also be considered, especially given the fact that 
TV-44749 has a similar profile to existing antipsychotic drugs. However, this carries the risk of 
negative results if maximal therapeutic effect is not obtained at 4 weeks, and the shorter duration 
is disadvantageous in terms of the ability to demonstrate stability of effect. 
4.3.2. 
Patient Selection  
This study will enroll patients diagnosed with schizophrenia according to the criteria of 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The diagnosis will 
be confirmed using a structured assessment tool (Structured Clinical Interview for DSM-5, 
Clinical Trials Version [SCID-5-CT]). 
The acute status will be confirmed by the total PANSS score between 80 and 120, inclusive, at 
screening and baseline (prior to randomization), with a score ≥4 on at least 2 of the following 
4 items of the PANSS positive subscale: hallucinatory behavior, delusions, conceptual 
disorganization, or suspiciousness/persecution, and a CGI-S score of ≥4 (moderately ill) at 
screening and baseline (prior to randomization). 
Further descriptive parameters, demographic characteristics, and a detailed disease history, such 
as age, sex, ethnicity, age at onset of illness, duration of current episode, baseline 
psychopathology, comorbid conditions, substance abuse, etc will be documented.  
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Exclusion of patient groups that may introduce confounding factors (eg, comorbidities or 
concomitant medication as detailed in study exclusion criteria) will maximize external validity 
and broad applicability to the intended patient population without unduly compromising internal 
validity. 
4.4. 
Stopping Rules for the Study  
A conditional power approach will be used in case the IDMC considers an ET of the study due to 
poor efficacy, as applicable. Full details of this approach will be depicted in the IDMC charter 
and the statistical analysis plan. During the conduct of the study, all safety data will be reviewed 
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 that invalidate the 
earlier positive benefit-risk assessment 
• discontinuation of the development of the IMP 
If the whole study or arms of the study will be stopped, the patients who are terminated early will 
be followed according to Withdrawal Criteria and Procedures for the Patient (Section 5.4). 
4.5. 
Schedule of Study Procedures and Assessments  
Study procedures and assessments with their time points are presented in Table 1 (Period 1) and 
Table 2 (Period 2). Detailed descriptions of each method of procedures and assessments are 
provided in Section 7 (efficacy assessments), Section 8 (safety assessments), and Section 9 
(pharmacokinetic and other assessments). Study procedures and assessments by visit are listed in 
Appendix B. 
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5. 
SELECTION AND WITHDRAWAL OF PATIENTS  
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized are not granted by Teva (Appendix C). 
5.1. 
Patient Inclusion Criteria  
Patients may be randomized in this study only if they meet all of the following criteria: 
a. [Revision 1] The patient is a male or female of any ethnic origin, 18 to 64 years of 
age, inclusive, at the time of screening. 
b. [Revision 1] The patient is capable of providing signed informed consent. Patients 
will be asked to consent to share their information with a vendor that will verify that 
they are not currently participating or have not recently participated in another 
clinical study, unless prohibited by local requirements. 
 
 
 
 
 
 
c. The patient has a current confirmed diagnosis of schizophrenia according to the 
DSM-5, for >1 year. Diagnosis must be reconfirmed by the SCID-5-CT. 
d. The patient has a total PANSS score between 80 and 120, inclusive, at screening and 
baseline (prior to randomization) with a score ≥4 on at least 2 of the following 4 items 
of the PANSS positive subscale: hallucinatory behavior, delusions, conceptual 
disorganization, or suspiciousness/persecution. 
e. The patient has exacerbation of schizophrenia that started ≤8 weeks prior to screening 
and would benefit from psychiatric hospitalization or continued hospitalization for 
symptoms of schizophrenia. 
f. The patient has a CGI-S score of ≥4 (moderately ill) at screening and baseline (prior 
to randomization). 
g. Patients who have received an antipsychotic treatment (other than clozapine) in the 
past year must have been responsive based on the investigator’s judgment (and based 
on discussions with family members, caregivers, or healthcare professionals, as 
applicable). 
h. [Revision 1] The patient has an identified responsible person (referred to as the 
caregiver) who has agreed to provide information about the patient’s location, 
condition, and overall status during outpatient portions of the study during Period 1. 
The site personnel must identify the caregiver at the screening visit and consider the 
caregiver a reliable contact person. The caregiver must have regular contact with the 
patient (defined as direct contact not fewer than 3 times per week), with the 
expectation that this frequency of contact would continue throughout the outpatient 
portion of Period 1 (it is also advised during the rest of the study, including Period 2 
and the FU period). This regular contact with the patient is not mandatory during the 
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hospitalization period of Period 1. The patient’s caregiver will be asked to sign a 
caregiver ICF during the screening period. 
i. Body mass index between 18.0 and 40.0 kg/m2, inclusive, at the time of screening. 
j. Women may be included only if they have a negative beta-human chorionic 
gonadotropin (β-HCG) test at screening and baseline (if a borderline result is obtained 
on a urine test, a serum test should be performed and a negative result obtained) or 
are sterile (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy or congenitally sterile) or postmenopausal (Appendix E). 
k. Women of childbearing potential 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 prior to the first administration of IMP, and agree to 
continue the use of this method for the duration of the study, and for 70 days after the 
last dose of IMP. Highly effective methods of contraception include the following: 
− Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at 
the screening visit before the first dose of IMP. 
− Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at the screening 
visit 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. 
l. The patient, if an adult 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 70 days after the last dose of IMP). 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 
70 days after the last dose of IMP. 
m. The patient is able to understand the nature of the study and follow protocol 
requirements, including the prescribed dosage regimens (oral and sc administration), 
non-use of prohibited concomitant medications, and hospitalization for at least 
4 weeks at the clinical site; can read and understand the written word in order to 
complete patient-reported outcomes measures by themselves; and can be reliably 
rated on assessment scales. 
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n. The patient must be willing and able to comply with study restrictions and to remain 
at the investigational center for the required duration during the study period 
(including hospitalization for at least 4 weeks at the clinical site) and must be willing 
to return to the investigational center for further visits, as applicable, and for the FU 
procedures and assessments as specified in this protocol. 
o. The patient has a stable place of residence for approximately 3 months before 
screening, and changes in residence are not anticipated over the course of study 
participation. 
p. The patient is in adequate health as determined by medical and psychiatric history, 
medical examination, electrocardiogram (ECG), serum chemistry, hematology, 
coagulation urinalysis, and serology. 
5.2. 
Patient Exclusion Criteria  
Patients will not be 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 (has a primary current diagnosis other than schizophrenia or a 
comorbid diagnosis that is primarily responsible for the current symptoms and 
functional impairment). 
b. The patient has a known history of the following: (a) borderline personality disorder, 
antisocial personality disorder, or bipolar disorder; (b) traumatic brain injury causing 
ongoing cognitive difficulties, Alzheimer’s disease, or another form of dementia, or 
any chronic organic disease of the central nervous system; and (c) intellectual 
disability of a severity that would impact ability to participate in the study. 
c. The patient has an improvement (reduction) in the total PANSS score of ≥20% 
between screening and day 1 (baseline [randomization] visit). 
d. The patient was hospitalized for >14 days (with the exception of social or 
administrative hospitalization) in the current exacerbation episode prior to screening. 
e. The patient has a significant risk of violent behavior based on the patient’s medical 
history or investigator’s judgment. 
f. The patient has a significant risk of committing suicide based on the patient’s medical 
history or C-SSRS, and the investigator’s judgment.  
Patients with a C-SSRS positive response to suicidal ideation items 3, 4, or 5 and/or 
positive suicidal behavior response in the past 6 months are not eligible. 
g. The patient meets criteria for moderate to severe substance use disorder (based on 
DSM-5 criteria) within the past 6 months, such as chronic alcohol abuse or drug 
abuse (excluding those related to caffeine or nicotine). If, per the investigator’s 
judgment, a patient does not meet the criteria for substance use disorder, a positive 
result on the urine drug test is not exclusionary. Patients’ eligibility in such case of 
positive result, without medical explanation, will be determined by the investigator 
based on the patient’s background, history of substance use, and the investigator’s 
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discussions with family members, caregivers, or healthcare professionals, as 
applicable. 
h. The patient is currently using an LAI antipsychotic or is still under the coverage 
period of the specific LAI at time of screening.  
i. The patient has taken clozapine or has received electroconvulsive therapy within the 
last 12 months prior to screening. 
j. The patient is currently receiving daily oral olanzapine at a dose >20 mg/day. 
k. The patient has current or a history of known hypersensitivity to olanzapine or any of 
the excipients of TV-44749 or the oral formulation of olanzapine. 
l. The patient has treatment-resistant schizophrenia according to medical and 
psychiatric history, as judged by the investigator or documented failure of 2 or more 
antipsychotic medications (administered at the maximum tolerated dose for at least 
6 weeks each). Participants who have responded to antipsychotics only when paired 
with clozapine are considered treatment resistant.  
m. The patient has had a significant sedation or delirium after antipsychotic treatment 
according to medical and psychiatric history and as judged by the investigator or 
suffered from delirium due to a medical condition. 
n. [Revision 1] The patient has any medical or psychiatric condition that, in the opinion 
of the investigator, could jeopardize study participant's safety (including in the 
context of local oral olanzapine label) or would compromise the patient’s ability to 
participate in this study. 
o. The patient has known risk factors for undiagnosed/instable arrhythmia, congenital 
long QT, hypokalemia, hypomagnesemia, or autonomic failure (mostly with clinically 
significant orthostatic hypotension). 
p. The patient has any clinically significant uncontrolled medical condition (treated or 
untreated). 
q. Any disorder that may interfere with absorption, metabolism, or elimination of 
olanzapine 
r. The patient has a non-fasting glucose level of ≥200 mg/dL at screening. 
s. The patient had a change in their diabetes treatment within 4 weeks before the first 
injection of the IMP. 
t. The patient has serum triglycerides levels of ≥500 mg/dL. 
u. The patient has low-density lipoprotein levels of ≥190 mg/dL. 
v. The patient has a history of ketoacidosis or hyperosmolar coma. 
w. [Revision 1] The patient has alanine aminotransferase (ALT)/serum glutamic pyruvic 
transaminase values ≥2 × the upper limit of normal (ULN) of the performing 
laboratory, and aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase values ≥2 × ULN, and total bilirubin values ≥1.5 × ULN at screening. 
Isolated parameters for exclusion are as follows: 
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− ALT or AST >5 × ULN 
− ALT or AST >3 × ULN, and in addition either total bilirubin level >2 × ULN or 
international normalized ratio >1.5 (if elevation of international normalized ratio 
is not caused by anticoagulants) 
− ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
x. The patient has a neutrophil count of <1200/mm3. 
y. The patient has platelet count ≤75 × 103 μL. 
z. The patient has serum creatinine >2.5 mg/dL. 
aa. The patient has a positive serology for human immunodeficiency virus (HIV)-1, 
HIV-2, hepatitis B surface antigen, and/or hepatitis C. If serology is positive for 
hepatitis C but the ribonucleic acid (RNA) test is negative, and the patient has no 
history of liver disease or symptoms of active liver disease, enrollment will be 
allowed based on clinical judgment.  
bb. The patient is a pregnant or lactating woman or plans to become pregnant during the 
study. 
cc. The patient has previously participated in this study (except for rescreening). 
dd. The patient is or has been using or consuming the medications prohibited in this 
protocol. 
ee. The patient used an investigational drug (new chemical entity) or a medical device in 
a clinical study within 30 days or 5 half-lives (whichever is longer), or, in case of a 
biologic investigational drug, within 3 months or 5 half-lives (whichever is longer) 
prior to the first TV-44749 administration. 
ff. The patient has donated or received any blood, plasma, or platelet transfusions within 
30 days prior to the study or have planned donations during the study period or 
6 months following the last dose of IMP administration. 
gg. The patient has a pending court appearance that may result in incarceration. 
5.3. 
Eligibility Criteria for Period 2  
In order to enter Period 2, the patient should meet the following eligibility criteria: 
1. Patient has completed Period 1. 
2. Patient is considered sufficiently clinically stable per the investigator’s judgment. 
3. Patient is an outpatient (ie, met RDQ criteria and was discharged prior to Period 2). 
Note: Patients who do not meet RDQ criteria, but in the opinion of the investigator show 
sufficient clinical stabilization for transition to Period 2 and may benefit from 
continuation of participation in the study, may continue to Period 2 as inpatients for up to 
an additional 8 weeks. For such patients, RDQ can be assessed periodically according to 
investigator discretion; if RDQ criteria are not met by the end of the additional 8-week 
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hospitalization period (week 16), then the patient will be discontinued from study 
treatment and will be asked to complete ET and FU visits. 
5.4. 
Withdrawal Criteria and Assessments/Procedures for the Patient  
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. 
Patients must discontinue treatment with IMP and/or withdraw from the study if any of the 
following events occur: 
1. Patient withdraws consent or requests discontinuation from the IMP and/or withdrawal 
from the study for any reason. 
2. Patient develops an illness that would interfere with his/her continued participation. 
3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs in the opinion of the investigator. 
4. Patient takes prohibited concomitant medications as defined in this protocol (final 
decision to withdraw the patient will be on a case-by-case basis per sponsor discretion).  
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. 
Additionally, patients who meet the following study-specific criteria will be early terminated (ie, 
discontinued from further treatment with IMP and encouraged to complete the EOT and FU 
visits): 
1. Patient is diagnosed with a clinically significant DSM-5 disorder other than 
schizophrenia. 
2. A patient demonstrates a significant clinical deterioration that cannot be managed with 
permitted rescue medication as judged by the investigator based on any relevant history 
or observation made by the investigative site, and/ or requires other antipsychotic 
treatment apart from TV-44749. Hospitalization due to deterioration of schizophrenia that 
does not require other antipsychotic treatment will not be a withdrawal criterion unless 
determined as such by the investigator. 
3. A patient experiences 3 events of pus-containing lesions (abscess, infection, or 
inflammation) at the site of injection requiring intervention/systemic treatment following 
3 separate IMP injections. 
Patients should be treated with standard of care after withdrawal from or termination of the study 
as appropriate. 
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Investigators should attempt to obtain information on patients in case of withdrawal from the 
study or discontinuation from the IMP. Results of any evaluations and observations, together 
with a narrative describing the reason(s) for withdrawal from the study or discontinuation from 
the IMP, must be recorded in the source documents. The CRF must document the primary reason 
for withdrawal from the study or discontinuation from the IMP. 
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 the 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 health care professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the CRF; both the adverse 
events page and the relevant page of the CRF will be completed at that time. 
The patient will be monitored as applicable (eg, until the event has resolved or stabilized, until 
the patient is referred to the care of a health care professional, or until a determination of a cause 
unrelated to the test IMP or study procedure is made). The investigator must inform the MM or 
other applicable 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 and/or discontinues the IMP for multiple reasons that 
include also adverse events, the relevant page of the CRF should indicate that the withdrawal 
was related to an adverse event. An exception to this requirement will be the occurrence of an 
adverse event that in the opinion of the investigator is not severe enough to warrant 
discontinuation but that requires the use of a prohibited medication, thereby requiring 
discontinuation of the patient. In such a case, the reason for discontinuation would be “need to 
take a prohibited medication,” not the adverse event. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF. 
Randomized patients who meet 1 or more of the study discontinuation or withdrawal criteria 
should be invited to perform the ET visit as soon as possible. An EOT visit will be conducted at 
4 weeks after the last dose of IMP, and a FU visit for safety evaluation will be conducted at 
8 weeks after the last dose of IMP. In case the ET visit is conducted during the time window of 
the EOT visit, the ET and EOT visits may be conducted on the same day (ie, the visits will be 
combined, and all assessments listed in the Study Procedures and Assessments tables [Table 1 or 
Table 2] for the ET and EOT visits must be performed). Patients who discontinue study 
treatment should be encouraged to complete the remaining visits until completion of the study 
(ie, ET, EOT, and FU visits). 
5.5. 
Replacement of Patients  
Randomized patients will not be replaced. 
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5.6. 
Rescreening  
A patient who is screened but not randomized (eg, because the inclusion and exclusion criteria 
were not met or randomization did not occur within the specified time) may be considered for 
screening again if, for example, there is a change in the patient’s medical background or a 
modification of study inclusion and exclusion criteria. 
Patients may be rescreened only once and at the same investigational center. In case rescreening 
is considered, the investigator should contact the MM or the sponsor, in order to determine 
which parameters need to be retested for the rescreening (eg, some parameters may not need to 
be retested if the repeated values for the laboratory, vital sign, or ECG screening criteria are 
within acceptable limits as judged by the investigator and the sponsor/MM or if repeated values 
show normalization of the out-of-range values, but their initial screening period has expired). 
If the patient is rescreened, informed consent will need to be provided again according to the 
different requirements described in this protocol. 
5.7. 
Screening Failure  
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. Minimal information should be collected that 
includes but is not limited to demography, screening failure details, eligibility criteria, and any 
serious adverse events. 
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6. 
TREATMENTS  
6.1. 
Investigational Medicinal Products Used in the Study  
IMP is defined as the test IMP and matching placebo IMP to the test IMP. 
Refer to Table 6 for a description of the test IMP (TV-44749) and placebo IMP. 
The test IMP and placebo IMP are not authorized products. 
6.1.1. 
Test Investigational Medicinal Product  
 
 
 
 
 
 
 
 
 
 
 
 
Detailed preparation and administration instructions are provided in the pharmacy manual. 
Additional details may be found in the IB for TV-44749. 
6.1.1.1. 
Dosing Groups  
TV-44749 is administered at 3 doses in this study: low (318 mg q1m), medium (425 mg q1m), 
and high (531 mg q1m). 
Table 5: 
Conversion Between Oral Olanzapine and TV-44749 Doses  
Oral dose of olanzapine 
TV-44749 dose 
TV-44749 volume to be dosed 
 
 
 
 
 
 
 
 
 
6.1.1.2. 
Dose Adjustment  
Refer to Section 4.1 for a description of the dose adjustments that are permitted during Period 2. 
6.1.2. 
Placebo Investigational Medicinal Product  
 
 
 
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Detailed preparation and administration instructions are provided in the pharmacy manual. 
6.1.3. 
Other Components  
The kit for IMP and placebo IMP contains the following: 
 
 
 
 
 
 
 
 
Table 6: 
Investigational Medicinal Products Used in the Study  
IMP name 
Test IMP 
Placebo IMP 
Trade name and INN, if 
applicable, or company-assigned 
number 
TV-44749 
TV-44749 placebo 
Formulation 
 
 
 
 
 
 
Unit dose strength(s)/Dosage 
level(s) 
 
 
 
 
 
 
 
Route of administration 
sc injection (abdomen) 
sc injection (abdomen) 
Dosing instructions 
q1m injections per the patient’s 
assigned treatment group 
q1m injections per the patient’s 
assigned treatment group 
Packaging 
IMP will be provided in a blister 
tray in a carton box. 
IMP will be provided in a blister 
tray in a carton box. 
Manufacturer 
 
 
 
 
 
 
 
 
 
 
IMP=investigational medicinal product; INN=international nonproprietary name; q1m=once monthly; 
sc=subcutaneous. 
6.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products  
The test IMP is TV-44749 (olanzapine for extended-release injectable suspension) for sc use. 
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Details of the preparation of the drug product will be fully described in the pharmacy manual. 
6.2.1. 
Storage and Security  
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all IMPs received, and any discrepancies are reported and resolved before use of 
the IMPs. 
The IMPs (TV-44749 [olanzapine] powder and empty 10-mL clear glass vial [for placebo]) must 
be stored at a controlled temperature in a secure area. The site should have a process for 
monitoring the storage temperature for unused IMP. 
6.2.2. 
Labeling  
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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. 
6.2.3. 
Accountability  
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMP 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 
used in accordance with this protocol. 
Only patients randomized in the study may receive IMPs, and only authorized unblinded staff at 
the investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored area (automated monitoring, including alerts in case 
of deviations, is highly recommended) in accordance with the labeled storage conditions or 
appropriate instructions with access limited to the investigator and authorized staff at the 
investigational center. 
The investigator is responsible for IMP accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
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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. 
Further guidance and information are provided in the pharmacy manual. 
6.3. 
Justification for Investigational Medicinal Products  
6.3.1. 
Justification for Dose of Test Investigational Medicinal Product  
 
 
 
 
 
 
 
 
 
 
 
 
6.3.2. 
Justification for Use of Placebo Investigational Medicinal Product  
Based on the pre-Investigational New Drug meeting with the Food and Drug Administration 
(FDA) in 2019, the Agency recommended that the sponsor conduct a prospective, randomized, 
placebo-controlled study to assess the safety and efficacy of TV-44749, with a primary endpoint 
of symptom severity, as measured by PANSS, at 8 weeks. 
The use of a placebo control treatment group for comparison is acceptable and commonly used 
in clinical studies assessing efficacy in patients with schizophrenia (Nasser et al 2016, Potkin et 
al 2020). 
Several measures to ensure adequate treatment of patients assigned to the placebo group are 
included in the study protocol. Patients will be treated with placebo for a limited period 
(8 weeks). All patients will be hospitalized and closely monitored for at least 4 weeks following 
the first IMP administration (Table 1). Patients who fail to meet discharge criteria (RDQ) at this 
point may continue as inpatients until the end of Period 1 (week 8), at which point active 
treatment will be administered to all patients who meet Period 2 entry criteria. Throughout 
Period 1 (placebo-controlled period), rescue medications use will be allowed per investigator 
clinical judgment (Section 6.7.1.1). At all times, patients may be withdrawn from the study per 
investigator discretion if participation in the study no longer provides a potential clinical benefit 
to the patient or per patient’s request for any reason (Section 5.4). If a patient is withdrawn from 
the study at investigator discretion, patients will be advised to return to their primary physician 
for treatment continuation consideration. 
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6.4. 
Other Medicinal Products/Auxiliary Medicinal Products  
Oral olanzapine is an authorized auxiliary medicinal product and will be used in accordance with 
the terms of its marketing authorizations. 
Note that oral olanzapine (Table 7) is provided during the screening period (only to patients who 
have not previously received oral olanzapine) in order to assess tolerability; however, for the 
purposes of this study, it is not considered an IMP. 
Table 7: 
Other Medicinal Products Used in the Study  
Medicinal product name 
Olanzapine 
Pharmaceutical form 
Tablets 
Unit dose strength(s)/Dosage level(s) 
2.5, 5, 7.5, and 10 mg 
Route of administration 
Oral use 
Dosing instructions 
2 consecutive doses (10 mg/day or higher [but not 
exceeding 20 mg/day] per investigator decision) at an 
interval of 24 hours apart 
6.5. 
Treatment after the End of the Study  
No further treatment is planned by the sponsor after the patient completes his or her participation 
in this study. Patients will be advised to return to their primary physician for treatment 
continuation consideration. During the FU period (4 to 8 weeks after the last dose of IMP), 
patients may be treated for schizophrenia per the investigator’s judgment. 
6.6. 
Restrictions  
Patients will be required to comply with the following restrictions: 
6.6.1. 
Activity  
 
 
 
 
 
 
 
 
 
6.6.2. 
Fasting  
Patients must fast for at least 8 hours prior to baseline (visit 2; week 0), visit 11 (week 8), and the 
EOT visit (and preferably the ET visit). 
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6.6.3. 
Specific Food and Beverages  
Meals will be provided throughout the hospitalization period. Patients will be required to comply 
with the following additional restrictions:  
• It is recommended that patients do not consume alcohol and cannabis-derived 
products (such as marijuana) throughout the study, including the FU period. 
• It is recommended that patients avoid excessive consumption of coffee, tea, and/or 
caffeine-containing beverages or food (ie, 600 mg or more of caffeine per day or 5 or 
more cups of coffee per day) from before the first dose of IMP and throughout this 
study, including the FU period. 
6.6.4. 
Blood Donation  
Patients may not have donated or received any blood, plasma, or platelet transfusions within 
30 days prior to the study or have planned donations during the study period or 6 months 
following the last dose of IMP administration. 
6.6.5. 
Cigarette/Tobacco Use  
Patients who smoke cigarettes or use other tobacco-containing products should not change their 
smoking habits during the study. In case there is any change in smoking habits, the patient 
should inform the investigator. 
Patients’ smoking habits will be recorded in the CRF. Data on cigarette use will be collected 
using the question, “How many packs of cigarettes did you smoke over the past 7 days?” at the 
time points specified in Table 1 and Table 2. 
6.7. 
Prior and Concomitant Medication or Therapy  
Any prior or concomitant medication a patient has had within 30 days before IMP administration 
and up to the end of study, including FU, will be recorded on the CRF. Trade name and 
international nonproprietary name (if available), indication, dose, and start and end dates of the 
administered medication will be recorded. The sponsor will encode all medication according to 
the World Health Organization drug dictionary.  
The following medications will be prohibited during this study: 
• antipsychotics other than the study treatment 
• strong or moderate inhibitors of CYP1A2 within 14 days or 5 half-lives (whichever 
occurs last) prior to randomization 
• strong inducers of CYP1A2 within 30 days prior to randomization 
• dopamine reuptake inhibitors or prescription psychostimulants 
• opiates or opiate-containing analgesics within 14 days prior to randomization 
• In addition to those listed above, medications that may be expected to significantly 
interfere with the metabolism or excretion of olanzapine, may be associated with a 
significant drug interaction with olanzapine, or may pose a significant risk to patients’ 
participation in the study.  
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• Olanzapine (except when given according to the study protocol) 
Allowed medications in this study include rescue medications (Section 6.7.1.1), protocol-
approved antidepressants (including selective serotonin reuptake inhibitors [other than 
fluvoxamine], serotonin and norepinephrine reuptake inhibitors, and trazodone), and mood 
stabilizers (except carbamazepine) (Section 6.7.1.2), medications required for the treatment of 
any adverse events, and contraceptives as per Appendix E.  
Medications prescribed for the treatment of chronic medical conditions, other than antipsychotic 
medications, or for the treatment of acute medical conditions (such as antibiotics) may be 
permitted per investigator judgment. 
COVID-19 and seasonal flu vaccines will be allowed during the study. Other vaccinations may 
be allowed after consultation with the MM or sponsor. 
A partial list of additional disallowed medications is provided in Appendix G. In the event that a 
new concomitant medication not specified in this protocol is initiated by the patient, the 
investigator is encouraged to approach the MM or the sponsor to discuss. 
It is advised not to allow benzodiazepines and anticholinergics within 8 hours or 12 hours, 
respectively, of rating scales’ assessments.  
At each visit at the investigational center after the screening visit, the investigator will ask 
patients whether they have taken any medications (other than IMP[s]), including 
over-the-counter medications, vitamins, or herbal or nutritional supplements, since the previous 
visit, and whether any of the allowed concomitant medications have been used. 
Concomitant medication and non-pharmacological treatment will be recorded from screening 
through the final visit. 
6.7.1. 
Allowed Concomitant Medications  
6.7.1.1. 
Rescue Medications  
Allowed rescue medications will include zolpidem, zopiclone, zaleplon, or diphenhydramine for 
insomnia; benztropine, trihexyphenidyl, or diphenhydramine for parkinsonian symptoms; and 
propranolol and benzodiazepines for akathisia. 
In addition, during the screening period and in Period 1, use of lorazepam (up to 6 mg/day or up 
to the maximal daily dose allowed locally [the lower of the two]) is permitted on an as-needed 
basis for indications other than akathisia (eg, anxiety). Use in this context must be limited to no 
more than 72 consecutive hours, and lorazepam should not be taken within 8 hours prior to rating 
scale assessments. 
In Period 2, use of lorazepam (per local label approved dose) is permitted on an as-needed basis 
for indications other than akathisia (eg, anxiety).  
Antihistamine and anticholinergic drugs will be permitted during the study for agitation and 
insomnia. 
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6.7.1.2. 
Antidepressants and Mood Stabilizers  
Screening Period and Period 1: Patients who are currently treated with antidepressants and/or 
mood stabilizers for at least 3 months prior to screening and with no change in dose for at least 
4 weeks prior to screening (except for indications excluding the patient from entering the study, 
such as schizoaffective disorder) may continue their treatment during the screening period/Period 
1. No change of dose or new treatment initiation with such medications will be permitted in the 
screening period/Period 1. 
Period 2: During Period 2, patients who received mood stabilizers and protocol-approved 
antidepressants prior to study entrance for at least 3 months prior to screening and with no 
change in dose for at least 4 weeks prior to screening and continued their treatment during Period 
1 will be allowed to continue their treatment. New administrations of mood stabilizers will be not 
permitted; dose adjustments of mood stabilizers may be allowed on a case-by-case basis after 
discussion with the MM. 
Dose adjustment of protocol-approved antidepressants will be allowed in Period 2 according to 
the investigator’s clinical judgment. Patients who did not receive antidepressants previously will 
be allowed to initiate treatment with protocol-approved antidepressants (including selective 
serotonin reuptake inhibitors [other than fluvoxamine], serotonin and norepinephrine reuptake 
inhibitors, and trazodone) during Period 2 based on the investigator’s clinical judgment.  
The use of other antidepressants (such as tricyclic and tetracyclic antidepressants and bupropion) 
will be prohibited for the entire duration of the study. Investigators are encouraged to approach 
the MM or the sponsor prior to initiating any new antidepressant treatment. 
6.8. 
Procedures for Monitoring Patient Compliance  
The investigator will be responsible for monitoring patient compliance until completion of the 
IMP administration according to the protocol or discontinuation from the IMP. A check of 
compliance with IMP intake and completion of protocol-specified assessments and procedures 
will be performed during each visit after the IMP has been administered; IMP accountability 
records will be completed. 
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 
reeducated on compliance or should be withdrawn from the study. 
6.9. 
Randomization and Blinding  
Period 1: Patients will be randomized to receive 1 of 3 doses of TV-44749 (low [318 mg q1m], 
medium [425 mg q1m], or high dose [531 mg q1m]) sc injection or placebo sc injection in a 
1:1:1:1 ratio. Randomization will be stratified by sex (male or female) and geographical region 
(North America; Europe and Asia; Far East; and the rest of the world). The doses of TV-44749 
will be comparable to low, medium, and high dose of oral olanzapine (10, 15, and 20 mg, 
respectively). Patients randomized to TV-44749 or placebo sc will receive a sc injection of TV-
44749 or placebo, respectively, at baseline (randomization) and visit 7 (week 4). 
During Period 1, patients and investigators will remain blinded to the identity of the treatment 
administered to each patient. Due to the differences between TV-44749 and placebo, unblinded 
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study personnel, not associated with rating the patient and assessments of safety and independent 
of the study team, will be required at each site to reconstitute and administer the IMP.  
The sponsor and delegates involved in the study as well as the blinded site staff and the study 
participants will be blinded to the identity of the IMPs until the Period 1 database is locked for 
final efficacy analysis. Site staff and study participants unblinding may be done only after 
authorization is given by the sponsor. The sponsor (and/or delegates) will assign designated 
unblinded personnel who will be responsible to oversee unblinded activities performed at the site 
during Period 1. This includes but is not limited to unblinded monitoring at the site and 
supporting the unblinded site staff as required during Period 1. During Period 1, the sponsor’s 
(and delegates) unblinded personnel will not be involved with managing the study and will not 
take part in any discussions or decisions related to it. 
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via a Randomization and Trial Supply Management (RTSM) system. The 
generation of the randomization list and management of the RTSM system will be done by a 
qualified service provider. The specifications for randomization will be under the responsibility 
and oversight of Teva Global Statistics. 
Period 2: Period 2 will be open-label and will not include a placebo group. Period 1 will remain 
blinded to the Sponsor, the site staff, and the study participants until database lock for Period 1. 
In order to maintain the blind in Period 1, all patients will be randomized again between Period 1 
and Period 2. 
Patients will be randomized to receive 1 of 3 doses of TV-44749 sc injection (low [318 mg q1m], 
medium [425 mg q1m], or high dose [531 mg q1m]). After completing all visit 11 (week 8) 
scales and assessments, eligible patients who were on active treatment in Period 1 will retain 
their Period 1 treatment assignment, and eligible patients who were on placebo in Period 1 will 
be randomized to one of the active treatment groups in a 1:1:1 ratio. To maintain the blind in 
Period 1, this procedure will be performed as patients enter Period 2 via the randomization 
system. 
Revealing of the treatment assignment in Period 2 will be performed only after completion and 
reporting of the relevant study procedures related to assessment of efficacy and safety endpoints 
in Period 1 (Section 6.9.1), on a patient-by-patient basis. The revealing of the Period 2 treatment 
assignment will be performed after week 8 (visit 11) by the authorized site staff according to a 
process predefined in the relevant study plans, provided that all requirements stipulated in this 
process were met. Therefore, the dosing at week 8, although assigned to Period 2, will be 
handled in a blinded manner by all parties, similarly to the dosing in Period 1. The sites are 
encouraged to complete the revealing of the treatment assignment procedure before IMP 
administration in week 12 (visit 12). 
6.9.1. 
Procedures and Assessments to be Performed Before and After Randomization 
into Period 2 at Visit 11 (Week 8)  
Procedures and assessments that need to be performed prior to randomization into Period 2 at 
visit 11 (week 8) are as follows: 
• Clinical laboratory tests 
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• Thyroid tests 
• Physical examination 
• ECG 
• Vital signs 
• Urine β-HCG 
• PANSS 
• CGI-S 
• CGI-I 
• Abnormal Involuntary Movement Scale (AIMS)  
• Barnes Akathisia Rating Scale (BARS) 
• Simpson-Angus Scale (SAS) 
• C-SSRS 
• Personal and Social Performance Scale (PSP) 
• CDSS 
• Patient Global Impression-Improvement (PGI-I) 
• Blood samples for plasma concentration of IMP 
• Adverse event inquiry 
• Injection site findings and pain assessment of last injection 
• Inquiry regarding alcohol consumption/illicit drug use 
• Concomitant medication inquiry 
Procedures and assessments that need to be performed after randomization into Period 2 at 
visit 11 (week 8) are as follows: 
• IMP administration 
• Blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose 
Remaining procedures and assessments at visit 11 (week 8) may be performed either before or 
after randomization. 
6.9.2. 
Blinding Procedures  
The unblinded pharmacist/study team member at the investigational center who will prepare and 
administer the IMPs will know the IMP assignments for each patient. In addition, during 
Period 1, up to 2 other unblinded individuals from the investigational center will know the IMP 
assignments to serve as backup staff or to provide quality assurance and oversight in their 
preparation and administration, as necessary. These individuals will not be involved in the 
conduct of any study procedures and assessment of any adverse events and must not discuss any 
unblinding information with the blinded site staff. 
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Additional details about the IMP preparation and injection procedure (including measures to 
mitigate the risk of unblinding) can be found in the pharmacy manual. In order to avoid 
nonintentional unblinding, the dosing procedure described in the pharmacy manual (including 
masking measures such as covering the IMP syringe contents, etc) will remain unchanged 
throughout the study, although after week 8 IMP administration, the treatment in Period 2 
allocation will be revealed. 
6.9.3. 
Discontinuation of the Placebo Treatment Group  
After approximately 440 patients complete the week 8 visit, depending on the need for additional 
data on exposure or safety, the placebo treatment group will be discontinued and additional 
patients may be randomized to the study (ie, to Period 1) to the TV-44749 treatment groups only. 
The patients randomized to the study from that time point will not be included in the primary 
efficacy analyses, as there will be no concurrent placebo group. The sponsor will notify the sites 
and the IDMC once the placebo treatment group is discontinued, and new patients from that time 
point will sign an updated ICF reflecting the actual available treatment groups. 
Once all patients who were still ongoing in Period 1 at the time of the placebo group 
discontinuation will either complete or early terminate from Period 1, and are randomized into 
Period 2 (if applicable), randomization into Period 2 will no longer be performed, as at that 
point, all patients in Period 1 will be assigned to TV-44749 treatment groups and will continue 
their treatment assignment in Period 2 as well. 
Period 1 will remain blinded to the Sponsor, the site staff, and the study participants until 
database lock for efficacy, including for patients randomized after the discontinuation of the 
placebo treatment group as long as they are still in Period 1. After the data are locked for the 
purpose of the Period 1 efficacy analyses, the study may continue in an unblinded manner. 
Period 1 efficacy data collected from patients randomized after discontinuation of the placebo 
treatment group will not be included in the primary analysis. Therefore, revealing of Period 1 
treatment assignment (ie, since patients will be continuing their treatment assignment in 
Period 2) for patients who were randomized to the study after discontinuation of the placebo 
treatment group will not be considered unblinding. 
6.9.4. 
Treatment of Study Participants Following the Outcome of Primary Efficacy 
Analysis Availability  
Following the completion of the efficacy analysis for Period 1, the Sponsor will communicate 
the topline results regarding TV-44749 efficacy to the Investigators. Subsequently, based on 
these results and guided by clinical judgment, Investigators will determine the course of action 
for Period 2 participants under their care. This may involve deciding whether participants will 
continue their current TV-44749 dose, adjusting their dose, or terminating their study 
participation. This also includes the option that a patient may remain on their current dose even if 
the population-level results indicate that the treatment arm for that dose was found futile, 
provided that the patient is stable on this dose and would benefit from continuing on it according 
to the investigator’s assessment. The rationale for this approach is rooted in olanzapine's high 
variability, where an exposure deemed inadequate on a population level may still offer a positive 
risk-benefit ratio for individual patients with specific intrinsic and extrinsic characteristics 
affecting Olanzapine PK and patient's psychiatric stabilization and safety profile. Therefore, PI 
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discretion is advised when deciding on continued participation and potential dose adjustments. 
The possibility that one or more treatment arms may show initial failure in the topline efficacy 
analysis does not necessarily preclude its submission for regulatory approval. The totality of 
data, including secondary endpoints and sensitivity analyses, will be considered, taking into 
account the established efficacy of olanzapine. 
It is the responsibility of the Investigator to convey the study top-line efficacy results to study 
participants once these become available, including the Investigator's recommendation regarding 
a change in TV-44749 dose or continuation of existing dose, or Investigator's decision regarding 
early termination. The investigator is responsible to obtain informed consent to continue 
participation in the study in case the participants were assigned to the dose level found to be 
futile. Notification of positive results to study participants, as relevant, will not require re-
consent. 
6.10. 
Maintenance of Randomization and Blinding  
6.10.1. 
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 (ie, after the efficacy portion of the 
study is completed), after receiving unblinding request from a Teva statistician, the service 
provider will provide the unblinded IMP assignment according to the processes defined in the 
relevant Standard Operating Procedure (SOP). 
6.10.2. 
Blinding and Unblinding  
Pharmacokinetic sample analysis by the bioanalytical laboratory may be performed during the 
course of the study. The population pharmacokinetic model for TV-44749 may be updated with 
new pharmacokinetic data emerging from the ongoing study. Population pharmacokinetic and 
pharmacokinetic analyses are required for the monitoring of the patients and enable IDMC 
evaluation of patient’s safety-related issues. The process to ensure study integrity, maintenance 
of the double blind during Period 1, and the responsibilities of the relevant study personnel will 
be described in a pharmacokinetic analysis plan that will be approved prior to any data transfer, 
per the unblinded analyses group’s interim analysis SOP and other relevant SOPs. 
In addition, if a prioritized sample analysis is needed (ie, assessment of a pharmacokinetic 
sample for a potential PDSS event), relevant sponsor personnel may be unblinded during 
Period 1. Additional information will be provided in the separate predefined unblinded 
pharmacokinetic analyses plan.  
As prolactin levels are highly affected by olanzapine and reach steady state approximately 
8 weeks after treatment initiation (Yang et al 2018), in order to maintain the blind, prolactin level 
results obtained after first IMP administration and before visit 13 (8 weeks into Period 2) will not 
be available for review by the sponsor or the sites until Period 1 database lock. The IDMC will 
review the unblinded data periodically. 
For information about personnel who may be aware of IMP assignments, see Section 6.9. These 
individuals will not be involved in the conduct of any study procedures or assessment of any 
adverse events. 
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In cases when knowledge of the IMP assignment is needed to make treatment decisions during 
Period 1, the investigator may unblind the patient’s IMP assignment as deemed necessary, 
mainly in emergency situations. Individual randomization codes indicating the IMP assignment 
for each randomized patient will be available to the investigator(s) or pharmacist(s) at the 
investigational center via the RTSM, via internet. A back-up process will be available to the 
investigator in case of internet connection issues. 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 during Period 1. The patient’s 
IMP assignment should not be revealed to the sponsor (during Period 1). 
If a blind is broken during Period 1, 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 during Period 1 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 8.1.4), the Global Patient Safety and 
Pharmacovigilance (GPSP) 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 during Period 1, blinding will be 
maintained for the investigator and for other personnel involved in the conduct of the study and 
in the analysis and reporting of the data. 
6.10.3. 
Independent Data Monitoring Committee  
There will be an IDMC in this study. Details are given in Appendix A. 
6.11. 
Total Blood Volume  
The total blood volume for routine sampling to be collected for each patient in this study is 
approximately 257 mL (at maximum), not including the optional samples for pharmacogenetics 
and biomarkers.  
 
 
 
 
 
 
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7. 
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. 
7.1. 
Assessments of Efficacy  
7.1.1. 
Positive and Negative Syndrome Scale  
The PANSS is a 30-item scale used to evaluate positive and negative symptoms of schizophrenia 
(Kay et al 1987). The PANSS is used 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/trained rater at screening and all the time 
points specified in Table 1 and Table 2. 
In addition to the patient and the rater, the information used for PANSS assessment may be 
obtained from 3rd party sources, such as the caregiver and an informant. In such cases, the name 
of the person/s who had provided the information and their relation to the patient (ie, caregiver or 
informant) should be recorded in the source documents.  
7.1.2. 
Clinical Global Impression–Improvement  
The CGI-I scale permits a global evaluation of the patient’s overall improvement in symptoms. 
The CGI-I scale rates the patient’s improvement relative to his or her symptoms on a 7-point 
scale ranging from 1 (very much improved) to 7 (very much worse) (Guy 1976b). 
The CGI-I will be administered by the investigator/trained rater at time points specified in 
Table 1 and Table 2. The CGI-I during Periods 1 and 2 will be relative to the CGI-S score at the 
baseline visit (visit 2 in Period 1). 
7.1.3. 
Clinical Global Impression–Severity of Illness Scale  
The investigator/trained rater will complete the CGI-S at the time points specified in Table 1 and 
Table 2. The CGI-S allows the rater to assess the patient’s current severity of illness on a scale of 
1 to 7, where 1=normal/not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 
5=markedly ill, 6=severely ill, and 7=among the most extremely ill patients (Guy 1976b). 
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7.1.4. 
Patient Global Impression-Improvement  
The PGI-I scale is a 1-item patient-rated instrument that measures improvement of the patient’s 
disease; the patient rates the perceived change in his/her condition in response to therapy (see 
time points specified in Table 1 and Table 2). 
The patient is instructed to select a response option on a scale of 1 to 7, where 1=very much 
better, 2=much better, 3=a little better, 4=no change, 5=a little worse, 6=much worse, 7=very 
much worse (Steinert et al 2010). 
7.1.5. 
Personal and Social Performance Scale  
The PSP will be administered to patients 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. The score is based on the assessment of patient’s functioning in 4 categories: 
1) socially useful activities, including work and study; 2) personal and social relationships; 3) 
self-care; and 4) disturbing and aggressive behaviors. Higher scores represent better personal and 
social functioning, with ratings from 91 to 100 indicating more than adequate functioning, while 
scores under 30 indicate functioning so poor that intensive supervision is required. 
7.2. 
Other Assessment  
7.2.1. 
Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT)  
The SCID-5-CT 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 who is familiar 
with the DSM-5 classification and diagnostic criteria. 
The SCID-5-CT can be used to ensure that the major DSM-5 diagnoses are systematically 
evaluated and that all 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). 
7.2.2. 
Quality of Life Scales  
The quality of life scales used in this study will include the 2 measures described below. 
7.2.2.1. 
Schizophrenia Quality of Life Scale  
The Schizophrenia Quality of Life Scale (SQLS) Revision 4 (Martin and Allan 2007) will be 
administered at the time points specified in Table 1 and Table 2 and will be used to capture 
quality of life. The 33-item measure yields 3 subscale scores: psychosocial, motivation/energy, 
and symptoms/side effects (Wilkinson et al 2000). Higher scores on the scales indicate worse 
quality of life. 
7.2.2.2. 
  
 
 
 
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8. 
ASSESSMENT OF SAFETY  
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events (including serious adverse events, extrapyramidal symptoms, injection pain and other 
injection site findings [local tolerability]), vital signs (blood pressure, pulse and orthostatic 
changes, and temperature), body weight, laboratory tests, ECG, concomitant medication use, 
time to all-cause discontinuation, all-cause discontinuation rates and discontinuation rates due to 
adverse events (tolerability), and rating scales (including AIMS, BARS, SAS, C-SSRS, and 
CDSS). 
Adverse events are categorized by ICH guidelines. 
8.1. 
Adverse Events  
8.1.1. 
Definition of an Adverse Event  
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An adverse event can, therefore, be any unfavorable and unintended 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. 
Accordingly, an adverse event can include any of the following:  
• a new condition or the worsening of a pre-existing condition  
• intercurrent illnesses  
• physical injuries and the mechanism that caused the injury  
• events possibly related to concomitant medication  
• drug/drug interactions  
• events occurring during diagnostic procedures or during any washout phase of this 
study 
• laboratory or diagnostic test abnormalities 
(Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.) 
In Period 2, worsening of the schizophrenia will be assessed using PANSS, CGI-I, and CGI-S 
and should be recorded as an adverse event per investigator judgment.  
A relapse event will be classified as an adverse event if specifically assessed as such by the 
investigator. 
An adverse device effect is an adverse event related to the use of a medical device or a 
combination product. This includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, operation, or any malfunction of the 
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medical device, including any event resulting from user error or from intentional misuse of the 
medical device. This definition includes events related to the procedures involved. For users or 
other persons, this definition is restricted to events related to medical devices. 
8.1.2. 
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 FU period. Treatment-emergent adverse events are 
defined as adverse events that occurred after the first dose of IMP was administered through the 
end of the study. 
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 and protocol-defined adverse events of special interest 
(PDAESIs) for expedited reporting to GPSP, the serious adverse event and PDAESI form must 
be completed, and the serious adverse event and the PDAESI must be reported immediately 
(Section 8.1.6.1). The investigator does not need to actively monitor patients for new adverse 
events after the end of the study. 
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 or 
PDAESI for expedited reporting to GPSP, on the serious adverse event and PDAESI form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; until the patient is referred for continued care to a health care 
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 the IMP and the severity and seriousness of each 
adverse event, as judged by the investigator, must be recorded as described in Section 8.1.3, 
Section 8.1.4, and Section 8.1.5. 
The investigator should make an initial determination whether the adverse event may be related 
to a device deficiency. If the AE/SAE could be related to the device, per Appendix I, the details 
of the AE/SAE related to the device will be forwarded to the manufacturer/wholesaler of the 
device. Adverse device effects must be recorded on the source documentation and the CRF. 
Further details are given in the Safety Monitoring Plan. 
8.1.3. 
Severity of an Adverse Event  
The severity of each adverse event must be recorded as one of the following: 
Mild: 
No limitation of usual activities 
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Moderate: Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 
8.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product  
The relationship of an adverse event to the IMP and/or device is characterized as follows 
(Table 8): 
Table 8: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product and/or Device  
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 and/or device. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least two of the following 
apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the IMP and/or device. 
• 
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 and/or device. 
• 
It does not reappear or worsen when the IMP 
and/or device 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 
and/or device cannot be ruled out 
with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least two of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the IMP and/or device. 
• 
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 and/or device, yet an 
IMP and/or device relationship clearly exists. 
• 
It follows a known pattern of response to the IMP 
and/or device. 
IMP=investigational medicinal product. 
8.1.5. 
Serious Adverse Events  
For recording of a serious adverse event, the study period is defined for each patient as the time 
period from signature of the ICF to the end of the FU period. Serious adverse events occurring in 
a patient after the end of study should be reported to the sponsor if the investigator becomes 
aware of them, following the procedures described in Section 8.1.6.1. 
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8.1.5.1. 
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 a 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 was 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 one of the outcomes listed in this definition 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, liver injury that meets the criteria for Hy's law, 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 >3x the ULN 
• total bilirubin increase of >2x 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. 
A serious adverse device effect is an adverse device effect that results in any of the consequences 
characteristic of a serious adverse event and is reported per Section 8.1.6. 
8.1.5.2. 
Expectedness  
A serious adverse event that is not included in the adverse reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. 
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The RSI for this study is the RSI section of the IB for TV-44749 and the ZYPREXA SmPC 2022 
or ZYPREXA USPI 2021 for the oral olanzapine treatment (where applicable) during the 
screening period. 
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies. 
The sponsor’s GPSP will determine the expectedness for all serious adverse events. 
8.1.6. 
Reporting a Serious Adverse Event  
8.1.6.1. 
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 new adverse events once this study has ended. 
Serious adverse events occurring after the patient has ended the study 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 (as 
applicable, for example, a contract research organization [CRO] in a country without a sponsor 
LSO); the LSO will forward the report to the sponsor’s GPSP. 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility) 
Additional information includes the following: 
• 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 
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• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event  
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death 
− cause of death (whether or not the death was related to IMP) 
− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report. 
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences form/MedWatch/Extensible Markup Language file to the LSO/CRO for 
submission to the competent authorities, Independent Ethics Committee (IEC)/Institutional 
Review Boards (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. Therefore, in case 
of a SUSAR during Period 1, only the LSO/CRO unblinded personnel will receive the unblinded 
report for regulatory submission; the others will receive a blinded report. 
8.1.6.2. 
Sponsor Responsibility  
If a serious unexpected adverse event is believed to be related to the IMP (ie, SUSAR), the 
sponsor will take appropriate steps to notify all investigators participating in sponsored clinical 
studies of the IMP and the appropriate competent authorities (and IEC/IRB, as appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following: 
• modifying the protocol and/or ICF 
• discontinuing or suspending the study 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to the IMP 
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8.1.7. 
Protocol-Defined Adverse Events of Special Interest  
8.1.7.1. 
Protocol-Defined Adverse Events of Special Interest that Require Reporting to 
the Sponsor’s Global Patient Safety and Pharmacovigilance  
 
 
 
 
 
 
 
 
8.1.7.2. 
Protocol-Defined Adverse Events of Special Interest that Do Not Require 
Reporting to the Sponsor’s Global Patient Safety and Pharmacovigilance  
 
  
 
 
 
 
8.1.8. 
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. 
8.2. 
Pregnancy  
Any female patient becoming pregnant during the study will discontinue IMP and will be 
discontinued from the study. 
All pregnancies of women participating in the study and female partners of men participating in 
the study that occur during the study or within 6 months after the last dose administration are to 
be reported immediately to the physician 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 (note that the pregnancy itself is not considered an adverse 
event). The process for reporting a pregnancy is the same as that for reporting a serious adverse 
event but using the pregnancy form (Section 8.1.6). 
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided that no protocol-related procedures were applied. 
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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 this IMP has suspected reproductive toxicity, 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, one of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
8.3. 
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 
in the patients’ source documents, regardless of whether or not an adverse event occurs as a 
result. When meeting important protocol deviation criteria (Appendix C), all instances of 
incorrect IMP administration should be categorized as “Noncompliance to IMP.” 
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 
protocol. Clinical judgment should always be applied. Any dose of IMP (whether the test 
IMP or placebo IMP), whether taken intentionally or unintentionally, in excess of that 
prescribed must be immediately reported to the sponsor (in a blinded manner during 
Period 1). 
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3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
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 that occur in infants following exposure to a 
medicinal product from breast milk. 
8.4. 
Clinical Laboratory Tests  
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
A laboratory test result that is assessed by the investigator as clinically significant will be 
recorded both on the source documentation and the CRF as an adverse event and monitored as 
described in Section 8.1.2. An event may include a laboratory or diagnostic test abnormality 
(once confirmed by repeated testing) that results in the withdrawal of the patient from the study, 
the withdrawal of IMP or medical treatment, or further diagnostic work-up. (Note: Abnormal 
laboratory or diagnostic test results at the screening visit that preclude a patient from entering the 
study or receiving IMP are not considered adverse events.) 
Clinical Laboratory Tests During Screening 
During screening, the site should collect and ship the screening blood samples as soon as 
possible (preferably on the first day of the screening period). In case the site faces a delay in 
obtaining the central laboratory results for the clinical laboratory tests performed during 
screening that are needed to determine eligibility, additional screening blood samples 
(specifically those with delayed results) may be collected as soon as possible and analyzed in a 
local laboratory to allow study eligibility determination within the 8-day screening window. For 
sites that are at high risk of encountering such delays (eg, a country or a region with long 
shipment durations and/or long turnaround time for receiving the central laboratory results, or 
sites that already experienced several incidents of delayed results during the study), additional 
screening blood samples for local laboratory analysis may be collected in advance at the same 
time when collecting the samples for the central laboratory analysis, provided that the site has the 
required capabilities for local analysis (consideration should be made to the specific samples that 
tend to have delayed results, and efforts should be made to only collect those samples twice). 
The sites’ level of risk should be determined by the sponsor or the CRO and will be 
communicated to the site.  
In case of a discrepancy between local and central laboratory results, the central laboratory 
results will determine the patient’s study eligibility. Specifically: 
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• In case both central and local laboratory results are available within the screening 
window, the central laboratory results will be used to determine eligibility. 
• In case only local laboratory results are available within the screening window and 
they indicate that the patient is eligible for randomization, the patient may be 
randomized (provided all other study criteria are met). When central laboratory 
results become available (after randomization), the patient’s eligibility should be 
confirmed. In case the central laboratory results indicate that the patients does not 
meet study eligibility criteria, the patient will be early terminated. 
• If only local laboratory results are available within the screening window and they 
exclude the patient from randomization (ie, the patient is a screening failure), but the 
central laboratory results later become available and confirm that the patient is 
eligible, the patient may be rescreened if all other study criteria are met.  
• In the less likely event that the central laboratory results are available during the 
screening window and the patient is randomized based on these results, but the local 
laboratory results become available after randomization and indicate that the patient 
does not meet eligibility criteria, the central laboratory results will determine the 
patient’s eligibility, and the patient may continue in the study per the investigator’s 
discretion.  
Any local laboratory results of blood samples collected for screening purposes, including any of 
the above scenarios, should be reported in the CRF. 
Clinical Laboratory Tests During Visit 3 
In cases where performing toxicological blood test is not feasible due to a lack of suitable 
analytical facilities, a urine drug screen may be performed instead. In case visit 3 safety 
laboratory blood samples cannot be shipped to the central laboratory on the same day, the 
samples may be processed in the local clinical laboratory instead. If needed, an additional set of 
safety laboratory tests may be collected for that purpose. In case visit 3 occurs over the weekend 
and the local safety laboratory tests cannot be processed on the collection day, visit 3 safety 
laboratory samples will be collected up to 2 days after the visit 3 nominal date and sent to the 
central laboratory. 
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Table 9: 
Clinical Laboratory Tests  
Serum chemistry 
Hematology and coagulation 
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatininea  
Glucose 
BUN 
Total cholesterol 
LDL 
HDL 
Triglycerides 
Urate 
ALT 
AST 
LDH 
GGT 
Alkaline phosphatase 
Creatine kinase 
Bicarbonate 
Protein 
Albumin 
Bilirubin 
Direct bilirubin 
Prolactinb  
Hematology 
Hemoglobin 
Hemoglobin A1Cc  
Hematocrit 
Erythrocytes 
Platelets 
Leucocytes 
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
Coagulationd  
PT 
INR 
Protein 
Glucose 
Ketones 
Hemoglobin 
pH 
Specific gravity 
Microscopic tests 
Bacteria 
Erythrocytes 
Leucocytes 
Crystals 
Casts 
a Glomerular filtration rate (to be calculated at screening only) will be calculated based on serum creatinine levels, 
weight, gender, and age using the Cockcroft-Gault equation. 
b At screening (prior to intake of oral olanzapine, where relevant), baseline (visit 2; week 0 [prior to IMP 
administration]), visit 11 (week 8 [prior to IMP administration]), visit 14 (week 20 [prior to IMP administration]), 
and at the EOT visit, clinical laboratory tests will also include prolactin. 
c At baseline (visit 2; week 0), visit 11 (week 8), visit 14 (week 20), visit 17 (week 32), visit 20 (week 44), and at 
the EOT visit, clinical laboratory tests will also include hemoglobin A1C. 
d At screening only. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; EOT=end-of-
treatment; ET=early termination; GGT=gamma-glutamyl transpeptidase; HDL=high-density lipoprotein; 
IMP=investigational medicinal product; INR=international normalized ratio; LDH=lactate dehydrogenase; 
LDL=low-density lipoprotein; PT=prothrombin time. 
8.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis  
Clinical laboratory tests (serum chemistry, hematology and coagulation, urinalysis) will be 
performed at the time points detailed in Table 1 and Table 2. They may also be performed at any 
other time if clinically indicated. Clinical laboratory tests will be performed using the central 
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laboratory (refer to Section 8.4 for exceptions during the screening period). Specific laboratory 
tests to be performed are provided in Table 9. 
8.4.2. 
Other Clinical Laboratory Tests  
At screening, patients will be tested for HIV, hepatitis B surface antigen, and hepatitis C 
antibody. At screening, visit 11, and ET and EOT visits, patients will be test for thyroid 
stimulating hormone, triiodothyronine, and thyroxine. 
8.4.2.1. 
Human Chorionic Gonadotropin and Follicle-Stimulating Hormone Tests  
A serum β-HCG test will be performed for all women of childbearing potential at screening and 
the FU visit (see Table 1 and Table 2). Urine β-HCG (dipstick) test will be performed for women 
of childbearing potential at all visits where study drug is administered (prior to study drug 
administration) and at the ET and EOT visits. A negative result must be obtained prior to study 
drug administration (if a borderline result is obtained on a urine test, a serum test should be 
performed and a negative result obtained prior to IMP administration). 
Postmenopausal women (no menses for at least 12 months [without an alternative medical cause] 
prior to screening and with follicle-stimulating hormone (FSH) concentration above 35 U/L) may 
be allowed not to use contraceptives during the study. An FSH test will be performed at the 
screening visit for any female who has been without menses for at least 12 months prior to 
screening to confirm postmenopausal status. 
8.4.2.2. 
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 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 is not exclusionary. 
Patients’ eligibility in such case of positive result, without medical explanation, will be 
determined by the investigator based on the patient’s background, history of substance use, and 
the investigator’s discussions with family members, caregivers, or healthcare professionals, as 
applicable. The patients should be advised that use of these substances should be avoided during 
the study. 
8.4.2.3. 
Prolactin  
Blood samples will be obtained for prolactin test at the time points specified in Table 1 and 
Table 2 (at screening [prior to intake of oral olanzapine, where relevant], baseline [visit 2; 
week 0 (prior to IMP administration)], visit 11 [week 8 (prior to IMP administration)], visit 14 
[week 20 (prior to IMP administration)], and at the EOT visit). As prolactin levels are highly 
affected by olanzapine and reach steady state approximately 8 weeks after treatment initiation 
(Yang et al 2018), in order to maintain the blind, prolactin level results obtained after first IMP 
administration and before visit 13 (8 weeks into Period 2) will not be available for review by the 
sponsor or the sites until Period 1 database lock. The IDMC will review the unblinded data 
periodically. 
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8.5. 
Physical Examinations  
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. Full physical examination 
will be conducted at the screening visit and unscheduled visits only; the rest of the visits will 
include an abbreviated physical examination (including weight). The full physical examination 
will consist of examining the following body systems: cardiovascular, respiratory, abdominal, 
skin, neurological, and musculoskeletal systems. The physical examination will also include 
examination of general appearance, including head, eyes, ears, nose, and throat; chest; abdomen; 
skin; lymph nodes; and extremities. An abbreviated physical examination (general appearance, 
head, eyes, ears, nose, throat, lung, heart, skin, and extremities) will be conducted at the other 
time points and will include a brief neurological examination that includes examination of a 
subset of cranial nerves controlling vision and motor examination of a subset of larger muscle 
groups, including an assessment of muscle tone, reflexes, gait, and involuntary movements.  
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 8.1.2. 
8.6. 
Vital Signs  
Vital signs (blood pressure [systolic/diastolic], pulse and orthostatic changes, respiratory rate, 
and temperature) should be measured at each in-clinic visit pre-injection.  
 
 Vital 
signs should also be measured in the event of an injection site pus-containing lesion (abscess, 
infection, or inflammation), ulceration, or necrosis (Table 1 and Table 2). All vital signs results 
outside of the reference ranges will be judged by the investigator as belonging to one of the 
following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
Before blood pressure and pulse are measured, the patient must rest in a supine or semi-erect 
position for at least 5 minutes; measurements should be taken again after standing for 
approximately 2 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 assessed by the investigator as clinically 
significant will be recorded both on the source documentation and the CRF as an adverse event, 
and monitored as described in Section 8.1.2. 
8.7. 
Electrocardiography  
A 12-lead ECG will be recorded at the time points detailed in Table 1 and Table 2. At screening 
and baseline, measurements will be done in triplicate (approximately 5 minutes apart). Single 
measurements will be performed at all other in-clinic visits where ECG recordings are taken. All 
ECG recordings should be sent to the central diagnostic center at screening, baseline, and 
throughout the study. A qualified physician at a central diagnostic center will interpret the ECG. 
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Patients’ eligibility at screening may be determined based on the investigator or designee ECG 
interpretation. 
In case only local ECGs interpretations are available within the screening period and they 
indicate that the patient is eligible for randomization, the patient may be randomized (provided 
all other study eligibility criteria are met). When central diagnostic ECG interpretation becomes 
available (after randomization), the patient’s eligibility should be re-confirmed. In case the 
central diagnostic interpretation suggest that the patient does not meet study eligibility criteria, it 
is recommended to repeat the ECG and consult the MM. 
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories: 
• abnormal and not clinically significant  
• abnormal and clinically significant 
Any ECG finding that is assessed 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 8.1.2. 
8.8. 
Assessment of Local Tolerability and Pain  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 10: 
Assessment of Local Tolerability (Injection Site Findings and Pain)  
Test 
Response 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.8.1. 
Procedures for Injection Site Pus-Containing Lesion (Abscess, Infection, or 
Inflammation), Ulceration, Necrosis, or Atrophy  
 
  
 
 
 
  
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8.9. 
Assessment of Suicidality  
The C-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior (Posner et al 2011). The C-SSRS Baseline/Screening version will be administered by a 
qualified HCP (ie, the investigator or a qualified person designated by the investigator) at 
screening, and the C-SSRS Since Last Visit version will be completed at all other time points, as 
described in Table 1 and Table 2. Following any positive finding on the C-SSRS Since Last Visit 
version, the patient must be evaluated by the Principal Investigator or a patient's mental health 
practitioner designated by the investigator, which may result in the patient’s withdrawal from the 
study. Recording of positive findings as adverse events will be per investigator decision. 
8.10. 
Post-injection Delirium/Sedation Syndrome Monitoring  
 
 
  
 
 
 
 
 
 
 
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8.11. 
Other Safety Assessments  
8.11.1. 
Abnormal Involuntary Movement Scale  
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 
1976a). The AIMS is a 14-item scale that includes assessments of orofacial movements, 
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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.  
8.11.2. 
Barnes Akathisia Rating Scale  
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 score ranging from 0 to 9. The BARS also includes a global clinical 
assessment of severity scored on a scale of 0 to 5. Higher scores are indicative of greater severity 
of akathisia. 
8.11.3. 
Simpson-Angus Scale  
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. 
8.11.4. 
Calgary Depression Scale for Schizophrenia  
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 
extrapyramidal symptoms 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). 
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9. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/BIOMARKERS/ 
PHARMACOGENETICS  
9.1. 
Pharmacokinetic Assessment  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Blood volumes are provided in the ICF and laboratory manual. Details on sample handling, 
storage, shipment, and analysis are provided in the laboratory manual. 
9.2. 
Pharmacodynamic Assessment  
 
 
 
 
9.3. 
Assessment of Exploratory Biomarkers  
 
 
 
 
 
 
 
 
 
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9.4. 
Pharmacogenetics  
 
 
 
 
 
For information regarding pharmacogenetic assessments, see Appendix H. 
9.5. 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
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10. 
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 and unblinding of Period 1, any 
additional analyses or changes to analyses that may be required will be fully disclosed in the 
clinical study report (CSR). In the event of any contradiction between the study protocol and the 
statistical analysis plan, the statistical analysis plan will prevail. 
The primary endpoint is change from baseline to week 8 in the PANSS total score. The sample 
size is designed to detect with 
 probability a standardized mean difference of 
 (eg, an 
improvement of at least 
 points in the PANSS total score, assuming a standard deviation of 
 points). The 3 primary efficacy hypotheses will be tested with an overall type I error of 
0.05, controlled using truncated Hochberg adjustment for multiplicity. 
10.1. 
Sample Size and Power Considerations  
The following assumptions are made for the sample size determination: 
1. Standardized mean difference of 
 
2. Homogenous variance 
3. Overall 2-sided alpha of 0.05 
4. Power of 
 
5. Randomization ratio of 1:1:1:1 
6. Truncated Hochberg adjustment for multiplicity 
For the sample size calculation, a 2-sample t-test and a 
 correction (ie, 2-sided alpha 
of 
) were used, which yielded a conservative sample size. A simulation study with the 
above assumptions was conducted to evaluate the power using mixed-model repeated measures 
(MMRM) with truncated Hochberg as a multiplicity control method; the power to demonstrate 
statistically significant superiority in the 3 active treatment groups versus placebo for the primary 
endpoint was about 
. 
Approximately 440 patients completing week 8 are needed to achieve the above power, per a 
comparison. Despite the fact that missing data after discontinuation will be imputed, for 
simplicity, it is assumed that the ET rate in Period 1 will be 
, and the overall sample size is 
adjusted for that; hence, the number of patients to be randomized is approximately 640. 
Once 440 patients complete week 8 in Period 1, randomization to placebo may be stopped, and 
new patients will then be randomized to the active treatment groups only (Section 6.9.3). The 
efficacy analysis will include all patients randomized until the time point at which randomization 
to placebo was stopped. Patients randomized after the randomization to placebo group was 
stopped will not be included in the efficacy analyses. 
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10.2. 
Analysis Sets  
10.2.1. 
Full Analysis Set  
The full analysis set will include all patients randomized to Period 1 regardless of the actual 
treatment the patients received. 
 
 
10.2.2. 
Efficacy Analysis Set  
The efficacy analysis set will include all patients randomized to Period 1 while patients are 
randomized to 1 of the 3 TV-44749 doses or placebo, regardless of the actual treatment the 
patients received.  
Patients randomized after randomization to the placebo group is stopped (Section 10.1) will not 
be included in the efficacy analysis set. 
This analysis set will be used for the primary efficacy estimand. 
10.2.3. 
Safety Analysis Set  
To address the safety objective by the safety estimand, the safety analysis set will include all 
randomized patients who received at least 1 dose of TV-44749 olanzapine or placebo. 
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. 
In cases of dosing error, treatment assignment of these patients will be decided in a blinded 
manner prior to unblinding of Period 1 and will be documented in the study data review 
document. 
10.2.4. 
Pharmacokinetic Analysis Set  
The pharmacokinetic analysis set will include those patients from the safety analysis set who 
have ≥1 plasma concentration measured. 
10.3. 
Data Handling Conventions  
Detailed data imputation rules will be described in the statistical analysis plan. 
10.3.1. 
Handling Withdrawals and Missing Data  
 
 
 
10.4. 
Study Population  
The full analysis set (Section 10.2.1) will be used for all study population summaries, unless 
otherwise specified. Summaries will be presented by treatment group and study period for all 
patients. 
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10.4.1. 
Patient Disposition  
Data from patients screened, patients screened but not randomized and reason for not 
randomized, patients who are randomized (full analysis set), patients randomized but not treated 
and reason, randomized and dosed (safety analysis set), and all other analysis sets, patients who 
complete the study, and patients who either discontinue IMP or withdraw from the study, will be 
summarized using descriptive statistics. Data from patients who discontinue IMP or withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics. 
10.4.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics, including medical history, prior medications 
and therapies, and ECG findings, will be summarized using descriptive statistics by full analysis 
set and safety analysis set. 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. 
10.5. 
Efficacy Analysis  
10.5.1. 
Primary Estimand  
Refer to Section 3.2.1 for a description of the primary estimand. 
10.5.2. 
Primary Endpoint  
The primary efficacy endpoint is the change from baseline to week 8 in the PANSS total score. 
10.5.3. 
Other Estimands  
Refer to Section 3.2.2 for a description of the other efficacy estimand. 
Refer to Section 3.2.3 for a description of the safety and tolerability estimand. 
10.5.4. 
Secondary Endpoints  
Secondary endpoints are listed in Section 3.1. 
10.5.5. 
Exploratory Endpoints  
Exploratory endpoints are listed in Section 3.3. 
10.5.6. 
Planned Method of Analysis  
The efficacy analysis set (Section 10.2.1) will be used for all efficacy analyses. Summaries will 
be presented by treatment group and study period, but only data from Period 1 will be considered 
for efficacy purposes. 
10.5.6.1. Primary Efficacy Analysis  
The efficacy analysis will employ multiple imputation, MMRM, and Rubin’s rule. 
1. One hundred completed datasets will be imputed using multiple imputation.  
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a. For ICEs of a use of prohibited antipsychotic medication or early discontinuation due 
to insufficient clinical response, imputations will be done assuming MNAR in order 
to estimate what would have happened if patients who discontinued early had 
remained in the study on placebo treatment.  
b. For ICEs of early discontinuation due to a reason that is not lack of efficacy or death, 
a multiple imputation assuming that the clinical effect in these patients is similar to 
those not experiencing ICE during the study (ie. assuming MAR) will be employed.  
Full details of the methods employed for the 2 types of ICEs and underlining 
assumptions will be detailed in the statistical analysis plan. 
2. MMRM on change from baseline to week 8: least squares means of change from baseline 
to week 8, for each of the 4 treatment arms and for the differences between each of the 
TV-44749 arms to placebo, 95% confidence interval, and p-values will be calculated 
using MMRM analysis for each complete dataset. The model will include treatment arm, 
study visit, treatment-visit interaction, stratification variables, and PANSS total score at 
baseline as covariates. Unless otherwise specified, unstructured covariance matrix will be 
used as a covariance matrix. Further details about the analysis will be presented in the 
statistical analysis plan. 
3. Summary statistics for the primary efficacy endpoint will be based on Rubin’s rule 
summary of least squares means of change from baseline to week 8, for each of the 
4 treatment arms and for the differences between each of the TV-44749 arms to placebo, 
95% confidence interval, and p-values. The Rubin’s-derived p-values that will be 
adjusted according to truncated Hochberg method (Section 10.6) will be used for the 
primary efficacy analysis. 
10.5.6.2. Sensitivity Analysis  
 
 
 
 
 
 
10.5.6.3. Supplementary Analysis  
The primary and key secondary endpoints will be repeated using treatment policy estimand (ie, 
intention to treat). The treatment policy estimand will be defined as: 
a. Treatment: The treatment of low, medium, or high dose of TV-44749 compared to 
placebo, separately, will be evaluated according to the randomization assignment at 
Period 1. 
b. Population: All randomized adult patients who have a confirmed diagnosis of 
schizophrenia, present with acute exacerbation of disease, and are eligible for 
olanzapine treatment. 
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c. Endpoint: Change from baseline to week 8 in the PANSS total score, regardless of 
the ICEs patients experienced during Period 1. 
d. Population-level summary: Least squares means of the difference in the change 
from baseline to week 8 between treatment groups according to the randomization 
assignment, regardless of the treatment actually received. 
Assuming that missing data generated in the study, such as ET, follow the MAR assumption, this 
analysis complies with estimation of the mean treatment effect comprised with the intention to 
treat principle. 
10.5.6.4. Key Secondary Efficacy Analysis  
 
 
10.5.6.5. Secondary Efficacy Analysis  
 
 
 
10.5.6.6. Other Efficacy Analysis  
 
 
10.6. 
Multiple Comparisons and Multiplicity  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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10.7. 
Safety Analysis  
Safety analyses will follow the safety estimand approach using the safety analysis set. 
The safety analysis will be by period with the respective randomization (for Period 1, 
randomization to Period 1 and for Period 2, randomization to Period 2). In addition, a safety 
analysis of the 2 periods together may be conducted; in this analysis, placebo patients in Period 1 
will be counted as placebo, and after the randomization to Period 2, they will be assigned the 
actual dose in Period 2. 
In case of dose adjustment, the patient may be regarded according to the randomized dose until 
the day of the dose adjustment, and from the first administration of the adjusted dose, the patient 
will be regarded according to the adjusted dose. 
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), 
adverse events related to test IMP and/or device (ie, reasonable possibility defined by the 
investigator as related or with missing relationship) (overall and by severity), serious adverse 
events, serious adverse device events, and adverse events and adverse device events causing 
withdrawal from the study. Summaries will be presented by treatment group and for all patients. 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented. 
Changes in laboratory, ECG, and vital sign measurements 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. 
For continuous variables, descriptive statistics (number [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. 
Descriptive summaries of serious adverse events, ISRs, patient withdrawals due to adverse 
events, and potentially clinically significant abnormal values (clinical laboratory or vital signs) 
based on predefined criteria will also 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. 
10.8. 
Tolerability Analysis  
 
 
 
 
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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. 
Tolerability analyses will be performed on the safety analysis set by treatment group and period. 
10.9. 
Pharmacokinetic, Population Pharmacokinetic, Pharmacodynamic, 
and Pharmacokinetic/Pharmacodynamic Analysis  
Plasma concentrations will be tabulated at each planned sampling time point by treatment group. 
In addition, the pharmacokinetics of TV-44749 will be evaluated using a population 
pharmacokinetics approach. 
 
 
 
Importantly, independent pharmacokinetic and population-based modeling analysis will take 
place during the study conduct, while maintaining the blind during Period 1, as will be described 
in the separate predefined unblinded pharmacokinetic analyses plan. Pharmacodynamic data 
from Period 1 will not be shared before database lock and unblinding for the efficacy analysis. 
 
 
 
 
  
The population pharmacokinetic/pharmacodynamic analysis of relevant pharmacodynamic 
variables and/or exposure-response analysis of relevant efficacy or safety endpoints may be 
performed and reported in a separate pharmacometrics report. 
Samples collected at 2.5 to 3 hours post IMP administration will not be analyzed routinely during 
the study but rather only in the event of potential PDSS that will be evaluated by the IDMC.  
10.10. 
Biomarker and Pharmacogenetic Analysis  
 
 
 
 
 
 
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10.11. 
  
 
 
 
 
10.12. 
Planned Interim Analysis  
Interim safety and efficacy data will be analyzed and reviewed periodically by an IDMC. Interim 
analyses will be performed by an unblinded analyses group independent of the sponsor (eg, 
unblinded statistician). The sponsor will remain blinded to the results of the interim analyses. 
Based on these reviews, the IDMC can make recommendations on study conduct including study 
termination. After at least 50% of patients complete Period 1, conditional power may be 
provided to the IDMC as part of the interim reviews. Full details of the approach will be depicted 
in the IDMC charter and the statistical analysis plan. 
10.13. 
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. In any case of contradiction between the protocol and the statistical analysis plan, 
the latter will prevail. 
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11. 
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. 
Refer to Appendix I for the definition of a clinical product complaint or device deficiency and 
investigator responsibilities in the management of a clinical product complaint or device 
deficiency. 
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12. 
COMPLIANCE STATEMENT  
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6 (R2), 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, 
Regulation (EU) No 536/2014 [Clinical Trial Regulation, as applicable], regulations and 
administrative provisions of the Member States relating to the implementation of GCP in the 
conduct of clinical trials on medicinal products for human use). Any episode of noncompliance 
will be documented. 
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities 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 prescribing information. 
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, the IEC/IRB, and competent authorities. 
See Appendix D for the ethics expectations of informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study. 
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13. 
DATA MANAGEMENT AND RECORD-KEEPING  
See Appendix J 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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14. 
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, for example, 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. 
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15. 
PUBLICATION POLICY  
See Appendix K for information regarding the publication policy. 
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First MB, Williams JBW, Karg RS, Spitzer RL. Structured Clinical Interview for DSM-5 
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Guy W. ECDEU Assessment Manual for Psychopharmacology (revised). Rockville (Maryland): 
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Martin CR, Allan R. Factor structure of the Schizophrenia Quality of Life Scale Revision 4 
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Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine 
long-acting injection, II: investigations of mechanism. BMC Psychiatry 2010;10:45. 
Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
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Nasser AF, Henderson DC, Fava M, Fudala PJ, Twumasi-Ankrah P, Kouassi A, et al. Efficacy, 
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schizophrenia: an 8-week, randomized, double-blind, placebo-controlled, multicenter Phase 3 
study. J Clin Psychopharmacol 2016;36(2):130-40. 
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Perkovic MN, Erjavec GN, Strac DS, Uzun S, Kozumplik O, Pivac N. Theranostic biomarkers 
for schizophrenia. Int J Mol Sci 2017;18(4):733. 
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. 
Potkin SG, Gharabawi GM, Greenspan AJ, Rupnow MF, Kosik-Gonzalez C, Remington G, et al. 
Psychometric evaluation of the readiness for discharge questionnaire. Schizophr Res 
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Potkin SG, Kunovac J, Silverman BL, Simmons A, Jiang Y, DiPetrillo L, et al. Efficacy and 
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Rainer MK. Risperidone long-acting injection: a review of its long term safety and efficacy. 
Neuropsychiatr Dis Treat 2008;4(5):919-27. 
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
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Steinert T, Eisele F, Längle G, Albani C, Flammer E, Borbé R. [PGI-I (patient's global 
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Stefan M, Travis M, Murray R. An atlas of schizophrenia. New York: The Parthenon Publishing 
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attitudes to depot antipsychotic medication. Br J Psychiatry 2001;179:300-7. 
Wilkinson G, Hesdon B, Wild D, Cookson R, Farina C, Sharma V, et al. Self-report quality of 
life measure for people with schizophrenia: the SQLS. Br J Psychiatry 2000;177:42-6. 
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales; J Clin Nurs 
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ZYPADHERA (olanzapine pamoate monohydrate) 210 mg, 300 mg, 405 mg powder and solvent 
for prolonged release suspension for injection. Summary of Product Characteristics. Eli Lilly 
Nederland B.V., 2022. 
ZYPREXA (olanzapine) Tablet for Oral use; ZYPREXA ZYDIS (olanzapine) Tablet, Orally 
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APPENDIX A. 
INDEPENDENT DATA MONITORING COMMITTEE  
During the conduct of this study, an Independent Data Monitoring Committee (IDMC) will 
review accumulated unblinded safety, pharmacokinetic, and efficacy data on a regular basis, as 
detailed in the IDMC charter, to evaluate the safety of the product for the purpose of ensuring the 
continuing safety of the study patients and overseeing study conduct issues, as applicable. 
The IDMC will be composed of independent physicians with expertise in the relevant therapeutic 
area and other relevant experts, such as a statistician and a pharmacokinetic expert. The IDMC 
will receive safety data periodically in an unblinded fashion. They will have the right to 
recommend termination of the study for safety reasons. 
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. 
Further details are given in the IDMC charter. 
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT  
1. Procedures for Screening/Visit 1 (Day -8, Weeks -2 to -1) 
The screening visit (visit 1) will take place not more than 8 days before the baseline visit 
(visit 2).  
Note: In the event that a patient meets all study inclusion criteria and does not meet any of 
the study exclusion criteria, but results of screening blood and urine samples taken within the 
8-day screening period are not available by day 8 of screening, the screening period may be 
extended by 2 days (until day 10 of screening) to allow the receipt of the results to confirm 
patients’ eligibility. In case results are not available by day 10, the patient will be considered 
a screening failure and may be considered for rescreening. In addition, the screening period 
may be extended by 2 days (until day 10 of screening) in exceptional cases, due to special 
conditions (eg, extreme weather) after receiving approval from the MM or the sponsor. In 
case the site faces a delay in obtaining the central laboratory results for the clinical laboratory 
tests performed during screening that are needed to determine eligibility, additional screening 
blood samples (specifically those with delayed results) may be collected as soon as possible 
and analyzed in a local laboratory to allow study eligibility determination within the 8-day 
screening window. Refer to Section 8.4 for more details. 
The following procedures and assessments will be performed at visit 1: 
• Informed consent 
• Inclusion and exclusion criteria 
• Medical and psychiatric history (including the number of relapse episodes and years 
post diagnosis) 
• Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT) 
• Prior medication and treatment history 
• Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) 
• Virology and thyroid screening tests 
• Follicle-stimulating hormone test (for women with no menses for 12 months prior to 
screening) 
• Administration of oral olanzapine (patients who received olanzapine within the last 
year will not be required to receive the 2 doses of oral treatment) 
• Urine drug screen 
• Full physical examination, including height and weight 
• 12-lead electrocardiogram (ECG) 
• Vital signs measurement 
• Serum beta-human chorionic gonadotropin (β-HCG) test for women of childbearing 
potential 
• Positive and Negative Syndrome Scale (PANSS) 
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• Clinical Global Impression-Severity (CGI-S) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson-Angus Scale (SAS) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Personal and Social Performance Scale (PSP) 
• Schizophrenia Quality of Life Scale (SQLS) 
• 
 
• Calgary Depression Scale for Schizophrenia (CDSS) 
• 
 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Inquiry regarding alcohol consumption/illicit drug use 
• Cigarette use assessment 
• Site confinement (for patients who are not already hospitalized) 
• Concomitant medication inquiry 
2. Procedures During Double-blind Treatment Period (Acute Treatment 
Phase; Period 1) 
All patients will be hospitalized upon study entry (screening) and will remain hospitalized 
during the screening period and for the first 4 weeks after randomization (until the second 
investigational medicinal product [IMP] administration). After the second injection, patients 
may be discharged if all discharge criteria are met and if, in the opinion of the investigator, 
discharge is appropriate. During the hospitalization period (ie, before the patient is 
discharged), a short-term leave from the site may be allowed if requested by the patient. 
Patient’s eligibility for such leave will be determined by the investigator clinical judgment, in 
accordance with the study conduct and with the patient’s best interest. During the leave, the 
patient will be escorted by a caregiver or another individual per investigator approval. The 
patient will return to the site on the same calendar day. In exceptional cases, an overnight 
stay outside the site may be approved by the investigator. Upon return to the site, after any 
period of leave, the patient will undergo a urine drug screen, an abbreviated physical 
examination (including weight), and a concomitant medication and alcohol 
consumption/illicit drug use inquiry. The results of these assessments, along with the date 
and time of site leave and return, will be captured in a dedicated case report form (CRF). 
a. Procedures for Baseline/Visit 2 (Day 1, Week 0) 
Patients who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2, when 
baseline assessments will be conducted. 
The following procedures and assessments will be performed at visit 2: 
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• Inclusion and exclusion criteria 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Randomization 
• Urine drug screen 
• Abbreviated physical examination, including weight 
• 12-lead ECG 
• Vital signs measurement 
• Urine β-HCG test for women of childbearing potential 
• PANSS 
• CGI-S 
• AIMS 
• BARS 
• SAS 
• C-SSRS 
• PSP 
• SQLS 
• 
 
• CDSS 
• 
 
• Abdominal fat measurement (waist-to-hip ratio) 
• Blood samples for plasma concentration of IMP 
• Blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose 
• Blood samples for biomarker analysis 
• Blood samples for pharmacogenetics 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Inquiry regarding alcohol consumption/illicit drug use 
• Cigarette use assessment 
• IMP administration 
• Concomitant medication inquiry 
b. Procedures for Visit 3 (Day 2, Week 0) 
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The following procedures and assessments will be performed at visit 3: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Abbreviated physical examination 
• Vital signs measurement 
• Blood samples for plasma concentration of IMP 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Concomitant medication inquiry 
c. Procedures for Visit 4 (Day 8, Week 1), Visit 5 (Day 15, Week 2), Visit 6 (Day 22, 
Week 3), Visit 8 (Day 36, Week 5), Visit 9 (Day 43, Week 6), and Visit 10 (Day 50, 
Week 7) 
The following procedures and assessments will be performed at visits 4, 5, 6, 8, 9, and 10: 
• Vital signs measurement 
• PANSS 
• CGI-S 
• AIMS 
• BARS 
• SAS 
• C-SSRS 
• Patient Global Impression-Improvement (PGI-I) (visit 5 only) 
• 
 
• Blood samples for plasma concentration of IMP 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Inquiry regarding alcohol consumption/illicit drug use (for outpatients only) 
• Concomitant medication inquiry 
d. Procedures for Visit 7 (Day 29, Week 4) and Visit 11 (Day 57, Week 8) 
The following procedures and assessments will be performed at visits 7 and 11: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Thyroid test (visit 11 only) 
• Randomization (visit 11 only) 
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− Note: Procedures and assessments that need to be performed prior to 
randomization into Period 2 at visit 11 (week 8) include clinical laboratory tests, 
thyroid tests, physical examination, ECG, vital signs, urine β-HCG, PANSS, CGI-
S, Clinical Global Impression of Improvement (CGI-I), AIMS, BARS, SAS, 
C-SSRS, PSP, CDSS, PGI-I, blood samples for plasma concentration of IMP, 
adverse event inquiry, injection site findings and pain assessment of last injection, 
inquiry regarding alcohol consumption/illicit drug use, and concomitant 
medication inquiry. Procedures and assessments that need to be performed after 
randomization into Period 2 at visit 11 (week 8) include IMP administration and 
blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose. 
Remaining procedures and assessments at visit 11 (week 8) may be performed 
either before or after randomization 
• Urine drug screen 
• Abbreviated physical examination, including weight 
• 12-lead ECG 
• Vital signs measurement 
• Urine β-HCG test for women of childbearing potential 
• PANSS 
• CGI-S 
• CGI-I 
• AIMS 
• BARS 
• SAS 
• C-SSRS 
• PSP 
• SQLS 
• 
 
• CDSS 
• PGI-I 
• 
 
• Abdominal fat measurement (waist-to-hip ratio) 
• Blood samples for plasma concentration of IMP 
• Blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose 
• Blood samples for biomarker analysis (visit 11 only) 
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• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Inquiry regarding alcohol consumption/illicit drug use (for outpatients only) 
• Cigarette use assessment 
• IMP administration 
• Readiness for Discharge Questionnaire (RDQ)-discharge from site confinement (visit 
7 only; see note above under “2. Procedures During Double-blind Treatment Period 
[Acute Treatment Phase; Period 1]”) 
• Concomitant medication inquiry 
• Review of eligibility (stability) criteria (visit 11 only) 
3. Procedures During Safety Period (Long-term Safety Phase; Period 2) 
The open-label safety period in Period 2 will be up to 48 weeks, with patients continuing 
until the end of Period 2 or until they meet 1 or more of the study discontinuation or 
withdrawal criteria. Randomized patients who meet 1 or more of the study discontinuation or 
withdrawal criteria (Section 5.4) should be invited to perform the ET visit as soon as 
possible. 
Visit 11 (week 8) assessments are included in both Table 1 (Period 1) and Table 2 (Period 2) 
for completeness; however, they need to be performed only once, prior to randomization to 
Period 2. They are listed only once in this appendix (under Period 1). 
Note: Patients who do not meet RDQ criteria, but in the opinion of the investigator show 
sufficient clinical stabilization for transition to Period 2 and may benefit from continuation of 
participation in the study, may continue to Period 2 as inpatients for up to an additional 8 
weeks. For such patients, RDQ can be assessed periodically according to investigator 
discretion; if RDQ criteria are not met by the end of the additional 8-week hospitalization 
period (week 16), then the patient will be discontinued from study treatment and will be 
asked to complete early termination (ET) and follow-up (FU) visits. 
a. Visit 12 (Week 12), Visit 14 (Week 20), Visit 16 (Week 28), Visit 18 (Week 36), 
Visit 20 (Week 44), and Visit 22 (Week 52) 
The following procedures and assessments will be performed at visits 12, 14, 16, 18, and 20: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) (visits 14 and 
20 only) 
• Urine drug screen 
• Concomitant medication inquiry 
• Abbreviated physical examination, including weight 
• Abdominal fat measurement (waist-to-hip ratio) 
• Vital signs measurement 
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• Urine β-HCG test for women of childbearing potential 
• PANSS 
• CGI-S 
• CGI-I (visits 14 and 20 only) 
• AIMS (visits 14 and 20 only) 
• BARS (visits 14 and 20 only) 
• SAS (visits 14 and 20 only) 
• C-SSRS 
• PSP (visits 14 and 20 only) 
• SQLS (visits 14 and 20 only) 
• 
 (visits 14 and 20 only) 
• CDSS 
• 
 
• Blood samples for plasma concentration of IMP 
• Blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose 
• IMP administration 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Inquiry regarding alcohol consumption/illicit drug use 
• Cigarette use assessment 
b. Visit 13 (Week 16), Visit 15 (Week 24), Visit 17 (Week 32), Visit 19 (Week 40), and 
Visit 21 (Week 48) 
The following procedures and assessments will be performed at visits 13, 15, 17, 19, and 21: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) (visit 17 only) 
• Urine drug screen 
• Concomitant medication inquiry 
• Abbreviated physical examination, including weight 
• Abdominal fat measurement (waist-to-hip ratio) 
• Vital signs measurement 
• 12-lead ECG 
• Urine β-HCG test for women of childbearing potential 
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• PANSS 
• CGI-S 
• CGI-I (visit 17 only) 
• AIMS (visit 17 only) 
• BARS (visit 17 only)  
• SAS (visit 17 only) 
• C-SSRS 
• PSP (visit 17 only) 
• SQLS (visit 17 only) 
• 
 (visit 17 only) 
• CDSS 
• 
 
• Blood samples for plasma concentration of IMP 
• Blood samples for plasma concentration of IMP at 2.5 to 3 hours postdose 
• IMP administration 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Inquiry regarding alcohol consumption/illicit drug use 
• Cigarette use assessment 
c. Telephone visits (Visit 11a [Week 9], Visit 11b [Week 10], Visit 11c [Week 11], 
Visit 12a [Week 13], Visit 12b [Week 14], Visit 12c [Week 15], Visit 13a 
[Week 17], Visit 13b [Week 18], Visit 13c [Week 19], Visit 14a [Week 21], 
Visit 14b [Week 22], Visit 14c [Week 23], Visit 15a [Week 25], Visit 15b 
[Week 26], Visit 15c [Week 27], Visit 16a [Week 29], Visit 16b [Week 30], Visit 16c 
[Week 31], Visit 17a [Week 33], Visit 17b [Week 34], Visit 17c [Week 35], Visit 
18a [Week 37], Visit 18b [Week 38], Visit 18c [Week 39], Visit 19a [Week 41], 
Visit 19b [Week 42], Visit 19c [Week 43], Visit 20a [Week 45], Visit 20b [Week 
46], Visit 20c [Week 47], Visit 21a [Week 49], Visit 21b [Week 50], Visit 21c [Week 
51], Visit 22a [Week 53], Visit 22b [Week 54], and Visit 22c [Week 55]) 
Telephone contacts (or other comparable form of remote communication) will occur weekly 
between clinic visits. These contacts will be referred to by the previous visit number and a 
letter (eg, the telephone contacts that take place 1, 2, and 3 weeks after visit 11 (week 8) will 
be referred to as “visit 11a,” “visit 11b,” and “visit 11c,” respectively). 
For patients who are inpatients (for up to the first 8 weeks of Period 2), in-clinic visits will 
take place instead of phone visits, using the same assessments specified for the phone visits. 
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The following procedures and assessments will be performed at each telephone contact: 
• Inquiry about pregnancy status (for women of childbearing potential) 
• C-SSRS 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Inquiry regarding alcohol consumption/illicit drug use 
• Brief set of clinical questions to detect psychotic symptoms 
d. End-of-Treatment Visit (4 weeks after the last dose of IMP) 
The following procedures and assessments will be performed at the end-of-treatment (EOT) 
visit: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Thyroid test 
• Urine drug screen 
• Concomitant medication inquiry 
• Abbreviated physical examination, including weight 
• Abdominal fat measurement (waist-to-hip ratio) 
• Vital signs measurement 
• 12-lead ECG 
• Urine β-HCG test for women of childbearing potential 
• PANSS 
• CGI-S 
• CGI-I 
• AIMS 
• BARS 
• SAS 
• C-SSRS 
• PSP 
• SQLS 
• 
 
• CDSS 
• PGI-I 
• 
 
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• Blood samples for biomarker analysis 
• Blood samples for plasma concentration of IMP 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment 
• Inquiry regarding alcohol consumption/illicit drug use 
4. Follow-up (8 Weeks After the Last Dose of IMP)/Early Termination 
In case the ET visit is conducted during the time window of the EOT visit, the ET and EOT 
visits may be conducted on the same day (ie, the visits will be combined, and all assessments 
listed in the Study Procedures and Assessments tables [Table 1 or Table 2] for the ET and 
EOT visits must be performed). 
The following procedures and assessments will be performed at the FU visit or ET visit: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Thyroid test (ET visit only) 
• Urine drug screen (ET visit only) 
• Concomitant medication inquiry 
• Abbreviated physical examination, including weight 
• Abdominal fat measurement (waist-to-hip ratio) 
• Vital signs measurement 
• 12-lead ECG 
• Serum β-HCG test for women of childbearing potential (FU visit only) 
• Urine β-HCG test for women of childbearing potential (ET visit only) 
• PANSS 
• CGI-S 
• CGI-I 
• AIMS 
• BARS 
• SAS 
• C-SSRS 
• PSP 
• SQLS 
• 
 
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• CDSS 
• PGI-I (ET visit only) 
• 
 
• Blood samples for biomarker analysis (FU visit only) 
• Blood samples for plasma concentration of IMP 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Injection site findings and pain assessment (ET visit only) 
• Inquiry regarding alcohol consumption/illicit drug use 
5. Unscheduled Visits 
An unscheduled visit may be performed at any time per investigator decision. 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 include: 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Concomitant medication inquiry 
• Full physical examination, including weight 
• Abdominal fat measurement (waist-to-hip ratio) 
• Vital signs measurement 
• PANSS 
• CGI-S 
• CGI-I 
• C-SSRS 
• CDSS 
• 
 
• Blood samples for plasma concentration of IMP 
• Blood samples for biomarker analysis (for patients with ISRs that require an 
unscheduled visit, ie, pus-containing lesion [abscess, infection, or inflammation], 
ulceration, necrosis, atrophy, or severe ISR) 
• Adverse events inquiry (including serious adverse event reporting and injection site 
related events [including pain]) 
• Inquiry regarding alcohol consumption/illicit drug use 
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Other procedures and assessments may be performed according to the discretion of the 
investigator. However, in order to reduce patient burden and to avoid unnecessary data 
collection, the investigator will have discretion in determining whether all unscheduled visit 
procedures should be performed during the unscheduled visit in the event that (i) the 
unscheduled visit is one of multiple in-clinic visits that are deemed necessary in close 
proximity (ie, 2 or more visits within 1 week) or (ii) the visit is for administrative purposes 
(eg, reconsenting) or technical reasons (eg, repeat laboratory sample collection for reasons 
unrelated to an adverse event) and not due to a change in the patient’s medical status per 
clinical judgment. 
6. Short-term Leave 
The following procedures and assessments will be performed following short-term leave: 
• Urine drug screen 
• Abbreviated physical examination, including weight 
• Inquiry regarding alcohol consumption/illicit drug use 
• Concomitant medication inquiry 
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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 
(IEC)/Institutional Review Board (IRB) and national and local competent authorities, as 
applicable, except when necessary to address immediate safety concerns to the patients or when 
the change involves only nonsubstantial logistics or administration. The principal investigator at 
each investigational center, the coordinating investigator (if applicable), and the sponsor will 
sign the protocol amendment. 
Important Protocol Deviations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety or the physical 
or mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include 
nonadherence on the part of the patient, the investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or Good Clinical Practice 
(GCP) guidelines; noncompliance to investigational medicinal product administration; use of 
prohibited medications. Important protocol deviations will be documented by investigational 
center personnel. All important protocol deviations will be reported to the responsible IEC/IRB, 
as required. 
When an important protocol deviation is reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important protocol deviation. If such patient has already completed the study or 
has withdrawn early, no action will be taken but the deviation will be recorded. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. 
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Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form 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 monitors 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 monitors will contact the investigator and visit the investigational center according to 
the monitoring plan. The study monitor will be permitted to review and verify the various 
records (case report forms and other pertinent source data records, including specific electronic 
source documents 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. 
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 competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 
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Appendix D. 
ETHICS  
Informed Consent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee (IEC)/Institutional Review Board (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. The patient 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. Patients will be 
asked to consent to share their information with a vendor that will verify that they are not 
currently participating or have not recently participated in another clinical study, unless 
prohibited by local requirements. 
 
 
 
 
 
 
 
 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. Additionally, the patient’s caregiver will be asked to sign a 
caregiver ICF. 
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national competent authority 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 competent authority (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. 
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 competent authorities. 
Personal medical information will always be treated as confidential. 
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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 clinical trial registries, if applicable. 
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APPENDIX E. 
BIRTH CONTROL METHODS  
Highly Effective Birth Control Methods in Females 
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: 
• Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at the 
screening visit (for both investigational medicinal products [IMPs] with and without 
suspected reproductive toxicity) before the first dose of IMP. 
• Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation; these should be initiated at the screening visit (for IMPs 
with or without suspected reproductive toxicity) 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, except for hysteroscopic bi-tubal ligation [Essure®], for 
which a hysterosalpingogram is required 3 months post-procedure to assess surgical 
success. 
• Vasectomized partner, provided he is the sole sexual partner and has received medical 
assessment of the surgical process. 
• Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient. Minimum time adherence prior to 
first dosing is 3 months. 
• Postmenopausal women (no menses for at least 12 months [without an alternative 
medical cause] prior to screening and with follicle-stimulating hormone [FSH] 
concentration above 35 U/L) may be allowed not to use contraceptives during the 
study. An FSH test will be performed at the screening visit for any female who has 
been without menses for at least 12 months prior to screening to confirm 
postmenopausal status. 
Unacceptable Birth Control Methods 
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and the lactational amenorrhea method are not acceptable 
methods of contraception. Female condom and male condom should not be used together. 
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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 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 caregiver continue to be unreachable, the patient will be 
considered to have withdrawn from the study, with a primary reason of “lost to 
follow-up.” 
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APPENDIX G. LIST OF DISALLOWED MEDICATIONS  
The following list describes the restricted medications for the study due to interactions with 
cytochrome P450 1A2. Several medications may require dose adjustments or specific monitoring 
when combined with olanzapine. This should be assessed based on the ZYPREXA official label. 
For any questions about prohibited medications, the sponsor or medical monitor should be 
contacted. 
Medication class 
Drug name 
Antidepressants 
Fluvoxamine 
Antipsychotics 
Any known antipsychotics besides oral olanzapine at screening and TV-44749  
Antibiotics  
Rifampin 
Antiepileptics 
Carbamazepine 
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APPENDIX H. PHARMACOGENETIC ASSESSMENTS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX I. 
PRODUCT COMPLAINTS  
I. 
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) and/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 deficiency (eg, any inadequacy of an investigational medical device or 
combination product with respect to its identity, quality, durability, reliability, 
usability, safety, or performance). This includes malfunctions, use errors, and 
inadequate labeling (eg, unintelligible label, incorrect expiry date) 
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 
TevaProductComplaintAndPotentialSB@teva.co.il as soon as possible of becoming aware of the 
issue. 
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. 
If the clinical product complaint is related to a device, rescue medication, or any other product 
planned in the protocol not manufactured by Teva, the complaint will be forwarded to the 
manufacturer/wholesaler of that product. 
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 
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• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
• description or nature of complaint 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.  
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s) 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP or device. 
If it is determined that the investigational center must return all of the IMP or devices, 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, if applicable. 
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 8.1.2 and Section 8.1.6, respectively). 
4. Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
the initial determination whether the deficiency could have led to a serious adverse event, 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. 
5. Device Deficiency That Could Have Led to Serious Adverse Event 
Device deficiencies that could have led to serious adverse events are defined as deficiencies that 
might have led to a serious adverse device effect if: 
• suitable action had not been taken (or) 
• intervention had not been made (or) 
• if circumstances had been less fortunate. 
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These device deficiencies shall be reported to the IRB/IEC by the investigator and to the 
regulatory authorities by the sponsor according to national and local regulations. Device 
complaints related to potential device malfunctions will be initially assessed by the sponsor to 
determine the root cause of the complaint. Device complaints that are assessed to be caused 
specifically by device deficiencies will be reported to the device manufacturer for evaluation and 
further reported according to national and local regulations. 
The investigator will record in the source documentation a description of the complaint, the 
initial determination whether the device deficiency could have led to a serious adverse event, and 
any actions taken to resolve the complaint and to preserve the safety of the patient. 
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APPENDIX J. 
DATA MANAGEMENT AND RECORD KEEPING  
Data protection and confidentiality 
All personal data will be processed in accordance with applicable data protection law. 
Teva has implemented measures to ensure that data will be adequately protected and 
confidentiality will be appropriately maintained, including the following: 
a. In addition to the measures set out in this appendix and the wider protocol, Teva has 
implemented technical measures (including encryption for data and emails) and 
organizational measures (including a robust governance structure, staff training, and 
policies dealing with document management and acceptable use) in order to prevent 
data loss and to ensure the integrity of data that it holds. Teva consults with 
independent data security experts to ensure the adequacy of these technical and 
organizational measures, and Teva’s Information Security team keeps the measures 
under continuous review to ensure the measures in place continue to be state of the 
art, taking into account the nature and context of the processing. 
b. Teva has completed Data Protection Impact Assessments in respect of the processing 
of personal data gathered in the course of clinical studies.  
c. Teva trains all of its staff regarding the handling of personal data in accordance with 
applicable law. 
d. Teva has implemented role-based access, which means that personal data will only be 
available to those who need access. 
e. There are appropriate technical and organizational measures in place to protect the 
confidentiality of patient data. For example, patient data will be randomized and 
blinded in accordance with Section 6.9 and Section 6.10 above, and Teva staff are 
subject to a contractual obligation of confidentiality. 
f. Teva has policies and procedures in place to identify and respond to data breaches, 
including internal reporting within Teva as well as reporting from partners and other 
involved third parties (contract research organizations, monitors, etc). In particular, 
Teva has adopted a data breach response policy that details internal reporting 
channels and immediate mitigation step; a data breach log that records all breaches; 
and a back-up and restore policy that details the measures in place to avoid data loss 
in the event of a service outage. 
Teva ensures that all contracts into which it enters with third parties involved in the data 
processing with or on behalf of Teva include provisions to ensure that such parties comply with 
applicable law, including General Data Protection Regulation. These contracts will effectively 
extend obligations that are equivalent to the above to all third parties who process patient data 
with or on behalf of Teva. 
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 
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directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF. 
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or other electronic source) 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 (IEC)/Institutional 
Review Board (IRB), and inspectors from competent authority (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 21CFR Part 11 (USA) and documents of other concerned 
competent authorities. 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 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. 
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 
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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 
• case report forms 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 
• reports of receipt, use, and disposition of the investigational medicinal products 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the contract 
research organization or sponsor notifies the institution in writing that records may be destroyed. 
If, after 25 years from study completion, or earlier in the case of the investigational center 
closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome, and sponsor has not provided written notification of 
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destruction, then the investigator may submit a written request to 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 K. PUBLICATION POLICY  
All unpublished information given to the investigator by or on behalf of 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 at the sponsor’s 
discretion. The investigator agrees to submit all manuscripts, abstracts, and/or publications 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. 
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. 
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. 
Additional information and instructions concerning confidentiality, publication and intellectual 
property are subject to the clinical trial agreement. 
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Appendix L. 
MANAGEMENT OF STUDY ACTIVITIES DURING 
COVID-19 OUTBREAKS  
This appendix is to address the modifications set-up in study conduct during coronavirus disease 
2019 (COVID-19) outbreaks. 
The changes will be effective for the period of the COVID-19 outbreaks and will be 
implemented exclusively at the sites impacted by COVID-19. Once the situation at specific 
sites/countries allows for a return to regular study activities, this appendix will become void for 
those sites/countries, except in the case of COVID-19 resurgence. 
The following sections of the protocol are affected: 
Section 2.3. Known and Potential Benefits and Risks to Patients 
In the event of COVID-19 outbreaks, the sponsor, in close collaboration with the investigators, 
will determine if the benefit-risk assessment remains positive as a whole, and will assess any 
additional risks on a patient-by-patient basis, as needed. The measures outlined in this appendix 
are aimed at further mitigating the additional risks in the event of a COVID-19 outbreak.  
It should be noted that patients diagnosed with active COVID-19 at screening may not be 
included in the study as they may meet exclusion criterion “n.” A patient may be rescreened once 
he/she fully recovers in the opinion of the investigator. 
If, in the opinion of the investigator, the patient’s diagnosis could jeopardize or would 
compromise the patient’s ability to participate in the study or their continued participation in the 
study, the patient should be early terminated. 
If a patient exhibits clinical symptoms during the study that may indicate COVID-19 infection 
according to the investigator or the patient’s physician, the patient may be tested for active 
COVID-19 infection (according to local requirements for conditions that warrant testing). If the 
patient tests positive, the patient should be managed and treated according to standard of care 
and local regulations. 
Section 4.1. General Study Design and Study Schematic Diagram; Section 4.5. Schedule of 
Study Procedures and Assessments 
In the event of COVID-19 outbreaks, in case a patient cannot return to the clinic for the 
scheduled visits (eg, due to quarantine, isolation, patient’s concern, active COVID-19 infection, 
or closure of the site clinic) within the pre-specified visit windows in Period 1 or within 35 days 
from the previous IMP administration in Period 2, the patient will be discontinued from the IMP, 
scheduled adverse event and concomitant medication monitoring will be continued, and the 
patient will attend an ET visit when that becomes possible. Remote assessment of safety via 
teleconference (TC) and/or videoconference (VC), with VC being the preferred method, is 
recommended until the patient attends the ET visit. All other tests (including safety laboratories, 
pharmacokinetics, and biomarkers (if applicable) are to be conducted once the patient can return 
to the study center for the ET visit. 
In the event that a patient completes the screening procedures but cannot come to the site for 
visit 2 (eg, due to quarantine, isolation, patient’s concern, or closure of the site clinic), the patient 
may be rescreened according to rescreening procedures described in Section 5.6 of this protocol 
following discussion between the investigator and the sponsor. 
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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 a COVID-19 outbreak. Preferably, the full protocol instructions will be 
followed whenever the modified instructions are not required. 
Section 5.2. Patient Exclusion Criteria; Section 6.7. Prior and Concomitant Medication or 
Therapy 
The eligibility criteria and list of prohibited medications can be updated to reflect new data on 
COVID-19 therapies. If a patient receives new COVID-19 therapies not in compliance with the 
eligibility criteria and list of prohibited medications at the time of the patient’s participation in 
the study, the investigator and sponsor will discuss how to proceed on a case-by-case basis. 
Section 5.5. Replacement of Patients 
In the event of COVID-19 outbreaks resulting in high rate of patients’ ET, the number of patients 
to be randomized may be increased to ensure the targeted number of completers per treatment 
group. 
Section 6.10. Maintenance of Randomization and Blinding 
Unblinded data review of COVID-19 patients by member(s) not part of the blinded study team 
(during Period 1) may be conducted upon Independent Data Monitoring Committee 
recommendations and Teva’s discretion. 
Section 7. Assessment of Efficacy 
In the event of COVID-19 outbreaks, in case a patient cannot return to the clinic for the 
scheduled visits (eg, due to quarantine, isolation, patient’s concern, active COVID-19 infection, 
or closure of the site clinic) within the pre-specified visit windows in Period 1 or within 35 days 
from the previous IMP administration in Period 2, the patient will be discontinued from IMP, 
remote monitoring will be performed, and the patient will attend for an ET visit when that 
becomes possible. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to a COVID-19 outbreak. Preferably, the full protocol instructions will be 
followed whenever the modified instructions are not required. 
Section 8. Assessment of Safety 
In the event of COVID-19 outbreaks, in case a patient cannot return to the clinic for the 
scheduled visits (eg, due to quarantine, isolation, patient’s concern, active COVID-19 infection, 
or closure of the site clinic), remote assessment of safety (ie, inquiries regarding adverse events 
and use of concomitant medication) via TC and/or VC, with VC being the preferred method (if 
local regulations allow), may be allowed. The results will be directly entered into the patient’s 
source document and reported in the case report form 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 a COVID-19 outbreak. Preferably, the full protocol instructions will be 
followed whenever the modified instructions are not required. 
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Section 8.4. Clinical Laboratory Tests 
For ET patients (patients who cannot be administered the IMP), all required samples scheduled 
for ET will be collected once the patient can return to the study center. 
Section 10.5.6. Planned Method of Analysis 
Sensitivity and supplementary analyses will be conducted to evaluate the impact of the change to 
remote monitoring (TC/VC visits) and the impact of COVID-19 on primary efficacy 
measurements. The analysis will include subgroup analysis (eg, pre-, during, and post-
COVID-19 outbreak, where each patient will be classified into 1 of the levels), a multivariate 
model (eg, Cox regression with time dependent covariates for COVID-19 and/or use of remote 
monitoring), and/or imputation methodology for patients’ attrition due to the COVID-19, 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 (when discussing Period 1) prior to database lock. 
Section 11. Quality Control and Quality Assurance 
Deviations from the study conduct due to COVID-19 outbreaks, including implemented 
contingency measures and their impact (eg, patient discontinuation from treatment with IMP 
and/or study, alternative procedures used to collect critical safety and/or efficacy data, etc), will 
be described in the appropriate sections of the clinical study report (CSR), as applicable. 
Appendix C. Quality Control and Quality Assurance 
Important Protocol Deviations 
Deviations from the study conduct due COVID-19 outbreaks, including implemented 
contingency measures and their impact (eg, patient discontinuation from treatment with IMP 
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 COVID-19 outbreaks, monitors may not be able to access the investigational centers 
for on-site visits in a timely manner. A Monitoring Manual will outline risk mitigation 
procedures for sites where on-site monitoring visits are not permitted due to an increased public 
health risk, in accordance with Institutional Review Board/Ethics Committee approval and local 
regulations. 
Audit and Inspection 
In case of a COVID-19 pandemic, where auditors may not be able to access the investigational 
centers for on-site visits, investigational centers will be audited remotely where allowed and in 
accordance with local regulations. 
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APPENDIX M. LIST OF SCALES  
Note: Full versions of each scale will be provided in a dedicated study plan outside of the 
protocol. 
Scale Title 
PRO or ClinRO 
Administration 
Mode 
Scale Version 
Reference 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
ClinRO 
eCOA 
Guy 1976a 
14-Item version 
Guy 1976a 
Rating scale for 
drug-induced 
akathisia (Barnes 
Akathisia Rating 
Scale) (BARS) 
ClinRO 
eCOA 
Reproduced from 
Barnes 1989 
©1989 The Royal 
College of 
Psychiatrists 
Reproduced from 
Barnes 1989 
Simpson-Angus 
Scale (SAS) 
ClinRO 
eCOA 
SAS ©Munksgaard, 
managed by Wiley 
Simpson and Angus 
1970 
Simpson and Angus 
1970 
Janno et al 2005 
Clinical Global 
Impression – 
Improvement 
(CGI-I) 
ClinRO 
eCOA 
Guy et al 1976b 
Public domain  
Reproduced from 
Guy et al 1976b 
Clinical Global 
Impression of 
Severity (CGI-S) 
ClinRO 
eCOA 
Guy et al 1976b 
Public domain  
Reproduced from 
Guy et al 1976b 
Positive and 
Negative Syndrome 
Scale (PANSS) 
Rating Criteria, 
PANSS Rating and 
Profile forms (ex 
Quickscore), 
SCI-PANSS 
ClinRO 
PANSS Rating 
Criteria + Rating 
and Profile form 
(eCOA) 
SCI-PANSS (Paper) 
Positive and 
Negative Syndrome 
Scale (PANSS™). 
©2022 NCS 
Pearson, Inc. All 
rights reserved. 
Kay et al 1987 
Personal and Social 
Performance Scale 
(PSP) 
ClinRO 
eCOA 
Morosini et al 2000 
Morosini et al 2000 
Columbia Suicide 
Severity Rating 
Scale (C-SSRS) 
ClinRO 
eCOA 
Since Last Visit 
version 1/14/09 
Posner et al 2011 
ClinRO 
eCOA 
Baseline/Screening 
version 1/14/09 
Posner et al 2011 
Calgary Depression 
Scale for 
Schizophrenia 
(CDSS) 
ClinRO 
eCOA 
©2018 (Dr. D. 
Addington). All 
rights reserved. 
Addington et al 
1990 
Addington et al 
1992 
Addington et al 
1993 
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Scale Title 
PRO or ClinRO 
Administration 
Mode 
Scale Version 
Reference 
 
 
 
 
 
 
 
 
 
SQLS R4 - 
Schizophrenia 
Quality of Life 
Scale Revision 4 
PRO 
eCOA 
SQLS-R4 (circle 
response version) 
Martin and Allan 
2007 
Patient Global 
Impression-
Improvement 
(PGI-I) 
PRO 
eCOA 
Public domain  
Steinert et al 2010 
Structured Clinical 
Interview for 
DSM-5 Clinical 
Trials Version 
(SCID-5-CT) 
ClinRO 
Paper 
SCID-5-CT for 
schizophrenia 
First et al 2015 
Readiness for 
Discharge 
Questionnaire 
(RDQ) 
ClinRO 
Paper 
Potkin et al 2005  
Potkin et al 2005 
Numeric Pain 
Rating Scales 0-10 
(NPRS) 
ClinRO 
Paper 
Reproduced from 
Williamson and 
Hoggart 2005 
Williamson and 
Hoggart 2005 
ClinRO=clinician-reported outcome; DSM-5=Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; 
eCOA=electronic clinical outcome assesment; 
; 
PANSS=Positive and Negative Syndrome Scale; PRO=patient-reported outcome; SCI=Structured Clinical 
Interview; USA=United States of America. 
 
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APPENDIX N. PRIOR PROTOCOL AMENDMENTS AND 
ADMINISTRATIVE LETTERS  
Administrative Letter 05 Dated 05 Sep 2023  
 
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Administrative Letter 04 Dated 31 Jul 2023  
 
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Administrative Letter 03 Dated 21 Mar 2023  
 
 
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VV-00457212 v4.0

 
Placebo-Controlled Study–Schizophrenia 
Clinical Study Protocol with Amendment 01 
Study TV44749-CNS-30096 
202 
 
 
VV-00457212 v4.0