A Multi-center, Open-label, Randomized, Parallel-group Trial to Characterize the Pharmacokinetics of Three SC Olanzapine Extended-release Formulations With Different Release Rates Following Single Administration in Participants With Schizophrenia or Schizoaffective Disorder
Phase: PHASE1
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: Teva Branded Pharmaceutical Products R&D LLC

 
 
 
Clinical Study Protocol 
 
 
A Multi-center, Open-label, Randomized, Parallel-group Trial to Characterize the 
Pharmacokinetics of Three SC Olanzapine Extended-release Formulations with 
Different Release Rates Following Single Administration in Participants with 
Schizophrenia or Schizoaffective Disorder 
 
 
Study Number TV44749-NPC-10205 
 
 
NCT06319170 
 
 
Protocol with Amendment 01 Approval Date: 11 May 2024 

Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
1 
 
  
Clinical Trial Protocol with Amendment 01 
 
Trial Number TV44749-NPC-10205 
 
A Multi-center, Open-label, Randomized, Parallel-group Trial to Characterize the 
Pharmacokinetics of Three SC Olanzapine Extended-release Formulations with Different 
Release Rates Following Single Administration in Participants with Schizophrenia or 
Schizoaffective Disorder 
 
Pharmacokinetic Trial 
Phase 1 
 
IND number: 128851; 
NDA number: not applicable; BLA number: not applicable;
 
EudraCT number: not applicable;  EU CT number: not applicable 
 
EudraVigilance Code for the IMP: not applicable 
EudraVigilance Code for the Drug Substance: SUB09426MIG 
 
Version Date: 11 May 2024 
 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway,  
West Chester, Pennsylvania 19380  
United States 
Sponsor’s Authorized Representative 
 
  
 
Teva Pharmaceutical Industries Ltd. 
 
 
Name and contact information of the Medical Monitor are provided separately. 
 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
2 
This clinical trial will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of Federal 
Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the region of 
the trial); national country legislation; and the Sponsor’s Standard Operating Procedures (SOPs). 
Confidentiality Statement 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc. and/or its affiliates. The recipient agrees that no information contained 
herein may be published or disclosed without written approval from the Sponsor. 
© 2024 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 
 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
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INVESTIGATOR AGREEMENT  
Clinical Trial Protocol with Amendment 01 
Version Date: 11 May 2024 
TV44749-NPC-10205 
A Multi-center, Open-label, Randomized, Parallel-group Trial to Characterize the 
Pharmacokinetics of Three SC Olanzapine Extended-release Formulations with Different 
Release Rates Following Single Administration in Participants with Schizophrenia or 
Schizoaffective Disorder 
IND number: 128851; NDA number: not applicable;  BLA number: not applicable;  
EudraCT number: not applicable; EU CT number: not applicable 
 
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 trial. I am qualified by education, experience, and training to conduct this clinical research trial. The 
signature below constitutes agreement with this protocol and attachments, and provides assurance that this 
trial 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 products (IMP) that 
were furnished to me by the Sponsor to all physicians and other trial personnel reporting to me who 
participate in this trial and will discuss this material with them to ensure that they are fully informed 
regarding the IMP and the conduct of the trial. I agree to keep records on all participant information, IMP 
shipment and return forms, and all other information collected during the trial, in accordance with national 
and local GCP regulations as well as all other national and international laws and regulations. 
Principal Investigator 
Signature 
Date 
Executed signature pages are maintained within the Investigator Site File and the Trial 
Master File 
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Trial TV44749-NPC-10205 
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SPONSOR PROTOCOL APPROVAL  
Clinical Trial Protocol with Amendment 01 
Version Date: 11 May 2024 
TV44749-NPC-10205 
A Multi-center, Open-label, Randomized, Parallel-group Trial to Characterize the 
Pharmacokinetics of Three SC Olanzapine Extended-release Formulations with Different 
Release Rates Following Single Administration in Participants with Schizophrenia or 
Schizoaffective Disorder 
IND number: 128851; 
NDA number: not applicable; BLA number: not applicable;
 
EudraCT number: not applicable; EU CT number: not applicable 
 
I have read the protocol with Amendment 01 and approve the design of this trial. 
Sponsor’s Authorized 
Representative 
 
 
 
 
 
 
 
 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
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PROTOCOL AMENDMENT DETAILS  
Document History 
Administrative Letter 01 
26 March 2024 
Protocol Revision 1 
13 September 2023 
Original Protocol 
01 August 2023 
Current Amendment 01, 11 May 2024 
As of 03 May 2024, 6 participants have been enrolled into cohort 1a (sentinel cohort). 
Overall Rationale for the Amendment 01: 
The primary reason for this amendment is to revise Section 9.7 (Interim Analyses) to clarify that, 
under the Sponsor’s current internal procedures and definitions, the originally planned reviews of 
emerging data in this open-label study are no longer considered formal interim analyses. The 
review of safety data of cohort 1a by the safety review committee (SRC) is described in 
Section 4.1.2. In addition, wording has been modified to allow more flexibility regarding the use 
of preliminary concentration data to initiate IVIVC modeling before database lock. 
Additional minor corrections/clarifications were made. None of these changes affect the safety or 
rights of the participants, the scope of the investigation, and/or the scientific integrity of the trial. 
One previous Administrative Letter (March 26th, 2024) was issued to provide corrections to 
editorial errors and clarifications; these revisions have been implemented in this protocol 
amendment. 
The modifications and clarifications implemented to the TV44749-NCP-10205 study protocol 
have no significant impact on the safety or scientific value of the clinical trial.  
 
 
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Section Number and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities: 
Table 1. Screening, Antipsychotic 
Washout Period, and ZYPREXA IM 
Treatment Period 1: Trial Procedures and 
Assessments (Day -40 Through Day 4) 
Footnote “c” of Table 1 was 
corrected to indicate that a 
separate written informed 
consent will be obtained from 
each participant before the 
biomarker samples are 
collected during period 3. 
To provide clarification and 
correct a prior error 
1.3 Schedule of Activities: 
Table 1. Screening, Antipsychotic 
Washout Period, and ZYPREXA IM 
Treatment Period 1: Trial Procedures and 
Assessments (Day -40 Through Day 4) 
Footnote “r” of Table 1 was 
updated to clarify that there are 
no specific time windows for 
conducting Numeric Pain 
Rating Scale assessments in 
case of injection site reaction 
adverse events. 
(Administrative Letter 01) 
To provide clarification 
1.3 Schedule of Activities: 
Table 3. Subcutaneous Olanzapine for 
Extended-release Treatment Period 3 for 
Cohort 1A: Trial Procedures and 
Assessments (Day R1 through Day R25) 
Table 4. Subcutaneous Olanzapine for 
Extended-release Treatment Period 3 for 
Cohort 1B, Cohort 2, and Cohort 3: Trial 
Procedures and Assessments (Day R1 
through Day R25) 
“PGx” is defined in the 
footnotes of Table 3 and Table 
4 as “pharmacogenetics”. 
However, the synonymous 
term, “pharmacogenomics”, is 
used consistently throughout 
the rest of the study protocol 
tables. As the 
“pharmacogenomics” term is 
the preferred term for use in the 
protocol, the footnotes will be 
corrected. 
To correct an editorial error 
1.3 Schedule of Activities: 
Table 7. Schedule of Assessments for 
Pharmacokinetic Sampling Before and 
After Olanzapine Extended-release SC 
Formulation Administration 
For the pharmacokinetic 
sampling schedule (Table 7), 
the ±3-hour time window for 
the day 1 pre-dose sample was 
not feasible as this range 
extends beyond the time of 
dosing. This window was 
revised to ±10 minutes. 
To correct an error 
4.1 Description of Trial Design 
Text was added to clarify that 
Visit 11, if deemed not 
necessary by the Principal 
Investigator and Sponsor, will 
be skipped and the participant 
will proceed to Visit 12. 
To provide clarification 
4.1 Description of Trial Design  
 
6.6.2 Randomization 
The number of participants in 
the sentinel cohort 1A was 
revised to be composed of 
“approximately” 2 to 4 
participants. 
To allow flexibility in 
participant recruiting and 
enrollment 
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Section Number and Name 
Description of Change 
Brief Rationale 
5.3 Inclusion Criteria 
Criterion “k” 
A technical correction was 
necessary to make the study 
protocol consistent with Section 
13 (Appendix) of the Study 
Protocol. 
To provide alignment 
throughout the protocol 
5.4 Exclusion Criteria 
Criterion “b” 
A procedure was added in case 
the QuantiFERON test result, 
needed for eligibility, came out 
indeterminate. The option to 
repeat the QuantiFERON test 
was added as the possible 
improper handling of the test 
kit may result in indeterminate 
result, prohibiting the 
completion of the eligibility 
process. 
To provide clarification 
5.4 Exclusion Criteria 
Criterion “r” 
The revision to exclusion 
criterion “r” clarifies that the 
temperature should be collected 
either orally or in both ears. 
(Administrative Letter 01) 
Each of these methods are 
acceptable and clarifying this 
provides flexibility to the sites. 
 
 
5.4 Exclusion Criteria 
Criterion “s” 
The total bilirubin's unit and 
value in the bracket in 
exclusion criterion “s” were 
incorrect and were deleted as 
their inclusion was an error. 
Total bilirubin's remaining 
value and unit, 2.5 mg/dL, are 
correct and will remain as a 
part of exclusion criterion “s”. 
(Administrative Letter 01) 
To correct an error 
5.4 Exclusion Criteria 
Criterion “bb” 
For exclusion criterion “bb”, 
text was added to align it with 
the relevant study population, 
as specified in inclusion 
criterion “f”, the study title, and 
the rest of the protocol. 
(Administrative Letter 01) 
To provide alignment 
throughout the protocol 
6.6.2.1. Maintenance of Randomization 
Text indicating that the 
randomization list will be 
maintained in a secure location 
has been removed. 
This study is not a blinded trial, 
so the randomization code list is 
technically not blinded and 
therefore does not need to be 
held in a secure location. 
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Section Number and Name 
Description of Change 
Brief Rationale 
6.8.2 Permitted Concomitant Therapy 
A revision was made to clarify 
that the medications that are 
prescribed to the patients are at 
the discretion of the 
investigator and that it is highly 
recommended to consult the 
sponsor to avoid prescribing 
medications that could 
potentially affect the olanzapine 
pharmacokinetic levels. 
(Administrative Letter 01) 
To provide clarification 
8.3.3 Electrocardiograms 
More flexibility was allowed 
regarding the interpretation of 
the ECGs by physician or 
designee. 
To provide clarification 
8.3.6 Assessment of Local Tolerability and 
Pain 
Sentences related to multiple 
injection sites were removed as 
there is only one (1) TV-44749 
subcutaneous injection in the 
trial. 
(Administrative Letter 01) 
To correct an error 
8.3.7 Procedures for Injection Site Pus-
containing Lesion (Abscess, Infection, or 
Inflammation), Ulceration, Necrosis, or 
Atrophy 
This was the only section in the 
protocol where the protocol-
defined adverse event of special 
interest (PDAESI) terms 
“necrosis or atrophy” were 
mistakenly not included. This 
revision aligns section text with 
other locations in the protocol 
where these terms are listed. 
(Administrative Letter 01) 
To provide consistency across 
the document 
9.1.2 Pharmacokinetics Analysis Set 
A sentence related olanzapine 
formulations in the 
pharmacokinetics analysis set 
description was revised to 
clarify the routes of 
administration and formulations 
used. 
(Administrative Letter 01) 
To provide clarification 
9.7 Interim Analyses 
Redundant interim analysis text 
was removed. The review of 
safety data of cohort 1a by the 
safety review committee (SRC) 
is described in Section 4.1.2. In 
addition, wording has been 
modified to allow more 
flexibility regarding the use of 
preliminary concentration data 
to initiate IVIVC modeling 
before database lock. 
To clarify that under the 
Sponsor’s current internal 
procedures and definitions the 
originally planned reviews of 
emerging data in this open-label 
study are no longer considered 
formal interim analyses.  
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Section Number and Name 
Description of Change 
Brief Rationale 
10.5 Early Investigational Center Closure 
or Trial Termination 
A sentence related to 
investigational center closures 
was deleted since it was not 
capturing accurately all the 
relevant cases stated in the 
paragraph, which were 
adequately specified in the rest 
of the paragraph. 
(Administrative Letter 01) 
To correct an error 
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 
SPONSOR PROTOCOL APPROVAL ...........................................................................................4 
PROTOCOL AMENDMENT DETAILS ........................................................................................5 
1. 
PROTOCOL SUMMARY ..........................................................................................17 
1.1. 
Protocol Synopsis .......................................................................................................17 
1.2. 
Trial Schema ...............................................................................................................21 
1.3. 
Schedule of Activities .................................................................................................22 
2. 
INTRODUCTION ......................................................................................................42 
2.1. 
Purpose of Trial ..........................................................................................................42 
2.1.1. 
Background on Schizophrenia ....................................................................................42 
2.1.2. 
Olanzapine for Oral and Intramuscular Use ...............................................................42 
2.1.2.1. 
Immediate-release Olanzapine Formulations .............................................................43 
2.1.2.2. 
Prolonged-release Olanzapine Formulations ..............................................................43 
2.1.3. 
Olanzapine for Extended-release Injectable Suspensions (TV-44749) for 
Subcutaneous Use .......................................................................................................43 
2.2. 
Summary of Benefits and Risks .................................................................................45 
2.2.1. 
Known and Potential Risks of TV-44749 ...................................................................45 
2.2.2. 
Known and Potential Risks of ZYPREXA IntraMuscular (Olanzapine) 
Injection ......................................................................................................................46 
2.2.3. 
Potential Benefits of TV-44749 ..................................................................................46 
2.2.4. 
Overall Benefit-Risk Conclusion ................................................................................46 
3. 
TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS .....................................48 
3.1. 
Primary and Secondary Trial Objectives and Endpoints ............................................48 
3.2. 
Primary Estimand .......................................................................................................48 
3.3. 
Secondary Estimand(s) ...............................................................................................49 
3.4. 
Exploratory Objectives and Endpoints .......................................................................49 
4. 
TRIAL DESIGN .........................................................................................................53 
4.1. 
Description of Trial Design ........................................................................................53 
4.1.1. 
Planned Number of Participants and Countries ..........................................................55 
4.1.2. 
Data Monitoring Committee/Safety Review Committee ...........................................55 
4.2. 
Rationale for Trial Design ..........................................................................................55 
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4.3. 
Access to Trial Intervention After End of Trial ..........................................................56 
4.4. 
Start of Trial and End of Trial ....................................................................................56 
5. 
TRIAL POPULATION ..............................................................................................57 
5.1. 
Selection of Trial Population ......................................................................................57 
5.2. 
Rationale for Trial Population ....................................................................................57 
5.3. 
Inclusion Criteria ........................................................................................................57 
5.4. 
Exclusion Criteria .......................................................................................................58 
5.5. 
Ongoing Confirmation of Participant Eligibility ........................................................62 
5.6. 
Lifestyle Considerations .............................................................................................63 
5.6.1. 
Meals and Dietary Restrictions ...................................................................................63 
5.6.2. 
Caffeine, Alcohol, Tobacco, and Other Habits ...........................................................63 
5.6.3. 
Physical Activity .........................................................................................................63 
5.6.4. 
Other Activity .............................................................................................................64 
5.7. 
Screen Failures ............................................................................................................64 
6. 
TRIAL INTERVENTION AND CONCOMITANT THERAPY ..............................65 
6.1. 
Description of Trial Intervention(s) ............................................................................65 
6.1.1. 
Investigational Medicinal Products Used in the Trial ................................................65 
6.1.1.1. 
Olanzapine for Extended-Release Injectable Suspension Formulations ....................67 
6.1.1.2. 
ZYPREXA IntraMuscular (Olanzapine) Injection .....................................................67 
6.2. 
Rationale for Trial Intervention(s) ..............................................................................68 
6.2.1. 
Justification for Investigational Medicinal Product and Dose ....................................68 
6.3. 
Dosing and Administration .........................................................................................69 
6.4. 
Treatment of Overdose ...............................................................................................69 
6.5. 
Preparation, Handling, Labeling, Storage, and Accountability ..................................70 
6.5.1. 
Preparation of Investigational Medicinal Product ......................................................70 
6.5.2. 
Handling, Storage, and Security .................................................................................70 
6.5.3. 
Labeling ......................................................................................................................71 
6.5.4. 
Accountability .............................................................................................................71 
6.6. 
Participant Assignment, Randomization, and Blinding ..............................................71 
6.6.1. 
Participant Assignment ...............................................................................................71 
6.6.2. 
Randomization ............................................................................................................71 
6.6.2.1. 
Maintenance of Randomization ..................................................................................72 
6.6.3. 
Blinding and Unblinding ............................................................................................72 
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6.7. 
Trial Intervention Compliance ....................................................................................72 
6.8. 
Prior and Concomitant Therapy ..................................................................................72 
6.8.1. 
Prohibited Concomitant Therapy ................................................................................72 
6.8.2. 
Permitted Concomitant Therapy .................................................................................73 
7. 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
WITHDRAWAL FROM TRIAL ...............................................................................75 
7.1. 
Discontinuation of Trial Intervention .........................................................................75 
7.2. 
Participant Withdrawal from the Trial ........................................................................76 
7.3. 
Lost to Follow-up .......................................................................................................77 
7.4. 
Trial Stopping Rules ...................................................................................................77 
8. 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................79 
8.1. 
Screening/Baseline Assessments and Procedures ......................................................79 
8.2. 
Efficacy Assessments and Procedures ........................................................................79 
8.3. 
Safety Assessments and Procedures ...........................................................................79 
8.3.1. 
Physical Examinations ................................................................................................80 
8.3.2. 
Vital Signs ..................................................................................................................80 
8.3.3. 
Electrocardiograms .....................................................................................................81 
8.3.4. 
Clinical Laboratory Tests ...........................................................................................81 
8.3.4.1. 
Chemistry, Hematology, Coagulation, and Urinalysis ...............................................81 
8.3.4.2. 
Other Laboratory Tests ...............................................................................................82 
8.3.5. 
Neurological and Clinical Symptoms Measures .........................................................83 
8.3.5.1. 
 ......................................................................83 
8.3.5.2. 
 .................................................................................................83 
8.3.5.3. 
 ....................................................................83 
8.3.5.4. 
....................................................................................84 
8.3.5.5. 
 ..............................................84 
8.3.5.6. 
 ....................................................................84 
8.3.6. 
Assessment of Local Tolerability and Pain ................................................................84 
8.3.7. 
Procedures for Injection Site Pus-containing Lesion (Abscess, Infection, or 
Inflammation), Ulceration, Necrosis, or Atrophy .......................................................86 
8.3.8. 
Post-injection Delirium and Sedation Syndrome (PDSS) Monitoring .......................87 
8.3.9. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................88 
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8.3.10. 
Overall Tolerability ....................................................................................................89 
8.4. 
Adverse Events and Serious Adverse Events .............................................................89 
8.4.1. 
Definitions of Adverse Events and Serious Adverse Events ......................................89 
8.4.1.1. 
Adverse Events ...........................................................................................................89 
8.4.1.2. 
Serious Adverse Events ..............................................................................................90 
8.4.1.3. 
Adverse Device Effects and Serious Adverse Device Effects ....................................90 
8.4.2. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................91 
8.4.3. 
Identifying Adverse Events and Serious Adverse Events ..........................................91 
8.4.4. 
Recording of Adverse Events and Serious Adverse Events .......................................91 
8.4.4.1. 
Severity of an Adverse Event .....................................................................................94 
8.4.4.2. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device ..............................................................................................................94 
8.4.4.3. 
Expectedness of Serious Adverse Events ...................................................................95 
8.4.5. 
Follow-up of Adverse Events and Serious Adverse Events .......................................96 
8.4.6. 
Reporting of Serious Adverse Events .........................................................................96 
8.4.7. 
Regulatory Reporting Requirements for Serious Adverse Events .............................96 
8.4.8. 
Adverse Events of Special Interest .............................................................................97 
8.4.8.1. 
Protocol-defined Adverse Events of Special Interest that Require Reporting 
to Sponsor’s Global Pharmacovigilance .....................................................................97 
8.4.8.2. 
Protocol-defined Adverse Events of Special Interest that do not Require 
Reporting to Sponsor’s Global PV .............................................................................97 
8.4.9. 
Protocol Deviations Because of an Adverse Event ....................................................98 
8.5. 
Pregnancy and Postpartum Information .....................................................................98 
8.6. 
Clinical Product Complaints .......................................................................................99 
8.6.1. 
Definition of Clinical Product Complaints .................................................................99 
8.6.2. 
Handling the IMP/Devices at the Investigational Center ...........................................99 
8.6.3. 
Product Complaint Associated with Adverse Events or Serious Adverse 
Events .........................................................................................................................99 
8.7. 
Pharmacokinetics ......................................................................................................100 
8.7.1. 
Timing of Pharmacokinetic Sampling ......................................................................100 
8.7.2. 
Changes to Pharmacokinetic Sampling Scheme .......................................................100 
8.7.3. 
Pharmacokinetic Parameters .....................................................................................100 
8.8. 
Pharmacodynamics ...................................................................................................101 
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8.9. 
Genetics ....................................................................................................................101 
8.9.1. 
Pharmacogenomics ...................................................................................................101 
8.10. 
Biomarkers ................................................................................................................101 
8.10.1. 
Digital Biomarkers ....................................................................................................102 
8.11. 
Immunogenicity Assessments ..................................................................................102 
8.12. 
Medical Resource Utilization and Health Economics ..............................................102 
8.13. 
Total Blood Volume .................................................................................................102 
8.14. 
Assessment of Leakage .............................................................................................102 
9. 
STATISTICAL CONSIDERATIONS .....................................................................104 
9.1. 
Analysis Sets .............................................................................................................104 
9.1.1. 
Enrolled Analysis Set ...............................................................................................104 
9.1.2. 
Pharmacokinetics Analysis Set .................................................................................104 
9.1.3. 
Safety Analysis Set ...................................................................................................104 
9.1.4. 
Pharmacogenomics Analysis Set ..............................................................................104 
9.2. 
Analyses Supporting Primary Objective(s) ..............................................................104 
9.2.1. 
Statistical Model, Hypothesis, and Method of Analysis...........................................104 
9.2.2. 
Handling of Missing Data .........................................................................................105 
9.2.3. 
Sensitivity Analyses ..................................................................................................105 
9.2.4. 
Supplementary Analyses ..........................................................................................105 
9.2.5. 
Multiplicity Adjustment............................................................................................105 
9.3. 
Analysis Supporting Secondary Objective(s) ...........................................................105 
9.4. 
Analysis of Exploratory Objective(s) .......................................................................105 
9.4.1. 
Pharmacogenomic Analyses .....................................................................................105 
9.5. 
Safety Analyses ........................................................................................................106 
9.6. 
Other Analyses ..........................................................................................................107 
9.6.1. 
Population Pharmacokinetic Analysis ......................................................................107 
9.6.2. 
Pharmacogenetic and Biomarker Analysis ...............................................................107 
9.7. 
Interim Analyses .......................................................................................................107 
9.8. 
Sample Size Determination ......................................................................................107 
9.9. 
Protocol Deviations ..................................................................................................108 
10. 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND 
TRIAL OVERSIGHT ...............................................................................................109 
10.1. 
Regulatory and Ethical Considerations ....................................................................109 
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10.2. 
Committees ...............................................................................................................110 
10.3. 
Informed Consent Process ........................................................................................110 
10.4. 
Data Protection .........................................................................................................111 
10.5. 
Early Investigational Center Closure or Trial Termination ......................................112 
11. 
GENERAL CONSIDERATIONS: RISK MANAGEMENT AND 
QUALITY ASSURANCE ........................................................................................114 
11.1. 
Quality Tolerance Limits ..........................................................................................114 
11.2. 
Data Quality Assurance ............................................................................................114 
11.3. 
Source Data ...............................................................................................................116 
12. 
APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS – 
DEFINITIONS, SEVERITY, AND CAUSALITY ..................................................119 
13. 
APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL 
DETAILS ..................................................................................................................120 
13.1. 
Contraception and Pregnancy Testing ......................................................................120 
13.1.1. 
Definitions Related to Childbearing Potential ..........................................................120 
13.1.2. 
Contraception ............................................................................................................121 
13.1.3. 
Pregnancy Testing ....................................................................................................122 
13.2. 
Clinical Laboratory Tests .........................................................................................123 
13.3. 
Prior Protocol Amendments .....................................................................................123 
13.4. 
List of Prohibited Medications .................................................................................129 
13.5. 
Financial Disclosure .................................................................................................129 
13.6. 
Recruitment Strategy ................................................................................................129 
13.7. 
Dissemination of Clinical Trial Data ........................................................................130 
13.8. 
Publication Policy .....................................................................................................130 
14. 
APPENDIX: GLOSSARY OF TERMS ...................................................................132 
15. 
REFERENCES .........................................................................................................135 
 
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LIST OF TABLES 
Table 1: 
Screening, Antipsychotic Washout Period, and ZYPREXA IM Treatment 
Period 1: Trial Procedures and Assessments (Day -40 Through Day 4) ....................23 
Table 2: 
ZYPREXA IM Follow-up Period 2: Trial Procedures and Assessments (Day 
5 through Day 12) .......................................................................................................26 
Table 3: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for 
Cohort 1A: Trial Procedures and Assessments (Day R1 through Day R25) ..............29 
Table 4: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for 
Cohort 1B, Cohort 2, and Cohort 3: Trial Procedures and Assessments (Day 
R1 through Day R25) ..................................................................................................33 
Table 5: 
Subcutaneous Olanzapine Extended-release Follow-up Period: Trial 
Procedures and Assessments (Day R29 through Day R84) ........................................37 
Table 6: 
Schedule of Assessments for Pharmacokinetic Sampling Before and After 
ZYPREXA IM Administration ...................................................................................40 
Table 7: 
Schedule of Assessments for Pharmacokinetic Sampling Before and After 
Olanzapine Extended-release SC Formulation Administration ..................................40 
Table 8: 
Trial Procedures and Assessments in Case of a Suspected Post-injection 
Delirium/Sedation Syndrome Event ...........................................................................41 
Table 9: 
Investigational Medicinal Products used in the Trial .................................................66 
Table 10: Dose Administration Details for Olanzapine in Treatment Period 3 ..........................69 
Table 11: Assessment of Local Tolerability (Injection Site Findings) .......................................86 
Table 12: The Relationship of an Adverse Event to the Investigational Medicinal 
Product and/or Device ................................................................................................95 
Table 13: Leakage Evaluation ..................................................................................................103 
Table 14: Contraceptives Allowed During the Trial .................................................................121 
Table 15: Clinical Laboratory Tests .........................................................................................123 
Table 16: Partial List of Prohibited Medications ......................................................................129 
 
LIST OF FIGURES 
Figure 1: 
Trial Schematic Diagram ............................................................................................21 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification .........93 
 
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1. 
PROTOCOL SUMMARY  
1.1. 
Protocol Synopsis  
Protocol Title: A Multi-center, Open-label, Randomized, Parallel-group Trial to Characterize 
the Pharmacokinetics of Three SC Olanzapine Extended-release Formulations with Different 
Release Rates Following Single Administration in Participants with Schizophrenia or 
Schizoaffective Disorder. 
Brief Title: Open-label Trial Characterizing the PK of 3 SC Olanzapine Extended-release 
Formulations in Participants with Schizophrenia/Schizoaffective Disorder.  
Regulatory Agency Identifier Number(s): IND 128851 
Rationale: To characterize the pharmacokinetics of 3 sc olanzapine extended-release injectable 
suspensions (TV-44749) with different release rates following single administration in 
participants with schizophrenia or schizoaffective disorder. The results from the current trial will 
be utilized for the development of an in vitro/in vivo correlation (IVIVC) model. The objective 
of developing an IVIVC is to establish a predictive mathematical model describing the 
relationship between an in vitro property (usually the rate or extent of drug dissolution or 
release) and a relevant in vivo response (plasma drug concentration or amount of drug absorbed), 
per the Food and Drug Administration (FDA) guidance (FDA, 1997) on the development, 
evaluation, and application of IVIVC for extended-release oral products. The results of the 
IVIVC analysis will be presented in a separate report. 
Name of IMP: The trial will include four IMPs: 
1. Olanzapine for Extended-release Injectable Suspension D (TV-44749) (hereafter referred 
to as Fast-D) 
2. Olanzapine for Extended-release Injectable Suspension (TV-44749) (hereafter referred to 
as the to-be-marketed formulation) 
3. Olanzapine for Extended-release Injectable Suspension C (TV-44749) (hereafter referred 
to as Slow-C) 
4. ZYPREXA IntraMuscular (olanzapine) Injection, Powder, for Solution for im use 
(immediate-release) (hereafter referred to as ZYPREXA im) 
Intervention Type: Drug 
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Primary and Secondary Objectives, Endpoints:  
The primary and secondary objectives and measures are presented below: 
Objectives 
Measures 
Primary 
To characterize the 
pharmacokinetics of 3 extended-
release sc olanzapine formulations 
with different release rates 
following single administration in 
participants with schizophrenia or 
schizoaffective disorder. 
The following pharmacokinetic parameters will be calculated for olanzapine, 
following single administration of 3 sc olanzapine extended-release 
formulations to support the primary objective of the trial: 
• 
Maximum observed plasma drug concentration (Cmax) over the 
84-day period following single-dose administration of 1 of the sc 
formulations to end of trial (EOT) (day R1 to day R84) 
• 
Area under the plasma drug concentration-time curve (AUC) 
following single-dose administration of 1 of the sc formulations to 
last measurable concentration (AUC0-t) (day R1 to day R84) 
• 
AUC extrapolated to infinity (AUC0-∞) calculated from last 
measurable olanzapine plasma concentration following single-dose 
administration of 1 of the sc formulations from time 0 to EOT (day 
R1 to day R84) 
Secondary 
To evaluate the safety and tolerability 
of 3 extended-release sc olanzapine 
formulations with different release 
rates in participants with 
schizophrenia or schizoaffective 
disorder. 
The following safety and tolerability measures/parameters will be evaluated: 
• 
Number (%) of participants with at least 1 treatment-emergent 
adverse event (TEAE) over the 28-day period following 
administration of 1 of the sc olanzapine formulations (day R1 to day 
R29)  
• 
Number (%) of participants with at least 1 serious adverse event 
(SAE) over the 28-day period following administration of 1 of the sc 
olanzapine formulations (day R1 to day R29)  
To characterize the 
pharmacokinetics of immediate-
release ZYPREXA im in 
participants with schizophrenia or 
schizoaffective disorder. 
The following pharmacokinetic parameters will be calculated for ZYPREXA 
im to support the secondary objective of the trial: 
• 
Cmax over the 24-hour period following single-dose administration of 
the im formulation (day 4) 
• 
AUC following single-dose administration of ZYPREXA im to 
last measurable concentration (AUC0-t) (pre-dose ZYPREXA 
im to 216 hours post im administration) 
• 
Apparent plasma terminal elimination rate constant (λz) over the 
216-hour period (9 days) following single-dose administration 
of ZYPREXA im (pre-dose ZYPREXA im to 216 hours post 
im administration) 
Overall Design: This is a multi-center, open-label, randomized, parallel-group trial to 
characterize the pharmacokinetics profile of 3 subcutaneous (sc) olanzapine extended-release 
formulations with different release rates, in participants with schizophrenia or schizoaffective 
disorder. The trial population will include clinically stable participants 18 to 64 years of age, not 
currently on antipsychotic treatment, with the exception of treatment with oral antipsychotics 
including aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone. The trial will be 
conducted in the US at approximately 5 investigational centers. 
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Participants currently treated with 1 of the antipsychotics allowed per the trial protocol 
(aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone) and who meet screening 
eligibility will undergo a 3-day inpatient washout (WO) period of the current antipsychotic 
treatment. Thereafter, participants will continue to period 1 that will include a single injection of 
5 mg of ZYPREXA im (day 4). Subsequently, participants will continue to the follow-up 
period 2 (day 5 to day 12) during which they will resume treatment with 1 of the allowed 
antipsychotics at the Investigator's discretion. Period 2 can be extended by up to 7 days 
maximum, post Visit 10 (Visit 10 counts as extension day 1, so extension day 7 is R1, at 
maximum) for all cohorts. Follow-up period 2 is followed by a 28-day treatment period (period 
3: day R1 to R29, where R1 is the first day post-randomization and the beginning of period 3), 
during which participants will be treated with 1 of the 3 single-dose sc olanzapine for 
extended-release IMP formulations (cohorts 1A and 1B will be treated with Fast-D; cohort 2 
with the to-be-marketed formulation; cohort 3 will be treated with Slow-C). During period 3, 
participants will discontinue treatment with the allowed antipsychotic medication received 
during period 2. Period 3 will be initiated with treatment of a sentinel cohort, cohort 1A 
(2-4 participants). Cohort 1A will serve for initial evaluation of systemic safety and tolerability 
of the Fast-D formulation. If no safety concerns are raised based on the review of cohort 1A 
safety data up to 15 days (R15) inclusive, period 3 for cohort 1B (n~16) may be initiated. 
Randomization to cohort 2 (n~20) and cohort 3 (n~20) will be initiated in parallel to cohort 1B. 
Following completion of period 3, all participants enter a 56-day follow-up period during which 
they will resume treatment with the allowed antipsychotics at the Investigator’s discretion 
(day R29 to day R84).  
The trial schematic diagram is presented in Figure 1. 
Number of Participants: Approximately 95 participants are planned to be enrolled. The aim is to 
achieve approximately 20 completers in each of the single-dose sc olanzapine extended-release 
cohorts, for a total of approximately 60 completers. Completers are defined as participants who 
have completed the procedures and assessments required through the follow-up period of sc 
olanzapine extended-release (ie, the 84 days after the sc injection, up to and including day R84). 
Trial Arms and Duration: Participants are expected to participate in this trial for its entire 
duration of approximately 19 weeks. The trial will consist of a screening period (up to 40 days), a 
3-day WO period (day 1 to day 3), an open-label 1-day treatment period with ZYPREXA im 
(period 1: day 4), an 8-day follow-up period (period 2: day 5 to day 12), an open-label 
randomized 28-day treatment period with 1 of the 3 sc olanzapine (TV-44749) for 
extended-release formulations (period 3: day R1 to day R29), and an up to approximately 8-week 
follow-up period (day R29 to day R84). During the follow-up periods (period 2 and follow-up 
period post-sc injection), treatment with 1 of the allowed antipsychotics (aripiprazole, 
risperidone, paliperidone, quetiapine, or lurasidone) will be resumed as per the Investigator’s 
discretion.  
Data Monitoring/Other Committee: A safety review committee composed of the Sponsor’s 
clinical trial physician, clinical leader, pharmacovigilance physician, and other relevant experts 
has been appointed for this trial. The committee will review all safety data available upon 
completion of the first 15 days of the sentinel cohort (cohort 1A), and no other ongoing safety 
monitoring by the committee is expected.  
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Ethical Considerations: The trial design, inclusion/exclusion criteria, and procedures have been 
developed in a manner to protect participant safety. The results of this trial may facilitate the 
development of TV-44749 with potential benefits for participants with schizophrenia and 
schizoaffective disorder. The availability of an extended-release antipsychotic agent may 
increase compliance in participants with schizophrenia.
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1.2. 
Trial Schema  
Figure 1: 
Trial Schematic Diagram  
 
 
AP=antipsychotic; EOT=end of treatment; IM=intramuscular; IR=immediate-release; OLZ=olanzapine; sc=subcutaneous; SD=single-dose; SRC=safety review committee; 
WO=washout 
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1.3. 
Schedule of Activities  
Trial procedures and assessments with their time points during screening, the antipsychotic 
washout period and treatment period 1 are presented in Table 1. Trial procedures and 
assessments with their time points during period 2 are presented in Table 2. Trial procedures and 
assessments during treatment period 3 for the Fast-D cohort 1A are presented in Table 3, and for 
cohorts 1B, 2, and 3 in Table 4. Trial procedures and assessments during the follow-up period 
following administration of sc olanzapine for extended-release are presented in Table 5. 
Trial procedures and assessments for pharmacokinetic sampling windows after ZYPREXA im 
administration are presented in Table 6, while those after olanzapine sc formulation 
administration are presented in Table 7. 
Trial procedures and assessments to be performed in the case of a suspected post-injection 
delirium/sedation syndrome (PDSS) event are present in Table 8.  
Detailed descriptions of each method of procedures and assessments are provided in Section 8 
(Trial Assessments and Procedures).  
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Table 1: 
Screening, Antipsychotic Washout Period, and ZYPREXA IM Treatment Period 1: Trial Procedures and 
Assessments (Day -40 Through Day 4)  
APPLICABLE TO ALL COHORTS: 1A, 1B, 2, and 3 
Procedures and assessments 
Screening 
Antipsychotic washout period 
Period 1: 
ZYPREXA IM 
Outpatienta         
Inpatient 
Visit number 
V1 
V2 
V3 
V4 
Trial day 
-40 through -1 
1b         
3 
4 
Informed consentc         
X 
 
 
 
Demographics 
X 
 
 
 
Medical and psychiatric history 
X 
 
 
 
Prior medication history 
X 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
Xd         
Enrollment 
 
X 
 
 
ZYPREXA IM injectione         
 
 
 
X 
Vital sign measurementsf         
X 
X 
X 
12-lead ECGg         
X 
X 
X 
Physical examinationh         
X 
 
X 
 
Physical measurementsi         
X 
X 
 
Clinical laboratory testsj         
X 
X 
 
Xk 
Alcohol and drug screenl         
X 
X 
X 
 
Pregnancy testm         
X 
X 
X 
 
Serology testn         
X 
 
 
 
FSH testo         
X 
 
 
 
 
X 
X 
 
 
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Table 1: 
Screening, Antipsychotic Washout Period, and ZYPREXA IM Treatment Period 1: Trial Procedures and 
Assessments (Day -40 Through Day 4) (Continued) 
APPLICABLE TO ALL COHORTS: 1A, 1B, 2, and 3 
Procedures and assessments 
Screening 
Antipsychotic washout period 
Period 1: 
ZYPREXA IM 
Outpatienta 
Inpatient 
Visit number 
V1 
V2 
V3 
V4 
Trial day 
-40 through -1 
1b 
3 
4 
 
X 
X 
 
Xp         
 
X 
X 
 
Xp 
 
X 
X 
 
Xp 
 
X 
X 
 
 
 
Xq         
X 
 
 
NPRS for painr         
 
 
 
X 
Adverse event recording 
 
X 
X 
X 
Concomitant medication review 
 
X 
X 
X 
Pharmacokinetic blood sample collections         
 
 
X 
Admission to CU 
 
X 
 
 
Inpatient in CU 
 
 
X 
X 
a Participants will visit the CU for screening as an outpatient.  
b Participant enrollment occurs on day 1. On day 1 of the washout period of antipsychotics, participants will be admitted to the CU for trial procedures and assessments. 
c Written informed consent will be obtained from each participant before any trial-specific procedures or assessments are performed. A separate written informed consent will be 
obtained from each participant before the biomarker samples are collected during period 3. 
d Participants’ continued eligibility will be reconfirmed by review of abbreviated inclusion and exclusion criteria prior to administration of ZYPREXA im. The abbreviated list 
will include the following inclusion criteria (g, h) and exclusion criterion (a); the clinical scales and laboratory tests taken on day 1 will be used to confirm eligibility on day 3. 
In case of a delay, laboratory results can be reviewed to perform abbreviated eligibility assessment on day 4, as long as this is done prior to administration of ZYPREXA im. 
Laboratory results from blood samples collected on day 4 are not required prior to initiating ZYPREXA im. Day 4 central clinical laboratory assessments will serve as baseline 
values and are based on samples collected prior to dosing of ZYPREXA im. Serology to support eligibility criteria will only be done at screening. 
e ZYPREXA im injection will be administered into the gluteal muscle. 
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f Vital signs include body temperature, respiratory rate, supine or semi-supine pulse rate and blood pressure. Pulse, blood pressure, and respiratory rate will be measured after the 
patient has been supine or semi-supine for at least 5 min. Orthostatic vital signs will be determined with measurements obtained after the patient has been supine or semi-supine 
for at least 5 min and repeated after the patient has been standing for 3 min. Body temperature will be measured only in the supine or semi-supine body position. Vital signs will 
be measured at screening on day 3 and on day 4. On day 4 vital signs will be measured at 45 min and at 6 h post-dose. Vital signs will be measured after ECGs but before 
scheduled blood draws, up to 30 min prior to the time point, when applicable. 
g ECGs will be performed at screening, day 3, and day 4 after the participant has been in a supine or semi-supine position for at least 5 min. At screening only, the ECG will be 
obtained in triplicate at 5-min intervals. On day 4 ECG will be performed at 0.5 h and 6 h post-dose. The ECGs will be recorded before vital sign assessments and scheduled 
blood draws, up to 30 min prior to the time point, when applicable.  
h A complete physical examination will be performed at screening and an abbreviated physical examination will be performed on day 3. The abbreviated physical examination 
will include general appearance, HEENT, lung, heart, skin, extremities, and a brief neurological examination. 
i Includes height, weight, and calculation of BMI at screening; on day 3 only weight will be measured. 
j Clinical laboratory tests will be performed following an overnight fast of at least 8 h and will include chemistry, hematology, coagulation, and urinalysis. HbA1c will be 
collected at screening. On day 1 and day 4 clinical laboratory tests may be performed via both local and central laboratories, as applicable. Non-fasting blood collection is 
permitted as needed, per Investigator assessment of adverse events. At each urinalysis collection, females will be asked if they are currently menstruating. Day 1 results will be 
used to confirm eligibility on day 3. In case of a delay, laboratory results can be reviewed to perform abbreviated eligibility assessment on day 4, as long as this is done prior to 
administration of ZYPREXA im.  
k Blood samples will be collected prior to dosing. Laboratory results from blood samples collected on day 4 are not required prior to initiating ZYPREXA im, but are required 
prior to initiating period 3. Serology to support eligibility criteria will only be done at screening. 
l Serum alcohol and serum drug screen will be performed at screening; urine dipstick for prohibited drugs and breathalyzer for alcohol will be performed on day 1 and day 3. 
Drug and alcohol screens may be conducted at additional time points at the discretion of the Investigator. 
m Serum pregnancy tests will be performed for all female participants at screening and on day 1. Serum or urine dipstick pregnancy tests will be performed for all women of 
childbearing potential on day 3. Negative result is required prior to ZYPREXA im injection. Additional pregnancy tests may be performed if clinically indicated. 
n Includes HBsAg, hepatitis C virus antibody, HIV-1 antibodies, and HIV-2 antibodies. 
o For confirmation of postmenopausal status (an increased concentration of FSH of more than 35 IU/L in women not using hormonal contraception or hormonal replacement 
therapy). 
p 
 
q 
 
r On day 4, pain will be assessed 30 min after the completion of ZYPREXA im administration, and pain and injection site findings will be assessed 3 h after the completion of 
administration. Allowed time windows for these local tolerability assessments are ±15 min. In case an adverse event associated with an ISR is reported, pain may be assessed 
periodically using an NPRS until resolution. No time windows are specified for these assessments.  
s Pharmacokinetic blood samples will be collected on day 4 pre-dose (up to 30 min prior to dosing); 10, 20, 30, 45 min and 1, 2, 3, 4, 6, 8, and 12 h post-dose relative to the 
single-dose of ZYPREXA im. For allowable time windows of sample collection, refer to Table 6.  
 
 BMI=body mass index; 
 
CU=clinical unit; 
 ECG=electrocardiogram; FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; 
HEENT=head, eyes, ears, nose, throat; HIV=human immunodeficiency virus; im=intramuscular; ISR=injection site reaction; NPRS=numeric pain rating scale; 
 
; 
 
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Table 2: 
ZYPREXA IM Follow-up Period 2: Trial Procedures and Assessments (Day 5 through Day 12)  
APPLICABLE TO ALL COHORTS: 1A, 1B, 2, and 3 
Procedures and 
assessments 
ZYPREXA IM Follow-Up Period 2 (Day 5 through Day 12) 
Period 2 Extension 
(as needed)a         
Unscheduled visitb 
Visit number 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Trial day 
5 
6 
7 
8 
9 
12c         
13 
Vital sign measurementsd         
X 
X  
 
 
X 
 
X 
12-lead ECGe         
X 
 
X 
 
 
X 
 
 
Physical examinationf         
 
 
X 
 
 
X 
 
 
Physical measurementsg         
 
 
 
 
X 
 
 
Clinical laboratory testsh         
X 
 
X 
 
 
X 
 
 
Pregnancy testi         
 
 
 
 
 
X 
 
 
Alcohol screenj         
 
 
 
 
 
X 
 
 
Drug screenk         
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
l         
 
 
 
 
 
X 
 
X 
Resumption of 
antipsychoticm         
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic blood 
sample collectionn         
X 
X 
X 
X 
X 
X 
X 
X 
Smoking statuso         
X 
 
 
 
 
X 
 
 
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Table 2: 
ZYPREXA IM Follow-up Period 2: Trial Procedures and Assessments (Day 5 through Day 12) (Continued) 
APPLICABLE TO ALL COHORTS: 1A, 1B, 2, and 3 
Procedures and 
assessments 
ZYPREXA IM Follow-Up Period 2 (Day 5 through Day 12) 
Period 2 Extension 
(as needed)a 
Unscheduled visitb 
Visit number 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Trial day 
5 
6 
7 
8 
9 
12c 
13 
Biomarker blood sample 
collection 
 
 
 
 
X 
 
 
Inpatient in CU 
X 
X 
 
 
 
 
 
 
Discharge from CUp         
 
 
X 
 
 
 
 
 
Outpatient visitsq         
 
 
 
X 
X 
 
 
 
Admission to CUr         
 
 
 
 
 
X 
 
 
Adverse event recording 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
a Period 2 may be extended up to an additional maximum of 7 days, post V10 (V10 counts as extension day 1, so extension day 7 is R1 at maximum) for all cohorts as needed, 
prior to allowing participants to begin period 3. Participants who enter this extension period and do not proceed directly into period 3 (outlined in Table 3 for cohort 1A and 
Table 4 for cohorts 1B, 2, and 3), should return to the clinic for a PK sample collection on day 13 (V11) at 216±3 h post the ZYPREXA im dosing. 
b All procedures marked in the table are mandatory during unscheduled visits. Other procedures may be performed at the discretion of the Investigator. In addition, to reduce 
patient burden and to avoid unnecessary data collection, the Investigator will have discretion in determining whether the procedures that are marked as mandatory actually need 
to be performed during the unscheduled visit in the case that the visit is for administrative purposes (eg, reconsenting) or clinical 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). 
c All participants should attend the day 12 visit at the clinic. 
d Vital signs include body temperature, respiratory rate, supine or semi-supine pulse rate and blood pressure. Pulse, blood pressure, and respiratory rate will be measured after the 
patient has been supine or semi-supine for at least 5 min. Body temperature will be measured only in the supine or semi-supine body position. Vital signs will be measured on 
days 5, 7, 12, and during unscheduled visits (if applicable). On day 5, vital signs will be measured 24 h following administration of ZYPREXA im. Vital signs will be measured 
after ECGs but before scheduled blood draws, up to 30 min prior to the time point, when applicable.  
e ECGs will be obtained after the patient has been in a supine or semi-supine position for at least 5 min. The ECG will be recorded before vital sign assessments and scheduled 
blood draws, up to 30 min prior to the time point, when applicable. On day 5, the ECG will be performed 24 h following administration of ZYPREXA im. 
f The abbreviated physical examination will include general appearance, HEENT, lung, heart, skin, extremities, and a brief neurological examination. 
g Includes weight measurement only. 
h Clinical laboratory tests will be performed following an overnight fast of at least 8 h and will include chemistry, hematology, coagulation, and urinalysis. Non-fasting blood 
collection is permitted as needed, per Investigator assessment of adverse events. At each urinalysis collection, females will be asked if they are currently menstruating. 
i A serum pregnancy test will be performed for all women, regardless of childbearing potential, only on day 12 (V10) and will be performed both in central and local laboratories. 
A negative result is required prior to administering olanzapine extended-release sc injection on day R1. Additional pregnancy tests may be performed if clinically indicated. 
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j Breathalyzer for alcohol, to be conducted at the discretion of the Investigator. Alcohol screens may be conducted at additional time points at the discretion of the Investigator. 
k In-house urine dipstick for prohibited drugs, to be conducted at the discretion of the Investigator. Drug screens may be conducted at additional time points at the discretion of 
the Investigator.  
l 
 
m Dosing (initial dose and any dose modifications) and administration of the allowed antipsychotic (aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone) at the 
discretion of the Investigator. At each visit, participants will be asked about whether or not they are taking 1 of the allowed antipsychotics and their response will be entered in 
the eCRF. 
n Pharmacokinetic blood samples to continue to characterize the elimination phase of the IM injection will be collected post-dose at the following time points: 24, 48, 72, 96, 120, 
and 192 h, at approximately the same time relative to the single-dose of ZYPREXA im. For participants who enter the optional extension period, a PK sample will also be 
collected at 216±3 h post-dose on day 13 (V11); for those who proceed directly to period 3, the 216 h post-dose sample will be collected prior to sc dosing as shown in Table 3 
for cohort 1A and Table 4 for cohorts 1B, 2, and 3. After 24 h of ZYPREXA im administration, where applicable, PK samples should be collected at approximately the same 
time of day as dosing. For allowable time windows of sample collection, refer to Table 6. 
o Data on smoking status will be collected using the following questions if cigars, pipes, or cigarettes are used: “How many cigarettes, cigars, or pipes did you smoke over the 
past 7 days?” and "Has your smoking status/tobacco use remained the same compared to at the time of screening”? Use of cigars and pipes will be converted into cigarette use 
with a ratio of 1 cigar or pipe = 2.5 cigarettes.  
p Participants will be followed up in the CU until day 3 after ZYPREXA im (day 7), when they be discharged from the CU after completion of day 7 assessments. 
q Day 8 and day 9 can be inpatient or outpatient per the Investigator’s discretion.  
r Participants will be readmitted to the CU on day 12 prior to administration of olanzapine extended-release sc. 
 
 
CU=clinical unit; 
 ECG=electrocardiogram; eCRF=electronic case report form; HEENT=head, eyes, ears, nose, throat; im=intramuscular; 
; 
 sc=subcutaneous. 
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Table 3: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for Cohort 1A: Trial Procedures and 
Assessments (Day R1 through Day R25)  
APPLICABLE TO COHORT 1A (Fast-D): SC Olanzapine for Extended-release  
Procedures and 
assessments 
SC olanzapine extended-release treatment period 3  
(day R1 through day R25) 
Unscheduled 
visita         
Visit number 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
Day from sc injection 
(visit window) 
R1 
R2 
R3 
R4 
R5 
R6 
R7 
R8 
R10 
R11 
R13 
R15b 
(±1)    
R18 
(±1) 
R22 
(±1) 
R25 
(±2) 
PGx blood sample 
collectionc         
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurementsd         
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
12-lead ECGe         
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Physical examinationf      
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Clinical laboratory 
testsg         
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pregnancy testh         
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Alcohol screeni         
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Drug screenj         
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
k         
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Olanzapine extended-
release administration  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
30 
Table 3: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for Cohort 1A: Trial Procedures and 
Assessments (Day R1 through Day R25) (Continued) 
APPLICABLE TO COHORT 1A (Fast-D): SC Olanzapine for Extended-release  
Procedures and 
assessments 
SC olanzapine extended-release treatment period 3  
(day R1 through day R25) 
Unscheduled 
visita 
Visit number 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
Day from sc injection 
(visit window) 
R1 
R2 
R3 
R4 
R5 
R6 
R7 
R8 
R10 
R11 
R13 
R15b 
(±1) 
R18 
(±1) 
R22 
(±1) 
R25 
(±2) 
Post-injection 
delirium/sedation 
syndrome monitoringl      
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection site 
tolerability and pain 
assessmentm         
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Smoking statusn         
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Pharmacokinetic 
blood sample 
collectiono         
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker blood 
sample collectionp         
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Inpatient period CUq        
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Discharge from CU 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Outpatient visitsr         
 
 
 
 
 
 
X 
X 
X 
X 
Adverse event 
recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a All procedures marked in the table are mandatory during unscheduled visits. Other procedures may be performed at the discretion of the Investigator. In addition, to reduce 
participant burden and to avoid unnecessary data collection, the Investigator will have discretion in determining whether the procedures that are marked as mandatory actually 
need to be performed during the unscheduled visit in the case that the visit is for administrative purposes (eg, reconsenting) or clinical reasons (eg, repeat laboratory sample 
collection for reasons unrelated to an adverse event and not due to a change in the participant’s medical status per clinical judgment). 
VV-00495638 v5.0

Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
31 
b The SRC will review safety data available up to day R15, inclusive, for cohort 1A. For participants who miss this visit, all assessments must be performed on the immediate 
next visit performed. 
c In case the pharmacogenomics sample cannot be collected on R1, it should be collected at the next possible visit. 
d Vital signs include body temperature, respiratory rate, supine or semi-supine pulse rate and blood pressure (systolic and diastolic), and their orthostatic changes. On R1, vital 
signs will be measured pre-dose. Pulse, blood pressure, and respiratory rate will be measured after the participant has been supine or semi-supine for at least 5 min. Orthostatic 
vital signs will be determined with measurements obtained after the participant has been supine or semi-supine for at least 5 min and repeated after the participant has been 
standing for 3 min. Vital signs will be measured after ECGs but before scheduled blood draws, up to 30 min prior to the time point, when applicable. 
e ECGs will be obtained after the participant has been in a supine or semi-supine position for at least 5 min. The ECG will be recorded before vital sign assessments and 
scheduled blood draws, up to 30 min prior to the time point, when applicable. On R1, the ECG will be performed pre-dose. On R2, the ECG will be performed 24 h following 
administration of the sc olanzapine extended-release formulation. 
f An abbreviated physical examination will be performed. The abbreviated physical examination will include general appearance, HEENT, lung, heart, skin, extremities, and a 
brief neurological examination. On R1, the abbreviated physical examination will be performed pre-dose. 
g Clinical laboratory tests will be performed following an overnight fast of at least 8 h and will include chemistry, hematology, coagulation, and urinalysis. HbA1c will be 
collected at day R1 pre-dose. Non-fasting blood collection is permitted as needed, per Investigator assessment of adverse events. At each urinalysis collection, females will be 
asked if they are currently menstruating. Blood and urine samples will be collected prior to dosing on day R1. Laboratory results from blood samples collected on day R1 are 
not required pre-dose. Day R1 central clinical laboratory assessments will serve as the baseline values for the sc olanzapine extended-release formulation. 
h A urine dipstick pregnancy test will be performed for all women of childbearing potential. In case period 2 is extended, a urine dipstick pregnancy test will be performed for all 
women of childbearing potential at visit R1 with a confirmation test of negative results prior to dosing. Additional pregnancy tests may be performed if clinically indicated. 
i Breathalyzer for alcohol. In case period 2 is extended, the alcohol screen will be performed on day R1. Alcohol screens may be performed at additional time points at the 
discretion of the Investigator. 
j An in-house urine dipstick screen for prohibited drugs. In case period 2 is extended, in-house urine dipstick screen for prohibited drugs will be performed on day R1. Drug 
screens may be performed at additional time points at the discretion of the Investigator. 
k 
 
l Participants will remain under clinical observation for at least 3 h after injection to monitor for any potential symptoms of PDSS. In any event of suspected PDSS, unscheduled 
pharmacokinetic samples will be collected as soon as PDSS is suspected and at 3, 6, 12, and 24 h after the onset of the event and 24 h after resolution, or when feasible. Vital 
signs should be measured as soon as a suspected PDSS event is suspected and at the same time points that additional pharmacokinetic samples are collected. Additionally, a 
toxicological blood test will be performed as soon as PDSS is suspected, and unscheduled biomarker samples will be collected as soon as PDSS is suspected, 24 h after the 
onset of the event, and 24 h after resolution, or when feasible. 
m On R1, pain will be assessed 30 min after the completion of administration of any of the 3 olanzapine for extended-release sc formulations, and pain and injection site findings 
will be assessed 3 h after the completion of olanzapine sc administration. Allowed time windows for these local tolerability assessments are ±15 min. In case an adverse event 
associated with an ISR is reported, pain may be assessed periodically using an NPRS until resolution. Thereafter the site of injection will be assessed for local tolerability 
weekly (R8, R15, R22). 
n Data on smoking status will be collected using the following questions if cigars, pipes, or cigarettes are used: “How many cigarettes, cigars, or pipes did you smoke over the 
past 7 days?” and "Has your smoking status/tobacco use remained the same compared to at the time of screening”? Use of cigars and pipes will be converted into cigarette use 
with a ratio of 1 cigar or pipe = 2.5 cigarettes.  
o Pharmacokinetic blood samples will be collected pre-dose (up to 1 h prior to dosing of sc olanzapine at approximately 216±3 h post the ZYPREXA im dosing) (applicable 
ONLY for participants who have entered period 3 directly from period 2), at 3 h post-dose, and on R2, R3, R4, R5, R6, R7, R8, R10, R11, R13, R15, R18, R22, and R25 at 
approximately the same hour of the day as dosing. 
p Blood samples will be collected for biomarker assessment on R8 and in the event of the appearance of an adverse event related to pus-containing injection site lesions. Blood 
for biomarker analyses will be collected as follows: 6 mL for plasma and 2.5 mL for PAXgene RNA. 
q Participants will be treated in the CU until R15, when they will be discharged from the CU after completion of R15 assessments. 
r Participants will return to the CU on an outpatient basis for scheduled assessments. All visits must be scheduled within the provided windows and 2 visits cannot occur on the 
same day. 
 
 BMI=body mass index; 
 
CU=clinical unit; 
; ECG=electrocardiogram; HEENT=head, eyes, ears, nose, throat; im=intramuscular; ISR=injection site 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
32 
reaction; NPRS=Numeric Pain Rating Scale; 
 PDSS=post-injection delirium/sedation syndrome; PGx=pharmacogenomics; 
RNA=ribonucleic acid; 
; sc=subcutaneous; SRC=safety review committee. 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
33 
Table 4: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for Cohort 1B, Cohort 2, and Cohort 3: 
Trial Procedures and Assessments (Day R1 through Day R25)  
APPLICABLE TO COHORT 1B (Fast-D), COHORT 2 (to-be-marketed), AND COHORT 3 (Slow-C):  
SC Olanzapine for Extended-release  
Procedures and 
assessments 
SC olanzapine extended-release treatment period 3 
(day R1 through day R25) 
Unscheduled 
visita         
Visit number 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
Day from sc 
injection 
(visit window) 
R1 
R2 
R3 
R4 
R5 
R6 
R7 
R8 
(+1) 
R10 
(±1) 
R11 
(±1) 
R13 
(±1) 
R15 
(±1) 
R18 
(±1) 
R22 
(±1) 
R25 
(±2) 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx blood sample 
collectionb         
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurementsc         
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
12-lead ECGd         
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Physical 
examinatione         
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Clinical laboratory 
testsf         
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pregnancyg         
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Alcohol screenh         
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Drug screeni         
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
34 
Table 4: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for Cohort 1B, Cohort 2, and Cohort 3: 
Trial Procedures and Assessments (Day R1 through Day R25) (Continued) 
APPLICABLE TO COHORT 1B (Fast-D), COHORT 2 (to-be-marketed), AND COHORT 3 (Slow-C):  
SC Olanzapine for Extended-release  
Procedures and 
assessments 
SC olanzapine extended-release treatment period 3 
(day R1 through day R25) 
Unscheduled 
visita 
Visit number 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
Day from sc 
injection 
(visit window) 
R1 
R2 
R3 
R4 
R5 
R6 
R7 
R8 
(+1) 
R10 
(±1) 
R11 
(±1) 
R13 
(±1) 
R15 
(±1) 
R18 
(±1) 
R22 
(±1) 
R25 
(±2) 
         
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Olanzapine 
extended-release 
administration  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-injection 
delirium/sedation 
syndrome 
monitoringk         
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection site 
tolerability and pain 
assessmentl         
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Smoking statusm         
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Pharmacokinetic 
blood sample 
collectionn         
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker blood 
sample collectiono         
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Inpatient in CUp         
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from CU  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient visitq         
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
35 
Table 4: 
Subcutaneous Olanzapine for Extended-release Treatment Period 3 for Cohort 1B, Cohort 2, and Cohort 3: 
Trial Procedures and Assessments (Day R1 through Day R25) (Continued) 
APPLICABLE TO COHORT 1B (Fast-D), COHORT 2 (to-be-marketed), AND COHORT 3 (Slow-C):  
SC Olanzapine for Extended-release  
Procedures and 
assessments 
SC olanzapine extended-release treatment period 3 
(day R1 through day R25) 
Unscheduled 
visita 
Visit number 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
Day from sc 
injection 
(visit window) 
R1 
R2 
R3 
R4 
R5 
R6 
R7 
R8 
(+1) 
R10 
(±1) 
R11 
(±1) 
R13 
(±1) 
R15 
(±1) 
R18 
(±1) 
R22 
(±1) 
R25 
(±2) 
Adverse event 
recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a All procedures marked in the table are mandatory during unscheduled visits. Other procedures may be performed at the discretion of the Investigator. In addition, to reduce 
participant burden and to avoid unnecessary data collection, the Investigator will have discretion in determining whether the procedures that are marked as mandatory actually 
need to be performed during the unscheduled visit in the case that the visit is for administrative purposes (eg, reconsenting) or clinical reasons (eg, repeat laboratory sample 
collection for reasons unrelated to an adverse event and not due to a change in the participant’s medical status per clinical judgment). 
b In case the PGx sample cannot be collected on R1, it should be collected at the next possible visit. 
c Vital signs include body temperature, respiratory rate, supine or semi-supine pulse rate and blood pressure (systolic and diastolic), and their orthostatic changes. On R1 vital 
signs will be measured pre-dose. Pulse, blood pressure, and respiratory rate will be measured after the participant has been supine or semi-supine for at least 5 min. Orthostatic 
vital signs will be determined with measurements obtained after the participant has been supine or semi-supine for at least 5 min and repeated after the participant has been 
standing for 3 min. Vital signs will be measured after ECGs but before scheduled blood draws, up to 30 min prior to the time point, when applicable. 
d ECGs will be obtained after the participant has been in a supine or semi-supine position for at least 5 min. The ECGs will be recorded before vital sign assessments and 
scheduled blood draws, up to 30 min prior to the time point, when applicable. On R1, ECG will be performed pre-dose. On R2, the ECG will be performed 24 h following 
administration of the sc olanzapine extended-release formulation. 
e An abbreviated physical examination be performed. The abbreviated physical examination will include general appearance, HEENT, lung, heart, skin, extremities, and a brief 
neurological examination. On R1, the abbreviated physical examination will be performed pre-dose. 
f Clinical laboratory tests will be performed following an overnight fast of at least 8 h and will include chemistry, hematology, coagulation, and urinalysis. HbA1c will be 
collected at day R1 pre-dose. Non-fasting blood collection is permitted as needed, per Investigator assessment of adverse events. At each urinalysis collection, females will be 
asked if they are currently menstruating. Blood and urine samples will be collected prior to dosing on day R1. Laboratory results from blood samples collected on day R1 are 
not required pre-dose. Day R1 
inical laboratory ass
central cl
essments will serve as baseline values for the sc olanzapine extended-release formulation. 
g A urine dipstick pregnancy test will be performed for all women of childbearing potential. In case period 2 is extended, a urine dipstick pregnancy test will be performed for all 
women of childbearing potential at visit 12 (R1) with a confirmation test of negative results prior to dosing. Additional pregnancy tests may be performed if clinically indicated. 
h Breathalyzer for alcohol. In case period 2 is extended, the alcohol screen will be performed on day R1. Alcohol screens may be performed at additional time points at the 
discretion of the Investigator. 
i An in-house urine dipstick screen for prohibited drugs. In case period 2 is extended, in-house urine dipstick screen for prohibited drugs will be performed on day R1. Drug 
screens may be performed at additional time points at the discretion of the Investigator. 
VV-00495638 v5.0

Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
36 
j 
 
k Participants will remain under clinical observation for at least 3 h after injection to monitor for any potential symptoms of PDSS. In any event of suspected PDSS, unscheduled 
pharmacokinetic samples will be collected as soon as PDSS is suspected and at 3, 6, 12, and 24 h after the onset of the event and 24 h after resolution, or when feasible. Vital 
signs should be measured as soon as a suspected PDSS event is suspected and at the same time points that additional pharmacokinetic samples are collected. Additionally, a 
toxicological blood test will be performed as soon as PDSS is suspected, and unscheduled biomarker samples will be collected as soon as PDSS is suspected, 24 h after the 
onset of the event, and 24 h after resolution, or when feasible. 
l On R1, pain will be assessed 30 min after the completion of administration of any of the 3 olanzapine for extended-release sc formulations, and pain and injection site findings 
will be assessed 3 h after the completion of olanzapine sc administration. Allowed time windows for these local tolerability assessments are ±15 min. In case an adverse event 
associated with an ISR is reported, pain may be assessed periodically using an NPRS until resolution. Thereafter the site of injection will be assessed for local tolerability 
weekly (R8, R15, R22). 
m Data on smoking status will be collected using the following questions if cigars, pipes, or cigarettes are used: “How many cigarettes, cigars, or pipes did you smoke over the 
past 7 days?” and "Has your smoking status/tobacco use remained the same compared to at the time of screening”? Use of cigars and pipes will be converted into cigarette use 
with a ratio of 1 cigar or pipe = 2.5 cigarettes. 
n Pharmacokinetic blood samples will be collected pre-dose (up to 1 h prior to dosing of sc olanzapine at approximately 216 ±3 h post the ZYPREXA im dosing) (applicable 
ONLY for participants who have entered period 3 directly from period 2), at 3 h post-dose, and on R2, R3, R4, R5, R6, R7, R8, R10, R11, R13, R15, R18, R22, and R25 at 
approximately the same hour of the day as dosing. 
o Blood samples will be collected for biomarker assessment on R8 and in the event of the appearance of an adverse event related to pus-containing injection site lesions. Blood 
for biomarker analyses will be collected as follows: 6 mL for plasma and 2.5 mL for PAXgene RNA. 
p Participants will be treated in the CU until R3, when they will be discharged from the CU after completion of R3 assessments. 
q Participants will return to the CU on an outpatient basis for scheduled assessments. All visits must be scheduled within the provided windows and 2 visits cannot occur on the 
same day. 
 
 
 CU=clinical unit; 
 ECG=electrocardiogram; HEENT=head, eyes, ears, nose, throat; NPRS=Numeric Pain Rating Scale; 
 
 PDSS=post-injection delirium/sedation syndrome; PGx=pharmacogenomics; RNA=ribonucleic acid; 
; sc=subcutaneous. 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
37 
Table 5: 
Subcutaneous Olanzapine Extended-release Follow-up Period: Trial Procedures and Assessments (Day R29 
through Day R84)  
Applicable to all cohorts: 1A, 1B, 2, and 3 
Procedures and assessments 
SC olanzapine extended-release follow-up period 
(day R29 through day R84) 
Unscheduled 
Visita         
Visit 
V27 
V28 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
Trial day 
(visit window) 
R29b 
(±1)      
R36 
(±2) 
R43 
(±2) 
R50 
(±2) 
R57 
(±2) 
R64 
(±2) 
R71 
(±2) 
R78 
(±2) 
EOT 
(R84±2) 
/ET 
Vital sign measurementsc         
X 
 
 
 
 
 
X 
X 
12-lead ECGd         
X 
 
 
 
 
 
 
X 
 
Physical examinatione         
X 
 
 
 
 
 
 
 
X 
 
Physical measurementsf         
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory testsg         
X 
 
 
 
 
 
 
 
X 
 
Pregnancy testh         
 
 
 
 
 
 
 
 
X 
 
Alcohol screeni         
 
 
 
 
 
 
 
 
X 
 
Drug screenj         
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
         
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resumption of antipsychoticl         
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Smoking statusm         
X 
 
 
X 
 
 
 
 
X 
 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
38 
Table 5: 
Subcutaneous Olanzapine Extended-release Follow-up Period: Trial Procedures and Assessments (Day R29 
through Day R84) (Continued) 
Applicable to all cohorts: 1A, 1B, 2, and 3 
Procedures and assessments 
SC olanzapine extended-release follow-up period 
(day R29 through day R84) 
Unscheduled 
Visita 
Visit 
V27 
V28 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
Trial day 
(visit window) 
R29b 
(±1)  
R36 
(±2) 
R43 
(±2) 
R50 
(±2) 
R57 
(±2) 
R64 
(±2) 
R71 
(±2) 
R78 
(±2) 
EOT 
(R84±2) 
/ET 
Pharmacokinetic blood sample 
collectionn         
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker blood sample 
collectiono         
 
 
 
 
 
 
 
 
X 
 
Outpatient visitsp         
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a All procedures marked in the table are mandatory during unscheduled visits. Other procedures may be performed at the discretion of the Investigator. In addition, to reduce 
participant burden and to avoid unnecessary data collection, the Investigator will have discretion in determining whether the procedures that are marked as mandatory actually 
need to be performed during the unscheduled visit in the case that the visit is for administrative purposes (eg, reconsenting) or clinical reasons (eg, repeat laboratory sample 
collection for reasons unrelated to an adverse event and not due to a change in the participant’s medical status per clinical judgment). 
b All assessments must be performed prior to returning a participant to antipsychotic treatment. 
c Vital signs include body temperature, respiratory rate, supine or semi-supine pulse rate and blood pressure (systolic and diastolic), and their orthostatic changes. Pulse, blood 
pressure, and respiratory rate will be measured after the participant has been supine or semi-supine for at least 5 min. Orthostatic vital signs will be determined with 
measurements obtained after the participant has been supine or semi-supine for at least 5 min and repeated after the participant has been standing for 3 min. Vital signs will be 
measured after ECGs but before scheduled blood draws, up to 30 min prior to the time point, when applicable. At the discretion of the Investigator, vital signs may be checked 
at every visit during this follow-up period. 
d ECGs will be obtained after the participant has been in a supine or semi-supine position for at least 5 min. The ECGs will be recorded before vital sign assessments and 
scheduled blood draws, up to 30 min prior to the time point, when applicable. At the discretion of the Investigator, an ECG may be performed at every visit during this 
follow-up period. 
e A complete physical examination will be performed at EOT/ET and an abbreviated physical examination at other time points. The abbreviated physical examination will 
include general appearance, HEENT, lung, heart, skin, extremities, and a brief neurological examination. At the discretion of the Investigator, a physical exam may be 
performed at every visit during this follow-up period. 
f Includes weight measurement only, except for at EOT/ET when height measurement and BMI calculation will also be performed. 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
39 
g Clinical laboratory tests will be performed following an overnight fast of at least 8 h and will include chemistry, hematology, coagulation, and urinalysis. Non-fasting blood 
collection is permitted as needed, per Investigator assessment of adverse events. At each urinalysis collection, females will be asked if they are currently menstruating. Clinical 
laboratory tests can be performed at every visit during this follow-up period. 
h A serum pregnancy test will be performed for all women, regardless of childbearing potential, on R84 (EOT). Additional pregnancy tests may be performed if clinically 
indicated. 
i Breathalyzer for alcohol. Alcohol screens may be performed at additional time points at the discretion of the Investigator. 
j An in-house urine dipstick screen for prohibited drugs. Drug screens may be performed at additional time points at the discretion of the Investigator. 
k 
 
l Dosing (initial dose and any dose modifications) and administration of the allowed antipsychotic (aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone) at the 
discretion of the Investigator. At each visit, participants will be asked about whether or not they are taking 1 of the allowed antipsychotics and their response will be entered in 
the eCRF. 
m Data on smoking status will be collected using the following questions if cigars, pipes, or cigarettes are used: “How many cigarettes, cigars, or pipes did you smoke over the 
past 7 days?” and "Has your smoking status/tobacco use remained the same compared to at the time of screening”? Use of cigars and pipes will be converted into cigarette use 
with a ratio of 1 cigar or pipe = 2.5 cigarettes. 
n Pharmacokinetic blood samples will be collected on R29, R36, R43, R50, R57, R64, R71, R78, and on R84 (EOT) or early termination, at approximately the same time of the 
day as dosing as specified in Table 7. 
o Blood samples will be collected for biomarker assessment on R84 (EOT) and in the event of the appearance of an adverse event related to pus-containing injection site lesions. 
Blood for biomarker analyses will be collected as follows: 6 mL for plasma and 2.5 mL for PAXgene RNA. 
p Participants will return to the CU on an outpatient basis for scheduled assessments. 
 
 BMI=body mass index; 
 
CU=clinical unit; 
; ECG=electrocardiogram; eCRF=electronic case report form; EOT=end of trial (visit); ET=early termination 
(visit); HEENT=head, eyes, ears, nose, throat; 
; RNA=ribonucleic acid; 
; sc=subcutaneous. 
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Clinical Trial Protocol with Amendment 01 
Trial TV44749-NPC-10205 
40 
Table 6: 
Schedule of Assessments for Pharmacokinetic Sampling Before and After ZYPREXA IM Administration  
Time points 
Time window 
Pharmacokinetic  
sample 
ZYPREXA im Treatment Period 1 
Day 4 pre-dose 
-30 min 
±10 min 
X 
Day 4  
10, 20, 30, 45 min  
±3 min 
X 
Day 4 
1, 2, 3, 4 h 
±15 min 
X 
Days 4-5a          
6, 8, 12, 24 h 
±30 min 
X 
Days 6-12b         
48, 72, 96, 120, 192 h 
±3 h 
X 
In case Period 2 is extended optional Day 13c   
216 
±3 h 
X 
a It is recommended that the PK samples collected at 24 h post-injection should be collected at approximately the same hour of day that the ZYPREXA im injection was 
performed on day 4. 
b It is recommended that the PK samples collected at 48, 72, 96, 120, 192 h post-injection should be collected at approximately the same hour of the day that the ZYPREXA im 
injection was performed on day 4. 
c In the event of extension of period 2, participants will return to the clinic on day 13 (V11) for an unscheduled visit to collect the 216 h PK sample. For those who proceed 
directly to period 3, the 216 h post-dose sample will be collected prior to sc dosing as shown in Table 7. 
im=intramuscular. 
Table 7: 
Schedule of Assessments for Pharmacokinetic Sampling Before and After Olanzapine Extended-release SC 
Formulation Administration  
Time points 
Time window 
Pharmacokinetic  
sample 
Olanzapine Extended-release sc Treatment Period 3 
Day R1 pre-dose 
-1 h 
±10 min 
X 
Day R1 
3 h 
±15 min 
X 
Days R2-R13 
Days R2, R3, R4, R5, R6, R7, R8, R10, R11, R13 
±4 h 
X 
Days R14-R23 
Days R15, R18, R22 
±1 day at approximately the same 
time of day as dosing 
X 
Days R24-R84 (EOT/ET) 
Days R25, R29, R36, R43, R50, R57, R64, R71, R78, R84 
±2 days at approximately the 
same time of day as dosing 
X 
EOT=end of trial; ET=early termination; sc= subcutaneous. 
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Table 8: 
Trial Procedures and Assessments in Case of a Suspected Post-injection Delirium/Sedation Syndrome Event  
         
 
 
 
 
 
 
 
 
 
 
         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. 
INTRODUCTION  
2.1. 
Purpose of Trial  
2.1.1. 
Background on Schizophrenia  
Schizophrenia is a severely debilitating psychotic disorder characterized by positive symptoms 
(eg, delusions, hallucinations, and grossly disorganized or catatonic behavior) and negative 
symptoms (eg, affective flattening, alogia, and avolition) (New York State Office of Mental 
Health 2018, Stefan et al 2002). Cognitive deficits are common; they include impairments of 
executive functioning and attention, and difficulties with short- and long-term memory. 
The worldwide lifetime morbidity risk of the disorder is approximately 1% across diverse 
geographic, cultural, and socio-economic regions. Since, in most patients, the disease follows a 
chronic course with long-lasting impairment, long-term treatment with antipsychotic agents is 
usually required. 
Noncompliance and high discontinuation rates are particularly problematic in patients with 
schizophrenia. Premature discontinuation of antipsychotic drug therapy is a common 
phenomenon; in the Clinical Antipsychotic Trials of Intervention Effectiveness trial, 74% of 
patients discontinued their drug within 18 months due to either poor tolerability or lack of 
efficacy. 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. As a result, many of these patients do not 
experience the full benefit of antipsychotic drug therapy and suffer frequent relapses or 
exacerbations that require rehospitalization, often in the context of psychiatric emergency 
(Rainer 2008). 
Thus, the availability of a long-acting injectable antipsychotic agent may increase compliance in 
patients with schizophrenia (Barnes and Curson 1994, Hughes 2008, Keith and Kane 2003, 
Walburn et al 2001). 
Note that the terms ‘long-acting’, ‘extended-release’, and ‘prolonged-release’ are used 
interchangeably within this document. 
The purpose of this trial is to characterize the pharmacokinetics (PK) of 3 subcutaneous (sc) 
olanzapine extended-release formulations with different release rates (described in Section 2.1.3) 
in participants with schizophrenia or schizoaffective disorder, with the purpose of establishing in 
vitro/in vivo correlation (IVIVC).  
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; it has not yet been approved for use 
as a subcutaneous (sc) injection. 
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Oral formulations of olanzapine 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 tablets (ZYPREXA® 2.5, 5, 7.5, 
10, 15, and 20 mg); orally disintegrating tablets (ZYPREXA® ZYDIS® 5, 10, 15, and 20 mg); 
and immediate-release ZYPREXA® IntraMuscular (Olanzapine) Injection (10 mg/mL) 
(ZYPREXA USPI 2021). 
2.1.2.2. 
Prolonged-release Olanzapine Formulations  
A prolonged-release olanzapine pamoate powder and diluent for suspension is currently 
marketed in the US as ZYPREXA® RELPREVV™ (150, 210, 300, and 405 mg) (ZYPREXA 
RELPREVV USPI 2021). Both products are administered by deep im gluteal injection either 
every 2 or 4 weeks, depending on the target oral olanzapine dose. ZYPREXA RELPREVV is 
currently only available through a restricted distribution program in the US. 
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 
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. 
2.1.3. 
Olanzapine for Extended-release Injectable Suspensions (TV-44749) for 
Subcutaneous Use  
To-be-marketed formulation 
Teva is developing a new formulation of olanzapine as a prolonged-release injectable suspension 
for sc use that is intended for the treatment of schizophrenia. The product is coded the “to-be-
marketed” formulation of Olanzapine for Extended-release Injectable Suspension (TV-44749) 
throughout this document. During period 3 of the trial, participants in cohort 2 will receive a 
single-dose of this formulation (the trial schematic is shown in Figure 1).  
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The TV-44749 to-be-marketed formulation is a co-packaged drug/device combination product 
that requires reconstitution (Section 6.1.1). Before administration, the drug product is 
reconstituted in the vial by adding the vehicle from the prefilled syringe (PFS) and mixing. A 
yellow, viscous suspension is obtained. 
Upon sc injection of this olanzapine suspension, dimethyl sulfoxide (DMSO) diffuses away and 
the block copolymers, which are not soluble in aqueous medium, precipitate and form a depot 
that entraps olanzapine. From this depot, olanzapine is slowly released to achieve and maintain 
therapeutic levels of the drug, resulting from drug diffusion and/or gradual depot degradation, 
over the period of 1 month. 
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 (ZYPADHERA SmPC 2022), which is identical to ZYPREXA RELPREVV, was 
also used to support the nonclinical development of TV-44749. 
The clinical program of the to-be-marketed TV-44749 formulation was initiated with Trial 
TV44749-SAD-10154. The objective of this trial was to evaluate the safety, tolerability, and PK 
of single doses and multiple doses of TV-44749 for sc use in healthy participants and 
participants with schizophrenia or schizoaffective disorder.  
Overall, 127 participants were enrolled in this trial and TV-44749 was administered to 
101 participants. The trial applied an adaptive dose escalation design in which healthy volunteers 
(n=30) received oral olanzapine (2.5 and 5 mg/day) for 7 days, followed by a 7-day washout 
period, and then received single injections of TV-44749 (70 or 105 mg). Participants with 
schizophrenia or schizoaffective disorder (n=71) received oral olanzapine (10, 15, or 20 mg/day) 
for 7 days followed by a washout period of 2 days for all cohorts, except for the cohort that was 
to receive 425 mg TV-44749 for which the washout period was 7 days. This washout period was 
followed by a treatment period during which participants received either a single injection of 
TV-44749 (318, 425, or 531 mg) or 3 once-monthly injections of 283 or 566 mg. The trial 
included safety assessments and PK sampling for all. 
Main PK observations: 
• 
 
 
 
 
  
• There was no burst or unexpected rise in olanzapine plasma concentrations following 
TV-44749 sc administration.  
• TV-44749 systemic exposure (Cmax and AUC) increased in an approximate 
dose-proportional manner over the clinically relevant dose range of 283 mg to 566 mg. 
Steady-state was attained after the second dosing interval (day 57), indicating modest 
accumulation.  
• At steady-state conditions over the 28-day dosing interval, the systemic exposure of 
TV-44749 at doses of 318, 425, and 531 mg was shown to be comparable to 
corresponding daily oral doses of 10 mg, 15 mg, and 20 mg, respectively.  
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The results of this trial supported the dose strengths of TV-44749 administered in the ongoing 
Phase 3 trial (Trial TV44749-CNS-30096; SOLARIS) of 318, 425, and 531 mg, which are 
comparable to corresponding daily oral doses of 10 mg, 15 mg, and 20 mg, respectively. 
SOLARIS is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial with 
an open-label, long-term safety phase evaluating the efficacy, safety, and tolerability of 
TV-44749 in adult participants with schizophrenia. 
Additionally, a Phase 1, 21-week, open-label, multiple-dose trial to assess the comparative 
bioavailability of olanzapine prolonged-release suspension for subcutaneous administration 
(TV-44749) to oral olanzapine (European Reference) in participants with schizophrenia is 
currently planned.  
Background information on completed nonclinical studies and clinical trials is provided in the 
current version of the Investigator’s Brochure (IB). 
Two additional formulations with different release rates relative to the to-be marketed 
formulation  
This trial will also characterize the PK of two additional sc olanzapine for extended-release 
formulations, Fast-D and Slow-C, with different release rates relative to the to-be-marketed 
TV-44749 formulation, in participants with schizophrenia or schizoaffective disorder. During 
period 3 of the trial, participants in cohorts 1A and 1B will receive a single-dose of the Fast-D 
formulation and participants in cohort 3 will receive a single-dose of the Slow-C formulation (the 
trial schematic is shown in Figure 1). Based on beagle PK data and in vitro release (IVR) data, it 
is expected that both of these formulations will provide extended-release of olanzapine during 
the 84-day period following single-dose sc administration. The formulations are expected to have 
the same bioavailability (ie, similar AUC at day R84) and differ only in Cmax as a consequence of 
different release rate relative to the to-be-marketed formulation, with no burst present. The 
Fast-D formulation is expected to exhibit a faster release rate (ie, higher Cmax), while the Slow-C 
formulation is expected to exhibit a slower release rate (ie, lower Cmax) relative to the 
to-be-marketed formulation.  
2.2. 
Summary of Benefits and Risks  
2.2.1. 
Known and Potential Risks of TV-44749  
Olanzapine is a well-characterized and commonly prescribed atypical antipsychotic drug 
available as oral and im formulations. Oral formulations (Section 2.1.2.1) are approved for the 
treatment of adults and adolescents with schizophrenia. The prolonged-release im depot 
preparation containing olanzapine pamoate (Section 2.1.2.2) is approved for the treatment of 
adults with schizophrenia, while an immediate-release im formulation of olanzapine 
(Section 2.1.2.1) is approved for the treatment of adults with acute agitation associated with 
schizophrenia. 
Data from Trial TV44749-SAD-10154, including PK, safety, and tolerability associated with 
TV-44749 are available (Section 2.1.3). The safety profile emerging from these data is consistent 
with that seen with other olanzapine formulations, with the exception of the identification of 
injection site reactions (ISRs). None of these were identified as serious events, and they do not 
significantly impact the benefit-risk profile of TV-44749. Overall, the Sponsor believes that the 
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safety data present no concerns that preclude continuation of TV-44749 clinical development. 
The anticipated risks are similar to those associated with the use of any other formulations of 
olanzapine. 
The current ZYPREXA tablet label contains warning language describing an association with 
hyperglycemia, diabetes mellitus, weight gain, and lipid elevations. 
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 (McDonnell et al 2010). 
Because the prolonged duration of release of TV-44749 arises as a consequence of slow 
degradation of the precipitated polymer depot (the water insoluble polymer matrix entraps and 
slowly releases olanzapine, rather than low tissue solubility of olanzapine pamoate salt) and 
because it is injected sc, the hypothesized causes of PDSS resulting from ZYPREXA 
RELPREVV administration are not relevant for TV-44749. No suspected PDSS events occurred 
in Trial TV44749-SAD-10154.  
Additional information regarding risks to participants may be found in the IB. 
2.2.2. 
Known and Potential Risks of ZYPREXA IntraMuscular (Olanzapine) Injection  
Information regarding benefits and risks to participants from use of ZYPREXA IntraMuscular 
(olanzapine) Injection, Powder, for Solution for im use in this trial during period 1 are available 
in the prescribing information (ZYPREXA USPI 2021). 
Specific risks associated with ZYPREXA im are similar to oral formulations. ZYPREXA im has 
not been shown to cause PDSS that has been seen with ZYPREXA RELPREVV. 
2.2.3. 
Potential Benefits of TV-44749  
Participating in a clinical trial can provide a number of benefits to patients, regardless of the 
effectiveness of the treatment. Clinical trial participants are closely monitored for their 
psychiatric and general health in a highly monitored clinical setting by medical professionals, 
including doctors, nurses, and research staff. This level of attention and care can help ensure that 
participants receive the best possible medical treatment and support. In addition, clinical trial 
participants have an opportunity to take an active role in their own healthcare. By working 
closely with medical professionals, participants can gain a deeper understanding of their 
condition and treatment options, and may feel more empowered to manage their health. Finally, 
clinical trials are a critical part of the process of developing new treatments and understanding 
how existing treatments work. By participating in a clinical trial, patients contribute to the body 
of medical knowledge, and help improve healthcare for future generations. 
2.2.4. 
Overall Benefit-Risk Conclusion  
The trial will be conducted in participants with schizophrenia or schizoaffective disorder. The 
trial design, inclusion/exclusion criteria, and procedures have been developed in a manner to 
protect participant safety. The results of this trial may facilitate the development of TV-44749 
with potential benefits for patients with schizophrenia and schizoaffective disorder. 
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In summary, the benefit and risk assessment for TV-44749 is favorable following review of the 
summarized data. 
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3. 
TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
3.1. 
Primary and Secondary Trial Objectives and Endpoints  
The primary and secondary objectives and measures are presented in the table below: 
Objectives 
Measures 
Primary 
To characterize the PK of 3 
extended-release sc olanzapine 
formulations with different release 
rates following single 
administration in participants with 
schizophrenia or schizoaffective 
disorder. 
The following PK parameters will be calculated for olanzapine, following 
single administration of 3 sc olanzapine extended-release formulations to 
support the primary objective of the trial: 
• 
Maximum observed plasma drug concentration (Cmax) over the 
84-day period following single-dose administration of 1 of the sc 
formulations to EOT (day R1 to day R84) 
• 
Area under the plasma drug concentration-time curve (AUC) 
following single-dose administration of 1 of the sc formulations to 
last measurable concentration (AUC0-t) (day R1 to day R84) 
• 
AUC extrapolated to infinity (AUC0-∞) calculated from last 
measurable olanzapine plasma concentration following 
single-dose administration of 1 of the sc formulations from time 0 
to EOT (day R1 to day R84) 
Secondary 
To evaluate the safety and 
tolerability of 3 extended-release sc 
olanzapine formulations with 
different release rates in 
participants with schizophrenia or 
schizoaffective disorder. 
The following safety and tolerability measures/parameters will be 
evaluated: 
• 
Number (%) of participants with at least 1 TEAE over the 28-day 
period following administration of 1 of the sc olanzapine 
formulations (day R1 to day R29) 
• 
Number (%) of participants with at least 1 serious adverse event 
(SAE) over the 28-day period following administration of 1 of the 
sc olanzapine formulations (day R1 to day R29) 
To characterize the PK of 
immediate-release ZYPREXA im 
in participants with schizophrenia 
or schizoaffective disorder. 
The following PK parameters will be calculated for ZYPREXA im to 
support the secondary objective of the trial: 
• 
Cmax over the 24-hour period following single-dose administration 
of ZYPREXA im (day 4) 
• 
AUC following single-dose administration of ZYPREXA im to 
last measurable concentration (AUC0-t) (pre-dose ZYPREXA im 
to 216 hours post im administration) 
• 
Apparent plasma terminal elimination rate constant (λz) over the 
216-hour period (9 days) following single-dose administration of 
ZYPREXA im (pre-dose ZYPREXA im to 216 hours post im 
administration) 
3.2. 
Primary Estimand  
For the primary objectives, the estimand is described by the following attributes: 
a. Population – adult participants, 18 to 64 years of age, with a clinically stable 
diagnosis of schizophrenia or schizoaffective disorder, not currently on antipsychotic 
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treatment, with the exception of oral treatment with aripiprazole, risperidone, 
paliperidone, quetiapine, or lurasidone, and meeting all trial eligibility criteria. For 
intercurrent events which could adversely affect the calculation of the PK parameters, 
the participant will be excluded. 
b. Endpoint – see parameters in Section 3.1. 
c. Treatment – the 3 formulations of Olanzapine for Extended-release Injectable 
Suspension, with different release rates, over the 84-day olanzapine sc treatment 
period (day R1 to day R84) following single-dose administration. 
d. Population level summary – descriptive statistics (n, mean, standard deviation, 
geometric mean [if appropriate], geometric coefficient of variation (%CV) [if 
appropriate], median, minimum, and maximum). 
Rationale for estimand: To characterize the PK of 3 olanzapine extended-release sc formulations 
with different release rates, following single administration in participants with schizophrenia or 
schizoaffective disorder, who are clinically stable and are not on antipsychotic treatment, with 
the exception of oral treatment with aripiprazole, risperidone, paliperidone, quetiapine, or 
lurasidone, and who meet all trial eligibility criteria. 
3.3. 
Secondary Estimand(s)  
There are no secondary estimands defined for this trial. 
3.4. 
Exploratory Objectives and Endpoints  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
  
 
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Exploratory Objectives 
Measures/Parameters 
To further evaluate the safety and 
tolerability of single doses of 3 
extended-release sc olanzapine 
formulations with different release 
rates in participants with 
schizophrenia or schizoaffective 
disorder.  
The following safety and tolerability parameters will be assessed: 
• 
Number (%) of participants with at least 1 injection site adverse 
event from baseline to the end of period 3 (day R1 to day R29)  
• 
Change in clinical laboratory parameters (chemistry, hematology) 
from baseline to the end of period 3 (day R1 to day R29)  
• 
Change in vital signs parameters (body temperature, respiratory 
rate, pulse rate, and blood pressure) from baseline to the end of 
period 3 (day R1 to day R29) 
• 
Number (%) of participants with QT interval corrected for heart rate 
using Fridericia’s formula (QTcF) change of ≥30 and ≥ 60 msec 
from baseline to the end of period 3 (day R1 to day R29) 
• 
Number (%) of participants who reported use of concomitant 
medications from baseline to the end of period 3 (day R1 to day 
R29)  
• 
Number (%) of participants who discontinued from the trial for any 
reason from baseline to the end of period 3 (day R1 to day R29) 
• 
Number (%) of participants who discontinued from the trial due to 
an adverse event from baseline to the end of period 3 (day R1 to day 
R29) 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Exploratory Objectives 
Measures/Parameters 
To evaluate the safety and 
tolerability following a single-dose of 
immediate-release ZYPREXA im in 
participants with schizophrenia or 
schizoaffective disorder. 
The safety and tolerability measures/parameters are: 
• 
Occurrence of adverse events during the 24-hour period following 
administration of ZYPREXA im (day 4 to day 5) 
• 
Change in clinical laboratory (chemistry, hematology) tests, vital 
sign measurements (body temperature, respiratory rate, pulse rate, 
and blood pressure) during the 24-hour period following 
administration of ZYPREXA im (day 4 to day 5) 
• 
ECG findings during the 24-hour period following administration of 
ZYPREXA im (day 4 to day 5) 
• 
Use of concomitant medication during the 24-hour period following 
administration of ZYPREXA im (day 4 to day 5) 
• 
Discontinuation for any reason during the 24-hour period following 
administration of ZYPREXA im (day 4 to day 5) 
• 
Discontinuation due to an adverse event during the 24-hour period 
following administration of ZYPREXA im (day 4 to day 5) 
• 
Local tolerability and pain during the 24-hour period following 
administration of ZYPREXA im (day 4 to day 5) 
 
 
 
To evaluate the overall safety of the 
trial in participants with 
schizophrenia or schizoaffective 
disorder. 
The safety measures/parameters are: 
• 
Occurrence of adverse events during trial participation (day 1 to 
day R84) 
• 
Change in clinical laboratory (chemistry, hematology) tests, vital 
sign measurements (body temperature, respiratory rate, pulse rate, 
and blood pressure) during trial participation (day 1 to day R84) 
• 
ECG findings during trial participation (day 1 to day R84) 
• 
Use of concomitant medication during trial participation (day 1 to 
day R84) 
• 
Discontinuation for any reason during trial participation (day 1 to 
day R84) 
• 
Discontinuation due to an adverse event during trial participation 
(day 1 to day R84) 
 
 
 
 
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4. 
TRIAL DESIGN  
4.1. 
Description of Trial Design  
This is a multi-center, open-label, randomized, parallel-group trial to characterize the PK profile 
of 3 olanzapine extended-release formulations for sc use with different release rates, in 
participants with schizophrenia or schizoaffective disorder. The trial will consist of a screening 
period (up to 40 days), a 3-day washout (WO) period (day 1 to day 3), a 1-day treatment period 
with immediate-release ZYPREXA im (period 1: day 4), an 8-day follow-up period (period 2: 
day 5 to day 12), a 28-day treatment period with 1 of the 3 extended-release sc olanzapine 
formulations (period 3: day R1 to day R29), and an up to approximately 8-week follow-up period 
(day R29 to day R84). 
The total duration of individual participation in the trial is planned to be approximately 19 weeks. 
Participants are expected to participate in this trial for its entire duration. See Section 4.4 for the 
definition of the EOT.  
The trial population will include clinically stable participants 18-64 years old, not currently on 
antipsychotic treatment, with the exception of oral treatment with an oral antipsychotic including 
aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone.  
The screening period of up to 40 days in duration will be performed in an outpatient setting. 
Participants who meet screening eligibility will undergo an inpatient WO of 3 days from their 
current antipsychotic treatment. Thereafter, participants will remain in the clinical unit (CU) and 
will continue to period 1 (day 4) that will include a single injection of 5 mg of ZYPREXA im, 
immediate-release solution, administered to the gluteal muscle. Prior to the im injection, 
participants’ eligibility will be reconfirmed (Table 1). Subsequently, participants will continue to 
the follow-up period 2 (day 5 to day 12). The first 3 days of period 2 will be performed in an 
inpatient setting. Participants will be discharged on day 7. The remaining visits of period 2 
(day 8 and day 9) may be performed in an inpatient or an outpatient setting per Investigator's 
discretion and participants' preference. Participants will be readmitted to the CU on day 12, 
which is a mandatory visit for all patients. Period 2 may be extended up to 7 days maximum, post 
Visit 10 (Visit 10 counts as day 1, so day 7 is R1, at maximum) for all cohorts per Principal 
Investigator and Sponsor discretion. In the event of extension of period 2, participants will return 
to the clinic on day 13 (Visit 11) for an unscheduled visit to collect the 216 h PK sample; if this 
extension is not required, participants will skip Visit 11 and proceed to Visit 12. For those who 
proceed directly to period 3, the 216 h post-dose sample will be collected prior to sc dosing as 
shown in Table 3  for cohort 1A and Table 4 for cohorts 1B, 2, and 3. During period 2, 
participants will resume treatment with the allowed antipsychotic treatments and discontinue 
24 h prior to sc injection on day R1. Participants will be readmitted to the CU on day 12 
(Table 2).  
Thereafter, on day R1, participants will enter treatment period 3 (day R1 to day R29). During 
this period participants will discontinue treatment with any of the allowed antipsychotics they 
were receiving during period 2. On day R1 of this period, participants will be assigned to 1 of the 
3 single-dose cohorts and will be administered 1 of 3 olanzapine extended-release sc 
formulations (TV-44749) in the abdomen. Period 3 includes both an inpatient and an outpatient 
period.  
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During period 3, participants will be treated with 1 of the following olanzapine extended-release 
(TV-44749) formulations: 
1. Cohort 1: Olanzapine for Extended-release Injectable Suspension D (TV-44749) (Fast-D) 
2. Cohort 2: Olanzapine for Extended-release Injectable Suspension (TV-44749) 
(to-be-marketed) 
3. Cohort 3: Olanzapine for Extended-release Injectable Suspension C (TV-44749) 
(Slow-C) 
The aim is to achieve approximately 20 completers in each cohort. Period 3 will be initiated with 
a sentinel cohort 1A (Fast-D) composed of approximately 2 to 4 participants. A safety review 
committee (SRC) composed of the Sponsor’s clinical trial physician, clinical leader, PV 
physician, and other relevant experts, will be summoned to review all safety data (including 
demography, vital signs, clinical laboratory tests, ECGs, adverse events (AEs), concomitant 
medications local tolerability and pain, leakage assessment) available upon completion of the 
first 15 days of the sentinel cohort (day R1 to day R15, inclusive) (cohort 1A). The sentinel 
cohort will serve for initial evaluation of the systemic safety and tolerability of the Fast-D 
formulation. Participants assigned to cohort 1A will be in an inpatient setting for 15 days 
following administration of the Fast-D formulation, to allow safety review prior to dosing of the 
rest of the Fast-D cohort (cohort 1B).  
For cohort 1B (n~16 participants), period 3 may be initiated only following SRC decision. 
Randomization to cohort 2 (n~20 participants) and cohort 3 (n~20 participants) will be initiated 
in parallel to cohort 1B. If no safety concern is raised from review of data from cohort 1A, the 
inpatient period of cohorts 1B, 2, and 3 will be identical and will include an inpatient period of 
3 days (day R1 to day R3) followed by a 25-day outpatient period (day R4 to day R29).  
Period 3 will include PK blood sampling and safety assessments (Table 3 and Table 4). 
In the case that a safety concern arises following a review of the safety results from cohort 1A, or 
one of the stopping rules in participants as detailed below (Section 7.4) is met, the following may 
be considered: 
• Adjust the olanzapine extended-release sc dose  
• Pause olanzapine extended-release sc dosing until additional data become available 
• Maintain the inpatient period of cohort 1B as in cohort 1A  
• Modification of the inpatient period of cohorts 1A and 1B to up to 28 days for close 
safety monitoring  
• Stop the trial 
At any time, the SRC may request additional evaluation including PK data before allowing 
continued dosing.  
Following completion of period 3, all participants enter a 56-day follow-up period during which 
they will resume treatment with 1 of the allowed antipsychotics at the Investigator’s discretion 
(day R29 to day R84). The follow-up period will be performed in an outpatient setting, and will 
include PK blood sampling, safety assessments, and an EOT visit on day R84 (Table 5). During 
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the follow-up period participants will resume treatment with 1 of the allowed antipsychotics 
(aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone) at the Investigator’s discretion.  
The trial schematic diagram is presented in Figure 1.  
4.1.1. 
Planned Number of Participants and Countries  
Approximately 95 adult participants are planned to be enrolled in order to achieve approximately 
60 completers. Details on the definition of completers and the sample size are given in Section 9. 
The trial is planned to be conducted in the US in approximately 5 investigational centers.  
4.1.2. 
Data Monitoring Committee/Safety Review Committee  
An SRC comprising the Sponsor’s clinical trial physician, clinical leader, PV physician, and 
other relevant experts will be summoned to review all safety data (including demography, vital 
signs, clinical laboratory tests and ECGs, AEs, concomitant medications use, local tolerability 
and pain, leakage assessment) available upon from the beginning of the study to completion of 
the first 15 days, inclusive of the sentinel cohort (cohort 1A). Following SRC decision that no 
safety concerns are raised based on the safety review of cohort 1A safety data up to day R15, 
inclusive, period 3 for cohort 1B may be initiated. Randomization to cohorts 2 and 3 will be 
initiated in parallel to cohort 1B. 
Further details are provided in Section 10.2. 
4.2. 
Rationale for Trial Design  
The trial design follows the recommendations provided in the FDA Guidance for Industry: 
Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In 
Vivo Correlations (FDA, 1997).  The objective of developing an IVIVC is to establish a 
predictive mathematical model describing the relationship between an in vitro property (usually 
the rate or extent of drug dissolution or release) and a relevant in vivo response (plasma drug 
concentration or amount of drug absorbed), per the FDA guidance (FDA, 1997) on the 
development, evaluation and application of IVIVC for extended-release oral products.  
With the purpose of establishing IVIVC, the PK of 3 olanzapine extended-release sc 
formulations with different release rates will be characterized following a single-dose 
administration in participants with schizophrenia or schizoaffective disorder. The trial design 
will include extensive characterization of the PK profiles over 84 days after olanzapine sc 
administration (day R1 to day R84) to characterize fully the absorption kinetics of all 
3 formulations for the purpose of IVIVC. All 3 formulations are expected to provide 
extended-release of olanzapine during the 84-day treatment period following single-dose sc 
administration and are expected to differ only in Cmax as a consequence of a different release rate, 
with no burst present. The trial design also includes a single-dose administration of ZYPREXA 
im, before sc administration of one of the 3 sc olanzapine extended-release formulations. The 
obtained PK data of this im immediate-release formulation will be used to characterize 
olanzapine disposition for the purpose of IVIVC analysis. These analyses will be conducted and 
reported separately from the main trial results. 
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4.3. 
Access to Trial Intervention After End of Trial  
Upon the completion of Follow-up Period on day R84, investigators should advise participants to 
return to the care of their primary physician for continuation of treatment with available 
medications. 
4.4. 
Start of Trial and End of Trial  
The trial start date is the date on which the clinical trial will be open for recruitment of 
participants. The first act of recruitment is the first investigational center open and will be the 
trial start date. EOT is defined as the last follow-up visit of the last participant. 
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5. 
TRIAL POPULATION  
5.1. 
Selection of Trial Population  
The trial population will include participants 18 to 64 years of age, with a diagnosis of 
schizophrenia or schizoaffective disorder. Participants must be clinically stable, not currently on 
antipsychotic treatment, with the exception of oral treatment with aripiprazole, risperidone, 
paliperidone, quetiapine, or lurasidone, and meet all trial eligibility criteria. During period 3, 
participants will be treated with 1 of 3 single-dose sc olanzapine extended-release formulations. 
For details regarding the study design, refer to Section 4.1. 
5.2. 
Rationale for Trial Population  
The selected trial population is representative of the demographics and disease state of 
individuals who are likely to be treated with TV-44749 in a clinical setting.  
5.3. 
Inclusion Criteria  
Participants may be included in this trial only if they meet all of the following criteria: 
a. Capable of giving signed informed consent as follows: 
− Able to understand the nature of the trial and any possible hazards in 
participating; willing to provide written informed consent to participate; and after 
reading the trial information and consent form and having the opportunity to 
discuss the trial with the Investigator or assigned delegate, sign the informed 
consent form (ICF).  
− Able to follow protocol requirements, including the prescribed dosage regimens, 
tablet ingestion, sc depot injection, and discontinuation of prohibited concomitant 
medications; able to participate in and comply with the requirements of the entire 
trial; able to read and understand the written word in order to complete 
participant-reported outcomes measures; and can be reliably rated on assessment 
scales. 
b. Males or females of any ethnic origin aged 18 to 64 years, inclusive, at the time of 
screening. 
c. Body weight >50 kg and body mass index (BMI) within the range 18.5 to 38.0 kg/m2, 
inclusive, at the time of screening. 
d. Agree to maintain current smoking or nonsmoking status at the time informed consent 
is obtained and throughout the trial until completion of the end of treatment or early 
termination (ET) visit (ie, nonsmoking participants must agree not to start smoking 
and participants who smoke will be excluded if they plan to discontinue smoking 
during the trial. 
e. Agree to the inpatient periods required during the trial period.  
f. Have a current confirmed diagnosis of schizophrenia or schizoaffective disorder 
according to an evaluation by the Investigator, using the Diagnostic and Statistical 
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Manual of Mental Disorders, Fifth Edition (DSM-5) (American Psychiatric 
Association 2013a).  
g. Are clinically stable, on oral aripiprazole, risperidone, paliperidone, quetiapine, or 
lurasidone (ie, dose has not changed in the last 4 weeks prior to screening) and not 
currently on other antipsychotic including olanzapine treatment at the time of 
screening. 
h. Have a 
 score ≤70 and a 
 score ≤3 at the time of screening. 
i. Have had no hospitalization for worsening of schizophrenic symptoms and no 
significant exacerbation of schizophrenic symptoms, as judged by the Investigator, 
within the 3 months prior to screening. 
j. Have no ongoing or expected significant life events (eg, pending loss of housing, 
marital status change, long travel abroad, surgery) that could affect trial outcomes 
throughout the period of trial participation. 
k. [Revision 1] Women may be included only if they have a negative serum beta human 
chorionic gonadotropin (HCG) test result at screening; they are surgically sterile 
(hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or 
postmenopausal (postmenopausal status will be confirmed by a follicle-stimulating 
hormone screen according to the clinical laboratory standard value) for at least 1 year; 
or they are practicing a highly effective method of birth control and not planning 
pregnancy for at least 30 days before the trial, for the duration of the trial, and for 
70 days after the last dose administration, if they are sexually active and of 
childbearing potential  (Section 13.1).  
l. Men must be sterile; or if they are potentially of reproductive competence and have 
sexual relationship with female partners of childbearing potential, they must use, 
together with their female partners, highly effective birth control methods for the 
duration of the trial and for 70 days after the last dose administration.  
m. Willing and able to comply with trial restrictions and to remain at the investigational 
center for the required durations during the trial period and willing to return to the 
investigational center for the follow-up procedures and assessments as specified. 
5.4. 
Exclusion Criteria  
Participants will be excluded from participating in this trial if they meet any of the following 
criteria: 
a. Presence or have a history of clinically significant diseases of the renal, hepatic, 
gastrointestinal, cardiovascular, or musculoskeletal system, or presence or history of 
clinically significant immunological, endocrine, or metabolic diseases, neurological 
or psychiatric disorder(s) (other than schizophrenia), or a history of any illness that, in 
the opinion of the Principal Investigator, might pose additional risk to the participant 
by participation in the trial or confound the results of the trial. 
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b. Infectious disease: 
− Acute infection and/or antibiotic treatment must be resolved 28 days prior to the 
first dose of IMP. 
− Any chronic infection. 
− [Revision 1] Known history of, or a positive test result for hepatitis B surface 
antigen and/or core antibody, known history of, or positive serology for hepatitis 
C and positive ribonucleic acid (RNA) test*, human immunodeficiency virus 
Types 1 or 2 antibody (according to enzyme-linked immunosorbent assay test), or 
active/latent tuberculosis (as determined by a positive result of the QuantiFERON 
test). If the QuantiFERON test result is indeterminate, then the test may be 
repeated once. If the second QuantiFERON test result is indeterminate also, the 
participant will be excluded from the study. 
*Note: If serology is positive but the 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. 
c. History or known risk of narrow-angle glaucoma. 
d. Uncontrolled diabetes (hemoglobin A1c 6.5% or above and/or fasting plasma glucose 
126 mg/dL or above). 
e. Major trauma or surgery in the 2 months before screening or at any time between 
screening and the first dose of IMP, or surgery scheduled during the trial or follow-up 
period, or open biopsy within 4 months prior to screening. 
f. History of malignancy or treatment of malignancy in the last 5 years, excluding 
resected basal cell or squamous cell carcinoma of the skin. 
g. The participant is a pregnant or lactating woman or plans to become pregnant during 
the trial or within 70 days after the last dose administration. 
h. 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, or ZYPREXA im 
in any formulation.  
i. Presence of excessive pigment, bruises, scars, or tattoos around the potential injection 
area. 
j. Presence of any local skin infection, rash, or anything else that limits injection 
administration and assessment of injection site. 
k. Donated or received any blood or blood products (eg, white blood cells, platelets) 
within 60 days prior to screening, or has donated blood or blood products on 2 or 
more occasions within 6 months prior to IMP administration, or has donated plasma 
within 7 days prior to screening, or has planned donations during the 56 days or 
5 half-lives following the last dose administration, whichever is longer. The minimum 
reference volume of whole blood lost or donated is 500 mL. 
l. Vulnerable participants (eg, prisoners or institutionalized individuals), participants 
who pose a significant risk of suicide attempt in the Investigator’s judgment based on 
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medical history, answered “yes” to Suicidal Ideation items 4 or 5 on the 
for 
“current” or “within 3 months prior to screening,” or had a suicide attempt or 
hospitalization due to suicide risk within 12 months prior to screening. 
m. 12-lead electrocardiogram (ECG) demonstrating intraventricular conduction delays 
(QRS interval ≥110 msec or PR interval ≥200 msec) and have a mean of triplicate 
QTcF values >450 msec for males and >470 msec for females at screening or other 
clinically significant ECG findings that would interfere with trial participation as 
judged by the Investigator. 
n. Personal or family history of arrhythmia, sudden unexplained death at a young age 
(before 40 years) in a first-degree relative, long QT syndrome, personal history of 
syncope, or history of uncontrolled high blood pressure. Participants with history of 
high blood pressure who no longer require treatment or participants who are treated 
with antihypertensive medications and whose blood pressure is currently 
well-controlled, may be enrolled. 
o. Supine or semi-supine blood pressure outside the range of 90 to 140 mm Hg for 
systolic or 50 to 90 mm Hg for diastolic (following at least a 5-minute rest). Note: 
If either value is out of range, blood pressure measurements may be repeated in the 
supine or semi-supine position at intervals of 5 to 10 minutes up to 2 times. If the 
systolic or diastolic measurement continues to exceed the stated limits, the participant 
will be excluded. 
p. Orthostatic hypotension defined as a decrease exceeding 20 mmHg in systolic blood 
pressure or 10 mm Hg in diastolic blood pressure, or both, occurring within 3 minutes 
of changing from supine to standing position, or orthostatic intolerance (only 
2 rechecks of orthostatic blood pressure are permitted for eligibility purposes). 
q. Postural tachycardia defined as a sustained heart rate increment of 30 beats per 
minute within 10 minutes of standing (only 2 rechecks allowed). 
r. [Revision 1] Body temperature (measurement performed either orally or on both ears, 
recording the highest value) outside the interval of 35.4°C to 37.5°C at the screening 
visit. 
s. [Revision 1] Clinical laboratory test abnormalities as listed below: 
− Clinical laboratory values with Common Terminology Criteria for AEs (CTCAE) 
Grade 2 or above 
− Blood urea nitrogen >31 mg/dL 
− Lactate dehydrogenase ≥3 × upper limit of normal (ULN) 
− Urinalysis with any clinically significant finding 
− Total bilirubin >2.5 mg/dL 
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × ULN 
− Creatinine >2 × ULN 
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− Creatine phosphokinase (CPK) >3 × ULN. Participants with CPK levels 
>1.5 × ULN and ≤3 × ULN may be enrolled, if the results are not clinically 
significant according to the Investigator’s review and judgment, in consultation 
with the Sponsor’s medical representative. 
− International normalized ratio ≥2.0 
− Absolute neutrophil count <1.5 × 109/L 
Any laboratory abnormality may be retested once per the Investigator’s clinical 
discretion. If the retested value is within normal limits, the participant does not need 
to be excluded from the trial. The retest limitation applies to the same day laboratory 
assessments but not to monitoring for trends (eg, CPK). Abnormal laboratory values 
that meet CTCAE Grades 1 and 2 may be accepted per consultation with Sponsor and 
where safety is not compromised. The severity of each clinical laboratory AE will be 
graded according to CTCAE, version 5.0. 
t. Any procedure or disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (appendectomies are acceptable procedures at the discretion 
of the Investigator). 
u. Received a prolonged-release formulation of olanzapine within 5 half-lives prior to 
screening. 
v. Use of an investigational drug or marketed drug (new chemical entity) within 30 days 
or 5 half-lives (whichever is longer) or in case of biologics (eg, tumor necrosis 
factor-alpha inhibitors such as adalimumab, etanercept, or infliximab) within 
3 months or 5 half-lives (whichever is longer) prior to the administration of 
ZYPREXA im. 
w. Using or consuming the following concurrent medications, over-the-counter (OTC) 
products, prescription drugs (any route of administration: eg, oral, topical), or foods: 
− strong and moderate inducers or inhibitors of CYP1A2 (Section 13.4) within 
30 days or 5 half-lives (whichever is longer) prior to the administration of 
ZYPREXA im. 
− dopamine reuptake inhibitors or prescription psychostimulants within 30 days 
prior to screening. 
− opioids or opioid-containing analgesics within 30 days prior to screening. 
− medications, in addition to those listed above, that may be expected to 
significantly interfere with the metabolism or excretion of olanzapine, that may be 
associated with a significant drug interaction with olanzapine, or that may pose a 
significant risk to participants if they were enrolled in the trial. 
x. 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 
participant does not meet the criteria for substance use disorder, a positive result on 
the serum drug test is not exclusionary. Participant’s eligibility in cases of a positive 
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result, without medical explanation, will be determined by the Investigator based on 
the participant’s background, history of substance use, and the Investigator’s 
discussions with family members, caregivers, or healthcare professionals, as 
applicable (American Psychiatric Association 2013b). 
y. Treatment-resistant schizophrenia according to medical and psychiatric history as 
judged by the Investigator or have taken clozapine for treatment-resistant 
schizophrenia. 
z. A significant sedation or delirium post-antipsychotic treatment according to medical 
and psychiatric history and as judged by the Investigator or suffered from delirium 
due to a medical condition. 
aa. A significant risk of violent behavior based on the participant’s medical and 
psychiatric history as judged by the Investigator. 
bb. [Revision 1] A current clinically significant DSM-5 diagnosis other than 
schizophrenia or schizoaffective disorder. 
cc. History of or a current active medical condition that may either compromise the 
participant’s safety or interfere with the safety or outcome evaluation of the trial drug, 
including, but not limited to, traumatic brain injury or seizure (excluding a single 
febrile or withdrawal seizure), neuroleptic malignant syndrome, clinically significant 
tardive dyskinesia, or are suffering with a clinically significant neurological disorder. 
dd. The participant cannot participate or successfully complete the trial, in the opinion of 
the Investigator, for any of the following reasons: 
− The participant is under the legal age of consent, mentally or legally 
incapacitated, or unable to give consent for any reason (unless a legal guardian is 
able to provide consent according to local requirements). 
− The participant is in custody due to an administrative or a legal decision, or under 
tutelage, or being admitted to a sanitarium or social institution. 
− The participant is unable to be contacted in case of emergency or in case a 
follow-up assessment is required within 30 days after trial completion. 
− The participant is an employee of the Sponsor or the site or a relative of an 
employee at the site conducting the trial. 
− Any other reason, at the discretion of the Investigator. 
5.5. 
Ongoing Confirmation of Participant Eligibility  
Participants’ continued eligibility will be reconfirmed by review of abbreviated inclusion and 
exclusion criteria prior to administration of ZYPREXA im. The abbreviated list will include the 
following inclusion criteria (g, h) and exclusion criterion (a). Clinical scales and laboratory tests 
taken on day 1 will be used to confirm eligibility on day 3. In case of a delay, laboratory results 
can be reviewed to perform abbreviated eligibility assessment on day 4, as long as this is done 
prior to administration of ZYPREXA im. Laboratory results from blood samples collected on 
day 4 are not required prior to initiating ZYPREXA im. Day 4 central clinical laboratory 
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assessments will serve as baseline values and are based on samples collected prior to dosing of 
ZYPREXA im. Serology to support eligibility criteria will only be done at screening. 
5.6. 
Lifestyle Considerations  
Participants will be required to comply with the following restrictions. 
5.6.1. 
Meals and Dietary Restrictions  
Participants are not required to fast before ZYPREXA im or any of the sc olanzapine 
extended-release injectable formulations.  
Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis) will be performed 
following an overnight fast of at least eight hours at the time points detailed in Table 1 to 
Table 5. Non-fasting blood collection is permitted as needed, per the Investigator’s assessment of 
AEs. 
5.6.2. 
Caffeine, Alcohol, Tobacco, and Other Habits  
It is recommended that participants do not consume alcohol and cannabis-derived products (such 
as marijuana) during the treatment period (excluding follow-up). Any positive result will be 
managed according to the Investigator’s review and judgment, in consultation with the Sponsor’s 
medical representative. 
Excessive consumption of coffee, tea, and/or caffeine-containing beverages or food (ie, 600 mg 
or more of caffeine per day or five or more cups of coffee per day) will be prohibited for a 
minimum of 2 weeks before the first dose of trial drug and during the treatment period 
(excluding follow-up). 
Participants must agree to maintain current smoking or nonsmoking status at the time informed 
consent is obtained and during the treatment period (excluding follow-up). 
The use of tobacco products will be recorded at the visits indicated in Table 1 to Table 5. Use of 
cigars and pipes will be converted into cigarette use with a ratio of 1 cigar or pipe = 
2.5 cigarettes. Use of vapes, e-cigarettes, nicotine gums, heat-non-burn tobacco products, snuffs, 
and nicotine patches will also be recorded but not be converted into cigarette use as these have 
minimal effect on CYP1A2 induction.    
5.6.3. 
Physical Activity  
Participants must remain lying down or semi-recumbent for safety reasons during administration 
of any of the 3 Olanzapine for Extended-release Injectable Suspensions (Fast-D, to-be-marketed, 
or Slow-C), and will remain under clinical observation for at least 3 hours after injection to 
monitor any possible symptom of PDSS.  
Following the administration of ZYPREXA im or olanzapine extended-release sc injectable 
formulations, the participants should be advised to stand up from the lying position after waiting 
for 30 to 60 seconds in a sitting position at the bed margin, in order to reduce the risk of 
occurrence of orthostatic hypotension often associated with olanzapine treatment. 
Participants will be instructed to not touch, rub, massage, or compress the injection site during 
the first 2 hours after administration of ZYPREXA im or olanzapine extended-release sc 
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injectable formulations. Participants may cover the injection site with loose-fitting clothing 
immediately after trial drug administration. Participants will not be allowed to lie on the injection 
site for the first 6 hours after the injection. Adhesive bandages may not be used during the period 
of leakage assessment following administration of olanzapine extended-release sc formulations. 
During all treatment periods (excluding follow-up), participants are not to engage in strenuous 
exercise, and the use of hot tubs, steam baths, and saunas are prohibited. 
5.6.4. 
Other Activity  
There are no additional restrictions in this trial. 
5.7. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently enrolled in the trial. The minimum information to be collected on screen 
failures includes, but is not limited to, demography, screening failure details, eligibility criteria, 
and AEs from the time of informed consent. 
At screening, abnormal laboratory values may be retested once per the Investigator’s clinical 
discretion. Vital signs may be repeated twice if initial values are out of range, to determine 
whether the participant is eligible for inclusion. 
A participant who is screened but not enrolled because enrollment did not occur within the 
specified time may be considered for screening again. Likewise, a participant who is screened 
and does not meet trial entry criteria may be considered for rescreening in consultation with the 
clinical leader and the clinical trial physician. 
The Investigator, in consultation with the Sponsor, will decide whether a participant can be 
rescreened. In the event a participant is rescreened, the following procedures will be followed: 
• a new screening number will be used for the participant 
• a participant may be rescreened only once 
• the participant must be reconsented at the second screening visit 
In the event of a participant being rescreened, all screening procedures will be repeated. 
Procedures performed during the screening period are listed in Table 1. 
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6. 
TRIAL INTERVENTION AND CONCOMITANT THERAPY  
6.1. 
Description of Trial Intervention(s)  
6.1.1. 
Investigational Medicinal Products Used in the Trial  
The IMPs in this trial are 3 sc formulations of Olanzapine for Extended-release Injectable 
Suspensions (TV-44749) with different release rates that are administered during period 3, and 
ZYPREXA IntraMuscular (olanzapine) Injection, immediate-release solution, administered to 
the gluteal muscle during period 1; these are described in Table 9. 
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Table 9: 
Investigational Medicinal Products used in the Trial  
IMP name 
Fast-D 
To-be-marketed 
formulation 
Slow-C 
ZYPREXA IM 
Trade name and INN, if applicable, 
or company-assigned number 
Olanzapine 
Olanzapine 
Olanzapine 
ZYPREXA (olanzapine) 
Formulation 
 
 
 
 
 
 
 
 
 
 
 
Unit dose strength(s)/Dosage level(s) 
425 mg 
 
425 mg 
 
425 mg 
 
10 mg (5 mg to be 
administered) 
Route of administration 
Subcutaneous 
Subcutaneous 
Subcutaneous 
Intramuscular 
Dosing instructions 
Single-dose injection 
during treatment period 3 
Single-dose injection 
during treatment period 3 
Single-dose injection during 
treatment period 3 
Single-dose injection during 
treatment period 1 
Intervention type 
Drug 
Drug 
Drug 
Drug 
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. 
IMP will be provided in a 
blister tray in a carton box. 
IMP will be provided in a 
vial in a carton box. 
Storage conditions 
2°C to 8°C 
2°C to 8°C 
2°C to 8°C 
20°C to 25°C, protect from 
light, do not freeze 
IM=intramuscular; IMP=Investigational Medicinal Product; INN=international nonproprietary name. 
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6.1.1.1. 
Olanzapine for Extended-Release Injectable Suspension Formulations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1.2. 
ZYPREXA IntraMuscular (Olanzapine) Injection  
 
 
 
 
 
 
 
 
 
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6.2. 
Rationale for Trial Intervention(s)  
6.2.1. 
Justification for Investigational Medicinal Product and Dose  
Olanzapine extended-release formulations will be administered sc. The 3 formulations differ in 
the content of excipients which is expected to result in different release rates of olanzapine from 
depot. The dosage of olanzapine to be administered in these formulations was selected on the 
basis of the existing safety and PK profile of olanzapine in trial TV44749-SAD-10154. 
The TV-44749 dose in this trial (425 mg) is comparable to 15 mg/day of oral olanzapine 
administered over a 28-day period and represents the intermediate dose within the range of 
clinically approved doses of oral olanzapine (10-20 mg/day). All 3 formulations are expected to 
have comparable overall exposure (AUC) over the dosing period. 
Based on PK studies conducted in beagles and in vitro release (IVR) data, it is expected that all 
formulations will provide extended-release of olanzapine during the 28-day period following 
single-dose sc administration. The Fast-D and Slow-C formulations are expected to have the 
same bioavailability (ie, similar AUC at day R84) and differ only in Cmax as a consequence of 
different release rate relative to the to-be-marketed formulation, with no burst or uncontrolled 
release expected. The Cmax for the Fast-D formulation is expected to be higher than the Cmax of 
the corresponding dose of the to-be-marketed formulation that has been assessed in previous 
clinical trials. However, the expected plasma concentration range of Fast-D is expected to be 
within that of the higher clinical dose of the to-be-marketed formulation previously established 
as safe and tolerable – 566 mg Q1M dose that was administered in trial TV44749-SAD-10154 
for 3 consecutive months. Similarly, the Cmax for olanzapine for the Slow-C formulation is 
expected to be lower than that of the to-be-marketed formulation, while still within the clinically 
relevant range of plasma concentrations. Slow-C plasma concentration is expected to be within 
that of the low clinical dose of the to-be-marketed formulation previously established as safe and 
tolerable – 283 mg Q1M dose that was administered in trial TV44749-SAD-10154 for 
3 consecutive months. 
Per the FDA guidance (FDA, 1997) on the development, evaluation, and application of IVIVC 
for extended-release oral products, the IVIVC should be demonstrated consistently with 2 or 
more formulations with different release rates to result in corresponding differences in 
absorption profiles. Although an IVIVC can be defined with a minimum of 2 formulations with 
different release rates, 3 or more formulations with different release rates are recommended. 
Thus, inclusion of 1 dose strength at the 425 mg at 2 different release rates (1 faster and 
1 slower) relative to the to-be-marketed TV-44749 (intermediate-release) is considered 
appropriate in the current trial.  
Therefore, the 3 olanzapine extended-release formulations administered to the participants of this 
trial are expected to result in therapeutic plasma olanzapine concentrations throughout the dosing 
interval. These concentrations are expected to be achieved within 1-2 days from IMP 
administration, as previously demonstrated in trial TV44749-SAD-10154.  
It is noted that the to-be-marketed formulation of TV-44749 exhibited dose linearity in the 
therapeutic dose range tested in participants with schizophrenia of 283 to 566 mg in 
trial TV44749-SAD-10154.  
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6.3. 
Dosing and Administration  
The dose of olanzapine extended-release sc formulations to be administered in treatment period 
3 is 425 mg. The volume per syringe are provided in Table 10. Detailed instructions relating to 
the preparation of the syringes and dose administration will be fully described in the Pharmacy 
Manual and provided separately. 
Table 10: 
Dose Administration Details for Olanzapine in Treatment Period 3 
Olanzapine dose level (subcutaneous injection in the abdomen) 
Dosing volume (mL) 
Olanzapine for Extended-release Injectable Suspension D (TV-44749) (Fast-D): 
425 mg 
 
Olanzapine for Extended-release Injectable Suspension (TV-44749) 
(to-be-marketed): 425 mg 
 
Olanzapine for Extended-release Injectable Suspension C (TV-44749) (Slow-C): 
425 mg 
 
The sc olanzapine extended-release formulations will be administered using a sterile 
stainless-steel needle closed with a sterile protective cap. For all participants, olanzapine 
extended-release will be injected sc in the abdomen. Dosing at the abdomen should be done 
below or at the level of the umbilicus to the left or right of the midline.  
The administration will be performed by a trained medical professional according to local 
regulations. The same person at each site, preferably, will administer the trial drug to all 
participants at their respective trial site. Participants should be instructed to not touch, rub, 
massage, or compress the injection site(s) for the first 2 hours following administration. 
Adhesive bandages may not be used during the period of leakage assessment. If leaked IMP is 
seen at the injection site 10 minutes post-injection, it should be gently wiped, while avoiding 
pressure or squeezing the injection site (see Section 8.14). A leakage score of 4 should be 
reported to the Medical Monitor (MM) within 24 hours. The leakage score will also be recorded 
in the eCRF. 
A leakage score of 4 is a criterion for exclusion from PK analysis set and the participant will be 
replaced (refer to Section 7.1).  
The dose of ZYPREXA im to be administered in period 1 is 5 mg. The contents of the vial 
should be reconstituted using 2.1 mL of sterile water for injection to provide a solution 
containing approximately 5 mg/mL of olanzapine. The resulting solution should appear clear and 
yellow. A volume of 1 mL of the reconstituted solution will be administered to the gluteal 
muscle. 
More detailed information will be provided in the Pharmacy Manual for this trial. 
Refer to Section 5.6.3 for restrictions on physical activity. 
6.4. 
Treatment of Overdose  
For this trial, any dose of olanzapine extended-release sc formulations greater than 425 mg or 
any dose of ZYPREXA im greater than 5 mg will be considered an overdose. There is no 
specific antidote to olanzapine. 
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In the event of an overdose, the Investigator/treating physician should take the following actions: 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
• Obtain a plasma sample for PK analysis immediately and obtain further sample(s) as 
requested by the MM and the Sponsor (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
• Follow the instructions specified in Table 8 and in Section 8.3.8 for suspected PDSS 
monitoring. 
In the event of acute overdose, appropriate supportive measures should be initiated and the 
Sponsor/MM should be notified. Hypotension and circulatory collapse should be treated with 
appropriate measures such as intravenous fluids and/or sympathomimetic agents; do not use 
epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta 
stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade. 
Respiratory support, including ventilation, may be required. Close medical supervision and 
monitoring should continue until the participant recovers. 
The possibility of multiple drug involvement should be considered. In case of acute overdose, 
establish and maintain an airway and ensure adequate oxygenation and ventilation, which may 
include intubation. The possibility of obtundation, seizures, or dystonic reaction of the head and 
neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular 
monitoring should commence immediately and should include continuous ECG monitoring to 
detect possible arrhythmias. 
6.5. 
Preparation, Handling, Labeling, Storage, and Accountability  
6.5.1. 
Preparation of Investigational Medicinal Product  
Detailed instructions relating to the preparation of the syringes and dose administration will be 
fully described in the Pharmacy Manual and provided separately from the protocol. 
6.5.2. 
Handling, Storage, and Security  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs. 
All IMPs (ZYPREXA im and sc olanzapine extended-release formulations) must be stored 
according to the specifications listed in the Pharmacy Manual in a securely-locked, 
temperature-controlled, and monitored storage area. 
Diversion is considered to have occurred when the legal supply chain of prescription medicinal 
products is broken, and medicinal products are transferred from a licit to an illicit channel of 
distribution or use. 
Further guidance and information are provided in the Pharmacy Manual. 
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6.5.3. 
Labeling  
Supplies of IMPs (ZYPREXA im and sc olanzapine extended-release formulations) will be 
labeled according to the current ICH guidelines on GCP, Good Manufacturing Practice, 
Regulation (EU) No. 536/2014 Annex VI (for EU Clinical Trial Application submissions) and 
will include any locally required statements. If necessary, labels will be translated into the local 
language. 
6.5.4. 
Accountability  
Each IMP (ZYPREXA im and sc olanzapine extended-release formulations) shipment will 
include a packing slip listing the contents of the shipment, and any applicable forms. 
The Investigator is responsible for ensuring that deliveries of IMP and other trial materials from 
the Sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the local regulations and used in accordance with this protocol. 
Only participants enrolled in the trial may receive IMPs and only authorized staff at the 
investigational centers may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the Investigator and 
authorized staff at the investigational center. 
The Investigator is responsible for IMP accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
A record of IMP accountability (ie, IMP and other 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.  
IMP can be destroyed at the investigational center in accordance with its SOPs, with Sponsor 
approval. In the event that the investigational center is unable to destroy the empty and/or 
unused units of IMP, the IMP will be disposed of, retained, or returned to the Sponsor or 
designee per Sponsor instructions. 
Further guidance and information are provided in the Pharmacy Manual. 
6.6. 
Participant Assignment, Randomization, and Blinding  
6.6.1. 
Participant Assignment  
Potential participants will be screened against the inclusion and exclusion criteria, and those 
individuals who have a successful screen will be enrolled into the trial. Individuals who do not 
meet criteria for trial eligibility must not be enrolled via protocol waivers or exemptions. 
6.6.2. 
Randomization  
Period 3 will be initiated with the sentinel cohort 1A (Fast-D) composed of approximately 2-4 
participants. Upon completion of the first 15 days (day R1 to day R15, inclusive) following sc 
administration of olanzapine to cohort 1A participants, the SRC will review all available safety 
and tolerability data from the beginning of the study, as described in Section 4.1. If no safety 
concern is raised by the SRC, period 3 can be initiated for cohort 1B participants (n~16). 
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Randomization to cohort 2 (n~20) and cohort 3 (n~20) will be initiated in parallel to cohort 1B. 
In order to achieve approximately 20 completers in cohorts 1, 2, and 3, participants for cohorts 
1B, 2, and 3 will be randomized at a ratio of 4:5:5. 
The randomization list will be generated by a qualified service provider under the oversight of 
the responsible function at Teva. The specifications for randomization will be under the 
responsibility and oversight of Teva Global Statistics. 
6.6.2.1. 
Maintenance of Randomization  
Participant randomization codes will be maintained by the service provider contracted to 
generate the codes. 
6.6.3. 
Blinding and Unblinding  
This is an open-label trial. 
6.7. 
Trial Intervention Compliance  
All IMPs will be administered by the Investigator or other clinical personnel to ensure 
compliance with IMP administration. 
6.8. 
Prior and Concomitant Therapy  
Any prior or concomitant therapy, medication, or procedure a participant has had within 30 days 
before ZYPREXA im and up to the EOT, including follow-up, will be recorded on the case 
report form (CRF). Generic or trade name, indication, and dosage will be recorded. The Sponsor 
will encode all therapy and medication according to the World Health Organization Drug 
Dictionary (WHO Drug). 
At each clinic visit after the screening visit, the Investigator or designee will ask participants 
whether they have taken any medications (other than IMPs), including prescription and OTC 
medications, vitamins, herbal or nutritional supplements and whether there has been any change 
in dosing regimen for previously reported medications, since the previous visit. Indication, 
dosage, and start and end dates should be entered on the CRF. 
6.8.1. 
Prohibited Concomitant Therapy  
Participants will be excluded from participating in this trial if they are using or consuming the 
following concurrent medications, OTC products, prescription drugs (any route of 
administration: eg, oral, topical), or foods during the treatment periods (excluding follow-up): 
• olanzapine products other than the IMPs of this trial.  
• any antipsychotic medications other than the trial drug (excluding allowed 
antipsychotics during period 2 and follow-up period after period 3, and rescue 
medications that may be required to ensure the safety of participants during the trial, 
as described in Section 6.8.2). 
• any of the following concurrent medications, OTC products, prescription drugs, or 
foods: 
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− strong or moderate inducers or inhibitors of CYP1A2 (Section 13.4) within 
30 days or five half-lives (whichever is longer) prior to the administration of 
ZYPREXA im, whichever is longer 
− dopamine reuptake inhibitors or prescription psychostimulants within 30 days 
prior to screening 
− opioids or opioid-containing analgesics within 30 days prior to screening 
− medications, in addition to those listed above, that may be expected to 
significantly interfere with the metabolism or excretion of olanzapine, that may 
be associated with a significant drug interaction with olanzapine, or that may pose 
a significant risk to participants in the trial  
During the treatment periods, participants may not receive treatment with any other formulations 
or doses of olanzapine. Antipsychotics other than aripiprazole, risperidone, paliperidone, 
quetiapine, or lurasidone are not allowed during the screening period. 
Any medications that interfere with the absorption, excretion, or metabolism of olanzapine, 
either directly or by liver enzyme induction or inhibition, are prohibited. A partial list of 
prohibited drugs can be found in Section 13.4. 
In addition, during the follow-up periods, any restrictions on concomitant medications use that 
are included in the US labels of any of the antipsychotics allowed to be received per protocol (ie, 
aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone) should be applied. 
6.8.2. 
Permitted Concomitant Therapy  
Allowed rescue medications will include zolpidem, zopiclone, zaleplon, and diphenhydramine 
for insomnia; benztropine, trihexyphenidyl, and diphenhydramine for parkinsonian symptoms; 
and benzodiazepines for akathisia. Lorazepam (at the approved dose per the local label) is 
permitted on an as -needed basis for indications other than akathisia (anxiety). The dose and 
duration of treatment with rescue medications will be at the discretion of the Investigator’s 
clinical judgment, based on acceptable practice standards in accordance with the local 
prescribing information. 
If additional rescue medications are needed, the following oral antipsychotics may be added at 
the Investigator's discretion: aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone. 
These should be used in accordance with the local prescribing information per Investigator's 
judgment/discretion. Dosing (initial dose and any dose modifications) and administration of the 
allowed antipsychotic (aripiprazole, risperidone, paliperidone, quetiapine, or lurasidone) is at the 
discretion of the Investigator. During visits to the CU, the participant will be asked whether or 
not they are receiving an antipsychotic from the list of allowed medications (yes/no question 
format), and the information will be recorded in the eCRF. Details regarding the antipsychotic, 
including name, dose, and date, will be recorded in a manner similar to that of all other permitted 
concomitant medications.  
Medications prescribed for the treatment of chronic medical conditions or for the treatment of 
acute medical conditions (such as antibiotics) may be permitted per Investigator judgment. The 
Sponsor may be consulted to avoid any effect on the olanzapine PK assessments. Medications 
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required for the treatment of any AEs, and contraceptives as per Section 13.1.2 are allowed (as 
long as they do not interfere with the absorption, excretion, or metabolism of olanzapine). 
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7. 
DISCONTINUATION OF TRIAL INTERVENTION AND 
PARTICIPANT WITHDRAWAL FROM TRIAL  
7.1. 
Discontinuation of Trial Intervention  
A participant will be discontinued from trial IMP if any of the following criteria are fulfilled: 
• The participant withdraws consent to continue in the trial for any reason. 
• A serious or intolerable AE develops that necessitates discontinuation from treatment 
at the discretion of the Investigator. 
• The Investigator believes continued participation is not in the best interest of the 
participant. 
• The Investigator believes that the participant has not adhered to the trial procedures or 
restrictions. 
• An important protocol deviation occurs that, in the opinion of the Investigator, 
warrants discontinuation from treatment. 
• A participant requires concomitant medication that may interfere with the PK of the 
trial drug. 
• A participant demonstrates a significant clinical deterioration that cannot be managed 
with rescue medication, as judged by the Investigator, based on any relevant history or 
observation made by the investigative site, including rating scales. 
• A participant meets 1 or more of the following hepatic enzyme criteria: 
− alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper 
limit of the normal range (ULN) 
− ALT or AST >5 × ULN for more than 2 weeks 
− ALT or AST >3 × ULN and total bilirubin level >2 × ULN 
− ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Participants who meet any of these hepatic enzyme criteria at any time during the 
trial will remain in the trial, and monitoring will be continued at the discretion of the 
Investigator until the criterion leading to treatment discontinuation has resolved, 
stabilized, or returned to baseline. If this occurs during either of the treatment periods 
(periods 1or 3), no further treatment will be administered to the participant. 
• A participant experiences a confirmed PDSS event. 
• A leakage score of 4 is reported after sc injection of 1 of the 3 olanzapine for 
extended-release formulations. A leakage score of 4 should be reported to the MM 
within 24 hours (refer to Section 8.14).  
• A participant becomes pregnant during the trial. 
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Note: Treatment discontinuation under any of the above criteria will be discussed and mutually 
agreed upon by the Investigator and the Sponsor.  
Participants discontinued following im immediate-release olanzapine injection due to AE will be 
monitored for safety until the event leading to discontinuation has resolved, and for PK until at 
least 9 days after the im immediate-release injection was administered, unless consent is 
withdrawn.  
Participants discontinued following olanzapine extended-release formulation injection due to AE 
will be monitored for safety until the event leading to discontinuation has resolved, and for PK 
until at least 56 days, after sc injection administration, unless consent is withdrawn.  
Participants who meet 1 or more of the treatment discontinuation criteria should be invited to 
perform the ET visit as soon as possible. Participants who discontinue during treatment period 3 
should be encouraged to also complete the EOT visit on day R84 (see Section 7.2 for details). 
Participants who destabilize should be referred directly to a psychiatric clinic or to a hospital 
emergency room with psychiatric capabilities if they are not deemed stable to return home. 
7.2. 
Participant Withdrawal from the Trial  
In accordance with the Declaration of Helsinki (and in accordance with the applicable country’s 
acceptance), each participant is free to withdraw from the trial at any time. The Investigator also 
has the right to withdraw a participant from the trial for any reason. Reasons for participant 
withdrawal include but are not limited to the following: 
1. Participant withdraws consent or requests discontinuation from the trial for any 
reason. 
2. Participant develops an AE that would interfere with his/her continued participation. 
3. Participant is noncompliant with the trial procedures and assessments or 
administration of IMP in the opinion of the Investigator. 
4. Confirmed pregnancy in a female participant. 
5. The Sponsor requests withdrawal of the participant. 
6. Participant experiences an AE or other medical condition that indicates to the 
Investigator that continued participation is not in the best interest of the participant. 
Participants should be treated with standard of care after withdrawal from the trial as 
appropriate. 
If a participant withdraws consent, every attempt will be made to determine the reason. For 
participants withdrawn from the trial, all efforts will be made to complete and report all 
observations up to the time of withdrawal. EOT procedures should be completed at the time of 
the participant’s withdrawal (assuming consent is not withdrawn) and an explanation given as to 
why the participant is withdrawing or being withdrawn from the trial. Participants who 
discontinue during treatment period 3 should be encouraged to also complete the EOT visit on 
day R84. 
If the reason for withdrawal is an AE and/or a clinically significant abnormal laboratory test 
result, monitoring will be continued at the discretion of the Investigator (eg, until the event has 
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resolved, stabilized, or returned to baseline; until the participant is referred to the care of a health 
care professional; or until a determination of a cause unrelated to any of the IMPs or trial 
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. If the 
Investigator determines that the AE is related to the IMP, monitoring should continue until the 
AE has resolved or stabilized. 
The Investigator must inform the clinical trial physician/clinical leader as soon as possible of all 
participants who are being considered for withdrawal due to AEs. Additional reports must be 
provided when requested. 
7.3. 
Lost to Follow-up  
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the investigational center. The following actions must be 
taken if a participant fails to return to the investigational center for a required trial visit: 
• The investigational center must attempt to contact the participant and/or the 
participant’s caregiver and reschedule the missed visit as soon as possible and 
counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the 
trial. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant and/or the 
participant’s caregiver in accordance with the clinical site standard procedures. These 
contact attempts should be documented in the participant’s medical record. 
Should the participant and the participant’s caregiver continue to be unreachable, the participant 
will be considered to have withdrawn from the trial with a primary reason of “lost to follow-up.” 
7.4. 
Trial Stopping Rules  
The Sponsor may suspend or terminate the trial 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 
• an SAE of interest considered by the Principal Investigator and/or Sponsor as related 
to the IMP 
If 3 or more participants meet stopping rules criteria during the trial, as described below, the 
Investigator, clinical lead, clinical trial physician, and pharmacovigilance physician will meet to 
decide on the need for trial discontinuation: 
• drug-induced liver injury 
• any drug-related SAE 
• any CTCAE Grade 3 laboratory test result, or a CTCAE Grade 2 laboratory test result 
lasting over 48 hours, graded according to the National Cancer Institute (NCI) 
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CTCAE, version 5.0. An exception to that rule is isolated Grade 3 
hypophosphatemia. 
At any time during the trial, and after discussion between the Sponsor and Investigator, the trial 
may be stopped, if the following occur: 
• previously unknown data that raise concern about the safety of the trial participants 
become available, and 
• following administration of 1 of the olanzapine extended-release formulations, 3 or 
more participants (cumulative across the trial, from all cohorts) meet the definition of 
PDSS.  
Any possible symptoms of a PDSS event will be monitored based on establishing evidence for 
all 5 criteria in the definition for a clinical diagnosis of a PDSS as described in Section 8.3.8 
(adapted from Detke et al 2010).  
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8. 
TRIAL ASSESSMENTS AND PROCEDURES  
8.1. 
Screening/Baseline Assessments and Procedures  
A signed and dated ICF will be obtained before screening procedures commence (Section 10.3). 
Evaluations obtained as part of routine medical care and performed during the screening period 
may be used in place of the protocol-specific evaluations. Participants will acknowledge and 
agree to the possible use of this information for the trial by giving informed consent. Participants 
will be provided with the option to provide a sample for pharmacogenomics analyses during 
period 3. A separate written informed consent will be obtained from each participant before 
pharmacogenomics samples will be collected. 
After informed consent is obtained, participants who are screened will be assigned an 8-digit 
permanent identification number such that all participants from each investigational center are 
given consecutive identification numbers in successive order of inclusion. The first two digits of 
the screening number will be the number assigned to the country where the investigational center 
is located, the next 3 digits will be the designated Investigator center number, and the last 
3 digits will be assigned at the Investigator center (eg, if the number assigned to the country is 
01, the third participant screened at center 5 would be given the number of 01005003). 
The screening period will take place within 40 days prior to the antipsychotic's 3-day WO 
period. Screening procedures and assessments may be performed at any time during the 
screening period. Confirmation of eligibility for the trial will be performed on day 3 and 
determined based on an abbreviated list of eligibility criteria using laboratory and clinical scale 
values collected on day 1. If, due to technical reasons, laboratory results are not available by 
day 3, eligibility may be confirmed on day 4, prior to dosing (Table 1). 
Participants who meet the inclusion criteria and do not meet the exclusion criteria at the 
screening visit may be enrolled in the trial. 
8.2. 
Efficacy Assessments and Procedures  
Efficacy assessments are not evaluated in this trial. 
8.3. 
Safety Assessments and Procedures  
The following safety and tolerability measures will be implemented throughout the trial at the 
time points listed in Table 1 to Table 5: 
• inquiries about AEs (Section 8.4) 
• physical examinations and physical measurement findings (Section 8.3.1) 
• vital signs measurements (Section 8.3.2) 
• ECG findings (Section 8.3.3) 
• clinical laboratory test results (Section 8.3.4) 
• neurological and clinical symptom assessments (
, 
 
 
, and 
) (Section 8.3.5) 
• local injection site tolerability and pain assessments (Section 8.3.6) 
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• injection site pus-containing lesion (abscess, infection, or inflammation), ulceration, 
necrosis, or atrophy monitoring (Section 8.3.7) 
• PDSS monitoring (Section 8.3.8) 
• medication error and special situations related to the IMP (Section 8.3.9) 
• overall tolerability (Section 8.3.10) 
• pregnancy and postpartum information (Section 8.5) 
• clinical product complaints (Section 8.6) 
• concomitant medication usage (Section 6.8)  
In the case of a suspected PDSS event, an adjudication committee will be summoned to review 
all cases of suspected PDSS. Further details on the adjudication committee are provided in 
Section 10.2. 
8.3.1. 
Physical Examinations  
Physical examinations and physical measurements (height, weight, and calculation of BMI) will 
be performed at the time points detailed in Table 1 to Table 5. 
A complete physical examination will be conducted at the screening and EOT visits. Physical 
examinations will include, at a minimum, assessments of general appearance, head, ears, eyes, 
nose, throat/neck [HEENT], lymph nodes, respiratory system, cardiovascular system, 
gastrointestinal system, musculoskeletal system including extremities, neurological system, and 
dermatological system. An abbreviated physical examination (general appearance, HEENT, 
lung, heart, skin, and extremities) will be conducted at the other time points and will include a 
brief neurological examination that includes assessment of mental status and 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 assessed by the Investigator as a clinically significant 
change (worsening) compared with a baseline value will be recorded as an AE, recorded on the 
CRF, and monitored as described in Section 8.4.4.  
8.3.2. 
Vital Signs  
Vital signs, including body temperature, respiratory rate, supine or semi-supine pulse rate and 
blood pressure (systolic and diastolic), and their orthostatic changes, will be measured at the time 
points detailed in Table 1 to Table 5.  
Orthostatic blood pressure and heart rate will be determined with measurements obtained after 
the participant has been supine or semi-supine for at least five minutes and repeated after the 
participant has been standing for 3 minutes. 
All vital sign results outside of the reference range will be interpreted by the Investigator as 
belonging to 1 of the following categories: 
• abnormal but not clinically significant 
• abnormal and clinically significant 
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When applicable, vital signs will be measured after ECGs but before scheduled blood draws. 
Before pulse, blood pressure, and respiratory rate are measured, the participants must be in a 
supine or semi-supine position and resting for at least 5 minutes. The same position and arm 
(opposite arm from the cannula site) should be used each time vital signs are measured for a 
given participant, when possible. For any abnormal vital signs finding, the measurement should 
be repeated as soon as possible. 
Any vital sign result that is assessed by the Investigator as clinically significant will be recorded 
on the source documentation, transcribed to the CRF as an AE, and monitored as described in 
Section 8.4.4. In addition, potentially clinically significant values may be predefined by the 
Sponsor for selected vital signs and, if so, this will be documented in the Statistical Analysis 
Plan or other relevant documents (eg, medical monitoring plan). 
8.3.3. 
Electrocardiograms  
ECGs will be measured at the time points detailed in Table 1 to Table 5. 
All ECG results outside of the reference range will be interpreted by a qualified physician as 
belonging to 1 of the following categories: 
• abnormal but not clinically significant 
• abnormal and clinically significant 
When applicable, ECGs will be performed before vital signs measurements and scheduled blood 
draws. Before each ECG is performed, the participants must be in a supine or semi-supine 
position and resting for at least 5 minutes. At screening only, the ECG will be performed in 
triplicate at 5-minute intervals. 
A qualified physician or designee at the clinical investigational site will be responsible for 
interpreting the ECGs. Any ECG finding that is assessed by the Investigator as a clinically 
significant change (worsening) compared with a baseline value will be considered as an AE, 
recorded on the source documentation, transcribed onto the CRF, and monitored as described in 
Section 8.4.4.  
8.3.4. 
Clinical Laboratory Tests  
8.3.4.1. 
Chemistry, Hematology, Coagulation, and Urinalysis  
Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis) will be performed 
following an overnight fast of at least eight hours at the time points detailed in Table 1 to 
Table 5. Non-fasting blood collection is permitted as needed, per the Investigator’s assessment 
of AEs. 
Clinical laboratory tests on samples collected during day 1 and day 3 may be performed via both 
local and central laboratories, as described below. Non-fasting blood collection is permitted as 
needed, per Investigator assessment of AEs. 
Specific laboratory tests to be performed are listed in Section 13.2. At each urinalysis collection, 
females will be asked if they are currently menstruating, and this information will be recorded in 
the source documents and CRF. 
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All clinical laboratory test results outside of the reference range will be interpreted by the 
Investigator as belonging to one of the following categories: 
• abnormal but not clinically significant 
• abnormal and clinically significant (AE, as described in Section 8.4.1) 
A laboratory test result that is assessed by the Investigator as clinically significant will be 
recorded as an AE and monitored as described in Section 8.4.4. An event may include a 
laboratory or diagnostic test abnormality (once confirmed by repeated testing) that results in the 
withdrawal of the participant from the trial, the temporary or permanent 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 participant from entering the trial or receiving IMP 
are not considered AEs). 
In addition, potentially clinically significant values will be predefined by the Sponsor for 
selected laboratory test variables and detailed in the Statistical Analysis Plan or other relevant 
documents (eg, medical monitoring plan or laboratory analysis plan). 
8.3.4.1.1. Laboratory Values Meeting Hy’s Law Criteria  
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the criteria listed below, must be reported by the Investigator to the Sponsor as an SAE: 
• ALT or AST increase of >3 × ULN 
• total bilirubin increase of >2 × ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase) 
8.3.4.2. 
Other Laboratory Tests  
8.3.4.2.1. Screening Laboratory Tests  
At screening, participants will be tested for hepatitis B surface antigen, hepatitis C virus 
antibody, human immunodeficiency virus (HIV)-1 antibodies, and HIV-2 antibodies. 
8.3.4.2.2. Follicle-stimulating Hormone  
At screening, women who have been amenorrheic for at least 1 year without an alternative 
medical cause will have a serum follicle-stimulating hormone (FSH) assessment to confirm 
postmenopausal status (an increased concentration of FSH of >35 IU/L in women not using 
hormonal contraception or hormonal replacement therapy [HRT]). 
For pregnancy testing, see Section 13.1.3. 
8.3.4.2.3. Human Chorionic Gonadotrophin Test  
HCG tests in serum or urine will be performed for all women at the time points specified in 
Table 1 to Table 5. 
A serum pregnancy test will be administered for all women, regardless of childbearing potential 
at screening, on day 1, day 12, and R84 (EOT). Serum or urine dipstick pregnancy tests will be 
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performed for all women of childbearing potential (WOCBP) on day 3. Negative pregnancy 
results on day 1, day 3, day 12 (which will be performed locally and centrally), and, if Period 2 
is extended, day R1 are mandatory prior to IMP dosing. Additional pregnancy tests may be 
performed, as determined necessary by the Investigator or required by local regulation, to 
establish the absence of pregnancy at any time during the participant’s participation in the trial. 
Any participant who becomes pregnant during the trial will be withdrawn. Procedures for 
reporting the pregnancy are provided in Section 8.5. 
8.3.4.2.4. Alcohol and Drug Screen  
A serum drug and alcohol screen will be performed at screening. The serum drug screen is to 
detect the presence of drugs of abuse, including amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, and tetrahydrocannabinol. 
An in-house urine dipstick screen for prohibited drugs and breathalyzer for alcohol will be 
performed on day 1, day 3, day 12 (to be conducted at the discretion of the Investigator), day R1 
(if Period 2 is extended), day R15, and day R84 (EOT). Alcohol and drug screens may be 
performed at additional time points at the discretion of the Investigator. 
Any positive result during trial conduct will be managed according to the Investigator’s review 
and judgment, in consultation with the Sponsor’s medical representative. 
8.3.5. 
Neurological and Clinical Symptoms Measures  
The following neurological and clinical symptoms measures (
, 
 
, and 
) will be administered by a trained rater at the time points specified in 
Table 1 to Table 5.  
8.3.5.1. 
  
 
 
 
 
 
 
 
8.3.5.2. 
  
 
 
 
 
 
8.3.5.3. 
  
 
 
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8.3.5.4. 
  
 
 
 
 
 
 
8.3.5.5. 
  
 
 
 
8.3.5.6. 
  
 
 
 
 
 
 
 
 
8.3.6. 
Assessment of Local Tolerability and Pain  
Local tolerability assessments should be performed after each administration of the IMPs 
(olanzapine immediate-release im or any of the olanzapine for extended-release sc formulations) 
(Table 1 to Table 5) and should include injection site findings and pain. Injection site findings 
(erythema, induration/swelling, and pus-containing lesions) and pain will be assessed using the 
scales provided in Table 11. Pain at the injection site will be reported using a standardized 
11-point NPRS for pain intensity, where 0 is “No pain” and 10 is “Worst possible pain.” 
Participants will be asked to respond to the following question: “How much pain do you feel at 
the drug injection site?” 
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. Pain and 
injection site findings will also be assessed on the planned trial days as detailed in Table 1 to 
Table 5.  
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Local tolerability should be assessed as described in Table 11. The surface diameter in 
millimeters should be recorded, and erythema and induration/swelling at the injection site will be 
measured as absent, 5 to ≤50 mm, >50 to ≤100 mm, and >100 mm. Erythema and 
induration/swelling under 5 mm in diameter should be assessed as absent. Care should be taken 
to avoid pressuring or squeezing the injection site while assessing induration via careful 
superficial palpation. 
Injection sites may be photographed, including between visits to the clinical center, to provide 
visual representation in addition to comments in the source documents. The photographs will not 
be used for analysis but can be used to the support the Investigators with their assessments. Any 
features that could be used to identify the participant will not be captured in the photograph. 
Injection site findings described in Table 11 and injection site pain will be recorded on the 
specified CRF. 
Injection site findings will not be captured as AEs unless they fulfill adverse event criteria and 
then must be recorded and reported as specified in Section 8.4.4. Appropriate treatment may be 
provided, if necessary, in which case such treatments must be recorded as concomitant 
medication(s). 
In case an AE associated with an ISR is reported, pain may be assessed periodically using an 
NPRS until resolution. 
Site-specific training to monitor for ISRs will be provided; participants will also be educated 
about ISRs. Additionally, each visit at the CU will include AE inquiry, including inquiry on 
injection site-related events. 
Refer to Section 8.4 for procedures and assessments that are performed for events of 
pus-containing lesion (abscess, infection, or inflammation), ulceration, necrosis, or atrophy.  
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Table 11: 
Assessment of Local Tolerability (Injection Site Findings)  
Test 
Response 
Erythemaa         
Absent 
Surface diameter 5 to ≤50 mm 
Surface diameter >50 to ≤100 mm 
Surface diameter >100 mm 
Induration/swellinga 
Absent 
Surface diameter 5 to ≤50 mm 
Surface diameter >50 to ≤100 mm 
Surface diameter >100 mm 
Paina 
0 to 10 (NPRS) 
Pus-containing lesion 
If “Yes,” it will be considered as 
an AESI, and the diameter 
should be recorded. 
Yes/No 
<5 mm 
5 to 15 mm 
>15 mm 
a The decision on whether any of the above meet AE criteria and whether it should be recorded as an AE is per the Investigator’s 
clinical judgment. 
AE=adverse event; AESI=adverse event of special interest; NPRS=Numeric Pain Rating Scale. 
8.3.7. 
Procedures for Injection Site Pus-containing Lesion (Abscess, Infection, or 
Inflammation), Ulceration, Necrosis, or Atrophy   
In case of injection site pus-containing lesion (abscess, infection, or inflammation), ulceration, 
necrosis, or atrophy, the following procedures and assessments will be performed: 
• Vital signs will be measured. 
• Hematology clinical laboratory tests will be performed. 
• In case of pus-containing lesion (abscess, infection, or inflammation), refer to the 
assessments described in the last row of Table 11. 
• In case of surgical drainage of pus-containing lesion (abscess, infection, or 
inflammation), every effort should be made to collect a discharge sample for culture, 
if possible, and every effort should be made to avoid contamination. 
• Treatment should be administered according to the local standard of care, with 
follow-up until resolution. 
• It is highly recommended that site staff photograph the injection site. Photographs 
may be shared with the Sponsor, but data analysis will not be performed on the 
photographs. The photographs should be taken at a standardized distance of the 
camera to the skin, using a standardized light source and two perpendicular rulers to 
provide scale. Any features that could be used to identify the participant should not 
be captured in the photograph. 
• Biomarker samples will be collected at any unscheduled visits as a result of the 
pus-containing lesion (abscess, infection, or inflammation), ulceration, necrosis, or 
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atrophy, and for 2 consecutive visits after the event is identified (where local 
regulations allow, unless the participant declines to provide consent). 
The procedures for reporting these events to the Sponsor’s Global PV is described 
in Section 8.4.8.1. 
Investigators at sites where participants experience pus-containing lesions may be asked by the 
sponsor to fill out a follow-up questionnaire regarding these events to further assess the 
subjective perception of these AEs. In addition, a follow-up discussion with the site 
representative/s may be conducted, with written documentation of the meeting minutes. 
8.3.8. 
Post-injection Delirium and Sedation Syndrome (PDSS) Monitoring  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3.9. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products  
Any administration of IMP that is not in accordance with the trial protocol should be reported as 
a protocol deviation and documented in the participant’s source documents (see Section 11.2), 
regardless of whether or not an AE occurs as a result. 
The following are types of medication errors and special situations: 
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
participant, or consumer. 
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the recommended dose according to this protocol as 
specified in Section 6.4. Clinical judgment should always be applied. Any dose of IMP, 
whether taken intentionally or unintentionally, in excess of that prescribed must be 
immediately reported to the Sponsor. 
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects. 
5. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation. 
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6. Off-label use: Situations where a medicinal product is intentionally used for a medical 
purpose not in accordance with the protocol or authorized product information, as 
applicable. 
7. Breastfeeding: Suspected AEs that occur in infants following exposure to a medicinal 
product from breast milk. 
8.3.10. 
Overall Tolerability  
Subjective overall tolerability will be assessed after all participants have completed the final 
assessments and will be based upon the number (%) of participants who failed to complete the 
trial and the number (%) participants who failed to complete the trial due to AEs. 
8.4. 
Adverse Events and Serious Adverse Events  
8.4.1. 
Definitions of Adverse Events and Serious Adverse Events  
8.4.1.1. 
Adverse Events  
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can, therefore, be any unfavorable and unintended physical sign, symptom, or laboratory 
parameter that develops or worsens in severity during the course of this trial, or significant 
worsening of the disease under study, or of any concurrent disease, whether or not considered 
related to the olanzapine sc formulations or ZYPREXA im. 
Accordingly, an AE can include any of the following:  
• a new condition or the worsening of a preexisting 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 
trial 
• laboratory or diagnostic test abnormalities 
Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a participant from entering the trial or receiving trial treatment are not 
considered AEs. 
• significant worsening (change in nature, severity, or frequency) of the disease under 
study or other preexisting conditions (Note: A condition recorded as preexisting that 
is intermittently symptomatic [eg, headache] and that occurs during this trial should 
be recorded as an AE). 
• events occurring during diagnostic procedures 
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• laboratory or diagnostic test abnormalities that result in the withdrawal of the 
participant from the trial, are associated with clinical signs and symptoms or an SAE, 
require medical treatment or further diagnostic work up, or are considered by the 
Investigator to be clinically significant 
• all events of possible drug-induced liver injury (Section 8.3.4.1.1) 
• any physical examination, vital signs measurement, ECG, or other safety assessment 
finding that is judged by the Investigator as a clinically significant change 
(worsening) compared with a baseline value 
8.4.1.2. 
Serious Adverse Events  
An SAE is an AE occurring at any dose that results in any of the following outcomes or actions: 
• results in death 
• is a life-threatening AE (ie, the participant was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if 
it were more severe 
• requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an AE, or that they occurred as a consequence of the event 
Hospitalizations scheduled before the participant signed the ICF will not be 
considered SAEs, unless there was worsening of the preexisting condition during the 
participant’s participation in this trial. 
• 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 participant 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; or 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. 
An AE that does not meet any of the criteria for seriousness listed above will be regarded as a 
nonserious AE. 
8.4.1.3. 
Adverse Device Effects and Serious Adverse Device Effects  
An adverse device effect is an AE related to the use of a medical device (standalone or in a 
combination product). This includes AEs resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, operation, or any malfunction of the 
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investigational medical device, including any event resulting from user error or from intentional 
misuse of the investigational medical device. This definition includes events related to the 
procedures involved. For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
A serious adverse device effect results in any of the consequences characteristic of an SAE 
(Section 8.4.1.2) and is reported per Section 8.4.7. 
8.4.2. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information  
For recording of AEs and SAEs, the trial period is defined for an individual participant as the 
time period from signature of the ICF to the EOT. TEAEs are defined as AEs that occurred after 
the first dose of IMP was administered through the EOT. SAEs occurring in a participant after 
the trial has ended should be reported to the Sponsor if the Investigator becomes aware of them, 
following the procedures described in Section 8.4.6 and Section 8.4.7. 
8.4.3. 
Identifying Adverse Events and Serious Adverse Events  
At each contact with the participant, the Investigator or designee must question the participant 
about AEs 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 an SAE or protocol-defined adverse 
event of special interest (PDAESI) for expedited reporting to Global PV, on the Serious Adverse 
Event and PDAESI Form. 
Any clinically significant change, as judged by the Investigator, in the 
, 
 
 and 
 scales should be reported as an AE. 
During the conduct of the trial, to identify safety concerns, AEs (both serious and nonserious) 
will be reviewed by the clinical trial physician as they are reported from the investigational 
center. 
8.4.4. 
Recording of Adverse Events and Serious Adverse Events  
All AEs that occur during the defined trial 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. The Investigator will record all relevant information regarding every AE/SAE and will 
categorize each as guided in Figure 2. For SAEs and PDAESI for expedited reporting to Global 
PV, the Serious Adverse Event and PDAESI Form must be completed and the SAE and the 
PDAESI must be reported within 24 hours (Section 8.4.6 and Section 8.4.7). The Investigator 
does not need to actively monitor participants for new AEs after the end of the trial. 
SAEs occurring in a participant after the EOT should be reported to the Sponsor if the 
Investigator becomes aware of them, following the procedures described in Section 8.4.7. 
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The onset and end dates, duration (in case of AE duration of less than 24 hours), action taken 
regarding IMP, treatment administered, and outcome for each AE must be recorded both on the 
source documentation and the CRF. 
The relationship of each AE to IMP (and relationship to the device, if applicable), and the 
severity and seriousness of each AE, as judged by the Investigator, must be recorded. 
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Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification  
AE
NO
YES
YES
YES
NO
AE
ADE
• 
Record on the source documentation and 
on the CRF
• 
Report the device deficiency according to 
Section 8.6
SAE
NO
SADE
• 
Notify Teva and IEC/IRB according to the 
process outlined in Section 8.4.7
• 
Report the device deficiency according to 
Section 8.6
Initial determination 
per Section 8.6: Could 
the SAE be related to 
the device?
Initial 
determination per 
Section 8.6: Could the 
AE be related to the 
device?
Does the AE meet the 
serious criteria? 
Is the device 
manufactured by Teva?
YES
NO
• 
Forward details of the AE related to the 
device to the manufacturer or wholesaler 
of the device
Is the device 
manufactured by Teva?
YES
• 
Forward details of the SAE related to the 
device, together with the CIOMS form, to 
the manufacturer or wholesaler of the 
device
NO
 
AE=adverse event; ADE=adverse device effect; CIOMS=Council for International Organizations of Medical Sciences; CRF=case report form; IEC=Independent Ethics 
Committee; IRB=Institutional Review Board; SADE=serious adverse device effect; SAE=serious adverse event. 
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8.4.4.1. 
Severity of an Adverse Event  
The severity of each AE will be graded according to the NCI CTCAE. 
AEs that are not included in the NCI CTCAE lists will be graded according to the NCI CTCAE 
general guideline for grades: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local intervention or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (eg, preparing meals, shopping 
for groceries or clothes, using the telephone, managing money). 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living (eg, bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
8.4.4.2. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device  
The relationship of an AE to the IMP and/or device is characterized in Table 12. 
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Table 12: 
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 AEs 
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 AE 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 
participant’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the 
participant. 
• 
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 AEs 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 AE 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 participant’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the participant. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an AE 
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. 
AE=adverse event; IMP=investigational medicinal product 
8.4.4.3. 
Expectedness of Serious Adverse Events  
An SAE that is not included in the Adverse Reaction section of the relevant reference safety 
information (RSI) by its specificity, severity, outcome, or frequency is considered an unexpected 
adverse event. The RSI of TV-44749 sc formulations for this trial is the IB. 
The RSI of ZYPREXA im in this trial to use is the prescribing information (ZYPREXA USPI 
2021). 
The Sponsor’s Global PV will determine the expectedness for all SAEs. 
For the purpose of SUSAR reporting, the version of the IB effective at the time of occurrence of 
the SUSAR applies. 
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8.4.5. 
Follow-up of Adverse Events and Serious Adverse Events  
The clinical course of each AE will be monitored at suitable intervals until resolved, stabilized, 
or returned to baseline; until the participant is referred for continued care to a healthcare 
professional; or until a determination of a cause unrelated to the IMP or trial procedure is made. 
The Investigator may perform additional laboratory tests or investigations, perform 
histopathological examinations, or consult with other healthcare professionals to elucidate the 
nature and/or causality of the AE or SAE as fully as possible. 
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide postmortem findings including histopathology, if available, within the 
Serious Adverse Event Form. 
New or updated information will be recorded in the originally submitted documents. 
The Investigator will submit any updated data on SAEs and PDAESI for expedited reporting to 
Global PV within 24 hours of receipt of the information, following the process described in 
Section 8.4.7. 
8.4.6. 
Reporting of Serious Adverse Events  
To satisfy regulatory requirements, the Investigator must report all SAEs that occur during the 
trial, regardless of the judgment of relationship to administration of the IMP, to the Sponsor. The 
Investigator must report the event within 24 hours of learning 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 Serious Adverse Event Form should be sent to the LSO or designee (as applicable, for eg, a 
CRO in a country without a Sponsor LSO); the LSO will forward the report to the Sponsor’s 
Global PV. 
Each report of a SAE 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, trial procedures, and 
to underlying disease. 
The investigational center should forward additional information (follow-up) about any SAE and 
PDAESI for expedited reporting unavailable at the initial reporting within 24 hours of when it 
becomes known, following the same process as for the initial report. 
The responsibilities and procedures for reporting, receiving, processing, submission, 
reconciliation, and follow-up of SAEs, pregnancies, and PDAESI that require expedited 
reporting to Global PV are detailed in the Serious Adverse Event Management Plan (SMP). The 
SMP will be provided as a separate document. 
Note: Although pregnancy is not an SAE, the process for reporting a pregnancy is the same as 
that for reporting an SAE but using the Pregnancy Form (Section 8.5). 
8.4.7. 
Regulatory Reporting Requirements for Serious Adverse Events  
If a serious unexpected adverse event (ie, the event fulfills the criteria for a SUSAR) is believed 
to be related to the IMP, the Sponsor will take appropriate steps to notify all Investigators 
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participating in sponsored clinical trials of the IMP and the appropriate regulatory authorities 
(and IRB/IEC, as applicable). 
For all countries, the Sponsor’s Global PV will distribute the Council for International 
Organizations of Medical Sciences (CIOMS) form/XML file to the LSO/CRO for submission to 
the competent authorities, IRBs/IECs, and Investigators, according to regulations. For trials in 
the European Economic Area (EEA), submission of SUSARs is done centrally to EMA by the 
Global PV. The Investigator must ensure that the IRB/IEC is also informed of the event, in 
accordance with national and local regulations. 
In addition to notifying the Investigators and competent authorities (and IRB/IEC, if 
appropriate), other measures may be required, including the following: 
• modifying the protocol and/or ICF 
• discontinuing or suspending the trial 
• modifying listings of expected toxicities to include AEs newly identified as related to 
IMP 
8.4.8. 
Adverse Events of Special Interest  
8.4.8.1. 
Protocol-defined Adverse Events of Special Interest that Require Reporting to 
Sponsor’s Global Pharmacovigilance  
For purposes of this protocol, the following are considered protocol-defined AEs of special 
interest (PDAESI) to be sent to the Sponsor’s Global PV for evaluation: 
• PDSS events 
• ISRs of pus-containing lesion (abscess, infection, or inflammation), ulceration, 
necrosis, and atrophy 
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting an SAE (Sections 8.4.6 and 8.4.7), using the same Serious Adverse Event/Protocol-
Defined Adverse Events of Special Interest Form. PDAESI to be reported to Global PV can be 
either serious or nonserious, according to the criteria outlined in Section 8.4.1. PDAESI that 
occur before trial drug administration do not require reporting to Global PV.  
8.4.8.2. 
Protocol-defined Adverse Events of Special Interest that do not Require 
Reporting to Sponsor’s Global PV  
The following are considered PDAESI that do not need to be sent to the Sponsor’s Global PV 
and will be recorded only in the clinical database:  
• ISR following sc administration, including, but not limited to, pain, bleeding, 
tenderness, skin induration, warmth, itching, erythema, inflammation/swelling, rash, 
skin irritation, dermal irritation, or bruising at the injection site 
Pain at the injection site will not be recorded as an AE (but will be captured as a trial safety 
measure) unless it is different in character, intensity, duration, or frequency from that expected, 
based on Investigator judgment. 
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8.4.9. 
Protocol Deviations Because of an Adverse Event  
If a participant experiences an AE or medical emergency, deviations from the protocol may be 
allowed on a case-by-case basis. To ensure participant safety, after the event has stabilized or 
treatment has been administered (or both), the Investigator or other physician in attendance must 
contact the Clinical Leader as soon as possible to discuss the situation. The Investigator, in 
consultation with the Sponsor, will decide whether the participant should continue to participate 
in the trial. 
8.5. 
Pregnancy and Postpartum Information  
Any female participant becoming pregnant during the trial will discontinue and will be 
withdrawn from the trial. 
All pregnancies of women participating in the trial and female partners of men participating in 
the trial, if applicable that occur during the trial or within six months from last IMP dose, 
whichever is longer, are to be reported within 24 hours. The completed Pregnancy Form should 
be sent to the LSO/CRO (as applicable, for eg, a CRO in a country without a Sponsor LSO); the 
LSO will forward the report to the Sponsor’s Global PV. The process for reporting a pregnancy 
is the same as that for reporting an SAE but using the Pregnancy Form (Section 8.4.7). 
The Investigator is not required to report participants who are found to be pregnant between 
screening and baseline, provided no protocol related procedures were applied.  
Because this IMP(s) has suspected reproductive toxicity, female partners of men participating in 
the trial who become pregnant will be asked to sign an ICF. All female participants and female 
partners of men participating in the trial 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 trial and any complication of pregnancy that the Investigator becomes aware of after 
withdrawal from the trial will be reported as an AE or SAE, as appropriate. 
If the pregnancy in the woman participating in the trial and/or the female partners of men 
participating in the trial does not continue to term, one of the following actions will be taken: 
• For a spontaneous abortion, report as an SAE (both Pregnancy and Serious Adverse 
Event Forms should be completed). 
• For an elective abortion due to developmental anomalies, report as an SAE (both 
Pregnancy and Serious Adverse Event Forms should be completed). 
• For an elective abortion not due to developmental anomalies, report on the 
Pregnancy Form; do not report as an AE. 
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8.6. 
Clinical Product Complaints  
8.6.1. 
Definition of Clinical Product Complaints  
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP supplies (TV-44749 sc formulations and ZYPREXA 
im) and/or clinical device supplies used in a clinical research trial sponsored by Teva.  
Examples of a clinical product complaint include, but are not limited to, the following:  
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling) 
• 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 
Each investigational center will be responsible for detecting, documenting, and reporting a 
clinical product complaint by completing the Product Complaint Form provided by Teva and 
emailing it to TevaProductComplaintAndPotentialSB@teva.co.il as soon as possible after 
becoming aware of the issue. 
Reporting a complaint must not be delayed even if not all the required information can be 
immediately obtained. Known information must be immediately reported. The Sponsor will 
collaborate with the Investigator to obtain any outstanding information. 
Once the complaint has been investigated by the Sponsor, when required, an event closure letter 
may be sent to the investigational center where the complaint originated or to all investigational 
centers using the product. 
If the clinical product complaint is related to a device, comparator, co-medication, 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. 
8.6.2. 
Handling the IMP/Devices at the Investigational Center  
The Investigator is responsible for retaining the product in question in a location separate from 
the Investigator’s clinical trial supplies. The Sponsor may request that the Investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical trial monitor or 
designee will provide the information needed for returning the IMP. 
If it is determined that the investigational center must return all IMPs, the Sponsor will provide 
the information needed to handle the return. 
8.6.3. 
Product Complaint Associated with Adverse Events or Serious Adverse Events  
If there is an AE or SAE due to product complaint, the protocol should be followed for recording 
and reporting of the AE or SAE (Section 8.4.2 to Section 8.4.7).  
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8.7. 
Pharmacokinetics  
8.7.1. 
Timing of Pharmacokinetic Sampling  
Blood samples (3 mL) will be obtained via direct venipuncture or indwelling catheter for the 
determination of plasma concentration of olanzapine and potentially for olanzapine metabolites 
at the time points detailed in Table 1 to Table 5.  
Specimen collection, processing, and handling requirements are detailed in the Laboratory 
Manual. 
Every effort must be made to obtain the PK samples within the allowed limits for sampling 
times, as defined in Table 6 and Table 7. The exact time of sample collection must be noted in 
the source documents and CRF. 
When the PK blood sample collection coincides with safety assessments, PK blood samples 
should be collected as close to the scheduled time point as possible. Assessment of vital signs 
and ECGs should precede PK blood sampling. 
8.7.2. 
Changes to Pharmacokinetic Sampling Scheme  
Not applicable. 
8.7.3. 
Pharmacokinetic Parameters  
Pharmacokinetic parameters will be calculated from concentration-time data using 
noncompartmental methods, when possible. 
The following PK parameters will be calculated following ZYPREXA im administration: 
• Cmax  
• AUC0-t  
• λz over the 216-hour period following administration 
• 
  
• 
  
• 
  
• 
  
• 
  
• 
  
Additional PK parameters for olanzapine (e.g. 
, AUC0-∞, etc) may be calculated if deemed 
necessary. 
The following PK parameters will be calculated following sc olanzapine extended-release 
formulation administration: 
• Cmax  
• AUC0-t  
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• AUC0-∞  
• 
 
• 
 
• 
 
• 
  
• 
 
• 
  
• 
  
• 
  
• 
  
Additional PK parameters for olanzapine may be calculated if deemed necessary. 
8.8. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this trial. 
8.9. 
Genetics  
8.9.1. 
Pharmacogenomics  
 
 
 
 
 
 
 
  
8.10. 
Biomarkers  
 
 
 
 
 
 
 
 
 
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8.10.1. 
Digital Biomarkers  
Digital biomarker or outcome measures are not evaluated in this trial. 
8.11. 
Immunogenicity Assessments  
Not applicable. 
8.12. 
Medical Resource Utilization and Health Economics  
Medical resource utilization and health economics parameters are not evaluated in this trial. 
8.13. 
Total Blood Volume  
The total volume of blood to be collected for each participant in this trial is approximately 
370 mL (at maximum). The total amount of blood will be drawn over a study duration of 
approximately 19 weeks. 
Additional blood samples for toxicology, PK, and/or biomarkers should be collected in case of 
severe ISRs (Section 8.3.6); pus-containing lesion (abscess, infection, or inflammation), 
ulceration, necrosis, or atrophy (Section 8.3.7); or suspected PDSS (Table 8 and Section 8.3.8). 
Details for all blood volumes and assessments will be included in the Laboratory Manual. 
8.14. 
Assessment of Leakage  
Immediately after injection of any of the olanzapine extended-release sc formulations, qualified 
investigational center personnel will observe the site of injection for the incidence of leakage (ie, 
to inspect whether the injected suspension appears at the injection site after completion of the 
injection). The leakage evaluation score will be recorded in the source documents and CRF 
using the rating scale (0 to 4) as described in Table 13. 
Continuous leakage assessment will be performed (ie, additional leakage assessment will be 
performed for these cohorts after the immediate assessment described above). Specifically, if 
leakage continues, the evaluation should be continued for up to 10 minutes and the leakage stop 
time should be recorded. The additional leakage score (0-4) will be recorded at the end of the 
leakage to capture the total volume of leakage observed post-injection. If leaked IMP is seen at 
the injection site 10 minutes post-injection, it should be gently wiped, while avoiding pressure or 
squeezing of the injection site. If leakage does not stop 10 minutes post-dose, record the 
re-evaluated leakage score, gently wipe the injection site and record 10 minutes for leakage 
reassessment time (ie, stop time). Whether or not wiping of IMP occurred at 10 minutes 
post-dose will be recorded on the eCRF as a Yes/No question. In case leakage continues after 
wiping the site (ie, after 10 minutes), this will also be recorded in the eCRF and the MM should 
be notified. 
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A recorded leakage score of 4 should be reported to the MM within 24 hours. Patients with a 
leakage score of 4 may be replaced. 
 
Table 13: 
Leakage Evaluation  
Appearance 
Score 
No sign of the injected suspension on the skin 
0 
Pinpoint to ballpoint size drop is visible on the skin 
1 
Only a small amount of injected suspension is visible on the skin (ie, most of the injected suspension 
penetrated the skin) 
2 
Approximately half of the injected suspension is visible on the skin (ie, approximately half of the 
injected suspension penetrated the skin) 
3 
Most of the injectable solution is visible on the skin (ie, little or no injectable solution penetrated the 
skin) 
4 
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9. 
STATISTICAL CONSIDERATIONS  
This section describes the statistical analysis as foreseen at the time of planning the trial. 
Changes, additions, and further details about the analyses will be described in the Statistical 
Analysis Plan (SAP). After finalization of the SAP, any additional analyses or changes to 
analyses that may be required will be fully disclosed in the CSR. 
9.1. 
Analysis Sets  
9.1.1. 
Enrolled Analysis Set  
The enrolled analysis set will include all participants who sign an ICF and are enrolled in the 
trial. This analysis set will be used for summarizing demography and baseline data. 
9.1.2. 
Pharmacokinetics Analysis Set  
The PK analysis set will include all participants who have sufficient data to calculate at least one 
PK parameter for any of the olanzapine formulations (IM immediate release or sc ER) and have 
no events of deviations that would affect the calculation of PK parameters. This analysis set will 
be used for all PK summaries. 
A drug metabolism and PK (DMPK) scientist and a clinical pharmacologist will identify each 
individual participant’s PK parameters to be included in the analysis. Individual PK parameters 
that are considered outliers (eg, parameters that were based on partial data) will be excluded 
from the primary analysis. Justification for exclusion of parameters will be provided in the PK 
parameter raw data file provided by DMPK. A Statistical Data Review meeting will be held 
prior to database lock of the trial (and prior to seeing any data results), and any protocol 
deviations that could potentially impact the PK will be identified. Data from these participants 
will also be excluded from the primary and secondary PK analyses. Criteria for exclusion of 
individual participant data will be defined in the SAP. A leakage score of 4 after TV-44749 sc 
administration will result in exclusion from the PK analysis set and the participant will be 
replaced. Data from excluded participants will be included in the relevant listing. 
9.1.3. 
Safety Analysis Set  
The safety analysis set will include all participants who receive at least 1 dose of IMP. This 
analysis set will be used for all safety summaries. 
In the safety analysis set, cohorts will be assigned based on the formulation that the participants 
actually received, regardless of the cohort they were randomized to, unless otherwise specified.  
9.1.4. 
Pharmacogenomics Analysis Set  
  
9.2. 
Analyses Supporting Primary Objective(s)  
9.2.1. 
Statistical Model, Hypothesis, and Method of Analysis  
The PK analysis set will be used for the analysis (Section 9.1.2). 
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Plasma concentration data will be individually listed and summarized by treatment and cohort 
using descriptive statistics (n, mean, standard deviation, geometric mean [if appropriate], 
geometric coefficient of variation [%coefficient of variation (CV)] [if appropriate], median, 
minimum, and maximum).  
No formal inferential statistical analyses of PK data are planned. Pharmacokinetic parameters 
will be individually listed and summarized for each treatment and cohort using descriptive 
statistics (n, mean, standard deviation, geometric mean [if appropriate], geometric coefficient of 
variation (%CV) [if appropriate], median, minimum, and maximum). 
9.2.2. 
Handling of Missing Data  
For all variables, only the observed data from the participants will be used in the statistical 
analyses, unless otherwise specified. 
In general, missing data will not be imputed. Partial or missing dates of AEs and concomitant 
medications may be imputed and detailed in the SAP. Other specific imputations for missing 
safety features at baseline will also be detailed in the SAP. 
9.2.3. 
Sensitivity Analyses  
No sensitivity analyses are planned. 
9.2.4. 
Supplementary Analyses  
No supplementary analyses are planned. 
9.2.5. 
Multiplicity Adjustment  
No adjustments will be made for the preplanned multiple comparisons/endpoints. 
9.3. 
Analysis Supporting Secondary Objective(s)  
No formal statistical analyses are planned.  
The PK parameters for ZYPREXA im and olanzapine extended-release formulations will be 
individually listed and summarized for each formulation and cohort using descriptive statistics (n, 
mean, standard deviation, geometric mean [if appropriate], geometric coefficient of variation 
(%CV) [if appropriate], median, minimum, and maximum). For the safety and tolerability 
measures/parameters, the participant counts and percentages will be provided. 
9.4. 
Analysis of Exploratory Objective(s)  
9.4.1. 
Pharmacogenomic Analyses  
 
  
 
 
 
 
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9.5. 
Safety Analyses  
Safety analyses will be performed on the safety analysis set (Section 9.1.3). No formal statistical 
analyses of safety data are planned. The safety analysis will be performed by any of the IMPs 
(ZYPREXA im or sc olanzapine). 
For continuous variables, descriptive statistics (n, mean, standard deviation, standard error [SE], 
median, minimum, and maximum) will be provided for actual values and changes from baseline 
to each time point. For categorical variables, participant counts and percentages will be 
provided. 
If any participant dies during the trial, a listing of deaths will be provided, and all relevant 
information will be discussed in the participant narrative included in the CSR. 
Subjective overall tolerability will be assessed by calculating the number (%) of participants who 
failed to complete the trial, and the number (%) of participants who failed to complete the trial 
due to AEs. 
The use of concomitant medications and rescue medications will be summarized by therapeutic 
class for each treatment and cohort using descriptive statistics. 
The analyses will include the following data: 
Adverse Events: All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each participant will be counted only once in each preferred term (PT) or system 
organ class (SOC) category for the analyses of safety. Summaries will be presented for all 
TEAEs and adverse device events (overall and by severity), including AEs determined by the 
Investigator to be related to IMP and/or medical device (defined as related or with missing 
relationship), SAEs, serious device adverse events, and AEs and adverse device events causing 
withdrawal from the trial. Summaries will be presented by treatment and cohort for all 
participants. Participant listings for TEAEs and adverse devise events that are serious and those 
leading to withdrawal will be presented. 
PDSS events (as defined above in the stopping criteria) and ISRs of pus-containing lesions 
(abscess, infection, or inflammation), ulceration, necrosis, and atrophy will be subject to 
expedited reporting. 
Local Tolerability Analysis: Injection site assessments (ie, local tolerability) will be carried out 
for each reported injection site AE. Injection site pain, erythema, induration/swelling, and 
pus-containing lesions will be assessed using standardized scales and the findings will be 
presented using descriptive statistics. For pain intensity, the NPRS scale will be applied. Listings 
and descriptive statistics will be presented.  
The frequency of each score measuring local tolerability at the injection site will be determined 
at each time point according to treatment and cohort. 
The incidence of TV-44749 leakage from the injection site post-administration, including 
leakage evaluation score, will be summarized descriptively. 
Changes in Laboratory, ECG, and Vital Sign Measurements: All collected data will be 
summarized descriptively. All values will be compared with predefined criteria to identify 
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potentially clinically significant values or changes, as detailed in the SAP, and such values will 
be listed.  
Actual values and changes from baseline in laboratory test results (chemistry, hematology, 
coagulation, and urinalysis), vital signs, and 12-lead ECG measurement data at each time point 
will be summarized descriptively by treatment and cohort.  
Concomitant Medications: Concomitant medications will include all medications taken from 
first dose of ZYPREXA im through the end of follow-up (EOT/ET). Therapeutic class using 
descriptive statistics will summarize the use of concomitant medications. Descriptive statistics 
for allowed rescue medications will be presented by treatment and cohort. 
Clinical Scales: Safety outcomes of the scale scores (change from baseline) including 
 
 
 
 
and 
from the treatment period will be presented using 
descriptive statistics. The 
 will be used to assess the risk of suicide events during the 
trial. Descriptive statistics will be presented by treatment and cohort. 
9.6. 
Other Analyses  
9.6.1. 
Population Pharmacokinetic Analysis  
Pharmacokinetic parameters of olanzapine will be calculated and may be combined with data 
from additional clinical studies to characterize the PopPK of TV-44749. 
The details of these analyses will be in a separate PopPK analysis plan for this trial. The results 
of this analysis will be reported separately from the main trial results. 
9.6.2. 
Pharmacogenetic and Biomarker Analysis  
 
 
 
 
 
 
9.7. 
Interim Analyses  
No formal interim analysis is planned in this open-label Phase 1 trial. Review of sentinel cohort 
1A data prior to dosing cohort 1B by the SRC is described in Section 4.1.2. 
The Sponsor may leverage preliminary concentration data to initiate IVIVC modeling activity 
prior to database lock, without impacting the study conduct. 
9.8. 
Sample Size Determination  
The planned sample size for this trial is approximately 95 enrolled participants in order to 
achieve approximately 60 completers (approximately 20 participants per cohort). Completers are 
defined as participants who have completed the procedures and assessments required through 
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follow-up period of sc olanzapine ER (ie, the 84 days after the sc injection, up to and including 
day R84).  
Given the descriptive and exploratory nature of the trial, which is intended to collect 
pharmacokinetic data for an IVIVC external analysis, no formal sample size calculation has been 
performed for this trial. 
If a participant is enrolled but terminates the trial early (for criteria of ET, see Section 7.1), or 
has events that would affect the calculation of PK parameters, an additional patient may be 
enrolled to ensure that approximately 20 participants per group have completed the PK portion 
of the trial and can be considered evaluable for the primary analysis of the study (see 
Section 9.1.2). 
9.9. 
Protocol Deviations  
The definition of and process for reporting important protocol deviations are discussed in 
Section 11.2. 
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10. 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, 
AND TRIAL OVERSIGHT  
10.1. 
Regulatory and Ethical Considerations  
Before this trial starts, the protocol will be submitted to competent authorities and to each 
IRB/IEC for review. As required, the trial will not start at a given investigational center before 
the IRB/IEC and competent authority (as applicable) for the investigational center give written 
approval or a favorable opinion. 
Compliance Statement 
This trial will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 
Code of Federal Regulations [CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of 
the European Parliament and of the Council on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of GCP in the 
conduct of clinical trials on medicinal products for human use). Any episode of noncompliance 
will be documented. 
The Investigator is responsible for performing the clinical trial 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 trial in accordance with the protocol and applicable regulations will be documented in 
separate clinical trial agreements with the Sponsor and other forms as required by national 
competent authorities in the country where each investigational center is located. 
The clinical trial agreement shall outline the Investigator’s and the institution’s responsibilities 
with respect to the conduct of the clinical trial, including the Investigator’s reporting obligation 
to the Sponsor for suspected cases of serious breach from GCP and/or protocol. 
The Investigator is responsible for ensuring the privacy, health, and welfare of the participants 
during and after the clinical trial; and must ensure that trained personnel are immediately 
available in the event of a medical emergency. The Investigator and the involved clinical trial 
personnel must be familiar with the background and requirements of the trial and with the 
properties of the IMPs (TV-44749 and ZYPREXA im) 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 trial at that investigational center and for contacts with 
trial management, with the IRB/IEC, and with competent authorities. 
See Section 10.3 for the ethics expectations of informed consent or assent, Section 10.4 for 
confidentiality regarding trial participants, and Section 13.7 for requirements for registration of 
the clinical trial. 
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10.2. 
Committees  
An SRC composed of the Sponsor’s clinical trial physician, clinical leader, PV physician, and 
other relevant experts will be summoned to review all safety data available upon completion of 
the first 15 days of the sentinel cohort (cohort 1A).  
In the case of a suspected PDSS event, an adjudication committee composed of the Sponsor’s 
clinical trial physician, clinical leader, PV physician, pharmacometrician, and other relevant 
experts, such as a statistician and a PK expert, will be summoned to review all cases of suspected 
PDSS to determine if each case fulfills all 5 criteria in the definition for a clinical diagnosis of 
PDSS (adapted from Detke et al 2010), as well as to evaluate the robustness of the available 
clinical evidence. An external independent physician with expertise in the relevant therapeutic 
area may be consulted, if needed. 
10.3. 
Informed Consent Process  
The Investigator, or a qualified person designated by the Investigator, should fully inform the 
participant of all pertinent aspects of the trial, including the written information approved by the 
IRB/IEC. All written and oral information about the trial will be provided in a language as 
nontechnical as practical to be understood by the participant. The participant should be given 
ample time and opportunity to inquire about details of the trial and to decide whether or not to 
participate in the trial. The above should be detailed in the source documents. 
If the trial is designed to treat participants in an emergency situation, specific rules for obtaining 
informed consent may be required to be added to the ICF, including cases where it is not possible 
within the therapeutic window to obtain prior informed consent from the participant or from his 
or her legally designated representative. Specific activities may need to be detailed in the 
protocol related to the unique informed consent process. 
Written informed consent will be obtained from each participant before any trial-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The participant’s willingness to participate in the trial will be 
documented in the ICF, which will be signed and personally dated by the participant and by the 
person who conducted the informed consent discussion. The Investigator will keep the original 
ICFs, and copies will be given to the participants. It will also be explained to the participants that 
the participant is free to refuse participation in the trial and free to withdraw from the trial at any 
time without prejudice to future treatment. 
Adult participants with a legally acceptable representative should provide informed consent 
according to national and local requirements. 
A separate written informed consent will be obtained from each participant before 
pharmacogenomics samples will be collected (Section 8.9.1). 
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10.4. 
Data Protection  
Data Protection and Confidentiality 
All personal data will be processed in accordance with applicable data protection law. 
Teva has implemented appropriate technical, physical, organizational, and administrative 
information, and privacy security measures to protect the confidentiality, integrity, and 
availability of data in its systems. Teva’s Information Security Team keeps the measures under 
continuous review to align with state-of-the-art standards, taking into account the nature and 
context of the processing. Teva systems and policies are aligned with industry-standard 
information security and privacy frameworks such as ISO 27001 covering categories of security 
controls including: 
• Access Control 
• Awareness and Training 
• Backup and Recovery 
• Change Control 
• Encryption and Communication Controls 
• Identity and Authentication 
• Incident Response and Recovery 
• Logging, Monitoring, and Alerting 
• Media Protection 
• Operations Control 
• Personnel Security 
• Physical and Environmental 
• Program and Risk Management 
• System and Communications Protection 
• Third Party/Supplier Relationship Control 
Teva employs an Information Security Team and where needed, Teva also leverages independent 
data security experts. 
Teva employs a Cyber Defense Center to direct and coordinate all security incident activity. 
Teva has implemented Incident Response and Recovery policies and processes to identify and 
respond to security incidents and/or data breaches both internally as well as from other involved 
third parties. These policies cover the full Incident Response and Recovery lifecycle from initial 
response/notification through triage and mitigation activities to recovery and root cause 
resolution. Teva also has a “Global Privacy Incident and Breach Reporting Policy” to address a 
privacy incident or breach (suspected or confirmed). 
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Where personal data are stored, transmitted, or processed externally utilizing third parties, Teva 
employs appropriate contractual language, and other controls requiring the third party to employ 
appropriate information security controls and protections to guard the confidentiality, integrity, 
and availability of such data. 
Teva has completed Data Protection Impact Assessments in respect of the processing of personal 
data gathered in the course of clinical trials. 
Teva trains its staff regarding the handling of personal data in accordance with applicable law. 
This includes training on how to recognize, respond to, and mitigate a personal data breach. 
Teva has implemented role-based access, which means that personal data will only be available 
to those who need access. 
The confidentiality of participant data is protected. Teva staff are subject to a contractual 
obligation of confidentiality. 
The Investigator must ensure that the privacy of the participants, including their identity, and all 
personal medical information will be maintained at all times. In CRFs and other documents or 
image material submitted to the Sponsor, participants will be identified not by their names, but 
by an identification number. 
Personal medical information may be reviewed for the purpose of participant safety or for 
verifying data in the source and the CRF. This review may be conducted by the trial monitor, 
properly authorized persons on behalf of the Sponsor, Global Quality Assurance, or competent 
authorities. Personal medical information will always be treated as confidential. 
10.5. 
Early Investigational Center Closure or Trial Termination  
The Sponsor or designee reserves the right to close the investigational center or terminate the 
trial at any time for any reason at the sole discretion of the Sponsor. An investigational center is 
considered closed when all required documents and trial supplies have been collected and an 
investigational center closure visit has been performed. 
The Investigator may initiate investigational center closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of an investigational center by the Sponsor or Investigator may 
include but are not limited to: 
For trial termination: 
• Discontinuation of further trial intervention development. 
For investigational center termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
• Total number of participants included earlier than expected. 
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If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any CRO(s) used in the trial of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should ensure appropriate participant 
therapy and/or follow-up. 
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11. 
GENERAL CONSIDERATIONS: RISK MANAGEMENT AND 
QUALITY ASSURANCE  
11.1. 
Quality Tolerance Limits  
Quality tolerance limits are being addressed through standard risk assessment and mitigation 
processes aligned with ICH guidelines and are documented in the relevant plans. 
11.2. 
Data Quality Assurance  
Refer to Section 8.6 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. Further details are given in a Pharmacy Manual. 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this trial. Data handling, including data quality control, will comply 
with international regulatory guidelines, including ICH GCP guidelines. Data management and 
control processes specific to this trial, along with all steps and actions taken regarding data 
management and data quality control, will be described in a Data Management Plan. 
Data will be verified by the trial 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. 
CRFs received will be processed and reviewed for completeness, consistency, and the presence 
of mandatory values. Applicable terms will be coded according to the coding conventions for 
this trial. Logical checks will be implemented to ensure data quality and accuracy. 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 clinical data management system (CDMS). Discrepancies found will be queried. 
Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes. 
At the conclusion of the trial, the CDMS and all other trial data will be locked to further 
additions or corrections. Locking the trial data represents the acknowledgment 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. An interim lock or locks may be 
performed during the trial, as described in Section 9.6.1 and in the SAP.  
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 IRB/IEC and national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
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concerns to the participants or when the change involves only non-substantial logistics or 
administration. The Principal Investigator at each investigational center, the Coordinating 
Investigator (if applicable), and the Sponsor will sign the protocol amendment. 
Important Protocol Deviations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the participants in the trial and/or (b) the scientific value of the trial will be 
considered an important protocol deviation. Important protocol deviations may include 
nonadherence on the part of the participant, the Investigator, or the Sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or GCP guidelines; 
noncompliance to IMP administration; and use of prohibited medications. Important protocol 
deviations will be documented by investigational center personnel. All important protocol 
deviations will be reported to the responsible IRB/IEC, as required. 
When an important protocol deviation is reported, the Sponsor will determine whether to 
withdraw the participant from the trial or permit the participant to continue in the trial, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the participant and preserving the integrity of the trial. 
If a participant experiences an AE or medical emergency, departures from the protocol may be 
allowed on a case-by-case basis. After stabilization and/or treatment has been administered to 
ensure participant safety, the Investigator or other physician in attendance must contact the 
Sponsor’s MM as soon as possible to discuss the situation. The Investigator, in consultation with 
the Sponsor, will decide whether the participant should continue to participate in the trial. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the Sponsor. If investigational center personnel learn that a participant who did not meet protocol 
inclusion and exclusion criteria was entered in a trial, they must immediately inform the Sponsor 
of the important protocol deviation. If such participant has already completed the trial or has 
withdrawn early, no action will be taken but the deviation will be recorded. 
Information to Trial Personnel 
The Investigator is responsible for giving information about the trial to all personnel members 
involved in the trial or in any element of participant management, both before starting the trial 
and during the course of the trial (eg, when new personnel become involved). The Investigator 
must ensure that all trial personnel are qualified by education, experience, and training to 
perform their specific task. These trial 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 trial, as necessary. 
Trial Monitoring 
To ensure compliance with GCP guidelines, the trial monitor or representative is responsible for 
ensuring that participants have signed the ICF and the trial is conducted according to applicable 
SOPs, the protocol, and other written instructions and regulatory guidelines. Details of the 
monitoring procedures are outlined in the trial’s monitoring plan which is maintained by the 
Sponsor. 
The trial monitor is the primary association between the Sponsor and the Investigator. The main 
responsibilities of the trial monitor are to explain the protocol to all trial staff including the 
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Investigator and to visit the Investigator before, during, and after the trial 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 participants before they participate in the trial and when 
changes to the consent form are warranted, in accordance with IRB/IEC approvals. 
The trial monitor will contact the Investigator and visit the investigational center according to the 
monitoring plan. The trial monitor will be permitted to review and verify the various records 
(CRFs and other pertinent source data records, including specific electronic source documents 
relating to the trial) to verify adherence to the protocol and to ensure the completeness, 
consistency, and accuracy of the data being recorded. 
If electronic CRFs are used for the trial, the trial monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly. 
As part of the supervision of trial progress, other Sponsor personnel may, on request, accompany 
the trial monitor on visits to the investigational center. The Investigator and assisting personnel 
must agree to cooperate with the trial 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. 
In case of an emergency situation (eg, the COVID-19 pandemic), where trial monitors may not 
be able to access the investigational centers for on-site visits, investigational centers will be 
monitored remotely, where allowed, and in accordance with global and/or local regulations. 
Audit and Inspection 
The Sponsor may audit the investigational center to evaluate trial conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The Sponsor’s Global 
Clinical Quality Assurance, independent of Global Clinical 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. 
In case of an emergency situation (eg, the 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 global and/or local regulations. 
11.3. 
Source Data  
Source Data 
Data will be collected at the investigational center by appropriately designated and trained 
personnel. The Investigator must maintain the original records (ie, source documents) of each 
participant’s data at all times. The Investigator will maintain a confidential participant 
identification list that allows the unambiguous identification of each participant. 
Examples of source documents are hospital records, office visit records, examining physician’s 
finding or notes, consultant’s written opinion or notes, laboratory reports, drug inventory, IMP 
label records, diary data, and protocol-required worksheets that are used as the source. 
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Data may not be recorded directly on the CRF and considered as source data unless the Sponsor 
provides written instructions in the trial-specific CRF Completion Guidelines specifying which 
data are permitted to be recorded directly to the CRF. 
If data are processed by other institutions or by other means (eg, clinical laboratory, central 
image center, eDiary data, or devices), the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise instructed by the Sponsor. 
These data may also be sent electronically to the Sponsor (or organization performing data 
management) for direct entry into the clinical database. 
The medical experts, trial monitors, auditors, IRB/IEC, and inspectors from health authorities (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 participant confidentiality is maintained in accordance with national and local requirements. 
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. 
Case Report Forms 
CRFs that were specifically designed for this trial must be completed for each participant who 
provided informed consent. Participant identity should not be discernible from the data provided 
on the CRF. All participant data must have supportive original source documentation in the 
medical records, or equivalent, before they are transcribed onto CRFs. 
The data collected on the CRFs will be captured in a CDMS that meets the technical 
requirements described in 21CFR Part 11 (US) and documents of other concerned competent 
authorities. The CDMS will be fully validated to ensure that it meets the scientific, regulatory, 
and logistical requirements of the trial before it is used to capture data from this trial. Before 
using the CDMS, all users will receive training on the system and trial-specific training. After 
they are trained, users will be provided with individual system access rights. 
For participants who enter a trial but do not meet entry criteria, the minimum information to be 
entered into the CRF includes, but is not limited to, screening failure details, demography, 
eligibility criteria, and AEs from the time of informed consent. 
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 trial 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 ICFs 
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• participant identification lists 
• CRFs for each participant on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, or eDiary) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMP 
• copies of all correspondence with Sponsor, the IRB/IEC, and any competent authority 
The Investigator will retain all records related to the trial and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
Sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
trial completion, or earlier in the case of the investigational center closing or going out of 
business, the Investigator reasonably determines that trial record retention has become unduly 
burdensome, and Sponsor has not provided written notification of destruction, then the 
Investigator may submit a written request to Sponsor at least 60 days before any planned 
disposition of trial 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 trial records. 
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12. 
APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS – DEFINITIONS, SEVERITY, AND CAUSALITY  
No information is provided for this section. 
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13. 
APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL 
DETAILS  
13.1. 
Contraception and Pregnancy Testing  
13.1.1. 
Definitions Related to Childbearing Potential  
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with >1 FSH 
measurement (>35 IU/L) is required. 
− Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the trial. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before trial enrollment. 
• Permanent sterilization methods (for the purpose of this trial) include the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
− For individuals with permanent infertility due to an alternate medical cause other 
than the above (eg, Mullerian agenesis, androgen insensitivity, or gonadal 
dysgenesis), Investigator discretion should be applied to determine trial entry. 
• Note: Documentation can come from the investigational center personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of IMP, additional evaluation should be considered. 
Women of Nonchildbearing Potential 
Women in the following categories are considered women of nonchildbearing potential: 
3. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this trial): 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
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• For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity, or gonadal dysgenesis), 
Investigator discretion should be applied to determine trial entry. 
Note: Documentation can come from the investigational center personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
4. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with >1 FSH 
measurement (>35 IU/L) is required. 
− Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before trial enrollment. 
13.1.2. 
Contraception  
The contraceptives allowed during the trial are listed in Table 14. 
Table 14: 
Contraceptives Allowed During the Trial  
Highly effective methodsa that have low user dependency 
Failure rate of <1% per year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb initiated at least 
14 days before the first dose of IMP. 
Intrauterine device in place at least 2 months before screening. 
Intrauterine hormone-releasing systemb in place at least 2 months before screening. 
Bilateral tubal occlusion, except for hysteroscopic bitubal ligation (Essure®), for which a hysterosalpyngogram is 
required 3 months post-procedure to assess surgical success. 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the investigational center personnel’s 
review of the participant’s medical records, medical examination, or medical history interview. 
Highly effective methodsa that are user-dependent 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb initiated at least 14 days before the first dose of IMP 
• oral 
• intravaginal 
• transdermal 
• injectable 
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Table 14: 
Contraceptives Allowed During the Trial (Continued) 
Progestogen-only hormone contraception associated with inhibition of ovulationb initiated at least 14 days before 
the first dose of IMP 
• oral 
• injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the administration of IMP. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the 
participant. Minimum time adherence prior to first dose of IMP is 6 months. 
Effective methodsc that are not considered highly effective 
Failure rate of ≥1% per year when used consistently and correctly. 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action. 
Male or female condom with or without spermicide. 
Cervical cap, diaphragm, or sponge with spermicide. 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods)b. 
a Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used 
consistently and correctly. 
b If locally required, in accordance with CTFG guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
c Considered effective, but not highly effective – failure rate of ≥1% per year. 
Notes: Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods 
for those participating in clinical trials. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Male condom and 
female condom should not be used together (due to risk of failure from friction). 
CTFG=Clinical Trial Facilitation Group; IMP=investigational medicinal product; WOCBP=women of childbearing potential. 
13.1.3. 
Pregnancy Testing  
HCG tests in serum or urine will be performed for all women at the time points specified in 
Table 1 to Table 5. 
A serum pregnancy test will be performed for all women at screening on day 1 and WOCBP on 
day 12. A serum pregnancy test on day 12 will be performed both in central and local 
laboratories. Serum or urine dipstick pregnancy tests will be performed for all WOCBP on day 3. 
A urine dipstick pregnancy test will be administered at other time points as specified in Table 1, 
Table 2, Table 3, Table 4, and Table 5 (WOCBP only). A serum pregnancy test will be 
administered to all women, regardless of childbearing potential, on day R84: EOT). 
• Refer to Section 5.3 for pregnancy testing inclusion criteria. 
• Additional pregnancy tests (HCG in urine or serum) may be performed, as 
determined necessary by the Investigator or required by local regulation, to establish 
the absence of pregnancy at any time during the participant’s participation in the trial. 
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13.2. 
Clinical Laboratory Tests  
Table 15: 
Clinical Laboratory Tests  
Chemistry 
Hematology 
Urinalysisa         
• Calcium 
• Phosphate 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate or carbon dioxide 
• Glucose 
• HbA1cb  
• Blood urea nitrogen 
• Creatinine 
• Cholesterol (low density 
lipoprotein/high density 
lipoprotein/total) 
• Triglycerides 
• Uric acid 
• Alanine aminotransferase 
• Aspartate aminotransferase 
• Lactic dehydrogenase 
• Gamma glutamyl transpeptidase 
• Alkaline phosphatase 
• Creatine phosphokinase 
• Total protein 
• Albumin 
• Total bilirubin 
• Hemoglobin 
• Hematocrit 
• RBC count 
• Platelet count 
• WBC count and differential 
count (absolute and percentage) 
o Polymorphonuclear 
leukocytes (neutrophils) 
o Lymphocytes 
o Eosinophils 
o Monocytes 
o Basophils 
• 
Coagulation tests 
o INR 
o PT 
o PTT 
• Protein 
• Glucose 
• Ketones 
• Blood (hemoglobin) 
• pH 
• Nitrates 
• Specific gravity 
• Microscopic 
o 
Bacteria 
o 
RBCs 
o 
WBCs 
o 
Casts 
o 
Crystals 
a At each urinalysis collection, females will be asked if they are currently menstruating. 
b HbA1c will be collected at screening and day R1 pre-dose (baseline). 
HbA1c=glycated hemoglobin; INR=international normalized ratio; PT=prothrombin time; PTT=partial thromboplastin time; 
RBC=red blood cell; WBC=white blood cell. 
13.3. 
Prior Protocol Amendments  
The original protocol was not submitted to the FDA. Revision 1, below, is the version that was 
submitted. 
Original Protocol with Revision 1, 13 September 2023 
The original protocol, dated 01 August 2023, was revised to address inconsistencies and correct 
procedural errors.  
Overall Rationale for the Revision: 
The original protocol required revisions due to inconsistencies between the Schedule of 
Activities tables and protocol body. In addition, the blood volumes table (Section 8.13, Table 13 
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in the original protocol), which is not required in the protocol per standard operating procedures, 
was removed and will be fully detailed in the Laboratory Manual. This revised protocol 
addresses these changes and clarifies other minor inconsistencies and typographical errors. 
 
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13.4. 
List of Prohibited Medications  
Some drugs have been reported to have a pharmacodynamic or PK drug-drug interaction with 
olanzapine (Table 16). Olanzapine is a CYP1A2 substrate. Thus, coadministration with inducers 
or inhibitors of CYP1A2 could lead to decreased or increased olanzapine concentrations, 
respectively. All medications that fall under prohibited medication classes should be excluded. 
For any questions about prohibited medications, the Sponsor or MM should be contacted. 
Table 16: 
Partial List of Prohibited Medications  
Medication class 
Drug name 
Enzymatic inducers 
Carbamazepine, albendazole, phenytoin, phenobarbital, primidone, St. John's 
wort, rifampin 
Anti-Parkinson agents 
Dopamine agonist, agomelatine, rasagiline, ropinirole, amantadine, biperidil 
Antipsychotics 
Olanzapinea         
CYP1A2 inhibitors 
Fluvoxamine, ciprofloxacin, thiabendazole 
Antiemetic  
Metoclopramide 
CYP1A2 substrates  
Aminophylline, theophylline 
Strong CYP2D6 inhibitorsb         
eg, quinidine, fluoxetine, paroxetine 
Strong CYP3A4 inhibitorsb 
eg, itraconazole, clarithromycin, fluconazole, ketoconazole, ritonavir, 
mibefradil, grapefruit juice 
a Other than provided during the trial. 
b Partial list. 
13.5. 
Financial Disclosure  
A separate clinical trial agreement, including a trial budget, will be signed between each 
Principal Investigator/institution and the Sponsor (or the CRO designated by the Sponsor) before 
the IMP is delivered. 
The participants in this clinical trial 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 participant had not taken 
part in the clinical trial. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
Sponsor. 
For covered clinical trials (see 21CFR Part 54), 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 trial and for 1 year after the trial has 
been completed. 
13.6. 
Recruitment Strategy  
Enrollment for this clinical trial will be competitive, which means each Investigator will be given 
equal opportunity to enroll into an open slot. Each participating clinical site will be given an 
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equal number of slots, but in the event a participant cannot be identified within a specified period 
of recruitment time (ie, days), that slot will be opened up to another clinical site to fill. 
A sufficient number of sites have been planned for this Phase 1 clinical trial, in accordance with 
standard industry strategy to ensure a robust recruitment rate, while also mitigating risks in data 
variances that can occur with too many sites in early phase trials. These risks are primarily 
related to variances in training and process that can affect small sample sizes to a greater degree. 
One or two backup sites will also be identified for inclusion in the event some of the selected 
sites are unable to recruit participants to the trial. The primary tool for assisting sites with their 
recruitment efforts will be direct and regular engagement with the site staff to discuss participant 
screening, enrollment, and retention of participants once they are enrolled into the trial. 
The trial team will also consider development of participant recruitment and retention materials, 
which will be translated to the local language(s). These tools may include, but are not limited to, 
the following: participant education materials for site use, direct to participant outreach 
materials, physician referral letters, trial landing pages, and recruitment/retention tools for site 
staff use. 
13.7. 
Dissemination of Clinical Trial Data  
The Sponsor is responsible for the preparation of a CSR, in cooperation with the CRO. The final 
report is signed by the Sponsor and Principal Investigator. 
The Sponsor is responsible for ensuring that the public has access to the appropriate information 
about the trial according to local and regional requirements. Policies regarding the publication of 
the trial results are defined in the contractual agreement signed by the Sponsor and CRO. 
Teva may register this Phase 1 trial. 
13.8. 
Publication Policy  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The results of this trial may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
Further details pertaining to publications and review periods are described in the clinical trial 
agreement with the Investigator/institution. 
The Sponsor will comply with the requirements for publication of trial 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 multi-center trials only in their entirety and not 
as individual investigational center data. In this case, a Coordinating Investigator will be 
designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements: 
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• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved 
The publications committee established by the Sponsor will oversee this process. Additional 
publications may follow. 
No patent applications based on the results of the trial may be made by the Investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the Sponsor. 
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14. 
APPENDIX: GLOSSARY OF TERMS  
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse event(s) of special interest 
 
 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
AUC 
area under the plasma drug concentration-time curve 
AUC0-t 
Area under the plasma drug concentration-time curve from IMP administration to last 
measurable concentration 
AUC0-∞ 
AUC extrapolated to infinity 
 
 
BMI 
body mass index 
 
 
 
 
CDMS 
clinical data management system  
CDSS 
clinical decision support system 
CFR 
Code of Federal Regulations (US) 
 
 
 
 
Cmax 
maximum observed plasma drug concentration 
 
 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CSR 
Clinical Study Report 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CU 
clinical unit 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DMPK 
drug metabolism and pharmacokinetics 
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Abbreviation 
Term 
DMSO 
dimethyl sulfoxide 
DNA 
deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
EEA 
European Economic Area 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
EOT 
end of treatment 
ER 
extended-release 
ET 
early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
glycated hemoglobin 
HCG 
human chorionic gonadotrophin 
HEENT 
head, ears, eyes, nose, throat/neck 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
im 
intramuscular 
IMP 
investigational medicinal product 
INN 
international nonproprietary name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISR 
injection site reaction 
IU 
international unit 
IVIVC 
in vitro/in vivo correlation 
LSO 
local safety officer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
medical monitor 
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Abbreviation 
Term 
NPRS 
Numeric Pain Rating Scale 
OTC 
over-the-counter 
 
 
PDAESI 
protocol-defined adverse event(s) of special interest 
PDSS 
post-injection delirium/sedation syndrome 
PFS 
prefilled syringe 
PK 
pharmacokinetic(s) 
PopPK 
population pharmacokinetic(s) 
PT 
prothrombin time/preferred term 
PTT 
partial thromboplastin time 
PV 
pharmacovigilance 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
 
 
sc 
subcutaneous(ly) 
SD 
single-dose 
SMP 
Serious Adverse Event Management Plan 
SmPC 
Summary of Product Characteristics  
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
 
 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
 
 
WBC 
white blood cell 
WHO 
World Health Organization 
WO 
Washout 
WOCBP 
women of childbearing potential 
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15. 
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