Clinical trial NCT03187769
Conditions: Schizophrenia Schizophreniform Disorders Bipolar I Disorder
Keywords: Alkermes ALKS 3831 Olanzapine Samidorphan Schizophrenia Schizophreniform Bipolar I
Sponsor: Alkermes, Inc.
Start date: 2017-06-08; Completion date: 2022-01-03
Enrollment: 426 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effect of ALKS 3831 compared to olanzapine on body weight in young adults with schizophrenia, schizophreniform, or bipolar I disorder who are early in their illness

Detailed description:
In the US adolescent subjects starting at age 16 will be enrolled. In the EU, subjects age 18 and older will be enrolled.

Arms: arm 1: Coated bilayer tablet arm 2: Coated bilayer tablet
Interventions: intervention 1: ALKS 3831 intervention 2: Olanzapine
Intervention descriptions: intervention 1: Olanzapine + samidorphan, daily oral dosing intervention 2: Daily oral dosing

Protocol documents:
Prot_000.pdf: 
1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK3831-A307 
EudraCT 2017-000497-11 
 
Study title: 
A Study to Evaluate the Effect of ALKS 3831 Compared to 
Olanzapine on Body Weight in Young Adults with 
Schizophrenia, Schizophreniform, or Bipolar I Disorder Who 
are Early in Their Illness 
Document date: 
Amendment 5.0: 19 Jun 2019 
Amendment 4.0: 10 Jan 2018 
Amendment 3.0: 12 Sep 2017 
Amendment 2.0: 10 May 2017 
Amendment 1.0: 13 Mar 2017 
Original Protocol: 07 Dec 2016 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


 
 
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Protocol ALK3831-A307 Amendment 5.0 
CONFIDENTIAL 
Page 3 of 69 
2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of Investigational Product: ALKS 3831 
Name of Active Ingredient: Olanzapine and samidorphan 
Title of Study: A Study to Evaluate the Effect of ALKS 3831 Compared to Olanzapine on Body Weight 
in Young Adults with Schizophrenia, Schizophreniform, or Bipolar I Disorder Who are Early in Their 
Illness 
Investigators: This is a multinational multicenter study. 
Study Period: 
Estimated date of first subject’s consent: Q2 2017 
Estimated date of last subject’s last visit: Q4 2021 
Phase of Development: 3 
 
Objectives: 
Primary: 
To evaluate the effect of ALKS 3831, compared to olanzapine, on body weight in young adults with 
schizophrenia, schizophreniform, or bipolar I disorder who are early in their illness 
Secondary: 
To evaluate the safety and tolerability of ALKS 3831 in young adults with schizophrenia, 
schizophreniform, or bipolar I disorder who are early in their illness 
Methodology: This is a Phase 3, multicenter, randomized, double-blind study to evaluate the effect of 
ALKS 3831 compared to olanzapine on body weight in young adults with schizophrenia, 
schizophreniform disorder, or bipolar I disorder who are early in their illness. 
Subjects will be screened at Visit 1, up to 30 days prior to randomization. At Visit 2, eligible subjects will 
be randomized (1:1) to ALKS 3831 or olanzapine and receive study drug for up to 12 weeks. 
Randomization will be stratified by diagnosis (schizophrenia/schizophreniform disorder vs bipolar I 
disorder), region (US vs non-US), and baseline BMI (<25 vs ≥25). Subjects on antipsychotic medications 
or mood stabilizers (excluding study medication) should be tapered off this medication by the end of 
Week 2 (Visit 4). Subjects may be inpatient or outpatient at Screening, however in the opinion of the 
Investigator, all subjects should be appropriate for eventual outpatient treatment. Subjects should be 
outpatient within 2 weeks post randomization. Cases that require inpatient treatment for longer than 
2 weeks will require review and approval by the Medical Monitor on a case by case basis. 
Starting with Week 2 (Visit 4), subjects will come for biweekly visits for the remaining 10 weeks. Study 
drug will be provided to subjects as coated bilayer tablets dispensed in blister packs at each visit to be 
taken at home (one tablet by mouth each day, preferably at bedtime). The doses of olanzapine will 
be 5, 10, 15, or 20 mg and the doses of ALKS 3831 will be 5, 10, 15, or 20 mg olanzapine combined with 
10 mg samidorphan (henceforth will be referred to as 5/10, 10/10, 15/10, or 20/10 mg). For the first week 
at the discretion of the Investigator, subjects will receive 5 mg, 10 mg, 15 mg, or 20 mg of olanzapine 
or 5/10 mg, 10/10 mg, 15/10 mg, or 20/10 mg of ALKS 3831. At the end of Week 1, for subjects initiated 
on 5 mg of olanzapine or 5/10 mg of ALKS 3831, the dose will be increased to 10 mg of olanzapine or 
10/10 mg of ALKS 3831. For all other subjects, the dose may also be increased to either 15 or 20 mg of 
olanzapine or 15/10 or 20/10 mg of ALKS 3831. Following this increase, the dose may be increased or 
decreased to 5, 10, 15, or 20 mg of olanzapine, or to 5/10, 10/10, 15/10, or 20/10 mg of ALKS 3831 at the 
Investigator’s discretion. Dosing will be flexible throughout the study; however, frequent adjustments are 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
CONFIDENTIAL 
Page 4 of 69 
discouraged. Dose adjustments can only be performed on-site at the study center. Subjects requiring dose 
adjustments between scheduled visits should arrange an unscheduled visit. 
Body weight, body composition (measured by Bioelectrical Impedance Analysis [BIA]), and metabolic 
parameters (including fasting triglycerides, cholesterol and glucose) will be measured throughout the 
12-week treatment period. Psychiatric symptoms will be evaluated using the Clinical Global Impressions 
(CGI) scales. Additional assessments will include Impact of Weight on Quality of Life-Lite Questionnaire 
(IWQOL-Lite). A daily medication adherence monitoring and reminder system (via smartphones) may be 
used in this study. In addition, subjects will be asked to participate in a supportive clinical care (SCC) 
program during the 12-week treatment period. Participation in the SCC program will be independent of 
study visits and based on clinician and subject preference. A schematic summarizing study design is 
presented below. 
 
Number of Subjects Planned: Approximately 425 subjects will be randomized in order to have 400 
subjects in the efficacy population (200 per treatment group). 
Main Criteria for Inclusion: For US sites, men and women ≥16 through <40 years of age at Screening. 
For non-US sites, men and women ≥18 through <40 years of age at Screening. Subjects will have a body-
mass index (BMI) of <30.0 kg/m2 at Screening and Visit 2, with a Diagnostic and Statistical Manual of 
Mental Disorders-Fifth Edition (DSM-5) primary diagnosis of schizophrenia, schizophreniform disorder, 
or bipolar I disorder and meet Sponsor criteria for previous antipsychotic treatment and duration of 
illness. Subjects with bipolar I disorder must have experienced an acute episode of mania as defined by 
DSM-5 within the last 14 days prior to Visit 1. 
Main Criteria for Exclusion: Subjects may be excluded based on diagnosis of additional psychiatric 
conditions, use of prohibited or contraindicated drugs and medications, pre-existing medical conditions, 
abnormal lab results during Screening, participation in any recent clinical trials or previous clinical trials 
of ALKS 3831 or samidorphan, pregnancy and relationship to an employee of the study Sponsor, CRO, 
Investigator, or study site. 
Investigational Product, Dosage, Duration, and Mode of Administration: ALKS 3831 refers to the 
fixed dose combination of olanzapine and samidorphan. ALKS 3831 will be supplied as a coated bilayer 
tablet containing 5, 10, 15, or 20 mg olanzapine and 10 mg samidorphan. The tablet will be taken by 
mouth once daily, preferably at bedtime, for up to 12 weeks. 
Reference Therapy, Dosage, Duration, and Mode of Administration: Olanzapine will be supplied as 
an identical bilayer tablet manufactured by Alkermes, Inc., containing 5, 10, 15, or 20 mg of olanzapine 
only and no additional active ingredients. Olanzapine tablets will be taken by mouth once daily, 
preferably at bedtime, for up to 12 weeks. 
Duration of Study: The total study duration will be approximately 20 weeks including a 4-week 
Screening Period, a 12-week Treatment Period, and a 4-week Follow-up Period. Subjects completing the 
treatment period will be eligible to enroll in a long-term safety study (ALK3831-A308) where it is 
Screening
12-week Double Blind Treatment Period
ALKS 3831 5/10, 10/10, 15/10, 20/10 mg
Olanzapine 5, 10, 15, 20 mg
4-week follow-up period
Long-term open label 
extension (ALK3831-A308)
Day -30 to -1


 
 
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approved by the local regulatory authority. Subjects not enrolling in the long-term safety study will enter 
the 4-week safety Follow-up Period. 
Criteria for Evaluation: 
Primary Endpoint: 
• 
Percent change from baseline in body weight at Week 12 
Secondary Endpoints: 
• 
Proportion of subjects with ≥10% weight gain at Week 12 
• 
Proportion of subjects with ≥7% weight gain at Week 12 
• 
Change from baseline in waist circumference at Week 12 
• 
Change from baseline in Clinical Global Impression-Severity (CGI-S) score within the ALKS 
3831 Group at Week 12 
Other Endpoints: 
• 
Absolute change from baseline in body weight by visit 
• 
Proportion of subjects with ≥5 cm increase in waist circumference from baseline at Week 12 
• 
Body composition endpoints, as assessed by bioimpedance analysis, including: 
− 
Change from baseline in fat mass by visit 
− 
Change from baseline in percent body fat by visit 
− 
Change from baseline in fat mass index by visit 
− 
Change from baseline in visceral adipose tissue by visit 
− 
Change from baseline in lean mass by visit 
− 
Change from baseline in fat free mass index by visit 
− 
Change from baseline in total skeletal muscle mass by visit 
• 
Percent and absolute change from baseline in fasting lipids (fasting triglycerides, low-density 
lipoprotein, high-density lipoprotein, total cholesterol), fasting glucose, HbA1c, and fasting 
insulin by visit 
• 
Percent and absolute change from baseline in additional laboratory parameters including 
apolipoprotein B (Apo B), apolipoprotein A1 (Apo A1), Apo B/Apo A1, high-sensitivity 
C-reactive protein, interleukin-6, and tumor necrosis factor α by visit 
• 
Change from baseline in CGI-S score (between and within treatment groups) by visit 
• 
Change from baseline in CGI-S score (between and within treatment groups) by visit and by 
diagnosis 
• 
CGI-I score by visit 
• 
Change from baseline in IWQOL-Lite score by visit 
Statistical Methods: In general, summary statistics (n, mean, standard deviation, median, minimum, and 
maximum for continuous variables, and number [%] of subjects in each category for categorical 
variables) will be provided by treatment group for all variables. Source data for the summary tables and 
statistical analyses will be presented as subject data listings. 
Study Populations: The Safety Population will include all randomized subjects who receive at least 


 
 
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one dose of study drug (ALKS 3831 or olanzapine). The efficacy population, ie full analysis set (FAS), 
will include all subjects in the Safety Population who have at least one post-Baseline weight assessment. 
Efficacy Analyses: The efficacy analysis will be carried out using the FAS population. The primary 
analysis of the primary endpoint will be carried out using an analysis of covariance method (ANCOVA) 
based on multiple imputation (MI) for missing data using on-treatment weight assessments. The model 
will include the treatment group and randomization strata as factors and the baseline weight as the 
covariate. Sensitivity analyses will be carried out to explore the impact of missing data. 
For the categorical secondary endpoints of proportion of subjects with ≥10% and ≥7% weight gain at 
Week 12, the analyses will be carried out using a logistic regression model based on MI for missing data. 
The model will include the treatment group and randomization strata as factors, and the baseline weight 
as the covariate. For the change from baseline in waist circumference at Week 12, the analysis will be 
based on the ANCOVA method with MI for missing data, same as the primary analysis of the primary 
endpoint. For change from baseline in CGI-S within ALKS 3831 Group at Week 12, the analysis will be 
based on the mixed model with repeated measurements. The model will include randomization strata, 
treatment, visit, and treatment-by-visit interaction term as factors; the baseline CGI-S value will be 
included as a covariate. 
To control the overall Type I error rate, hierarchical testing will be performed in the following order: (1) 
percent change from baseline in body weight at Week 12, (2) proportion of subjects with ≥10% weight 
gain from baseline at Week 12, (3) proportion of subjects with ≥7% weight gain from baseline at Week 
12, (4) change from baseline in waist circumference at Week 12, (5) change from baseline in CGI-S score 
within the ALKS 3831 Group at Week 12. 
Safety Analyses: The safety analysis will be carried out using the Safety Population. All safety 
assessments will be summarized using descriptive statistics. All safety analyses will be based on observed 
data only, and no missing values will be imputed. Reported AE terms will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and summarized by preferred term and system organ 
class categories. 
Observed values and change from baseline in laboratory parameters, vital signs, and ECG parameters will 
be summarized by treatment group and study visit. 
Prior and concomitant medication use will be summarized by World Health Organization Anatomical 
Therapeutic Chemical (WHO ATC) classification system. Listings will be provided for all concomitant 
medications. 
Pharmacokinetic Analyses: Listings will be provided for concentrations of olanzapine, samidorphan and 
metabolites of interest. Pharmacokinetic concentrations may be used in a subsequent population PK 
analysis conducted outside of this study. 
Sample Size Considerations: Approximately 425 subjects will be randomized in order to have 400 
subjects in the efficacy population (200 per treatment group). Assuming the percent weight gain at 
week 12 is 5% and 8.5% for ALKS 3831 and olanzapine groups, respectively, a common standard 
deviation of 8%, and a cumulative dropout rate of 35%, 200 subjects per treatment group (400 subjects in 
total) will provide at least 90% power to demonstrate a difference of ALKS 3831 relative to olanzapine at 
a 2-sided significance level of 0.05.  
 


 
 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................7 
4. 
LIST OF ABBREVIATIONS.....................................................................................12 
5. 
INTRODUCTION ......................................................................................................14 
5.1. 
Background .................................................................................................................14 
5.2. 
Study Drugs ................................................................................................................15 
5.2.1. 
Samidorphan ...............................................................................................................15 
5.2.2. 
Olanzapine ..................................................................................................................16 
5.3. 
Study Rationale ...........................................................................................................16 
5.4. 
Dose Rationale ............................................................................................................17 
5.5. 
Benefit-Risk Assessment ............................................................................................17 
6. 
OBJECTIVES .............................................................................................................19 
6.1. 
Primary Objective .......................................................................................................19 
6.2. 
Secondary Objective ...................................................................................................19 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................20 
7.1. 
Subject Inclusion Criteria ...........................................................................................20 
7.2. 
Subject Exclusion Criteria ..........................................................................................22 
7.2.1. 
Psychiatric Exclusion Criteria ....................................................................................22 
7.2.2. 
Exclusion Criteria based on Treatment History ..........................................................22 
7.2.3. 
Exclusion Criteria based on Drug/Alcohol Use and Concomitant 
Medications .................................................................................................................22 
7.2.4. 
Exclusion Criteria based on Medical Conditions/Medical History ............................23 
7.2.5. 
Exclusion Criteria Based on Laboratory Assessments ...............................................23 
7.2.6. 
General Exclusion Criteria .........................................................................................24 
7.3. 
Subject Withdrawal ....................................................................................................24 
7.4. 
Replacement of Subjects .............................................................................................25 
8. 
STUDY DESIGN .......................................................................................................26 
8.1. 
Overall Study Design and Plan ...................................................................................26 
8.2. 
Schedule of Visits and Assessments ...........................................................................27 
8.3. 
Study Procedures Descriptions ...................................................................................31 


 
 
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8.3.1. 
Informed Consent .......................................................................................................31 
8.3.2. 
Eligibility Review .......................................................................................................31 
8.3.3. 
Demographics and Medical / Psychiatric History ......................................................31 
8.3.4. 
Concomitant Medication Review ...............................................................................31 
8.3.5. 
Vital Signs ..................................................................................................................31 
8.3.6. 
Physical Examination .................................................................................................31 
8.3.7. 
Height, Body Weight, Body Composition Analysis, and Waist 
Circumference .............................................................................................................32 
8.3.8. 
12-Lead Electrocardiogram ........................................................................................32 
8.3.9. 
Structured Interviews and Questionnaires ..................................................................32 
8.3.9.1. 
Rater Review ..............................................................................................................32 
8.3.9.2. 
Diagnostic Assessments ..............................................................................................33 
8.3.9.3. 
Safety Assessments .....................................................................................................33 
8.3.9.4. 
Antipsychotic Efficacy Assessments ..........................................................................33 
8.3.9.5. 
Other Assessments ......................................................................................................33 
8.3.10. 
Supportive Clinical Care .............................................................................................34 
8.3.11. 
Laboratory Assessments .............................................................................................34 
8.3.11.1. 
Drug Testing ...............................................................................................................34 
8.3.11.2. 
Hematology, Biochemistry, and Urinalysis ................................................................34 
8.3.11.3. 
Urine Pregnancy Testing ............................................................................................36 
8.3.12. 
Serology Testing .........................................................................................................36 
8.3.13. 
Genotype Sampling ....................................................................................................36 
8.3.14. 
Pharmacokinetic Assessments ....................................................................................36 
8.3.15. 
Randomization ............................................................................................................36 
8.3.16. 
Drug Dispensation and Reconciliation .......................................................................36 
8.3.16.1. 
Medication Adherence and Reminder System ...........................................................36 
8.3.17. 
Emergency Treatment Card ........................................................................................37 
8.3.18. 
Adverse Event Monitoring .........................................................................................37 
8.4. 
Study Requirements and Restrictions .........................................................................37 
8.4.1. 
Contraception and Pregnancy .....................................................................................37 
8.4.2. 
Prohibited Medications ...............................................................................................38 
8.4.3. 
Permitted Medications ................................................................................................39 
8.4.4. 
Pain Management .......................................................................................................39 


 
 
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8.4.5. 
Fasting.........................................................................................................................40 
8.4.6. 
Other Restrictions and Requirements .........................................................................41 
9. 
TREATMENT OF SUBJECTS ..................................................................................42 
9.1. 
Study Drug Dose and Administration .........................................................................42 
9.2. 
Treatment Adherence ..................................................................................................42 
9.3. 
Randomization/Method of Assigning Subjects to Treatment .....................................42 
9.4. 
Blinding ......................................................................................................................43 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................44 
10.1. 
Study Drug ..................................................................................................................44 
10.2. 
Packaging and Labeling ..............................................................................................44 
10.3. 
Storage ........................................................................................................................44 
10.4. 
Accountability .............................................................................................................45 
10.5. 
Handling and Disposal ................................................................................................45 
11. 
ASSESSMENT OF EFFICACY ................................................................................46 
11.1. 
Primary Efficacy Endpoint .........................................................................................46 
11.2. 
Secondary Efficacy Endpoints ....................................................................................46 
11.3. 
Other Endpoints ..........................................................................................................46 
12. 
ASSESSMENT OF PHARMACOKINETICS ...........................................................48 
13. 
ASSESSMENT OF SAFETY .....................................................................................49 
13.1. 
Definition of Adverse Event .......................................................................................49 
13.2. 
Definition of Serious Adverse Event ..........................................................................49 
13.3. 
Relationship to Study Drug ........................................................................................50 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................52 
13.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................52 
14. 
STATISTICS ..............................................................................................................54 
14.1. 
Sample Size Considerations .......................................................................................54 
14.2. 
General Statistical Methodology ................................................................................54 
14.2.1. 
Study Populations .......................................................................................................54 
14.2.1.1. 
Safety Population ........................................................................................................54 
14.2.1.2. 
Efficacy Population ....................................................................................................54 
14.3. 
Demographics and Baseline Data ...............................................................................54 
14.4. 
Efficacy Analyses .......................................................................................................55 
Primary Endpoint ...........................................................................................................................55 


 
 
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Secondary Endpoints .....................................................................................................................55 
Other Endpoints .............................................................................................................................55 
14.5. 
Pharmacokinetic Analyses ..........................................................................................56 
14.6. 
Safety and Tolerability Analyses ................................................................................57 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................58 
15.1. 
Study Monitoring ........................................................................................................58 
15.2. 
Audits and Inspections ................................................................................................58 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................58 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................59 
16.1. 
Case Report Forms .....................................................................................................59 
16.2. 
Confidentiality of Data ...............................................................................................59 
17. 
ETHICAL CONSIDERATIONS................................................................................60 
17.1. 
Ethics Review .............................................................................................................60 
17.2. 
Ethical Conduct of the Study ......................................................................................60 
17.3. 
Written Informed Consent ..........................................................................................60 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................62 
18.1. 
Data Capture ...............................................................................................................62 
18.2. 
Inspection of Records .................................................................................................62 
18.3. 
Retention of Records ..................................................................................................62 
18.4. 
Use of Information and Publication Policy ................................................................63 
19. 
REFERENCES ...........................................................................................................64 
20. 
APPENDIX A: PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A INHIBITORS AND INDUCERS ..............................................................67 
21. 
APPENDIX B: PARTIAL LIST OF CYP1A2 MODERATE-TO-STRONG 
INHIBITORS AND MODERATE INDUCERS ........................................................68 
22. 
APPENDIX C: PARTIAL LIST OF MEDICATIONS KNOWN TO BE 
ASSOCIATED WITH PROLONGED QTC INTERVAL AND TORSADE 
DE POINTES ..............................................................................................................69 
 
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ..........................................................12 
Table 3: 
Schedule of Assessments ............................................................................................28 
Table 4: 
Clinical Laboratory Assessments ...............................................................................35 


 
 
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Table 5: 
Adverse Event Causality Guidelines ..........................................................................51 
Table 6: 
Partial List of CYP3A Inhibitors and Inducers ...........................................................67 
Table 7: 
Partial List of CYP1A2 Inhibitors and Inducers .........................................................68 
Table 8: 
Partial List of Medications Known to Be Associated with Prolonged QTc 
Interval and Torsade de Pointes ..................................................................................69 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................27 
 


 
 
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Protocol ALK3831-A307 Amendment 5.0 
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4. 
LIST OF ABBREVIATIONS 
Table 2: 
List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Full Form or Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BIA 
Bioelectrical Impedance Analysis 
BMI 
Body-mass index 
CATIE 
Clinical Antipsychotic Trials of Intervention Effectiveness 
CGI 
Clinical Global Impressions 
CGI-I 
Clinical Global Impressions-Improvement 
CGI-S 
Clinical Global Impressions-Severity 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
EU 
European Union 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
hs-CRP 
high-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 


 
 
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Abbreviation or Term 
Full Form or Definition 
IEC 
Independent Ethics Committee 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board 
IWQOL-Lite 
Impact of Weight on Quality of Life–Lite 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MINI v7.0 
Mini International Neuropsychiatric Interview 7.0 for Schizophrenia and 
Psychotic Disorder Studies 
MINI KID v7.0 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 7.0 for Schizophrenia and Psychotic Disorder Studies 
MMRM 
Mixed model with repeated measurements 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic 
PI 
Principal Investigator 
PORT 
Patient Outcomes Research Team 
QTcB 
QT interval corrected using the Bazett formula 
QTcF 
QT interval corrected using the Fridericia formula 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCC 
Supportive clinical care 
SOP 
Standard operating procedures 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
TNFα 
Tumor necrosis factor alpha 
WHO 
World Health Organization 


 
 
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5. 
INTRODUCTION 
5.1. 
Background 
First- and early-episode schizophrenia and bipolar I disorder are critical phases of the diseases 
where optimal antipsychotic efficacy is crucial. Patients in these early stages are at higher risk 
for suicide and violence (Hawton et al, 2005; Hayes et al, 2015; Hodgins 2008; Kuo et al, 2005). 
Additionally, many therapeutic experts consider this time in the course of the disease as the best 
opportunity for aggressive treatment in order to retain brain function, alter disease trajectory and 
improve long term treatment outcomes in patients with schizophrenia or bipolar I disorder (Berk 
et al, 2011; Berk et al, 2009; Lieberman et al, 2006; Tohen et al, 2010). 
Olanzapine has been commercially available for over 20 years as a treatment for schizophrenia 
and bipolar I disorder (see local olanzapine label) and is regarded as a highly effective treatment 
with demonstrated antipsychotic efficacy and decreased incidence of extrapyramidal symptoms. 
However, the greater antipsychotic efficacy of olanzapine is undermined by its propensity to 
cause significant weight gain and increased cardio metabolic risk compared to other atypical 
antipsychotic drugs (Allison et al, 1999; Leucht et al, 2013; Lieberman et al, 2005; Meyer et al, 
2008; Wirshing et al, 1999). Drug-induced weight gain is a major problem in terms of reduced 
adherence, treatment discontinuation, and exposure to serious long-term obesity-related risks that 
may shorten life expectancy. In the Clinical Antipsychotic Trials of Intervention Effectiveness 
(CATIE) study, olanzapine demonstrated robust antipsychotic efficacy with a rapid and 
significant decrease in Positive and Negative Syndrome Scale (PANSS) and Clinical Global 
Impressions-Severity (CGI-S) scores, as well as the least hospitalizations due to exacerbation of 
schizophrenia compared to other antipsychotics tested, and the lowest all-cause discontinuation 
rate. However, a larger proportion of subjects in the olanzapine group (9%) discontinued 
treatment during the 18 month period due to drug-induced weight and metabolic issues compared 
to the other treatment groups (quetiapine: 4%; risperidone: 2%; perphenazine: 1%; and 
ziprasidone: 3%; (Lieberman et al, 2005). Furthermore, for subjects in the olanzapine group with 
Baseline body mass index (BMI) ≤30 kg/m2, weight increased over the study duration (4.7% at 
12 weeks, 7.7% at 24 weeks, 9.3% at 48 weeks, and 10.1% at 60 weeks). From a physician’s 
perspective, olanzapine-induced weight gain and metabolic issues, not lack of efficacy, are the 
primary reasons for discontinuing or not starting treatment with olanzapine. 
Olanzapine is recommended as a second-line treatment in patients early in illness according to 
the Schizophrenia Patient Outcomes Research Team (PORT) treatment guidelines (Buchanan et 
al, 2010). This is largely due to the fact that olanzapine-induced weight gain and metabolic risk 
are especially pronounced in patients who are early in illness for both schizophrenia and bipolar 
disorder (Correll et al, 2014). 
Alkermes is developing ALKS 3831 as a fixed-dose combination of olanzapine and samidorphan 
(a µ-opioid receptor antagonist) to address the serious side effect of weight gain and metabolic 
consequences associated with olanzapine treatment. The novel combination of olanzapine and 
samidorphan in ALKS 3831 has the potential to deliver the therapeutic benefits of olanzapine to 
patients, while avoiding the harmful weight gain and associated metabolic risks. The potential to 
reduce the weight gain and metabolic effects is even more important in patients who are very 


 
 
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early in their illness of schizophrenia or bipolar disorder. In these patients, the weight gain and 
metabolic effects associated with olanzapine treatment are even greater than those seen in 
patients who have been treated with multiple different antipsychotics and who are later in the 
course of their illness. 
A Phase 2 study (Study ALK3831-302) was conducted to evaluate the antipsychotic efficacy and 
body weight effect of ALKS 3831 in adults with established schizophrenia (first antipsychotic 
treatment lasted longer than 1 year, symptoms lasting greater than 2 years). In Part A (a 12-week, 
double-blind, randomized, olanzapine-controlled phase), ALKS 3831 demonstrated similar 
antipsychotic efficacy compared with olanzapine, based on PANSS total score. ALKS 3831 also 
led to clinically and statistically significantly less body weight gain compared to olanzapine.  
In a 24-week Phase 3 study (ALK3831-A303) comparing ALKS 3831 and olanzapine treatment, 
ALKS 3831 limited olanzapine-induced weight gain and increases in waist circumference in 
subjects with schizophrenia. Subjects treated with ALKS 3831 gained less weight across a range 
of clinically meaningful cutoffs, and had a lower mean percent change in body weight at the end 
of the treatment period. The inclusion of samidorphan in ALKS 3831 limited olanzapine-induced 
weight gain and retained similar antipsychotic efficacy. 
In a 52-week open-label Phase 3 study (ALK3831-A306) designed to evaluate the long-term 
safety and tolerability of ALKS 3831 in subjects with schizophrenia, ALKS 3831 was generally 
well tolerated and continued antipsychotic efficacy was observed. 
A Phase 3 study (ALK3831-A305) was conducted to evaluate antipsychotic efficacy and safety 
in adults with an acute exacerbation of schizophrenia. In the 4-week study ALKS 3831 
demonstrated antipsychotic efficacy as evidenced by a statistically significant and clinically 
meaningful improvement in PANSS and CGI-S scores relative to placebo.  
Another open-label Phase 3 study (ALK3831-A304) is ongoing to assess the efficacy, associated 
weight changes, and long-term safety of ALKS 3831 in adults.  
The current Phase 3 study will further evaluate the effect of ALKS 3831 compared to olanzapine 
on body weight in young adults with schizophrenia, schizophreniform, or bipolar I disorder with 
a recent onset of symptoms and early in medical treatment. 
5.2. 
Study Drugs 
In this study, a fixed-dose combination of olanzapine and samidorphan will be administered in a 
single bilayer tablet. The following sections provide an overview of samidorphan and 
olanzapine. Detailed information about the study drugs can be found in the current ALKS 3831 
Investigator’s Brochure. 
5.2.1. 
Samidorphan 
Samidorphan is a new molecular entity in clinical development by Alkermes. Samidorphan is a 
µ-opioid receptor antagonist. It is currently being investigated in combination with olanzapine 
for the treatment of schizophrenia (ALKS 3831) and in combination with buprenorphine for the 
treatment of major depressive disorder (ALKS 5461). Based on its chemical structure, 
samidorphan is considered a Schedule II controlled substance according to the US Drug 
Enforcement Agency, and will require proper handling (see Section 10). At least 10 clinical 
studies of samidorphan have been conducted to date, eight of which included subjects that 


 
 
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received samidorphan alone (not in combination with another product). Overall, over 
2000 subjects have been exposed to samidorphan as a single agent, or in combination with 
olanzapine or buprenorphine in completed and ongoing clinical studies. Commonly reported 
adverse events (AEs) observed across all studies included nausea, fatigue, and somnolence. 
Overall, no trends or clinically meaningful changes have been observed in clinical laboratory 
analytes, vital sign parameters, or electrocardiogram (ECG) data. 
5.2.2. 
Olanzapine 
Olanzapine has been commercially available for over 20 years as a treatment for schizophrenia 
and bipolar I disorder (see local olanzapine label). The safety and tolerability profile of 
olanzapine is well documented, supported by extensive clinical studies and clinical experience of 
over 20 years (see local olanzapine label). Commonly reported AEs consistent across all or most 
dosage forms in short-term, placebo-controlled trials include somnolence, constipation, dry 
mouth, accidental injury, weight gain, postural hypotension, dizziness, asthenia, fever, and 
abnormal gait. 
5.3. 
Study Rationale 
This study will be the first study to evaluate the effect of ALKS 3831 compared to olanzapine on 
body weight in subjects who are very early in their course of illness, have bipolar I disorder, or 
are adolescents. Previous studies of ALKS 3831 have excluded subjects who had less than 1 year 
since initiating first antipsychotic treatment or since the onset of initial symptoms. The effects of 
the combination of olanzapine and samidorphan to prevent the weight and metabolic changes 
seen with olanzapine alone are expected to be independent of the diagnosis of the subjects. 
Significant weight gain is seen in both schizophrenia and bipolar subjects treated with olanzapine 
and, thus, it is important to include both diagnoses in a study assessing, in particular, the 
differences in weight gain seen between olanzapine and ALKS 3831. The onset of schizophrenia 
is rare before the age of 13, but the rate steadily increases in adolescence, with a peak onset 
of 15 to 30 years (Sham et al, 1994). The most common age of onset of bipolar disorder is 
17 to 21 years (with a mean age of onset of 18 years (Merikangas et al, 2007). As the age of 
onset of both disorders is frequently around 18 years old or slightly younger, it was decided in 
this study to permit the inclusion in the US of older adolescent subjects (≥16 years old). 
Schizophrenia and bipolar I disorder are both characterized by a typical age of onset in the 
early- to mid-twenties (American Psychiatric Association 2013; Blanco et al, 2016). Gender 
differences have been described with schizophrenia such that women tend to experience their 
first episode later than men, showing a peak age of onset in the late twenties, with a second peak 
in the mid- to late-forties (Hafner 2003; Rabinowitz et al, 2006). Given the range of ages over 
which patients can be considered early in illness, this study will include young adults and 
adolescents, ages 16 to 39. 
The major focus of this study is to evaluate weight gain on treatment, irrespective of diagnosis, 
in a particularly sensitive population. Based on ALK3831-302, the addition of samidorphan to 
olanzapine in ALKS 3831 does not appear to affect the antipsychotic efficacy of olanzapine. 
Thus, all subjects in this study will be treated with active antipsychotic treatment. It is expected 
that the antipsychotic efficacy will be similar in both treatment arms. The antipsychotic efficacy 
of treatment during the study will be assessed by the CGI-S and CGI-Improvement (CGI-I) 
scales, which quantify clinicians’ overall impression of clinical severity and clinical change in 


 
 
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individuals’ psychiatric condition (Lepping et al, 2011). The CGI scales have been widely used 
as a primary outcome measure in clinical trials of medications for depression, schizophrenia, and 
many other illness conditions (including bipolar disorder; (Spearing et al, 1997). Relapse of 
schizophrenia, schizophreniform disorder, or bipolar I disorder will be defined by a worsening in 
a subject’s CGI-S score or a hospitalization for worsening of the underlying illness. Additional 
information regarding nonclinical and clinical studies conducted to date with ALKS 3831 is 
available in the current version of the Investigator’s Brochure. 
5.4. 
Dose Rationale 
The selected doses of ALKS 3831 in the current study are supported by the dosing 
recommendations for olanzapine per the local olanzapine label and the clinical safety, 
tolerability, and efficacy data from prior studies with ALKS 3831. The 10 mg samidorphan dose 
was identified as the minimal effective dose in adults based on the efficacy and optimal safety 
profile observed in Study ALK3831-302. A fixed dose of samidorphan was selected due to the 
fact that data from Study ALK3831-302 demonstrated no correlation between the ratio of 
samidorphan/olanzapine dose and percent change from Baseline in body weight after 12 weeks 
of treatment, indicating that, even with higher olanzapine doses, a fixed dose of samidorphan is 
sufficient to achieve maximal effect in reducing olanzapine-induced weight gain. 
All subjects will be randomized to receive ALKS 3831 or olanzapine. Treatment assignment will 
be blinded; however, olanzapine dose will be unblinded. The doses of olanzapine will 
be 5, 10, 15, or 20 mg, and the doses of ALKS 3831 will be 5, 10,15, or 20 mg olanzapine 
combined with 10 mg samidorphan (henceforth referred to as 5/10, 10/10, 15/10, or 20/10 mg). 
5.5. 
Benefit-Risk Assessment 
As stated in the background section, first- and early-episode schizophrenia and bipolar I disorder 
are critical phases of the diseases, where optimal antipsychotic efficacy is crucial. Treatment 
with ALKS 3831 combines the advantages of the antipsychotic efficacy of olanzapine in treating 
both schizophrenia and bipolar disorder, with the potential to mitigate the known effect of 
olanzapine treatment of excessive weight gain. The antipsychotic efficacy seen in stable subjects 
treated in study ALK3831-302 was similar between ALKS 3831 and olanzapine as measured by 
Total PANSS and CGI scores. Based on the available data from the completed studies in healthy 
volunteers (ALK33-301) and in subjects with schizophrenia (ALK3831-302), subjects treated 
with ALKS 3831 have been shown to gain less weight compared to subjects treated with 
olanzapine alone. In ALK3831-302, the prevention of weight gain persisted during the 3-month 
ALKS 3831 treatment period. 
The important identified risks associated with the use of olanzapine include weight gain, glucose 
dysregulation, and dyslipidemia. For additional information on the known risks of olanzapine, 
see the local label. The safety profile of ALKS 3831 is consistent with that of olanzapine (see 
local label). In study ALK3831-302, the only adverse events reported with ALKS 3831 treatment 
occurring in ≥5% of subjects and at ≥2 times the rate of olanzapine alone were somnolence, 
sedation, dizziness, and constipation. Notably, these are all labeled events for olanzapine. The 
most common adverse events noted in clinical studies in >2% of subjects with ALKS 3831 to 
date have been somnolence, dizziness, weight increased, sedation, increased appetite, headache, 
orthostatic hypotension, and liver function test abnormal (see current ALKS 3831 Investigator’s 


 
 
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Brochure). In summary, data from the completed ALKS 3831 studies have demonstrated a 
favorable benefit-risk profile for further investigating ALKS 3831 in subjects with 
schizophrenia, schizophreniform disorder, or bipolar I disorder. 


 
 
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6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the effect of ALKS 3831, compared to 
olanzapine, on body weight in young adults with schizophrenia, schizophreniform, or bipolar I 
disorder who are early in their illness. 
6.2. 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of ALKS 3831 in 
young adults with schizophrenia, schizophreniform, or bipolar I disorder who are early in their 
illness. 


 
 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Each subject must meet all of the inclusion and none of the exclusion criteria to be qualified to 
participate in this study. 
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to qualify for participation in this 
study. 
1. Subject is willing and able to give informed consent/assent, as per local requirements 
2. Subject meets the following antipsychotic treatment and duration of illness eligibility 
requirements: 
• Subject has less than 24 weeks previous treatment with antipsychotics (cumulative; 
lifetime) 
− Subject treated with aripiprazole can receive an additional 1 year of treatment at 
≤5 mg/day, and this treatment will not be considered as part of the 24 weeks of 
previous treatment with antipsychotics 
• Subject has less than 4 years elapse since the initial onset of active phase of 
symptoms 
• For subjects currently taking antipsychotic medication, the subject and the treating 
physician feel that a switch in medication is needed (ie, unsatisfactory clinical 
response, AEs, or nonadherence to current medication) 
3. For US sites, subject is ≥16 and <40 years of age at Screening. For subjects ≥16 and 
<18 years of age, must have had previous antipsychotic exposure. For non-US sites, 
subject is ≥18 and <40 years of age at Screening 
4. Subject has a BMI <30.0 kg/m2 at Screening  
5. Subject agrees to use an acceptable method of contraception for the duration of the study 
and for 30 days after any study drug administration, unless surgically sterile or 
postmenopausal (please refer to Section 8.4.1 for additional details regarding 
contraception) 
6. Subject meets the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
(DSM-5) criteria for a primary diagnosis of schizophrenia, schizophreniform disorder, or 
bipolar I disorder, confirmed with the Mini International Neuropsychiatric Interview 7.0 
for Schizophrenia and Psychotic Disorder Studies (MINI v7.0) for subjects ≥18 years of 
age, or with the Mini International Neuropsychiatric Interview for Children and 
Adolescents 7.0 for Schizophrenia and Psychotic Disorder Studies (MINI KID v7.0) for 
subjects 16 to <18 years of age at Visit 1 
7. For subjects with bipolar I disorder, they must have been experiencing an episode of 
acute mania as defined by DSM-5 within the last 14 days prior to Visit 1 


 
 
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8. Subject is suitable for eventual outpatient treatment based on the opinion of the 
Investigator and review of medical and clinical history by the Sponsor (or designee) 


 
 
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7.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions to qualify for participation in this 
study. 
7.2.1. 
Psychiatric Exclusion Criteria 
1. Subject has any of the following psychiatric conditions per DSM-5 criteria, as assessed 
by the MINI v7.0 or MINI KID v7.0. Conditions not assessable by the MINI v7.0 or 
MINI KID v7.0 should be assessed by clinical judgment: 
• Diagnosis of schizoaffective disorder, bipolar II disorder or current, untreated, or 
unstable major depressive disorder 
• Clinically significant cognitive difficulties, including dementia, delirium, or amnestic 
syndromes, or any other cognitive disorder, except for cognitive impairment 
associated with schizophrenia and bipolar I disorder present within the past 2 years 
that could interfere with participation in the study 
• Drug-induced or toxic psychosis 
• Alcohol or drug use (with the exception of nicotine) disorder, moderate or severe, 
currently or at any time during the 3 months prior to Visit 1 
• Any other psychiatric condition that could interfere with participation in the study 
2. Subject poses a current suicide risk at Visit 1 or Visit 2, in the opinion of the Investigator, 
and as confirmed by the following: 
• Answers “Yes” on items 4 or 5 from the Columbia-Suicide Severity Rating Scale 
(C-SSRS) with ideation or suicidal behavior occurring within the past year 
7.2.2. 
Exclusion Criteria based on Treatment History 
3. Subjects on medications that are prohibited (see Section 8.4.2) 
4. Subject has a history of using olanzapine >14 days (cumulative) during the 6 months 
prior to Visit 1, or a has a lifetime history of using olanzapine for >3 weeks (cumulative), 
or has a history of poor or inadequate response to treatment with olanzapine  
5. Subject has been treated with long-acting injectable antipsychotic medication within the 2 
months prior to screening, or has >6 months cumulative lifetime use; subject has received 
treatment with electroconvulsive therapy in their lifetime 
6. Current treatment with mood stabilizers (eg, lithium, valproate, etc.) that exceeds 2 
months prior to Visit 1 
7.2.3. 
Exclusion Criteria based on Drug/Alcohol Use and Concomitant Medications 
7. Subject has a positive drug screen for opioids, phencyclidine, amphetamine, 
methamphetamine, or cocaine at Visit 1 or Visit 2 
8. Subject has taken opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) within 
the 14 days prior to Visit 1 and/or anticipates a need to take opioid medication during the 


 
 
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study period (eg, planned surgery), or has taken opioid antagonists including naltrexone 
(any formulations) and naloxone within 60 days prior to Visit 1 
9. Subject is taking any weight loss agents or hypoglycemic agents at Visit 1 
7.2.4. 
Exclusion Criteria based on Medical Conditions/Medical History 
10. Subject has a known or suspected intolerance, allergy, or hypersensitivity to olanzapine, 
opioid antagonists, or any of the ingredients of the study drug (see Section 10.1) at Visit 1 
11. Subject has a clinically significant or unstable medical illness, condition, or disorder that 
would be anticipated to potentially compromise subject safety or adversely affect the 
evaluation of efficacy 
12. Subject has a personal or family history of neuroleptic malignant syndrome, or has had 
clinically significant tardive dyskinesia 
13. Subjects with a history of or current neurologic conditions, including seizures (excluding 
febrile seizures), head trauma, or brain injury, should be discussed with the Sponsor prior 
to study entry 
14. Subjects with a history of any illness or procedures (including inflammatory bowel 
disease, GI surgery, liposuction, or eating disorders) that could change weight should be 
discussed with the Sponsor prior to study entry 
15. Subject has joined a weight management program or had significant changes in diet or 
exercise regimen within the 6 weeks prior to Visit 1 or plans to join a weight 
management program during the study 
16. Subject has started a smoking cessation program within the 6 months prior to Visit 1 or 
anticipates quitting smoking during the study 
17. Subject has a history of diabetes 
18. Subject has had a significant blood loss (>500 mL) or blood product donation (including 
platelets or plasma) within 60 days of Visit 1, or anticipated blood or blood product 
donation at any time during the study period 
19. Subject has known risk of narrow-angle glaucoma 
7.2.5. 
Exclusion Criteria Based on Laboratory Assessments 
20. Subject has a laboratory abnormality that would compromise the well-being of the 
subject, or has any of the following specific laboratory results at Visit 1: 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value ≥2 times 
the upper limit of the laboratory normal reference range 
• Absolute neutrophil count (ANC) <1.2 × 103 per μL 
• Platelet count ≤75 × 103 per μL 
• Serum creatinine >2.0 mg/dL for males and >1.5 mg/dL for females 


 
 
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21. Subject has a positive serology test for hepatitis B surface antigen, hepatitis C antibody 
confirmed by ribonucleic acid (RNA) testing, or human immunodeficiency virus (HIV) 
antibody at Visit 1 
22. Subject has dyslipidemia, defined for this study as total fasting cholesterol >280 mg/dL 
or fasting triglycerides >500 mg/dL, at Visit 1 
23. Subject has a Hemoglobin A1c (HbA1c) ≥6.0% at Visit 1 
24. Subject has a fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) at Visit 1 
25. Subject has a clinically significant ECG abnormality at Visit 1 
• Subject has a QT interval >450 msec for men and >470 msec for women, as corrected 
by the Fridericia formula (QTcF), observed at Visit 1 
7.2.6. 
General Exclusion Criteria 
26. Subjects with an electronic implant of any kind (eg, pacemaker) or any active prostheses 
27. Subject is currently pregnant or breastfeeding, or is planning to become pregnant during 
the study or within 30 days of the last study drug administration 
28. Subject has any finding that, in the view of the Investigator or Medical Monitor, would 
compromise the subject’s ability to fulfill the protocol visit schedule or study 
requirements 
29. Subject has participated in another clinical trial in which the subject received an 
experimental or investigational drug or agent within 3 months before Visit 1 by 
self-report or through confirmation using a clinical trial subject registry 
30. Subject has participated in a prior clinical study of ALKS 3831 or samidorphan 
31. Subject is employed by the Sponsor, contract research organization (CRO), Investigator, 
or study site (permanent, temporary contract worker, or designee responsible for the 
conduct of the study), or is immediate family1 of the Sponsor, Investigator, or study site 
employee 
7.3. 
Subject Withdrawal 
A subject may be discontinued from the study at any time if the subject, Investigator, or Sponsor 
determines that it is not in the best interest of the subject to continue participation. If a subject 
has an ANC <1.0 × 103 per µL or HbA1c ≥6.5% at any time, the Principal Investigator (PI; or 
designee) should discontinue the subject from participation immediately. Reasons for 
discontinuation include: 
• AE 
• Lack of efficacy 
 
1 Immediate family is defined as a spouse, parent, sibling, or child, whether biological or legally 
adopted. 


 
 
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• Lost to follow-up 
• Withdrawal by subject 
• Protocol deviation (including noncompliance with study drug or study procedures) 
• Pregnancy 
• Study terminated by Sponsor 
• Other 
If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the Investigator, or until the subject is deemed by the 
Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is necessary to 
monitor a subject beyond the Safety Follow-up Visit, the Follow-up Period may be extended, 
as necessary. In such instances, the Sponsor and the Investigator will agree to an acceptable 
follow-up schedule. 
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Randomized subjects who terminate the treatment early (prior to Visit 9) will be asked to 
complete an Early Termination (ET) Visit and the Safety Follow-up Period (Visits 10 and 11). 
The ET Visit should be scheduled as close as possible to the subject’s last dose and will mimic 
the assessments scheduled to be conducted at Visit 9. Subjects will then be asked to return to the 
study center for biweekly visits until the end of planned treatment, to collect the following 
information: weight, waist circumference, body composition, AEs, and concomitant medications. 
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. 
The Investigator must maintain a record of all subjects who fail to complete the study. The 
reason for study discontinuation will be documented and made on the appropriate electronic case 
report form (eCRF). If a subject is lost to follow-up, a reasonable attempt to contact the subject 
must be made and documented. 
7.4. 
Replacement of Subjects 
Subjects who withdraw from the study after randomization will not be replaced. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a Phase 3, multicenter, randomized, double-blind study to evaluate the effect of 
ALKS 3831 compared to olanzapine on body weight in young adults with schizophrenia, 
schizophreniform disorder, or bipolar I disorder who are early in their illness. 
Subjects will be screened at Visit 1, up to 30 days prior to randomization. At Visit 2, eligible 
subjects will be randomized 1:1 to ALKS 3831 or olanzapine, and receive study drug for up to 
12 weeks. Randomization will be stratified by diagnosis (schizophrenia/schizophreniform 
disorder vs bipolar I disorder), region (US vs non-US), and baseline BMI (<25 vs ≥25). Subjects 
on antipsychotic medications or mood stabilizers (excluding study medication) should be tapered 
off this medication by the end of Week 2 (Visit 4). Subjects may be inpatient or outpatient at 
Screening; however, in the opinion of the Investigator, all subjects should be appropriate for 
eventual outpatient treatment. Subjects should be outpatient within 2 weeks postrandomization. 
Cases that require inpatient treatment for longer than 2 weeks will require review and approval 
by the Medical Monitor on a case by case basis. 
Starting with Week 2 (Visit 4), subjects will come for biweekly visits for the remaining 
10 weeks. Study drug will be provided to subjects as coated bilayer tablets dispensed in blister 
packs at each visit to be taken at home (one tablet by mouth each day, preferably at bedtime). 
For the first week, at the discretion of the Investigator, subjects will receive 5, 10, 15, or 20 mg 
of olanzapine, or 5/10, 10/10, 15/10, or 20/10 mg of ALKS 3831. At the end of Week 1, for 
subjects initiated on 5 mg of olanzapine or 5/10 mg of ALKS 3831, the dose will be increased to 
10 mg of olanzapine or 10/10 mg of ALKS 3831. For all other subjects, the dose may also be 
increased to either 15 or 20 mg of olanzapine, or 15/10 or 20/10 mg of ALKS 3831. Following 
this increase, the dose may be increased or decreased to 5, 10, 15, or 20 mg of olanzapine, or 
to 5/10, 10/10, 15/10, or 20/10 mg of ALKS 3831 at the Investigator’s discretion. Dosing will be 
flexible throughout the study; however, frequent adjustments are discouraged. Dose adjustments 
can only be performed on-site at the study center. Subjects requiring dose adjustments between 
scheduled visits should arrange an unscheduled visit for the following procedures: study drug 
return and dispensation, adherence review, AE, and concomitant medication monitoring. 
Body weight, body composition (measured by Bioelectrical Impedance Analysis [BIA] using a 
Body Composition Analyzer), and metabolic parameters (including fasting triglycerides, 
cholesterol, and glucose) will be measured throughout the 12-week treatment period. Psychiatric 
symptoms will be evaluated using the CGI scales. Additional assessments will include Impact of 
Weight on Quality of Life – Lite Questionnaire (IWQOL-Lite). A daily medication adherence 
monitoring and reminder system (via smartphones) may be used in this study. In addition, 
subjects will be asked to participate in a supportive clinical care (SCC) program during the 
12-week treatment period. Participation in the SCC program will be independent of study visits 
and based on clinician and subject preference. 
The total study duration will be approximately 20 weeks, including a 4-week Screening Period, a 
12-week Treatment Period, and a 4-week Follow-up Period. Subjects completing this study will 
be eligible to enroll in a long-term safety study (ALK3831-A308), where it is approved by the 


 
 
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local regulatory authority. Subjects not enrolling in the long-term safety study will enter the 4-
week Safety Follow-up Period and return to their normal standard of care once their participation 
has ended. A schematic of the study design is provided in Figure 1. 
The end of trial is defined as the date of the last subject’s last visit. 
Figure 1: 
Study Design 
 
8.2. 
Schedule of Visits and Assessments 
The schedule of assessments is shown in Table 3. 
For a missed visit, the site should attempt to contact the subject to reschedule. 
Premature discontinuation procedures are provided in Section 7.3.
Screening
12-week Double Blind Treatment Period
ALKS 3831 5/10, 10/10, 15/10, 20/10 mg
Olanzapine 5, 10, 15, 20 mg
4-week follow-up period
Long-term open label 
extension (ALK3831-A308)
Day -30 to -1


 
 
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Table 3: 
Schedule of Assessments 
Visit Number 
SCN  
Day -
30  
to -1 
12-Week Double-Blind Treatment 
Safety Follow-upa 
Bi-
Weekly 
Visitsb 
1 
2c 
3 
4 
5 
6 
7 
8 
9/ET 
10 
11 
12-15b 
Study Week 
(Visit Window of ±2 Days for Visits 3-15) 
 
1 
2 
4 
6 
8 
10 
12 
14 
16 
 
Qualification/Diagnostic Assessments 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical/ 
Psychiatric History  
X 
 
 
 
 
 
 
 
 
 
 
 
MINI v7.0/MINI KID v7.0 
X 
 
 
 
 
 
 
 
Xd 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Qualification Safety Assessments 
 
Serology Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testing (all women) 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Biochemistry, Hematology, and 
Urinalysis Samples 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
Pharmacokinetic Samplese 
 
 
 
X 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
X 
 
 
 
Weightf, Waist Circumferenceg, and 
Body Compositionf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
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Table 3: 
Schedule of Assessments (Continued) 
Visit Number 
SCN  
Day -
30  
to -1 
12-Week Double-Blind Treatment 
Safety Follow-up 
Bi-
Weekly 
Visitsb 
1 
2c  
3 
4 
5 
6 
7 
8 
9/ET 
10 
11 
12-15b 
Study Week 
(Visit Window of ±2 Days for Visits 3-15) 
 
1 
2 
4 
6 
8 
10 
12 
14 
16 
 
AE Monitoring 
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 
C-SSRSh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Psychiatric Efficacy/Quality of Life Assessments 
 
CGI-S 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
IWQOL-Lite 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Other/General Procedures 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Genotype Sample 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dispensation 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Drug Return 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Abbreviations: AE=adverse event; BIA=Bioelectrical Impedance Analysis; CGI-I=Clinical Global Impressions-Improvement; CGI-S=Clinical Global 
Impressions-Severity; C-SSRS=Columbia-Suicide Severity Scale; d=day; ECG=electrocardiogram; ET=early termination; IWQOL-Lite=Impact of Weight on 
Quality of Life–Lite; MINI v7.0=Mini International Neuropsychiatric Interview 7.0 for Schizophrenia and Psychotic Disorder Studies; MINI KID v7.0=Mini 
International Neuropsychiatric Interview for Children and Adolescents 7.0 for Schizophrenia and Psychotic Disorder Studies; PK=pharmacokinetic; 
SCN=screening 
a Subjects who consent for the open label safety extension study (ALK3831-A308) will continue to Visit 1 in that study and will not complete the Safety 
Follow-up Visits 
b Only for subjects who terminate the study early: subjects who terminate the study early will be asked to schedule an ET Visit as close as possible to the 
subject’s last dose, and then to return for the Safety Follow-up visits. Subjects will then return for up to 4 biweekly assessments. Assessments at the biweekly 
visits include weight, body composition, waist circumference, adverse event monitoring, and concomitant medication review. 
c All assessments will be conducted predose 
d This assessment will only be completed at Visit 9 for subjects diagnosed with schizophreniform disorder at Visit 1 


 
 
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e One PK draw to occur during each indicated visit. When PK and safety blood samples are scheduled to be collected on the same day, efforts should be made to 
collect during the same draw 
f Will be collected by Body Composition Analyzer 
g Waist circumference to be measured in triplicate at all indicated visits  
h “Baseline/Screening” version to be completed at Screening. “Since Last Visit” version to be completed at subsequent timepoints


 
 
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8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedule of assessments is 
provided in Table 3. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the Principal 
Investigator or designated study personnel, as outlined in Section 17.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent/assent, as per local requirements, from each potential subject. 
8.3.2. 
Eligibility Review 
An eligibility review will be conducted by the Investigator at the visits specified in Table 3 using 
the subject inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. Eligibility 
criteria will be reviewed by the Medical Monitor or designee prior to subject randomization.  
8.3.3. 
Demographics and Medical / Psychiatric History 
Subject’s demographic data and medical/psychiatric history will be reviewed and documented at 
the timepoint specified in Table 3. 
8.3.4. 
Concomitant Medication Review 
All medications (prescription and nonprescription, including vitamins and herbal supplements) 
taken by a given subject within 60 days of Screening through Follow-up will be recorded. This 
includes review and recording of all psychotropic and antipsychotic medications. 
At each study visit (see Table 3), the Investigator or designee will record the following data on 
all medications used by the subject: name, dose, regimen, route of administration, start and stop 
dates, and the indication for use. 
8.3.5. 
Vital Signs 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
assessed at the timepoints specified in Table 3. An effort will be made to consistently use the 
same arm (preferably the subject’s dominant arm) to measure blood pressure and heart rate 
throughout the study. The blood pressure cuff will be calibrated per study site standard operating 
procedures (SOP). Automated measurement is preferred, but if performed manually, heart rate 
will be measured in the brachial artery for at least 30 seconds. 
Blood pressure, heart rate, and respiratory rate will be measured after the subject has been in the 
supine position for at least 5 minutes. Vital signs may be collected at any time during a 
scheduled visit, unless otherwise noted. 
8.3.6. 
Physical Examination 
A physical examination will be performed at the timepoints specified in Table 3. Full physical 
examination at Screening (Visit 1); brief physical examination at all other indicated visits. 


 
 
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8.3.7. 
Height, Body Weight, Body Composition Analysis, and Waist Circumference 
Height will be measured at Screening only. Waist circumference will be measured at all the 
timepoints specified in Table 3, and will be measured 3 consecutive times at each time point. The 
Body Composition Analyzer will collect multiple measures related to body composition using 
BIA, including, but not limited to, weight, fat mass, lean mass, and percentage body fat, at all the 
timepoints specified in Table 3. 
For the Body Composition Analyzer measurements, subjects should be asked to void 
immediately prior to measurement and should be dressed in a hospital gown with consistent 
under-attire for each measurement. Subjects should remove all personal items (including shoes, 
watches, and jewelry) and they should be weighed on a study-approved and calibrated scale for 
each measurement under the same conditions. The body composition analysis should not be 
performed when the subject is attached to any portable electronic equipment (eg, a portable ECG 
machine). 
8.3.8. 
12-Lead Electrocardiogram 
A 12-lead ECG will be conducted at the timepoints specified in Table 3. All scheduled ECGs 
must be performed after the subject has rested quietly for at least 5 minutes in the supine 
position. 
A qualified clinician will conduct ECGs and assess ECG results using equipment that has been 
calibrated according to the site’s SOP. The following ECG parameters will be collected: pulse, 
RR, PR, QRS, QT, QTcF, and QT interval corrected using the Bazett formula (QTcB). 
All ECGs will be evaluated by a central reader. 
8.3.9. 
Structured Interviews and Questionnaires 
Brief descriptions of each of the interviews and questionnaires to be distributed are available 
below. All interviews and questionnaires will be administered by trained and qualified study 
personnel. 
For assessments performed at multiple visits, every effort should be made to pair the same 
clinician/rater with the same subject across visits. 
Table 3 provides information on the timepoints at which each assessment should be 
administered. 
8.3.9.1. 
Rater Review 
Rater (ie, study staff) accuracy for the MINI interview at Screening will be reviewed by central 
raters. Rater review is necessary for mitigating inaccurate inclusion/exclusion assessments. 
Rater assessments require subject interviews to be audio recorded. The audio recording will be 
disclosed and explained to the subject by study staff and will be disclosed in the ICF during the 
informed consent process. No subject will be recorded without the knowledge that a recording is 
being made. 


 
 
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8.3.9.2. 
Diagnostic Assessments 
8.3.9.2.1. Mini International Neuropsychiatric Interview/Mini International 
Neuropsychiatric Interview for Children and Adolescents 
The Mini International Neuropsychiatric Interview 7.0 for Schizophrenia and Psychotic Disorder 
Studies (MINI v7.0) and the Mini International Neuropsychiatric Interview for Children and 
Adolescents 7.0 for Schizophrenia and Psychotic Disorder Studies (MINI KID v7.0) are short, 
clinician-administered, structured diagnostic interviews, with an administration time of 
approximately 15 minutes (Sheehan et al, 1998). The MINI v7.0 and MINI KID v7.0 have been 
validated against the much longer Structured Clinical Interview for DSM Diagnoses. The MINI 
v7.0 and MINI KID v7.0 will be administered by the PI or designee at the timepoints in Table 3. 
The MINI v7.0 will be conducted with subjects ≥18 years of age and the MINI KID v7.0 will be 
conducted with subjects <18 years of age. 
8.3.9.3. 
Safety Assessments 
8.3.9.3.1. Columbia-Suicide Severity Rating Scale 
The PI or designee will administer the C-SSRS according to the timepoints in Table 3. The 
“Baseline/Screening” version of the C-SSRS will be completed at Screening (Posner et al, 
2009a). The “Since Last Visit” version will be completed at all other scheduled timepoints 
(Posner et al, 2009b). The C-SSRS should be administered by a qualified clinician trained in 
assessing and managing suicidal ideation and behavior. 
8.3.9.4. 
Antipsychotic Efficacy Assessments 
For assessments performed at multiple timepoints, every effort should be made to pair the same 
clinician/rater with the same subject across timepoints. 
8.3.9.4.1. Clinical Global Impressions-Severity 
The PI or designee will complete the CGI-S scale at the timepoints specified in Table 3. The 
CGI-S measures mental illness severity. Clinicians are asked to rate subjects based on their prior 
experience working with individuals in a similar patient population (Guy 1976). 
8.3.9.4.2. Clinical Global Impressions-Improvement 
The PI or designee will complete the CGI-I scale at the timepoints specified in Table 3. The 
CGI-I measures mental illness improvement. Clinicians are asked to rate subjects based on their 
prior experience working with individuals in a similar patient population (Guy 1976). 
8.3.9.5. 
Other Assessments 
8.3.9.5.1. Impact of Weight on Quality of Life-Lite 
Subjects will complete the IWQOL-Lite questionnaire (Kolotkin et al, 2001) at the timepoints 
specified in Table 3. 


 
 
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8.3.10. 
Supportive Clinical Care 
Subjects will be offered SCC during the 12-week Treatment Period. Participation in the SCC 
program will be independent of study visits and based on clinical and subject preference. The 
SCC component modules may include individual psychotherapy, supported education services, 
and family education and support. Investigators and subjects will be able to select the modules to 
be used based on their judgment of appropriateness. The use of any or all modules will not be 
mandatory for each subject. 
8.3.11. 
Laboratory Assessments 
8.3.11.1. Drug Testing 
A urine drug test for opioids and drugs of abuse, including amphetamine/methamphetamine, 
phencyclidine, and cocaine, will be performed at the timepoints specified in Table 3. Results 
must be negative at Screening (Visit 1) and Baseline (Visit 2) for the subject to be eligible for the 
study. Centralized drug testing will be performed at Screening (Visit 1) and local drug testing 
(via dipstick) at other timepoints, as specified in Table 3. The urine drug screen may be repeated 
at any point during the study based on the Investigator’s discretion. 
8.3.11.2. Hematology, Biochemistry, and Urinalysis 
Fasting blood and urine samples for laboratory assessments will be collected at the timepoints 
specified in Table 3 for specific hematology, biochemistry, and urinalysis assessments listed in 
Table 4. Subjects will be instructed not to eat or drink anything (except water) for 8 hours before 
each visit where blood samples for biochemistry and hematology assessments will be collected. 
Samples will be collected in accordance with the site’s usual procedures and analyzed by a 
central laboratory. Laboratory assessments may be repeated at the Investigator’s discretion. 


 
 
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Table 4: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
Total and differential (absolute) 
white blood cell counta 
General Chemistry 
Albumin 
Bicarbonate 
Calcium 
Chloride 
Creatine phosphokinase 
Glucose 
hs-CRP 
Interleukin 6 
Lactic dehydrogenase 
Potassium 
Sodium 
Total protein 
Tumor necrosis factor α 
Uric acid 
Endocrine Function Test 
Thyroid-stimulating hormoneb 
HbA1cc 
Prolactin 
Insulin 
Liver Function Tests 
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Total bilirubin 
Renal Function Tests 
Blood urea nitrogen 
Creatinine 
Lipid Panel 
High-density lipoprotein 
Low-density lipoprotein 
Total cholesterol 
Triglycerides 
Apolipoprotein B 
Apolipoprotein A1 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Cotinine 
Microscopic examination of 
sediment, only if urinalysis dipstick 
results are abnormal 
Abbreviations: ANC=absolute neutrophil count; HbA1c=Hemoglobin A1c; hs-CRP=high-sensitivity C-reactive 
protein; PI=Principal Investigator 
a At screening, if a subject has an ANC <1.2 × 103 per µL, a repeat will be allowed. However, if a subject has an 
ANC <1.0 × 103 per µL at any time, the PI (or designee) should discontinue the subject from participation 
immediately, as indicated in Section 7.3 


 
 
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b At Screening only; if the thyroid-stimulating hormone results indicate the value is outside of normal limits, the 
central lab will automatically test the same Screening visit sample and provide a free T4 and T3 analysis 
c No repeats will be allowed. If a subject has HbA1c ≥6.5% at any time, the PI (or designee) should discontinue the 
subject from participation immediately, as indicated in Section 7.3 
8.3.11.3. Urine Pregnancy Testing 
A urine pregnancy test will be administered to all women at the timepoints specified in Table 3. 
Results must be negative for the subject to be eligible for the study at Screening (Visit 1) and 
Baseline (Visit 2). As highlighted in Section 7.3, a positive pregnancy test result at any time will 
necessitate the subject’s immediate withdrawal from the study. Additional follow-up may be 
necessary, as indicated in Section 8.4.1. 
8.3.12. 
Serology Testing 
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C 
antibodies, and HIV will be performed at Screening only, as specified in Table 3. A positive 
hepatitis C antibody test must be confirmed by RNA testing to be exclusionary. 
8.3.13. 
Genotype Sampling 
A blood sample may be collected (at the timepoint indicated in Table 3) for evaluation of 
genotypes that are potentially related to response and to explore potential genetic associations 
with efficacy, adverse effects, symptoms, or outcomes. No other tests will be performed with 
these samples. 
8.3.14. 
Pharmacokinetic Assessments 
Concentrations of olanzapine, samidorphan, and metabolites of interest will be determined from 
plasma samples collected according to the schedule in Table 3. The time of last study drug 
administration (when applicable) and the time of each pharmacokinetic (PK) blood draw must be 
documented in the subject’s source documents. Samples for PK analysis will be stored 
at -20°C ±10°C. Pharmacokinetic data from these samples may be included in a subsequent 
population PK analysis or other post-hoc analyses conducted outside of this study. 
8.3.15. 
Randomization 
At the timepoints specified in Table 3, subjects will be randomized, as outlined in Section 9.3. 
8.3.16. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
dispensed/administered at the timepoints specified in Table 3. The study drug use and storage 
information will be explained to/reviewed with the subject. 
8.3.16.1. Medication Adherence and Reminder System 
A daily medication adherence monitoring and reminder system (via smartphones) may be used in 
this study to automatically confirm medication ingestion. After confirmation, all collected data 
and video recordings will be encrypted and may be transmitted to a secure centralized location, 
in accordance with local regulations, for further analysis, including testing for duplicate 


 
 
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enrollment. The captured data and video are reviewable only through a roles- and rules-restricted 
system ensuring privacy of the information. The system is compliant with the Health Insurance 
Portability and Accountability Act (HIPAA), which protects the privacy and security of 
healthcare information. In addition, built-in reminders and a communication system will allow 
real-time intervention in case of drug interruptions. Phone numbers of the patients may also be 
collected and stored in an encrypted manner. At no time is the phone number visible to 
healthcare providers or monitoring personnel. Use of this system will in no way supersede or 
replace the physician- and/or trial-prescribed medication protocol of the patients. 
8.3.17. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject at Screening (Visit 1) and 
collected at Visit 9. The card will indicate that the subject is receiving an opioid antagonist 
and/or olanzapine, and will include the PI’s contact information, a suggested pain management 
plan, and information regarding opiate blockade. Subjects will be instructed to keep the card with 
them at all times. Study personnel will confirm that subjects have the card in their possession at 
each study visit. 
8.3.18. 
Adverse Event Monitoring 
All AEs will be monitored continuously from the time a subject signs the informed consent 
document until the completion of the final study visit (see Table 3). Adverse events and serious 
AEs (SAEs) are defined in Section 13.1 and 13.2, respectively. Section 13.4 provides guidance 
on the monitoring and recording requirements for AEs. Section 13.5 provides guidance on the 
reporting requirements for SAEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study. All female subjects must agree to use an acceptable method for 30 days 
after the last dose of study drug, unless they are surgically sterile or postmenopausal (see below). 
The following are considered acceptable methods of contraception: 
1. Intrauterine device 
2. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, contraceptive implant) 
3. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
4. Abstinence (see below) 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. Abstinence is defined as “true abstinence” in which 
subjects must refrain from heterosexual intercourse for the full duration of the study and must be 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), declaration of abstinence for the duration of 
exposure to the study drug, and withdrawal are not acceptable methods of contraception. 


 
 
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Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
are considered surgically sterile. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female subject. 
Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to Screening in women who are 45 years of age or older. 
If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The ET and Safety Follow-up Visits will be scheduled and the 
pregnancy will be reported to Alkermes. Additional follow-up may be required. Pregnancies in 
female partners of male subjects should also be reported and will be followed in the same 
manner. If a female partner of a male subject becomes pregnant, she may be required to sign an 
informed consent form to obtain pregnancy follow-up information, per local requirements. 
A Pregnancy Report Form must be submitted to Alkermes via Premier Research Group Limited 
(per Section 13.5) immediately, within 24 hours of awareness of the pregnancy, irrespective of 
whether an AE has occurred. The pregnancy will be followed until completion or termination. If 
the outcome of the pregnancy meets the criteria for classification as an SAE, it should be 
reported following the SAE procedure (see Section 13.5). 
8.4.2. 
Prohibited Medications 
The use of any antipsychotic other than study drug is prohibited, except when subjects are 
tapering off of current medication (see Section 8.1). The following medications will be 
prohibited for the duration of the study, unless otherwise indicated: 
• The following psychotropic medications, other than study drug: 
− Antipsychotics (subjects must be tapered off any previous antipsychotic 
medications within 14 days after randomization) 
− Antidepressants for bipolar I disorder subjects at Visit 1 and Visit 2 (subjects may 
be initiated on antidepressants after Visit 2, as described in Section 8.4.3) 
− Mood stabilizers (subjects must be tapered off any mood stabilizer medications 
within 14 days after randomization) 
• Chantix® (varenicline; however, nicotine replacement therapy, including nicotine 
replacement patch and oral nicotine gum, is permitted) 
• All prescription or over-the-counter (OTC) agents taken for the purpose of weight 
reduction 
• Systemic steroids administered by oral, intravenous, or intramuscular route 
• Topiramate (Topamax®) and combination products containing topiramate; calcitonin 
(eg, Miacalcin®) 
• Diabetes treatments and hypoglycemic agents, including metformin and insulin 


 
 
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• Moderate-to-strong inducers or inhibitors of cytochrome P450 (CYP) 3A 
(prescription medications, OTC medications, or dietary supplements) within 30 days 
before randomization through Follow-up (refer to Appendix A for a list of CYP3A 
inhibitors and inducers) 
The CRO Medical Monitor should be consulted for any questions about use of any psychotropic 
medications during a subject’s participation in this study. 
8.4.3. 
Permitted Medications 
• Medications that exhibit drug interaction potential with olanzapine, including known 
inhibitors and inducers of CYP1A2 (Appendix B), may affect olanzapine 
concentrations. Hence, investigators must use caution with inhibitors and inducers of 
CYP1A2 and monitor for need for study drug dose adjustment  
• Medicinal products known to be associated with increase in QTc interval should be 
used with caution given the increased risk of torsade de pointes (Appendix C) 
• Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, 
contraceptive patch, contraceptive implant) will be permitted 
• Antidepressants 
− Bipolar I disorder: Antidepressants are not permitted at Visit 1 and Visit 2. 
However, a selective serotonin reuptake inhibitor (SSRI) antidepressant may be 
initiated during the Treatment Period, if clinically indicated. Treatment with 
SSRIs that may cause significant weight gain should be avoided (eg, paroxetine). 
− Schizophrenia and schizophreniform disorder: May remain on the medication if 
stable on antidepressants for greater than 30 days prior to study entry. However, 
an SSRI antidepressant may be initiated during the Treatment Period, if clinically 
indicated. Treatment with SSRIs that may cause significant weight gain should be 
avoided (eg, paroxetine). 
8.4.4. 
Pain Management 
Because ALKS 3831 contains samidorphan, a μ-opioid antagonist, subjects may experience 
reduced or ineffective analgesia when taking an opioid analgesic agent concurrently with 
ALKS 3831, including several days after last dosing of ALKS 3831. 
In the event of an emergency, pain management of the subject should include the following: 
• Regional analgesia or use of non-opioid analgesics 
• If opiate anesthesia or analgesia is required, the subject should be continuously 
monitored, in an anesthesia care setting, by persons not involved in the conduct of the 
surgical or diagnostic procedure. The opioid therapy must be provided by individuals 
specifically trained in the use of anesthetic drugs and the management of the 
respiratory effects of potent opioids, specifically the establishment and the 
maintenance of a patent airway and assisted ventilation 


 
 
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• Close monitoring by appropriately trained personnel in a setting equipped and staffed 
for cardiopulmonary resuscitation 
For subjects requiring emergency opioid analgesics prior to dosing, the study drug should not be 
administered. If opioid analgesics are required after the study drug has been dosed, it may take 
several days for opiate sensitivity to be restored, since samidorphan functions as a μ-opioid 
antagonist and could interfere with opioid-mediated pain management. 
8.4.5. 
Fasting 
Subjects are required to fast for at least 8 hours (no food or drink, except water) prior to 
laboratory blood draws. 


 
 
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8.4.6. 
Other Restrictions and Requirements 
Additional restrictions and requirements include: 
• Prohibited substances include opioids, amphetamines (including methamphetamine), 
cocaine, and phencyclidine 
• Subjects will be required to abstain from blood or blood product donation during the 
study and for 30 days following the Follow-up Visit 
• Subjects will be instructed to maintain their normal caffeine intake and/or tobacco 
use, as well as normal activity/exercise, throughout the study. Subjects will be asked 
to abstain from strenuous physical activity for 48 hours prior to each study visit 
• Subjects are prohibited from participating in a weight management program 
(including weight loss surgery) or from entering a smoking cessation program for the 
duration of the study 
• Subjects will be asked to refrain from driving, operating machinery, or engaging in 
hazardous activities until they and the Investigator are sure the study drug is not 
impairing their judgment and/or ability to perform skilled tasks 
See Section 8.3.4 for details regarding the concomitant medication review. 


 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
Study drugs include: 
• ALKS 3831 5/10, 10/10, 15/10, or 20/10 mg, administered as a coated bilayer tablet 
• Olanzapine 5, 10, 15, or 20 mg, administered as a coated bilayer tablet 
For the first week, at the discretion of the Investigator, subjects will receive 5, 10, 15, or 20 mg 
of olanzapine or 5/10, 10/10, 15/10, or 20/10 mg of ALKS 3831. At the end of Week 1, for 
subjects initiated on 5 mg of olanzapine or 5/10 mg of ALKS 3831, the dose will be increased to 
10 mg of olanzapine or 10/10 mg of ALKS 3831. For all other subjects, the dose may also be 
increased to either 15 or 20 mg of olanzapine, or 15/10 or 20/10 mg of ALKS 3831. Following 
this increase, the dose may be increased or decreased to 5, 10, 15, or 20 mg of olanzapine, or 
to 5/10, 10/10, 15/10, or 20/10 mg of ALKS 3831, at the Investigator’s discretion. Dosing will be 
flexible throughout the study; however, frequent adjustments are discouraged. Dose adjustments 
can only be performed on-site at the study center. 
For subjects requiring initial inpatient care, study drug will be administered orally, once daily, 
preferably at bedtime. Following discharge, subjects will be given study drug to take home and 
will be instructed to take one tablet orally, preferably at bedtime. If there are tolerability 
problems, dosing may be switched to another time, based on the judgment of the Investigator; 
frequent switching is discouraged. 
Subjects will be instructed to keep all unused tablets in their blister card and to return unused 
tablets to the study site at their next visit. If dosing is to occur at that visit, the dose should be 
taken from the subject’s next blister card, not from the card they are returning.  
If a dose is missed or forgotten, subjects will be instructed to resume regular dosing the 
following night. Subjects will be instructed not to take a double dose to try to “make up” for the 
missed dose. 
9.2. 
Treatment Adherence 
A daily medication adherence monitoring and reminder system (via smartphones) may be used in 
this study (as described in Section 8.3.16.1). Subjects will be instructed to keep all unused tablets 
in their original containers and to return the original containers with any unused study drug at 
each visit following dispensation. Study drug accountability will be documented as the number 
of tablets dispensed, dosed, lost/missing, or remaining. If applicable, the site will discuss 
nonadherence with the subject. 
9.3. 
Randomization/Method of Assigning Subjects to Treatment 
Subjects meeting eligibility criteria at baseline (Visit 2) will be randomized in a (1:1) ratio to 
ALKS 3831 or olanzapine. The randomization will be stratified by diagnosis 
(schizophrenia/schizophreniform disorder vs bipolar I disorder) , region (US vs non-US), and 
baseline BMI (<25 vs ≥25). 


 
 
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Randomization will be performed centrally through an Interactive Web Response System 
(IWRS). A unique randomization number will be assigned by the IWRS once eligibility has been 
determined. Once a randomization number has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study. Codes will be prepared by an 
independent biostatistician who is not otherwise involved in this study. 
9.4. 
Blinding 
All Alkermes staff, CRO staff, clinical staff, subjects, and caregivers will be blinded to treatment 
assignment until database lock. 
The PI is responsible for all trial-related medical decisions. If the Investigator deems it necessary 
to break the study blind in the interest of a subject’s medical safety, he or she is encouraged to 
contact the CRO/Sponsor Medical Monitor to discuss their rationale for unblinding. However, to 
prevent delays to the Investigator or medical personnel responding to a potentially emergent 
situation, unblinding of study drug will not be dependent upon the Investigator receiving 
approval from the Sponsor/CRO Medical Monitor (ie, the Investigator will be able to obtain the 
code break information independent of the Sponsor/CRO Medical Monitor). If the site is unable 
to contact the Medical Monitor prior to breaking the blind, the Medical Monitor must be 
contacted within 24 hours following disclosure of study drug assignment. Any premature 
unblinding should be promptly documented and explained to the Medical Monitor. 
Breaking the blind for a single subject will not affect the blind for the remaining subjects. 


 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The ALKS 3831 drug product will be supplied as a coated bilayer tablet in four fixed-dose 
combinations: 
• ALKS 3831 5/10 (5 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 15/10 (15 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) 
The tablets contain olanzapine and samidorphan L-malate (RDC-0313-02), and the following 
excipients commonly used in pharmaceutical drug products: microcrystalline cellulose, lactose 
monohydrate, crospovidone, colloidal silica dioxide, and magnesium stearate. 
The tablet coating contains hydroxypropyl methylcellulose 2910 (HPMC 2910), titanium 
dioxide, lactose monohydrate, and triacetin as well as one or more of the following dye 
components; iron oxide yellow, iron oxide red, and/or FD&C blue #2/indigo carmine AL.  
Matching olanzapine-only drug will be manufactured by Alkermes, Inc and will be supplied as a 
coated bilayer tablet in four dose strengths: 
• OLZ 5 (5 mg olanzapine) 
• OLZ 10 (10 mg olanzapine) 
• OLZ 15 (15 mg olanzapine) 
• OLZ 20 (20 mg olanzapine) 
The tablets contain olanzapine and the following excipients commonly used in pharmaceutical 
drug products: microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silica 
dioxide, and magnesium stearate. 
The tablet coating contains hydroxypropyl methylcellulose 2910 (HPMC 2910), titanium 
dioxide, lactose monohydrate, and triacetin as well as one or more of the following dye 
components; iron oxide yellow, iron oxide red, and/or FD&C blue #2/indigo carmine AL.  
10.2. 
Packaging and Labeling 
ALKS 3831 and olanzapine will be supplied in blister packs. Blister cards will be in weekly and 
biweekly configurations. Weekly blister cards will contain 9 tablets, enough for 1 week of 
dosing, plus sufficient overage for two additional once daily doses. Biweekly blister cards will 
contain 16 tablets, enough for 2 weeks of dosing, plus sufficient overage for two additional once 
daily doses. 
10.3. 
Storage 
Product should be stored at no more than 25°C. 


 
 
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Under the US Controlled Substances Act, samidorphan is considered a Schedule II substance 
because it is derived from opium alkaloids. Therefore, samidorphan and/or blinded study drug 
must be stored in accordance with restrictions related to Schedule II substances. The site will 
take adequate precautions, including storage of the investigational drug in a securely locked, 
substantially constructed cabinet, or other securely locked, substantially constructed enclosure, 
access to which is limited, to prevent theft or diversion of the substance. 
10.4. 
Accountability 
The clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Refer to Section 8.3.16 for additional study drug reconciliation procedures. 
10.5. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. Packages may be destroyed on site according to Good Clinical Practice (GCP) and 
site practice. Alternatively, the sponsor may arrange for destruction with a third party vendor 
operating in accordance with GCP and/or Good Manufacturing Practice (GMP), as applicable. 


 
 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Primary Efficacy Endpoint 
• Percent change from baseline in body weight at Week 12 
11.2. 
Secondary Efficacy Endpoints 
• Proportion of subjects with ≥10% weight gain at Week 12 
• Proportion of subjects with ≥7% weight gain at Week 12 
• Change from baseline in waist circumference at Week 12 
• Change from baseline in CGI-S score within the ALKS 3831 Group at Week 12 
11.3. 
Other Endpoints 
• Absolute change from baseline in body weight by visit 
• Proportion of subjects with ≥5 cm increase from baseline in waist circumference at 
Week 12 
• Body composition endpoints, as assessed by bioimpedance analysis, including 
− Change from baseline in fat mass by visit 
− Change from baseline in percent body fat by visit 
− Change from baseline in fat mass index by visit 
− Change from baseline in visceral adipose tissue by visit 
− Change from baseline in lean mass by visit 
− Change from baseline in fat free mass index by visit 
− Change from baseline in total skeletal muscle mass by visit 
• Percent and absolute change from baseline in fasting lipids (fasting triglycerides, low-
density lipoprotein [LDL], high-density lipoprotein [HDL], total cholesterol), fasting 
glucose, HbA1c, and fasting insulin by visit 
• Percent and absolute change from baseline in additional laboratory parameters 
including apolipoprotein B (Apo B), apolipoprotein A1 (Apo A1), Apo B/Apo A1, 
high-sensitivity-C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis 
factor α (TNFα) by visit 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
and by diagnosis 
• CGI-I score by visit 


 
 
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• Change from baseline in IWQOL-Lite score by visit 


 
 
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12. 
ASSESSMENT OF PHARMACOKINETICS 
Concentrations of olanzapine, samidorphan, and metabolites of interest will be determined from 
plasma samples collected according to the schedule in Table 3. Data from these PK samples may 
be included in a subsequent population PK analysis conducted outside of this study. By-subject 
listings of plasma concentrations will be provided. 


 
 
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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• AEs 
• Vital signs (ie, oral temperature, respiratory rate, blood pressure, and heart rate) 
• Clinical laboratory parameters, including chemistry, hematology, and urinalysis 
• ECG results 
• C-SSRS 
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been administered a pharmaceutical product. The occurrence, which may or may not have a 
causal relationship with the investigational treatment, may include any clinical or laboratory 
change that does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the ICF are considered to be pre-existing conditions 
and are documented on the medical history eCRF. Pre-existing conditions that worsen during the 
study are entered on the AE eCRF. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the Investigator. Clinically significant values will be considered AEs and will be 
recorded as such on the eCRFs. 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy, including a partner’s pregnancy, 
must be reported to Alkermes, and additional follow-up may be required. 
Transition from schizophreniform to schizophrenia is not considered an AE, unless deemed so by 
the Investigator. 
13.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include a reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent and significant disability/incapacity (eg, a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 


 
 
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Important medical events that may not result in death, be immediately life-threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require intervention to prevent one of the 
other outcomes listed above. 
Admission to a hospital or an inpatient unit for a nonmedical reason (ie, social stay admission) 
during the study, in the absence of an untoward medical occurrence, will not be considered an 
SAE, but will be reported as an AE. Hospitalization due to worsening of behavioral health-
related issues should be reported as an SAE. 
13.3. 
Relationship to Study Drug 
The assessment of study drug relationship to each AE will be reported on the appropriate source 
document (and SAE form, in the event of an SAE) by the Investigator (or designated 
Subinvestigator) according to his/her best clinical judgment. The criteria listed in Table 5 should 
be used to guide this assessment. Please note that not all criteria must be present to be indicative 
of a particular drug relationship. All study drugs are considered “test drugs” for the purposes of 
the definitions listed in the table. 


 
 
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Table 5: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for assessment 
Definitely related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Rechallenge (if feasible) is positive. 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class. 
Probably related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Possibly related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE could have been due to another equally likely cause. 
Dechallenge (if performed) is positive. 
Probably not 
related 
There is evidence of exposure to the test drug. 
AND 
There is another more likely cause of the AE. 
Dechallenge (if performed) is negative or ambiguous. 
Rechallenge (if performed) is negative or ambiguous. 
Definitely not 
related 
The subject did not receive the test drug. 
OR 
Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable.  
OR 
There is another obvious cause of the AE. 
Abbreviation: AE=adverse event 


 
 
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13.4. 
Monitoring and Recording of Adverse Events 
Adverse event data collection will begin after a subject signs the ICF and will continue until 
completion of the Safety Follow-up Visit (Visit 11). Any AE or SAE having an onset after the 
Safety Follow-up Visit will not be collected or reported unless the Investigator feels that the 
event may be related to the study drug. 
Subjects will be instructed by the Investigator or designee to report the occurrence of any AE. 
All volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The Investigator will assess all AEs regarding any causal relationship to the study drug 
(see Section 13.3), the intensity (severity) of the event, action taken, and subject outcome. 
The following criteria should be used to guide the assessment of intensity (severity): 
• Mild: Causes awareness of sign or symptom, but is easily tolerated; does not interfere 
with usual activities 
• Moderate: Causes discomfort enough to interfere with usual activities 
• Severe: Is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE, and any therapeutic measures that are taken, 
shall be at the discretion of the Investigator. If a subject withdraws from the study for any reason, 
any ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or 
until the subject is deemed by the Investigator to be lost to follow-up. 
13.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported to Alkermes via Premier Research Group 
Limited immediately, within 24 hours of discovery, by emailing or faxing the report to the 
following: 
Attention: Safety Premier Medical Monitor 
US Email: GlobalPV-US@premier-research.com 
EU/Rest of the world (ROW) Email: PVDS-ROW@premier-research.com 
US Fax Number: + 1 (215) 972-8765 
EU/ROW Fax Number: + 421 2 6820 3713 
The written report for SAEs should be submitted on the SAE form provided for this purpose. 
The SAE report must include the Investigator’s opinion as to whether the event is study drug-
related. If this relationship is determined to be possibly, probably, or definitely related to study 
drug, evidence to support this assessment must also be provided. 


 
 
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The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 


 
 
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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
Approximately 425 subjects will be randomized in order to have 400 subjects (200 per treatment 
group) in the efficacy population. Assuming the percent weight gain at Week 12 is 5% and 8.5% 
for ALKS 3831 and olanzapine groups, respectively, a common standard deviation of 8%, and a 
cumulative dropout rate of 35%, 200 subjects per treatment group (400 subjects in total) will 
provide at least 90% power to demonstrate a difference of ALKS 3831 relative to olanzapine at a 
two-sided significance level of 0.05. 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details are provided in the 
Statistical Analysis Plan (SAP). 
Baseline is defined as the last nonmissing values on or before the first dose of study drug in the 
double-blind Treatment Period. 
In general, summary statistics (n, mean, standard deviation, median, minimum and maximum for 
continuous variables, and number [%] of subjects in each category for categorical variables) will 
be provided by treatment group for all variables. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
All statistical tests and confidence intervals, unless stated otherwise, will be two-sided and will 
be set at α=0.05. 
14.2.1. 
Study Populations 
14.2.1.1. Safety Population 
The Safety Population, defined as all randomized subjects who receive at least one dose of study 
drug (ALKS 3831 or olanzapine), will be used in the safety analyses. 
14.2.1.2. Efficacy Population 
The Efficacy Population (ie, full analysis set [FAS]), defined as all subjects in the Safety 
Population who have at least one postbaseline weight assessment, will be used in the efficacy 
analyses. 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics, such as gender, age, race, weight, BMI, and 
psychiatric history, will be summarized with descriptive statistics. If there are heterogeneities 
between study groups in any of the subject characteristics that are of clinical importance or could 
affect the treatment outcome, the impact of the imbalances will be investigated and, if necessary, 
appropriate adjustments will be made in the efficacy and safety analyses. 


 
 
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14.4. 
Efficacy Analyses 
All efficacy analyses will be based on the FAS Population.  
Primary Endpoint 
The primary endpoint is: 
• Percent change from baseline in body weight at Week 12 
The primary analysis will be carried out using an analysis of covariance (ANCOVA) method 
based multiple imputation (MI) for missing data. The model will include the treatment group and 
randomization strata as factors, and the baseline weight as the covariate. Sensitivity analyses will 
be carried out to explore the impact of missing data. 
Secondary Endpoints 
The secondary endpoints are: 
• Proportion of subjects with ≥10% weight gain at Week 12 
• Proportion of subjects with ≥7% weight gain at Week 12 
• Change from baseline in waist circumference at Week 12 
• Change from baseline in CGI-S score within the ALKS 3831 Group at Week 12 
For the categorical secondary endpoints of proportion of subjects with ≥10% and ≥7% weight 
gain at Week 12, the analyses will be carried out using a logistic regression model based on MI 
for missing data. The model will include the treatment group and randomization strata as factors, 
and the baseline weight as the covariate. For the change from baseline in waist circumference at 
Week 12, the analysis will be based on the ANCOVA method with MI for missing data, same as 
the primary analysis of the primary endpoint. For change from baseline in CGI-S within 
ALKS 3831 Group at Week 12, the analysis will be based on the mixed model with repeated 
measurements (MMRM). The model will include randomization strata, treatment, visit, and 
treatment-by-visit interaction term as factors; the baseline CGI-S value will be included as a 
covariate. 
To control the overall Type I error rate, hierarchical testing will be performed in the following 
order: (1) percent change from baseline in body weight at Week 12, (2) proportion of subjects 
with ≥10% weight gain from baseline at Week 12, (3) proportion of subjects with ≥7% weight 
gain from baseline at Week 12, (4) change from baseline in waist circumference at Week 12, (5) 
change from baseline in CGI-S score within the ALKS 3831 Group at Week 12. 
Other Endpoints 
Other endpoints are: 
• Absolute change from baseline in body weight by visit 
• Proportion of subjects with ≥5 cm increase from baseline in waist circumference at 
Week 12 
• Body composition endpoints, as assessed by bioimpedance analysis, including 


 
 
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− Change from baseline in fat mass by visit 
− Change from baseline in percent body fat by visit 
− Change from baseline in fat mass index by visit 
− Change from baseline in visceral adipose tissue by visit 
− Change from baseline in lean mass by visit 
− Change from baseline in fat free mass index by visit 
− Change from baseline in total skeletal muscle mass by visit 
• Percent and absolute change from baseline in fasting lipids (fasting triglycerides, 
LDL, HDL, total cholesterol), fasting glucose, HbA1c, and fasting insulin by visit 
• Percent and absolute change from baseline in additional laboratory parameters 
including Apo B, Apo A1, Apo B/Apo A1, hs-CRP, IL-6, and TNFα by visit 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
and by diagnosis 
• CGI-I score by visit 
• Change from baseline in IWQOL-Lite score by visit 
Absolute change from baseline in body weight and all body composition endpoints will be 
analyzed using ANCOVA method with MI for missing data, same as the primary analysis of the 
primary endpoint. 
The proportion of subjects with ≥5 cm increase from baseline in waist circumference at Week 12 
will be analyzed by logistic regression model based on MI for missing data, in a similar fashion 
as the proportion of subjects with ≥10% weight gain.  
The percent and absolute change from baseline in the laboratory parameters will be analyzed by 
MMRM model. The model will include randomization strata, treatment, visit, and 
treatment-by-visit interaction term as factors; the corresponding baseline value will be included 
as a covariate. 
Change from baseline in CGI-S score between and within ALKS 3831 and olanzapine treatment 
groups (by visit, and by visit and by diagnosis) and change from baseline in IWQOL-Lite will be 
analyzed similarly by MMRM model. 
CGI-I score, and CGI-I responder status (≤2 versus >2) at each visit will be summarized by 
descriptive statistics. 
Details of statistical methods will be listed in SAP. 
14.5. 
Pharmacokinetic Analyses 
Listings will be provided for concentrations of olanzapine, samidorphan, and metabolites of 
interest. Pharmacokinetic concentrations may be used in a subsequent population PK analysis 
conducted outside of this study. 


 
 
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14.6. 
Safety and Tolerability Analyses 
All safety assessments will be summarized using descriptive statistics. All safety analyses will be 
based on observed data only, and no missing values will be imputed. Safety will be evaluated 
based on the occurrence of AEs, vital signs, results of clinical laboratory tests, and ECG 
findings. Reported AE terms will be coded using the MedDRA and will be summarized by 
preferred terms and system organ class categories. 
Treatment-emergent AEs (TEAEs) are defined as AEs that occur or worsen after the first dose of 
study drug. 
The summary tables will include the number and percentage of subjects with TEAEs by system 
organ class, and by preferred term within each system organ class. All SAEs, TEAEs leading to 
discontinuation, as well as additional categories of AEs, as defined in the SAP, will be 
summarized. The number and percentage of subjects with TEAEs will also be summarized for 
each study group by severity and by relationship to the study drug. 
Observed values and change from Baseline in laboratory parameters, vital signs, and 
ECG parameters will be summarized by treatment group and study visit. 
The number and percentage of subjects who have met potentially clinically significant (PCS) 
criteria at any post-Baseline visit will be summarized by treatment group for laboratory 
parameters, vital signs, and ECG parameters. Supporting listings will be provided. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will also be summarized. 
Prior and concomitant medications will be summarized using the World Health Organization 
Anatomical Therapeutic Chemical (WHO-ATC) classification system. Listings will be provided 
for all concomitant medications. 


 
 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by an Alkermes Monitor or designee. 
15.2. 
Audits and Inspections 
By signing the protocol, the Investigator agrees that, within local regulatory restrictions, and 
institutional and ethical considerations, authorized representatives of Alkermes, a regulatory 
authority, and/or an institutional review board (IRB)/independent ethics committee (IEC) may 
visit the site to perform audits or inspections, including the drug storage area, study drug stocks, 
drug accountability records, subject charts and source documents, and other records relative to 
study conduct. The purpose of an Alkermes audit or inspection is to systematically and 
independently examine all study-related activities and documents (eg, laboratory reports, x-rays, 
workbooks, subject medical records) to determine whether these activities were conducted, and 
whether data were recorded, analyzed, and accurately reported, according to the protocol, GCP 
guidelines of the International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH), and any applicable regulatory 
requirements. 
The Investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
15.3. 
Institutional Review Board/Independent Ethics Committee 
The Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, 
as well as all materials approved by the IRB/IEC for this study, including the subject consent 
form and recruitment materials, must be maintained by the Investigator and made available for 
inspection. 


 
 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness, and compliance, the study site should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 15.2 for details regarding the audit process. 
16.1. 
Case Report Forms 
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data (ie, data directly reported on the eCRF). All eCRFs will be completed by the 
clinic staff prior to review by the Alkermes Monitor or designated representative. 
The Alkermes Monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF. 
16.2. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to Alkermes that he or she will maintain in 
confidence information furnished to him or her by Alkermes and will divulge such information 
to his or her respective IRB or IEC under an appropriate understanding of confidentiality with 
such board. All data will be considered the sole property of Alkermes. Please refer to the Clinical 
Study Agreement (CSA) for details. 


 
 
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17. 
ETHICAL CONSIDERATIONS 
17.1. 
Ethics Review 
The clinical site’s IRB/IEC must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB/IEC prior to enrolling subjects into the study; written 
approval from the committee must be received by Alkermes before drug will be released to 
the Investigator. The protocol must be re-approved by the IRB/IEC upon receipt of amendments 
and annually, as local regulatory requirements require. 
The Investigator is responsible for submitting all protocol changes and SAE reports to the 
IRB/IEC according to local procedures. At a minimum, all SAEs requiring an investigational 
new drug safety report must be immediately reported. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. Good Clinical Practice is an international ethical and 
scientific quality standard used for designing, conducting, recording, and reporting studies 
involving the participation of human subjects. Alkermes is committed to complying with this 
standard to provide assurance that the rights, safety, and well-being of study subjects will be 
protected, consistent with the principles having their origin in the Declaration of Helsinki. 
17.3. 
Written Informed Consent 
The Investigator (or authorized designee) at each center will ensure that the subject and 
parent/caregiver (as per local requirements) or the subject’s legal representative is given full and 
adequate oral and written information about the nature, purpose, potential and possible risks and 
benefits of the study. Each prospective subject and parent/caregiver (as per local requirements) 
will receive an IRB/IEC-approved ICF that summarizes the pertinent study information and will 
be given ample time to read the form and ask questions about the study. All information is to be 
provided in a language understandable to the subject and must not include any language that 
waives the subject’s legal rights. Prospective subjects must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the subject chooses to 
participate, he/she must sign the ICF and, if required, the parent/caregiver must sign the 
parent/caregiver ICF before any study-specific procedures are conducted. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB/IEC, the CRO, if applicable, and to regulatory authorities 
for review and evaluation for the duration of the study and until the project has been approved 
for marketing, or is withdrawn from investigation. They will also be informed that the Study 
Monitor may inspect their medical records to verify the accuracy and completeness of the study 
records and results. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
Page 61 of 69 
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB/IEC, and then signed by all applicable 
study participants. 
The time that informed consent is obtained must be documented. The Investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
Page 62 of 69 
18. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the Investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail. 
A paper copy of all laboratory reports will remain with the source documents at the study site. 
All electronic source data collected outside of the eCRF, such as e-diaries, central laboratory, 
central ECG, or central MRI data, will be transferred directly to the electronic data capture 
system or directly to Alkermes for incorporation into the final datasets. All out-of-range 
laboratory values will be deemed as clinically significant or not clinically significant by the 
Investigator. Clinically significant values will be considered AEs and will be recorded as such on 
the eCRFs. 
Adverse events will be coded using the MedDRA. Concomitant medications will be categorized 
using the WHO-ATC classification system. 
18.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the Monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and source documents, and other records relative to study conduct. 
18.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements, as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the Sponsor to inform the Investigator/institution as to when 
these documents no longer need to be retained. 
Subject medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
Page 63 of 69 
18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that are the sole property of Alkermes. 
Results of the study are to be held in confidence by both the investigators and the Sponsor. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
Page 64 of 69 
19. 
REFERENCES 
Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive 
research synthesis. Am J Psychiatry. 1999;156(11):1686-1696. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). 5th ed. Washington, DC. American Psychiatric Association; 2013. 
Berk M, Brnabic A, Dodd S, et al. Does stage of illness impact treatment response in bipolar 
disorder? Empirical treatment data and their implication for the staging model and early 
intervention. Bipolar disorders. 2011;13(1):87-98. doi: 10.1111/j.1399-5618.2011.00889.x. 
Berk M, Malhi GS, Hallam K, et al. Early intervention in bipolar disorders: clinical, biochemical 
and neuroimaging imperatives. J Affect Disord. 2009;114(1-3):1-13. doi: 
10.1016/j.jad.2008.08.011. 
Blanco C, Compton Wilson M, Saha Tulshi D, et al. Epidemiology of DSM-5 bipolar I disorder: 
Results from the National Epidemiologic Survey on Alcohol and Related Conditions – III. J 
Psychiatr Res. 2016. doi: 10.1016/j.jpsychires.2016.10.003. 
Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT 
psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 
2010;36(1):71-93. doi: 10.1093/schbul/sbp116. 
Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic risk in patients with first-episode 
schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA 
Psychiatry. 2014;71(12):1350-1363. doi: 10.1001/jamapsychiatry.2014.1314. 
Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. 2016; 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Department of 
Health, Education, and Welfare; 1976. 
Hafner H. Gender differences in schizophrenia. Psychoneuroendocrinology. 2003;28 Suppl 2:17-
54. 
Hawton K, Sutton L, Haw C, Sinclair J, Harriss L. Suicide and attempted suicide in bipolar 
disorder: a systematic review of risk factors. J Clin Psychiatry. 2005;66(6):693-704. 
Hayes JF, Miles J, Walters K, King M, Osborn DP. A systematic review and meta-analysis of 
premature mortality in bipolar affective disorder. Acta Psychiatr Scand. 2015;131(6):417-425. 
doi: 10.1111/acps.12408. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
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Hodgins S. Violent behaviour among people with schizophrenia: a framework for investigations 
of causes, and effective treatment, and prevention. Philos Trans R Soc Lond B Biol Sci. 
2008;363(1503):2505-2518. doi: 10.1098/rstb.2008.0034. 
Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief measure to assess 
quality of life in obesity. Obes Res. 2001;9(2):102-111. doi: 10.1038/oby.2001.13. 
Kuo CJ, Tsai SY, Lo CH, Wang YP, Chen CC. Risk factors for completed suicide in 
schizophrenia. J Clin Psychiatry. 2005;66(5):579-585. 
Lepping P, Sambhi RS, Whittington R, Lane S, Poole R. Clinical relevance of findings in trials 
of antipsychotics: systematic review. Br J Psychiatry. 2011;198(5):341-345. doi: 
10.1192/bjp.bp.109.075366. 
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic 
drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951-962. 
doi: 10.1016/S0140-6736(13)60733-3. 
Lieberman JA, Malaspina D, Jarskog LF. Preventing clinical deterioration in the course of 
schizophrenia: the potential for neuroprotection. CNS Spectr. 2006;11(4):13. 
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar 
spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 
2007;64(5):543-552. doi: 10.1001/archpsyc.64.5.543. 
Meyer JM, Davis VG, McEvoy JP, et al. Impact of antipsychotic treatment on nonfasting 
triglycerides in the CATIE Schizophrenia Trial phase 1. Schizophr Res. 2008;103(1-3):104-109. 
doi: 10.1016/j.schres.2008.04.023. 
Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS): 
Baseline/Screening Version. New York, NY: New York State Psychiatric Institute; 2009a. 
Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS): Since last 
visit. New York, NY: New York State Psychiatric Institute; 2009b. 
Rabinowitz J, Levine SZ, Hafner H. A population based elaboration of the role of age of onset on 
the course of schizophrenia. Schizophr Res. 2006;88(1-3):96-101. doi: 
10.1016/j.schres.2006.07.007. 
Sham PC, MacLean CJ, Kendler KS. A typological model of schizophrenia based on age at 
onset, sex and familial morbidity. Acta Psychiatr Scand. 1994;89(2):135-141. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
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Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global 
Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 
1997;73(3):159-171. 
Tohen M, Vieta E, Gonzalez-Pinto A, Reed C, Lin D. Baseline characteristics and outcomes in 
patients with first episode or multiple episodes of acute mania. J Clin Psychiatry. 
2010;71(3):255-261. doi: 10.4088/JCP.08m04580. 
University of Washington: School of Pharmacy. In Vivo CYP3A Inducers. Seattle, WA: M and 
T Drug Interaction Database; 2017a. 
University of Washington: School of Pharmacy. In Vivo Inhibitors of CYP3A Probes. Seattle, 
WA: M and T Drug Interaction Database; 2017b. 
Wirshing DA, Wirshing WC, Kysar L, et al. Novel Antipsychotics: Comparison of Weight Gain 
Liabilities. J Clin Psychiatry. 1999;60(6):358-363. 


 
 
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Protocol ALK3831-A307 Amendment 5.0 
 
CONFIDENTIAL 
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20. 
APPENDIX A: PARTIAL LIST OF PROHIBITED 
CYTOCHROME P450 (CYP) 3A INHIBITORS AND INDUCERS 
The following is a list of CYP3A inhibitors and inducers that subjects are to avoid within 
30 days of Screening and throughout the study. This list is not comprehensive. 
Table 6: 
Partial List of CYP3A Inhibitors and Inducers 
Moderate-to-Strong Inhibitors 
Moderate-to-Strong Inducers 
Aprepitant 
Idelalisib 
Avasimibe 
Boceprevir  
Indinavir/Ritonavira 
Bosentan 
Cimetidine 
Itraconazole 
Carbamazepine 
Ciprofloxacin 
Ketoconazole 
Efavirenz 
Clarithromycin 
Lopinavir/Ritonavira 
Enzalutamide 
Clotrimazole 
Mibefradil 
Etravirine 
Cobicistat 
Nefazodone 
Mitotane 
Conivaptan 
Nelfinavir 
Modafinil 
Crizotinib 
Paritaprevir/Ritonavir and 
(Ombitasvir and/or Dasabuvir)a 
Phenobarbital 
Cyclosporine 
Posaconazole 
Phenytoin 
Danoprevir/Ritonavira  
Ritonavira 
Rifabutin 
Diltiazem 
Saquinavir/Ritonavira 
Rifampin 
Dronedarone 
Telaprevir 
St. John’s Wort 
Elvitegravir/Ritonavira 
Telithromycin 
— 
Erythromycin 
Tipranavir/Ritonavira 
— 
Fluconazole  
Tofisopam 
— 
Fluvoxamine 
Troleandomycin 
— 
Grapefruit Juice 
Verapamil 
— 
Imatinib 
Voriconazole 
— 
a Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution 
should be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on 
CYP3A activities 
Source: (Food and Drug Administration 2016; University of Washington: School of Pharmacy 2017a; University of 
Washington: School of Pharmacy 2017b) 


 
 
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21. 
APPENDIX B: PARTIAL LIST OF CYP1A2 MODERATE-TO-
STRONG INHIBITORS AND MODERATE INDUCERS 
Table 7: 
Partial List of CYP1A2 Inhibitors and Inducers 
Moderate-to-Strong CYP1A2 Inhibitors 
Moderate CYP1A2 Inducers 
Ciprofloxacina 
Oral Contraceptives 
Phenytoina 
Enoxacin 
Zafirlukast 
Rifampina 
Fluvoxaminea 
— 
Ritonavira 
Methoxsalen 
— 
Teriflunomide 
Mexiletine 
— 
Tobacco 
a These drugs are also known to be CYP3A inhibitors or inducers and are prohibited, as shown in Appendix A 
Source: (Food and Drug Administration 2016) 


 
 
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Protocol ALK3831-A307 Amendment 5.0 
 
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22. 
APPENDIX C: PARTIAL LIST OF MEDICATIONS KNOWN TO 
BE ASSOCIATED WITH PROLONGED QTC INTERVAL AND 
TORSADE DE POINTES 
The following is a list of medications known to be associated with prolonged QTc interval and 
torsade de pointes. This list is not comprehensive. 
Table 8: 
Partial List of Medications Known to Be Associated with Prolonged QTc 
Interval and Torsade de Pointes 
Generic Name 
Amiodarone 
Domperidone 
Oxaliplatin 
Anagrelide 
Donepezil 
Papaverine HCl (Intra-coronary) 
Arsenic trioxide 
Dronedaronea 
Pentamidine 
Azithromycin 
Droperidolb 
Pimozideb 
Chloroquine 
Erythromycina 
Procainamide 
Chlorpromazineb 
Escitalopram 
Propofol 
Cilostazol 
Flecainide 
Quinidine 
Ciprofloxacina 
Fluconazolea 
Sevoflurane 
Citalopram 
Haloperidolb 
Sotalol 
Clarithromycina 
Ibutilide 
Thioridazineb 
Cocaineb 
Levofloxacin 
Vandetanib 
Disopyramide 
Methadoneb 
— 
Dofetilide 
Ondansetron 
— 
a These drugs are also known to be CYP3A inhibitors or inducers and are prohibited, as shown in Appendix A 
b Antipsychotics (other than the study drug), drugs of abuse, and prescribed opioids are prohibited in the study 
 

SAP_001.pdf: 
Clinical Study Report 
Alkermes, Inc. 
ALK3831-A307 
CONFIDENTIAL 
16.1.9. 
Documentation of Statistical Methods 
The final Statistical Analysis Plan and document history are provided in this section, as 
described below.  
Statistical Analysis Plan 
Description 
Date 
Statistical Analysis Plan (Version 1.0) 
20 Jun 2019 
Statistical Analysis Plan (Version 2.0) 
10 Jun 2021 
Statistical Analysis Plan (Version 3.0) 
06 Oct 2021 


 
 
STATISTICAL ANALYSIS PLAN 
 
ALK3831-A307 
NCT03187769 
 
Study Title: 
A Study to Evaluate the Effect of ALKS 3831 Compared to Olanzapine 
on Body Weight in Young Adults with Schizophrenia, 
Schizophreniform, or Bipolar I Disorder Who are Early in Their Illness 
Document Status: 
Final Version 3.0 
Document Date: 
06 Oct 2021  
Based on: 
ALK3831-A307 Protocol Amendment 5.0 Date: 19 Jun 2019 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 


Alkermes, Inc. 
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Statistical Analysis Plan 
2 
TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.2  
Summary of the Study Design ......................................................................................7 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................9 
3. 
DATA ANALYSIS ......................................................................................................9 
3.1. 
General Statistical Methodology ..................................................................................9 
3.2. 
Analysis Sets .................................................................................................................9 
3.2.1. 
Safety Population ..........................................................................................................9 
3.2.2. 
Efficacy Population ......................................................................................................9 
3.3. 
Disposition ..................................................................................................................10 
3.4. 
Demographics and Baseline Characteristics ...............................................................10 
3.5. 
Protocol Deviation ......................................................................................................10 
3.6. 
Prior and Concomitant Medication .............................................................................10 
3.7. 
Treatment Adherence Rate and Extent of Exposure ...................................................11 
3.7.1. 
Treatment Adherence Rate .........................................................................................11 
3.7.2. 
Treatment Exposure ....................................................................................................11 
3.8. 
Efficacy Analyses .......................................................................................................11 
3.8.1. 
General Considerations ...............................................................................................11 
3.8.2. 
Primary Efficacy Endpoint .........................................................................................11 
3.8.2.1. 
Primary Analysis ........................................................................................................11 
3.8.2.2. 
Sensitivity Analysis ....................................................................................................12 
3.8.3. 
Secondary Endpoints ..................................................................................................13 
3.8.3.1. 
Secondary Endpoint: Proportion of Subjects with ≥10% Weight Gain at 
Week 12 in FAS Population .......................................................................................13 
3.8.3.2. 
Secondary Endpoint: Proportion of Subjects with ≥7% Weight Gain at Week 
12 in FAS Population..................................................................................................14 
3.8.3.3. 
Secondary Endpoint: Change from Baseline in Waist Circumference at 
Week 12 in FAS Population .......................................................................................14 
3.8.3.4. 
Secondary Endpoint: Change from Baseline in Clinical Global Impression-
Severity (CGI-S) score within the ALKS 3831 Group at Week 12 ...........................15 
3.8.4. 
Multiple Comparison/ Multiplicity .............................................................................15 
3.8.5. 
Examination of Subgroups .........................................................................................15 


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Statistical Analysis Plan 
3 
3.8.6. 
Other Endpoints ..........................................................................................................15 
3.9. 
Safety Analysis ...........................................................................................................19 
3.9.1. 
Adverse Events ...........................................................................................................19 
3.9.1.1. 
Deaths, Serious and Other Significant Adverse Events ..............................................20 
3.9.2. 
Clinical Laboratory Parameters ..................................................................................20 
3.9.3. 
Vital signs and Electrocardiograms ............................................................................24 
3.9.3.1. 
Vital Signs ..................................................................................................................24 
3.9.3.2. 
Electrocardiograms .....................................................................................................25 
3.9.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................25 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................26 
3.11. 
Other Analysis ............................................................................................................26 
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ......................26 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................26 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........27 
6.1. 
Analysis Visit Windows .............................................................................................27 
6.2. 
Handling of Partial Dates of Concomitant Medication ..............................................28 
6.3. 
Handling of Safety Data .............................................................................................28 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................28 
7.1. 
Reporting Precision ....................................................................................................29 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................29 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) ............................................29 
10. 
REFERENCES ...........................................................................................................30 
APPENDIX 1. COVID-19 ANALYSIS .....................................................................................31 
APPENDIX 2. ADVERSE EVENTS ASSOCIATED WITH MOVEMENT 
DISORDERS (INCLUDING EXTRAPYRAMIDAL SYNDROME AND 
TARDIVE DYSKINESIA) ........................................................................................32 
APPENDIX 3. ADVERSE EVENTS ASSOCIATED WITH SUICIDAL IDEATION 
AND BEHAVIOR ......................................................................................................36 
 


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Statistical Analysis Plan 
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LIST OF TABLES 
Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................22 
Table 2: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters ...................................................................................................................23 
Table 3: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c ...............23 
Table 4: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test ...............24 
Table 5: 
Prolactin – Shift Categories from Baseline to Any Postbaseline ...............................24 
Table 6: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate .............................................................................................................................25 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) QTcF ........................................25 
Table 8: 
C-SSRS Categories for Analysis ................................................................................26 
Table 9: 
Visit Window for Efficacy and Safety Assessments for CGI, Body Weight, 
Waist Circumference and Body Composition ............................................................27 
Table 10: Visit Window for Laboratory Assessments ................................................................27 
Table 11: Visit Window for IWQOL-Lite ..................................................................................28 
Table 12: Visit Window for Vital Sign .......................................................................................28 
Table 13: Visit Window for ECG ...............................................................................................28 
Table 14: Degree of Precision .....................................................................................................29 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................8 


Alkermes, Inc. 
ALK3831-A307 
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Statistical Analysis Plan 
5 
ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
AEDC 
Adverse event leading to treatment discontinuation 
ANCOVA 
Analysis of covariance 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BMI 
Body mass index 
BPM 
Beats per minute 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence interval 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of Treatment 
EPS 
Extrapyramidal symptoms 
ET 
Early termination 
FAS 
Full analysis set 
HbA1C 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
hs-CRP 
High-sensitivity C-reactive protein 
IL-6 
Interleukin 6 
IWQOL 
Impact of Weight on Quality of Life 
LDL 
Low-density lipoprotein 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed model with repeated measurements 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
QTcF 
QT corrected with Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


Alkermes, Inc. 
ALK3831-A307 
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Statistical Analysis Plan 
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Abbreviation or Term 
Explanation or Definition 
TEAE 
Treatment-emergent adverse event 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


Alkermes, Inc. 
ALK3831-A307 
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Statistical Analysis Plan 
7 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for analyses and 
data presentation for reporting efficacy and safety results for study ALK3831-A307. This 
document has been prepared based on Alkermes ALK3831-A307 Study Protocol. 
1.1. 
Study Objectives 
Primary objective: 
• To evaluate the effect of ALKS 3831, compared to olanzapine, on body weight in 
young adults with schizophrenia, schizophreniform, or bipolar I disorder who are 
early in their illness. 
Secondary objective: 
• To evaluate the safety and tolerability of ALKS 3831 in young adults with 
schizophrenia, schizophreniform, or bipolar I disorder who are early in their illness. 
1.2  
Summary of the Study Design 
This is a Phase 3, multicenter, randomized, double-blind study to evaluate the effect of 
ALKS 3831 compared to olanzapine on body weight in young adults with schizophrenia, 
schizophreniform disorder, or bipolar I disorder who are early in their illness. 
Subjects will be screened at Visit 1, up to 30 days prior to randomization. At Visit 2, eligible 
subjects will be randomized 1:1 to ALKS 3831 or olanzapine, and receive study drug for up to 
12 weeks. Randomization will be stratified by diagnosis (schizophrenia/schizophreniform 
disorder vs bipolar I disorder), region (US vs non-US), and baseline BMI (<25 vs ≥25). Subjects 
on antipsychotic medications or mood stabilizers (excluding study medication) should be tapered 
off this medication by the end of week 2 (Visit 4). Subjects may be inpatient or outpatient at 
Screening; however, in the opinion of the Investigator, all subjects should be appropriate for 
eventual outpatient treatment. Subjects should be outpatient within 2 weeks post randomization. 
Cases that require inpatient treatment for longer than 2 weeks will require review and approval 
by the Medical Monitor on a case by case basis. 
Starting with Week 2 (Visit 4), subjects will come for bi-weekly visits for the remaining 10 
weeks. Study drug will be provided to subjects as coated bilayer tablets dispensed in blister 
packs at each visit to be taken at home (one tablet by mouth each day, preferably at bedtime). For 
the first week, at the discretion of the Investigator, subjects will receive 5, 10, 15 or 20 mg of 
olanzapine, or 5/101, 10/10, 15/10 or 20/10 mg of ALKS 3831. At the end of Week 1, for 
subjects initiated on 5 mg of olanzapine or 5/10 mg of ALKS 3831, the dose will be increased to 
10 mg of olanzapine or 10/10 mg of ALKS 3831. For all other subjects, the dose may also be 
increased to either 15 or 20 mg of olanzapine, or 15/10 or 20/10 mg of ALKS 3831. Following 
this increase, the dose may be increased or decreased to 5, 10, 15, or 20 mg of olanzapine, or to 
5/10, 10/10, 15/10, or 20/10 mg of ALKS 3831 at the Investigator’s discretion. Dosing will be 
 
1 ALKS 3831 dose is represented as XX/XX where the first number represents the OLZ dose in mg and the second 
number represents the SAM dose in mg.  
 


Alkermes, Inc. 
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Statistical Analysis Plan 
8 
flexible throughout the study; however, frequent adjustments are discouraged. Dose adjustments 
can only be performed on-site at the study center. Subjects requiring dose adjustments between 
scheduled visits should arrange an unscheduled visit for the following procedures: study drug 
return and dispensation, adherence review, adverse event (AE), and concomitant medication 
monitoring. 
Body weight, body composition (measured by Bioelectrical Impedance Analysis [BIA] using a 
Body Composition Analyzer), and metabolic parameters (including fasting triglycerides, 
cholesterol, and glycemic parameters) will be measured throughout the 12-week treatment 
period. Psychiatric symptoms will be evaluated using the CGI scales. Additional assessments 
will include Impact of Weight on Quality of Life – Lite Questionnaire (IWQOL-Lite). A daily 
medication adherence monitoring and reminder system (via smartphones) may be used in this 
study. In addition, subjects will be asked to participate in a supportive clinical care (SCC) 
program during the 12-week treatment period. Participation in the SCC program will be 
independent of study visits and based on clinician and subject preference. 
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Randomized subjects who terminate the treatment early (prior to Visit 9) will be asked to 
complete an Early Termination (ET) Visit and the Safety Follow-up Period (Visits 10 and 11). 
The ET Visit should be scheduled as close as possible to the subject’s last dose and will mimic 
the assessments scheduled to be conducted at Visit 9. Subjects will then be asked to return to the 
study center for biweekly visits until the end of planned treatment, to collect the following 
information: weight, waist circumference, body composition, AEs, and concomitant medications.  
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. 
The total study duration will be approximately 20 weeks, including an up to 4-week Screening 
Period, a 12-week Treatment Period, and a 4-week Follow-up Period. Subjects completing this 
study will be eligible to enroll in a long-term, single-arm, open-label safety study 
(ALK3831-A308), where it is approved by the local regulatory authority. Subjects not enrolling 
in the long-term safety study will enter the 4-week Safety Follow-up Period and return to their 
normal standard of care once their participation has ended. A schematic of the study design is 
provided in Figure 1. 
Figure 1: 
Study Design  
 
Screening
12-week Double Blind Treatment Period
ALKS 3831 5/10, 10/10, 15/10, 20/10 mg
Olanzapine 5, 10, 15, 20 mg
4-week follow-up period
Long-term open label 
extension (ALK3831-A308)
Day -30 to -1


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2. 
SAMPLE SIZE CONSIDERATION 
Approximately 425 subjects will be enrolled in order to have 400 subjects (200 per treatment 
group) in the primary efficacy population, which is defined in Section 3.2.2. Assuming the 
percent weight gain at Week 12 is 5% and 8.5% for ALKS 3831 and olanzapine groups, 
respectively, a common standard deviation of 8%, and a cumulative dropout rate of 35%, 
200 subjects per treatment group (400 subjects in total) will provide at least 90% power to 
demonstrate a difference of ALKS 3831 relative to olanzapine at a two-sided significance level 
of 0.05. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for the efficacy or safety analysis is defined as the last non-missing efficacy or safety 
assessment on or before the first dose of double-blind study drug. 
In general, descriptive statistics: n, mean, standard deviation (SD), median, minimum, and 
maximum, for continuous variables and number and percentage of subjects in each category for 
categorical variables will be provided by treatment group for all endpoints. 
The metabolic laboratory parameters will be analyzed on a linear and log-transformed scale. If 
log-transformed data is not normally distributed, Wilcoxon rank sum test and Hodges-Lehmann 
estimator will be used. 
All statistical tests and confidence intervals (CIs), unless stated otherwise, will be 2-sided and 
will be set at an alpha level of 0.05. 
All source data will be presented as subject data listings. 
3.2. 
Analysis Sets 
3.2.1. 
Safety Population 
The Safety Population will include all randomized subjects who receive at least 1 dose of study 
drug (ALKS 3831 or olanzapine). The Safety Population will be used for the safety analyses. 
3.2.2. 
Efficacy Population 
The Primary Efficacy Population (ie, full analysis set [FAS]), will include all subjects in the 
Safety Population who have at least one postbaseline weight assessment. The FAS will be used 
for the efficacy analyses, unless specified otherwise. 
The Retrieved Dropout population will include FAS subjects with at least one postbaseline off-
treatment body weight assessment on or before Week 12. The Retrieved Dropout Population will 
be used for the sensitivity analysis of the primary endpoint and secondary endpoints. 


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3.3. 
Disposition 
The number and percentage of subjects completing or prematurely discontinuing the study 
including reasons for discontinuation will be summarized overall and by treatment group for the 
following. 
• Subjects who were randomized 
• Subjects in the Safety Population 
• Subjects in the FAS Population 
• Subjects who completed the Double-blind Treatment Period 
• Subjects who discontinued the study during the Double-blind Treatment Period along 
with reasons for discontinuation 
• Subjects in the Retrieved Dropout Population 
3.4. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as sex, age, race, ethnicity, weight, and body 
mass index (BMI), psychiatric history and disease diagnosis will be summarized overall and by 
treatment group for the Safety Population and the FAS. If there are heterogeneities between 
study groups in any of the subject characteristics that are of clinical importance or could affect 
the treatment outcome, the impact of the imbalances will be investigated and, if necessary, 
appropriate adjustments made in the efficacy and safety analyses. 
Medical history will be coded by System Organ Class and Preferred Term using the Medical 
Dictionary for Regulatory Activities (MedDRA®) Version 23.0 or higher. Medical history will 
be summarized for the Safety Population by treatment group and overall using the number of and 
percentage of subjects by Preferred Term. 
3.5. 
Protocol Deviation 
Subjects with major protocol deviations in the following categories will be summarized by 
treatment group along with supportive listings for each category. 
• Did not meet study entry criteria 
• Received prohibited medications 
• Lack of adherence with study medication, as defined by subjects taking less than 70% 
of the protocol-specified amount of study medication 
• Randomization or dosing error 
3.6. 
Prior and Concomitant Medication 
Prior medications are defined as medications taken prior to the first dose of study drug. 
Concomitant medications are defined as medications taken on or after the first dose study drug. 
All medications as documented by the investigator will be coded using the World Health 
Organization Anatomical Therapeutic Chemical (WHO-ATC) drug dictionary Enhanced 
Extended with Herbal version WHODD B3 March 2021 or higher. 


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Prior and concomitant medications will be summarized by the preferred drug name for the Safety 
Population, separately. Concomitant medications that are taken during the Double-blind 
Treatment Period will be included in the summary table. Additionally, concomitant medications 
will be summarized by the WHO-ATC code. For subjects in the Retrieved Dropout Population, 
all antipsychotic medications that are taken after the last dose of study medication will be 
summarized separately. For the summary tables, if a subject has taken a prior or concomitant 
medication more than once, the subject will be counted only once for the medication. All 
reported medications (including those initiated after the last dose of double-blind study 
medication) will be included in the listing. 
3.7. 
Treatment Adherence Rate and Extent of Exposure 
3.7.1. 
Treatment Adherence Rate 
Treatment adherence to the daily dosing schedule during the Double-blind Treatment Period will 
be summarized by treatment group for the Safety Population. Treatment adherence will be 
calculated as follows: 
100 × Total tablets dispensed −total tablets returned −total tablets lost
Total tablets scheduled to be taken
 
3.7.2. 
Treatment Exposure 
Duration of exposure (ALKS 3831 and olanzapine) will be defined as the number of days from 
the date of the first dose of study drug taken to the date of the last dose taken, inclusive (ie, last 
dose date – first dose date + 1). Duration of exposure will be summarized for the Safety 
Population by treatment group. 
The overall mean and modal dose of olanzapine will be summarized by treatment group. The 
proportion of subjects at each olanzapine dose level at randomization and at final dose will also 
be summarized by treatment group. 
3.8. 
Efficacy Analyses 
3.8.1. 
 General Considerations 
Only the on-treatment weight assessments will be included in the analyses, unless specified 
otherwise. 
3.8.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
• Percent change from baseline in body weight at Week 12 
3.8.2.1. 
Primary Analysis 
The null hypothesis is that there is no difference in percent change from baseline in body weight 
at Week 12 between ALKS 3831 and olanzapine. The alternative hypothesis is that there is a 
difference between ALKS 3831 and olanzapine. 


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The primary endpoint will be analyzed by analysis of covariance (ANCOVA) with the multiple 
imputation (MI) method for handling of missing values. The model will include the treatment 
group and randomization strata (diagnosis [schizophrenia/schizophreniform disorder vs bipolar I 
disorder], region [US vs non-US] and baseline BMI [<25 vs ≥25 kg/m2]) as factors, and the 
baseline weight as the covariate.  Only the on-treatment measurements will be included in the 
analysis. The following steps will be performed: 
1. The missing data on body weight will be imputed using MI. If there is any subject whose 
missing data pattern is non-monotonic (defined as having missing data in between visits), 
the Markov Chain Monte Carlo (MCMC) method will be used to impute the data to a 
monotonic missing pattern (i.e., if the data is missing at the current visit, the data at all 
following visits are missing). A single Markov chain will be used with 200 burn-in 
iterations, 100 iterations between imputations and a Jeffrey’s prior. Next, the missing 
data will be imputed sequentially by each visit using a regression method. The imputation 
regression model includes treatment group, all randomization strata as factors, and body 
weight at all previous visits (including baseline weight) as covariates. At least 100 
imputations will be carried out. More imputations may be performed to improve the 
precision. The initial seed for both steps of the imputation will be 8704011. 
2. Percent change from baseline in weight at Week 12 of each of these multiple imputed 
datasets will be analyzed by the ANCOVA model with treatment group, all 
randomization strata as factors, and the baseline weight as covariate. 
3. Results from Step 2 will be combined using Rubin’s method. Estimated treatment effect, 
standard error (SE), 95% CI, and p-value will be reported. 
Descriptive statistics of body weight and percent change from baseline at each visit (including 
last assessment during treatment period) will be presented by treatment group based on observed 
and MI data. 
3.8.2.2. 
Sensitivity Analysis 
To assess the robustness of the primary analysis, the following sensitivity analyses will be 
performed: 
• Delta-adjusted pattern mixture model: To assess the potential impact of missing data 
due to missing not at random (MNAR), the delta-adjusted Pattern Mixture Model 
(Ratitch et al, 2013) will be conducted to assess the impact of missing data. It 
incorporates the clinical assumption that olanzapine subjects who discontinue at a given 
time point would have, on average, their unobserved weight gain decreased by some 
amount δ compared with the observed weight gain of subjects on the olanzapine arm who 
continue to the next time point. Subjects who discontinue from the ALKS 3831 arm 
would have the same weight gain trajectory as the ALKS 3831 subjects who stay on the 
study. A sequential regression-based MI procedure will be used to incorporate the 
assumption and to allow uncertainty in the imputations to be reflected appropriately in 
the analysis. The imputation model will use the measurement at the current time point as 
the response variable and include the measurements at the previous time points as 
covariates and all randomization strata as factors. One hundred imputations will be 
carried out. For each of the 100 imputed data sets, the same ANCOVA model as in the 


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primary analysis will be fitted to the percent change from baseline at Week 12 to obtain 
the treatment effect estimate and standard error. Rubin’s rule will be used to combine the 
treatment effect estimates and standard errors across imputations. The shift parameters 
will account for 10%, 20%, 30%, 40%, 50%, and up to 100% of the observed treatment 
difference between olanzapine and ALKS 3831 from the primary analysis of the percent 
change from baseline in body weight at Week 12 in FAS population. 
• Including on and off-treatment assessments: To further assess the potential impact of 
missing data due to MNAR, the primary analysis will be repeated including both 
on-treatment and off-treatment weight assessments after premature discontinuation of 
study drug. 
• Additional covariates: The ANCOVA and MI approach may adjust for additional 
covariates and/or factors, including but not limited to study sites. 
• Average treatment effect: Average treatment difference across visits through Week 12 
between ALKS 3831 and olanzapine will be analyzed using mixed model with repeated 
measurements (MMRM) model. The MMRM model will include treatment, visit, 
treatment-by-visit interaction term, all randomization strata as categorical fixed effects; 
baseline weight will be included as a covariate. An unstructured covariance structure will 
be applied. The Kenward-Roger approximation (Kenward and Roger 1997) will be used 
to adjust the denominator degree of freedom. The analysis will be performed on all 
observed post-randomization on-treatment weight measurements without imputation of 
missing data. 
3.8.3. 
Secondary Endpoints 
The secondary endpoints are: 
• Proportion of subjects with ≥10% weight gain at Week 12 
• Proportion of subjects with ≥7% weight gain at Week 12 
• Change from baseline in waist circumference at Week 12 
• Change from baseline in Clinical Global Impression-Severity (CGI-S) score within the 
ALKS 3831 Group at Week 12 
3.8.3.1. 
Secondary Endpoint: Proportion of Subjects with ≥10% Weight Gain at Week 
12 in FAS Population 
3.8.3.1.1. Analysis 
The analysis will be carried out using a logistic regression model. The logistic regression model 
will include the treatment group, all randomization strata as factors; and the baseline weight as 
the covariate. The proportion of subjects with ≥10% weight gain at Week 12 will be derived 
based on the same complete datasets obtained from the multiple imputation procedure as 
described in Section 3.8.2.1 for the primary endpoint. Rubin’s rule will be used to combine the 
results from each imputed dataset. Estimated odds ratio, 95% CI and p-value will be reported. 
Risk difference and 95% CI will be reported as well as the number needed to treat (NNT). NNT 
is calculated as the absolute value of the inverse of the risk difference, rounded up to the nearest 


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integer.  For subjects who prematurely discontinue the study drug but are willing to come back 
for weight assessments, only on-treatment weight assessments will be included in the analysis. 
In addition, to assess the impact of different cutoffs for weight gain (ie, 5%, 7%, 10%, etc), a plot 
of cumulative responder distribution at Week 12 for each treatment group will be presented. The 
horizontal axis will present percent weight gain, and the vertical axis will present the proportion 
of subjects with at least that amount of weight gain. The analysis will be based on MI for missing 
data. 
3.8.3.1.2. Sensitivity Analysis  
To assess the robustness of the analysis, the following sensitivity analyses will be performed: 
• Delta-adjusted pattern mixture model: To assess the potential impact of missing data 
due to MNAR, the delta-adjusted Pattern Mixture Model will be conducted to assess the 
impact of missing data. Proportion of subjects with ≥10% weight gain at Week 12 will be 
derived based on the same complete datasets obtained from the multiple imputation 
procedure of the sensitivity analysis of the primary endpoint (Section 3.8.2.2). The 
logistic regression model will include the treatment group, all randomization strata as 
factors; and the baseline weight as the covariate. It will be fitted to obtain the treatment 
effect estimate and standard error. Rubin’s rule will be used to combine the treatment 
effect estimates and standard errors across imputations. 
• Including on and off-treatment assessments: To further assess the potential impact of 
missing data due to MNAR, the approach described in Section 3.8.3.1.1 will be repeated 
including both on-treatment and off-treatment weight assessments after premature 
discontinuation of study drug. 
• Additional covariates: The logistic regression model may also adjust for additional 
covariates and/or factors, including but not limited to study sites. 
• Average treatment effect: Average treatment difference across visits through Week 12 
between ALKS 3831 and olanzapine will be analyzed. 
3.8.3.2. 
Secondary Endpoint: Proportion of Subjects with ≥7% Weight Gain at Week 12 
in FAS Population 
The analyses will be the same as proportion of subjects with ≥10% weight gain at Week 12, 
including relevant sensitivity analyses (Section 3.8.3.1). 
3.8.3.3. 
Secondary Endpoint: Change from Baseline in Waist Circumference at Week 12 
in FAS Population 
For the change from baseline in waist circumference at Week 12, the analysis will be the same as 
the primary endpoint, including relevant sensitivity analyses (Section 3.8.2.1 and 
Section 3.8.2.2). 


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3.8.3.4. 
Secondary Endpoint: Change from Baseline in Clinical Global Impression-
Severity (CGI-S) score within the ALKS 3831 Group at Week 12 
To assess the change from baseline in CGI-S at Week 12 within the ALKS 3831 Group, the 
MMRM will be used. The model will include treatment, visit, treatment-by-visit interaction and 
all randomization strata as factors. An unstructured variance-covariance matrix will be used. The 
least squares (LS) mean, 95% CI and p-value of change from baseline at Week 12 within the 
ALKS 3831 Group will be reported. 
3.8.4. 
Multiple Comparison/Multiplicity 
The study will be claimed positive when the primary analysis of the primary efficacy endpoint is 
statistically significant. The primary endpoint will be tested at a full α level of 0.05. To control 
the overall Type I error rate of the primary and secondary endpoints, hierarchical testing will be 
performed in the following order: (1) percent change from baseline in body weight at Week 12, 
(2) proportion of subjects with ≥10% weight gain from baseline at Week 12, (3) proportion of 
subjects with ≥7% weight gain from baseline at Week 12, (4) change from baseline in waist 
circumference at Week 12, (5) change from baseline in CGI-S score within the ALKS 3831 
Group at Week 12. 
3.8.5. 
Examination of Subgroups 
Subgroup analyses of the primary and secondary endpoints will be performed for each of the 
following categories: 
• Diagnosis (schizophrenia/schizophreniform disorder, bipolar I disorder) 
• Sex (male, female) 
• Age (<18 years, ≥18 years) 
• Age (<30 years, ≥30 years) 
• Race (Black or African American, Non-Black or Non-African American) 
• Baseline BMI (<25 kg/m2, ≥25 kg/m2) 
• Region (US, Non-US) 
A forest plot of the estimated treatment effect along with 95% CIs will be provided by the 
subgroup factors listed above. Only summary statistics for the age <18 years subgroup will be 
provided due to its limited enrolment expected. 
3.8.6. 
Other Endpoints 
Other endpoints include: 
• Absolute change from baseline in body weight by visit 
• Absolute change from baseline in BMI by visit 
• Proportion of subjects in each BMI category (normal weight: <25, overweight: ≥25 
to <30, obese: ≥30 kg/m2) by visit and proportion of subjects with shifts in BMI 
category from baseline by visit 


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• Proportion of subjects with ≥5 cm increase from baseline in waist circumference at 
Week 12 
• Body composition endpoints, as assessed by bioimpedance analysis, including: 
− Change from baseline in fat mass by visit 
− Change from baseline in percent body fat by visit 
− Change from baseline in fat mass index by visit 
− Change from baseline in visceral adipose tissue by visit 
− Change from baseline in lean mass by visit 
− Change from baseline in fat free mass index by visit 
− Change from baseline in total skeletal muscle mass by visit 
• Percent and absolute change from baseline in fasting lipids (fasting triglycerides, 
low-density lipoprotein [LDL], high-density lipoprotein [HDL], total cholesterol), 
fasting glucose, hemoglobin A1c (HbA1c), fasting insulin, and homeostatic model 
assessment of insulin resistance (HOMA-IR) by visit 
• Percent and absolute change from baseline in additional laboratory parameters 
including apolipoprotein B (Apo B), apolipoprotein A1 (Apo A1), Apo B/Apo A1, 
high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis 
factor α (TNFa) by visit 
• Change from baseline in blood pressure (supine systolic and diastolic) by visit 
• Proportion of subjects in each blood pressure category (normal, elevated, stage 1 
hypertension, stage 2 hypertension) and proportion of subjects shifting from normal 
or elevated blood pressure at baseline to Stage 1 or 2 hypertension by visit 
• Proportion of subjects meeting criteria for metabolic syndrome by visit and 
proportion of subjects shifting from no metabolic syndrome at baseline to having 
metabolic syndrome by visit 
• Proportion of subjects meeting individual metabolic syndrome component criterion 
by visit  
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
and by diagnosis 
• CGI-I score by visit 
• Change from baseline in IWQOL-Lite score by visit 
For all the other endpoints, presentation of analysis results will be limited to estimated treatment 
effect, 95% CI and/or descriptive statistics. 
Absolute change in body weight, BMI, systolic and diastolic blood pressure and all body 
composition endpoints will be analyzed similarly by ANCOVA model and MI for missing data 


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as noted in Section 3.8.2.1. The ANCOVA model will include treatment and all randomization 
strata as factors and baseline value as a covariate. The proportion of subjects with ≥5 cm increase 
of waist circumference will be analyzed by the logistic regression model and MI method in a 
similar fashion as the proportion of subjects with ≥10% weight gain, using the same imputed 
dataset from the primary analysis of change from baseline in waist circumference in 
Section 3.8.3.3. 
The proportion of subjects in each BMI category will be analyzed based on each subject’s by-
visit assessment status using a logistic regression model including treatment group and 
randomization strata as factors, and baseline BMI as covariate. The model is based on the MI for 
missing postbaseline assessments. Rubin's rule is used to combine results from applying the 
logistic regression model on imputed datasets. 
Proportion of subjects with shifts in BMI category by visit will also be analyzed based on each 
subject’s by-visit assessment status using the logistic regression model mentioned above. Shifts 
are defined as follows: 
• Proportion of subjects shifting from BMI <25 kg/m2 at baseline to BMI ≥25 kg/m2 by 
visit 
• Proportion of subjects shifting from BMI <30 kg/m2 at baseline to BMI ≥30 kg/m2 by 
visit 
The proportion of subjects in each blood pressure category will be analyzed based on the 
subject’s by-visit assessment status using a logistic regression model including treatment group 
and randomization strata as factors, and baseline systolic and diastolic blood pressure as 
covariates. The model is based on the MI for missing postbaseline assessments. Rubin's rule is 
used to combine results from applying the logistic regression model on imputed datasets. 
Number of responders and proportion for each blood pressure category are the mean number of 
responders and mean proportion from the imputed datasets, respectively. 
Proportion of subjects with shifts in blood pressure category by visit will also be analyzed based 
on each subject’s by-visit assessment status using the logistic regression model described above. 
Shifts are defined as follows: 
• Proportion of subjects shifting from Normal blood pressure at baseline to Stage 1 or 
Stage 2 Hypertension 
• Proportion of subjects shifting from Normal or Elevated blood pressure at baseline to 
Stage 1 or Stage 2 Hypertension 
The blood pressure categories will be defined as follows based on American Heart Association 
criteria: 
• Normal: systolic and diastolic blood pressure of <120 and <80 mmHg, respectively 
• Elevated: systolic and diastolic blood pressure of ≥120 to ≤129 and <80 mmHg, 
respectively 
• Stage 1: systolic blood pressure of ≥130 to ≤139 mmHg or diastolic blood pressure of 
≥80 to ≤89 mmHg 


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• Stage 2: systolic blood pressure of ≥140 mmHg or diastolic blood pressure of 
≥90 mmHg. 
The following laboratory parameters will be analyzed by MMRM model as described in 
Section 3.8.3.4 . The model will include treatment, visit, treatment-by-visit interaction, all 
randomization strata as categorical fixed effects; the baseline value will be included as the 
covariate. An unstructured variance-covariance matrix will be used. 
• Percent and absolute change from baseline in fasting lipids (fasting triglycerides, 
LDL, HDL, total cholesterol), fasting glucose, HbA1c, fasting insulin, and HOMA-IR 
by visit 
• Percent and absolute change from baseline in additional laboratory parameters 
including Apo B, Apo A1, Apo B/Apo A1, hs-CRP, IL-6 and TNFa by visit. 
The proportion of subjects with metabolic syndrome at each visit will be analyzed by logistic 
regression model including treatment group and randomization strata as factors and baseline 
metabolic syndrome as covariate. 
The proportion of subjects meeting each individual component criterion for metabolic syndrome 
(listed below) will be analyzed by visit using the same logistic regression model described above 
with the respective baseline value for each component as the covariate. 
Additionally, a similar logistic regression model including treatment and randomization strata as 
factors will be used to analyze the proportion of subjects shifting from no metabolic syndrome at 
baseline to developing metabolic syndrome postbaseline. Data are based on observed values with 
no imputation for missing values. 
Metabolic syndrome is defined as meeting at least 3 of the following individual component 
criteria: 
− Waist circumference, cm>88 (women), >102 (men) 
− Triglycerides, mg/dL ≥150 
− HDL cholesterol, mg/dL <50 (women), <40 (men) 
− Glucose, fasting mg/dL ≥100 
− Blood pressure, mm Hg ≥130/85 
The following endpoints will be analyzed by MMRM model as described in Section 3.8.3.4, as 
applicable. 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
• Change from baseline in CGI-S score (between and within treatment groups) by visit 
and by diagnosis 
• Change from baseline in IWQOL-Lite score by visit 
IWQOL-Lite scale is a 31-item self-report measure of obesity-specific quality of life. The 
IWQOL-Lite provides an overall total score as well as scores on five domains: (1) physical 
function, (2) self-esteem, (3) sexual life, (4) public distress, and (5) work. The raw IWQOL 
scores will be transformed as follows (Tessier et al, 2012) before analyzed by the MMRM 


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method. The transformed scores range from 0 to 100, with 100 representing the best and 0 the 
most impaired quality of life. 
Transformed Score = maximum theoretical score −actual score
test score range
× 100 
CGI-I score and CGI-I responder status (≤2 versus >2) at each visit will be summarized by 
treatment group. Descriptive statistics will be presented. 
3.9. 
Safety Analysis 
3.9.1. 
Adverse Events 
AEs will be coded by System Organ Class and Preferred Term using the Medical Dictionary for 
Regulatory Activities (MedDRA®) Version 23.0 or higher. The verbatim term will be included in 
the AE listings. 
An AE (classified by preferred term) will be considered as a treatment-emergent AE (TEAE) if 
the event is newly occurring or worsening on or after the date of first dose of study drug and 
within 7 days after the date of last dose of the study drug. 
An overview table, including number and percentage of subjects with TEAEs, study-drug-related 
TEAEs, severe TEAEs, AEs leading to treatment discontinuation (AEDCs), serious AEs (SAEs), 
study drug-related SAEs, and deaths will be provided. 
The number and percentage of subjects reporting TEAEs during the Double-blind Treatment 
Period will be presented by treatment group for the following categories:  
• System organ class and preferred term 
• Preferred terms in decreasing frequency, and also including the following subsets: 
− Experienced by ≥2% of subjects in any treatment group 
− Experienced by ≥5% of subjects in any treatment group and ≥2 times of 
olanzapine Group 
• System organ class, preferred term, and severity 
• System organ class, preferred term for severe TEAEs 
• System organ class, preferred term, and relationship 
• System organ class, preferred term for drug-related TEAEs 
− Experienced by ≥2% of subjects in ALKS 3831 group by preferred term 
If more than one AE is coded to the same preferred term for the same subject for the same 
period, the subject will be counted only once for that preferred term using the most severe and 
most related occurrence for the summarization by severity and by relationship to study drug. 
In addition, the number and percentage of subjects reporting AEs and SAEs during the Safety 
Follow-up Period will be tabulated by the system organ class, preferred term, and treatment 
group. 


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For the subjects who prematurely discontinue the study drug and return for the bi-weekly visits, 
all AEs collected after discontinuation of the study drug will be summarized by system organ 
class, preferred term, and treatment group. 
3.9.1.1. 
Deaths, Serious and Other Significant Adverse Events 
The number and percentage of subjects who have SAEs and AEDCs will be summarized by 
preferred term and treatment group, and will be sorted by decreasing frequency for the 
ALKS 3831 group. 
3.9.1.1.1. AEs of Special Interest 
The incidence of a selected subset of relevant AEs in this class of drugs (eg, Movement 
Disorders (Including Extrapyramidal Sydrome [EPS] and Tardive Dyskinesia), and suicidal 
ideation and behavior) will be summarized by treatment group and preferred term. The selection 
of AEs per subset will be based on the preferred term, Standardized MedDRA queries (SMQs) or 
customized MedDRA queries (CMQs) in Appendix 2 and Appendix 3. 
3.9.2. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Unless specified 
otherwise, only scheduled laboratory parameters will be included in the summaries. 
All laboratory data, including those collected at unscheduled visits, will be included in the 
listings. 
Laboratory results (baseline and change from baseline) for the Safety Population during Double-
blind Treatment Period for chemistry and hematology parameters will be summarized by 
treatment group and by visit. 
The number (percentage) of subjects with potentially clinically significant (PCS) values at any 
postbaseline visit, will be summarized by treatment group. PCS criteria are presented in Table 1. 
The denominator will be all subjects with non-PCS baseline and at least one postbaseline 
assessment in the Safety Population and the numerator will be the number of subjects with non-
PCS baseline and PCS at postbaseline. All PCS values including baseline PCS values will be 
included in supportive listings. 
For selected metabolic parameters (fasting total cholesterol, fasting HDL, fasting LDL, fasting 
triglycerides, fasting glucose, and HbA1c), an analysis of sustained PCS values will also be 
conducted. The percentage of subjects with sustained PCS values through the treatment period 
will be summarized. The denominator is all subjects with non-PCS at baseline and at least two 
postbaseline assessments, and the numerator is the number of subjects who met PCS criteria at 
the last 2 assessments within the treatment period.  
Shift tables for metabolic parameters (fasting total, fasting HDL, fasting LDL cholesterol, fasting 
triglycerides, fasting glucose, and HbA1c) and liver function tests will be presented. The criteria 
are summarized in Table 2, Table 3, Table 4 and Table 5. 


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A listing of subjects who met Hy’s Law will be provided. Subjects who met Hy’s Law is defined 
as subjects who meet all of the following three criteria:  
1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3× upper limit of 
normal (ULN) 
2.  Total bilirubin ≥2× ULN 
3. A non-elevated alkaline phosphatase (ALP) <2× ULN 


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameter 
Criteria 
Chemistry 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase (U/L) 
≥3 × ULN 
Alanine Aminotransferase (U/L) 
≥3 × ULN 
Aspartate Aminotransferase (U/L) 
≥3 × ULN 
Bilirubin, Total 
≥2.0 mg/dL 
Blood Urea Nitrogen 
>30 mg/dL 
Cholesterol, Random 
>300 mg/dL 
Cholesterol, Fasting 
≥240 mg/dL 
Cholesterol, HDL Fasting 
≤40 mg/dL 
Cholesterol, HDL Fasting 
Decrease ≥20 mg/dL 
Cholesterol, LDL Fasting 
≥160 mg/dL 
Cholesterol, LDL Fasting 
Increase ≥30 mg/dL 
Creatine Kinase (U/L) 
≥3 × ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<50 mg/dL or  
≥200 mg/dL 
Glucose, Fasting 
<50 mg/dL or  
≥126 mg/dL 
Glucose, Fasting 
Increase ≥10 mg/dL 
HbA1c  
≥ 5.7% 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
Lactate Dehydrogenase (U/L) 
>3 × ULN 
Prolactin (Female) 
>30 ng/mL 
Prolactin (Male) 
>20 ng/mL 
Prolactin (Female) 
>3 x ULN 
Prolactin (Male) 
>3 x ULN 
Sodium 
<130 mmol/L or 
>150 mmol/L 
Triglycerides, Fasting  
≥200 mg/dL 
Triglycerides, Fasting 
Increase ≥50 mg/dL 


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes (Continued) 
Parameter 
Criteria 
Hematology 
Hematocrit (Female) 
≤32% 
Hematocrit (Male) 
≤37% 
Platelets 
<75.0 × 103 cells/μL or 
≥ 700.0 × 103 cells/μL 
Leukocytes 
≤ 2.8 × 103/μL or 
≥ 16.0 ×103/μL 
Neutrophils, Absolute  
<1.5 x 103/μL 
<1.0 x 103/μL 
Abbreviations: HDL= high-density lipoprotein; LDL=low-density lipoprotein; ULN=upper limit of normal. 
Table 2: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters 
Parameter 
Shift Criterion 
Total cholesterol (fasting) mg/dL 
Normal (<200) to borderline (≥200 and <240) 
Borderline (≥200 and <240) to high (≥240) 
Normal (<200) to high (≥240) 
LDL cholesterol (fasting) mg/dL 
Normal (<100) to borderline (≥100 and <160) 
Borderline (≥100 and <160) to high (≥160) 
Normal (<100) to high (≥160) 
HDL cholesterol (fasting) mg/dL 
Normal (≥40) to low (<40) 
Triglycerides (fasting) mg/dL 
Normal (<150) to borderline (≥150 and <200) 
Borderline (≥150 and <200) to high (≥200) 
Normal (<150) to high (≥200) 
Abbreviations: HDL=high-density lipoproteins; LDL=low-density lipoproteins. 
Table 3: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c 
Parameter 
Shift Criterion 
Glucose (fasting) mg/dL 
Normal (<100) to impaired (≥100 and <126) 
Impaired (≥100 and <126) to high (≥126) 
Normal (<100) to high (≥126) 
HbA1c %a 
Normal (<5.7%) to borderline (≥5.7% and <6.5%) 
Borderline (≥5.7% and <6.5%) to high (≥6.5%) 
Normal (<5.7%) to high (≥6.5%) 
a Subjects with HbA1c ≥6.0% were excluded from enrolling in the studies. 


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Table 4: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test 
Parameter 
Criterion 
Alanine Aminotransferase (ALT) (U/L) 
Shift from Normal to ≥3 × ULN  
Shift from Normal to ≥5 × ULN  
Shift from Normal to ≥10 × ULN  
Aspartate Aminotransferase (AST) (U/L) 
Shift from Normal to ≥3 × ULN  
Shift from Normal to ≥5 × ULN  
Shift from Normal to ≥10 × ULN  
Bilirubin, Total (mg/dL) 
 
Shift from Normal to >1 × ULN 
Shift from Normal to ≥2 × ULN 
Abbreviations: ULN=upper limit of normal. 
Table 5: 
Prolactin – Shift Categories from Baseline to Any Postbaseline 
Prolactin (ng/mL) 
Shift from (Low or Normal) to (≥3 × ULN) 
Shift from ( ≥3 × ULN) to (Low or Normal) 
Abbreviations: ULN=upper limit of normal. 
3.9.3. 
Vital signs and Electrocardiograms 
3.9.3.1. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values at each scheduled time 
point will be presented by treatment group for the double-blind period. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change from-baseline criteria listed in Table 6. The number and percentage of subjects with PCS 
postbaseline values will be tabulated by treatment group for the Double-blind Treatment Period. 
The percentages will be calculated relative to the number of subjects with available non-PCS 
baseline values and at least 1 postbaseline assessment for the double-blind period. The numerator 
will be the total number of subjects with available baseline values and at least 1 PCS 
postbaseline value for double-blind period. A supportive tabular display of subjects with PCS 
postbaseline values will be provided, including the subject ID number, and baseline and all 
postbaseline (including non-PCS) values. 
All vital signs will be presented in the subject data listing. 


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Table 6: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate 
Parameter 
Criteria 
Supine Systolic Blood Pressure 
≤90 and decrease ≥20 mm Hg 
≥180 and increase ≥20 mm Hg 
Supine Diastolic Blood Pressure 
≤50 and decrease ≥15 mm Hg 
≥105 and increase ≥15 mm Hg 
Supine Heart Rate 
≤50 and decrease ≥15 bpm 
≥120 and increase ≥15 bpm 
3.9.3.2. 
Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc interval) at baseline and change from baseline values at the end of the 
Double-blind Treatment Period will be presented by treatment group. QTc interval will be 
calculated using Fridericia (QTcF = QT/(RR)⅓) corrections; if RR is not available, it will be 
replaced with 60/HR in the correction formula. 
Electrocardiogram parameter values are considered PCS if they meet or exceed the higher-limit 
PCS criteria listed in Table 7. The number and percentage of subjects with PCS postbaseline 
ECG values will be tabulated by treatment group for the Double-blind Treatment Period. The 
percentages will be calculated relative to the number of subjects with non-PCS baseline values 
and at least 1 postbaseline assessment for the Double-blind Treatment Period. The numerator is 
the total number of subjects with non-PCS baseline values and at least 1 PCS postbaseline value 
for the Double-blind Treatment Period. A supportive tabular display of subjects with PCS 
postbaseline values will be provided, including the subject ID number, study center number, the 
baseline value, all postbaseline (including non-PCS) values, and change from baseline. 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) QTcF 
Parameter 
Criteria 
QTcF 
>450 to ≤480 msec 
>480 to ≤500 msec 
>500 msec 
Change from baseline >30 to ≤60 msec 
Change from baseline >60 msec 
3.9.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used to measure the presence and intensity of suicidal ideation 
and behavior. 
Suicidal behavior and suicidal ideation will be summarized descriptively (Table 8). The number 
of subjects with suicidal ideation and suicidal behavior during the Double-blind Treatment 
Period will be summarized by treatment group when applicable. 


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Supportive tabular display of subjects with all values will be provided, including subject ID 
number, treatment group, visit number, intensity of suicidal ideation, suicidal behavior type, and 
lethality of suicidal behavior. 
Table 8: 
C-SSRS Categories for Analysis 
Category 
C-SSRS Item response is “YES” 
Suicidal behaviora 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideationa 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without intent to act 
Active suicidal ideation with some intent to act, without specific plan 
Active suicidal ideation with specific plan and intent 
Non-suicidal self-injurious 
behavior 
Non-suicidal self-injurious behavior 
a Derived based on responses to individual items listed within the category  
3.10. 
Pharmacokinetic/Pharmacodynamic Data Analysis 
Subject listings for the PK sampling time and concentrations of olanzapine, samidorphan, and 
metabolites of interest will be provided. PK data obtained from plasma samples collected in this 
study may be included in a subsequent population PK analysis or other post hoc analyses 
conducted outside the scope of this SAP. 
3.11. 
Other Analysis 
Analyses to evaluate the potential impact of the covid-19 pandemic to efficacy and safety results 
will be conducted as outlined in Appendix 1. 
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
Interim analysis is not planned. 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
If, after the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the protocol 
will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. 
Post hoc exploratory analyses will be clearly identified in the CSR. 


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6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits upon scheduled time points as specified in the protocol 
(Table 3 Schedule of Visits and Assessments). 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in the eCRF. There will be one valid value of assessment kept for each scheduled analysis 
visit in summary/ analysis statistics. 
Unscheduled visits are visits with data not collected on the scheduled time point. Unscheduled 
visits will not be used for by-visit summary/analysis statistics unless specified otherwise. 
All unscheduled visit data as collected in eCRFs will be included in listings. 
Last postbaseline values are defined as the last valid postbaseline values collected for each 
subject during the Double-blind Treatment Period. 
An early termination (ET) visit during the on-treatment period can be mapped to a scheduled 
visit, if there is no valid value already at that visit. Visit windows are defined for CGI, weight or 
body composition related endpoints (Table 9), laboratory assessments (Table 10), IWQOL-Lite 
(Table 11), vital sign (Table 12) and ECG (Table 13). An ET visit that is not mapped will not be 
summarized in the tables or figures, but will be included in the listing. 
Table 9: 
Visit Window for Efficacy and Safety Assessments for CGI, Body Weight, 
Waist Circumference and Body Composition 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Daya 
Visit Window 
Visit 3 
Week 1 
Day 8 
[2, 11] 
Visit 4 
Week 2 
Day 15 
[12, 21] 
Visit 5 
Week 4 
Day 29 
[22, 35] 
Visit 6 
Week 6 
Day 43 
[36, 49] 
Visit 7 
Week 8 
Day 57 
[50, 63] 
Visit 8 
Week 10 
Day 71 
[64, 77] 
Visit 9 
Week 12 
Day 85 
[78, 91] 
a Visit Day is calculated as date of visit – date of the first dose of study drug + 1 day. 
Table 10: 
Visit Window for Laboratory Assessments 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Day 
Visit Window 
Visit 4 
Week 2 
Day 15 
[2, 50] 
Visit 9 
Week 12 
Day 85 
[51, 91] 


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Table 11: 
Visit Window for IWQOL-Lite 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Day 
Visit Window 
Visit 5 
Week 4 
Day 29 
[2, 57] 
Visit 9 
Week 12 
Day 85 
[58, 91] 
Table 12: 
Visit Window for Vital Sign 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Day 
Visit Window 
Visit 4 
Week 2 
Day 15 
[2, 28] 
Visit 6 
Week 6 
Day 43 
[29, 63] 
Visit 9 
Week 12 
Day 85 
[64, 91] 
Table 13: 
Visit Window for ECG 
Analysis Visit to be 
Mapped to 
Target Study Week 
Target Visit Day 
Visit Window 
Visit 1 
Screening 
Day [-30,-1] 
[-50, 0] 
Visit 9 
Week 12 
Day 85 
[64, 91] 
6.2. 
Handling of Partial Dates of Concomitant Medication 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. In 
the case of a completely missing stop date, medication will be assumed to be ongoing. 
6.3. 
Handling of Safety Data 
All efforts should be made to obtain any missing information from the investigator. For C-SSRS, 
vital signs, laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only 
observed data will be used for analyses, and missing data will not be imputed. 
7. 
GENERAL STATISTICAL METHODOLOGY 
In general, summary statistics (n, mean, standard deviation [SD], median, minimum, and 
maximum for continuous variables, and number and percentage of subjects in each category for 
categorical variables) will be provided by treatment group. All summary tables will be based on 
observed data, and missing values will not be imputed unless otherwise indicated. Measurements 
collected from unscheduled visits or repeated assessments will not be included in the by-visit 
summary tables or figures, the analyses for the PCS postbaseline values, and subject listings. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 


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7.1. 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Table 14: 
Degree of Precision 
Statistics 
Degree of Precision 
Mean, Median, Confidence limit boundaries 
One more than the raw data, up to 3 decimal places 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places 
Minimum, Maximum 
The same as the raw data, up to 2 decimal places 
p-value 
Rounded to 3 decimal places and therefore presented as 0.xxx; 
p-values smaller than 0.001 as ‘<0.001’; p-values greater than 
0.999 as ‘>0.999’ 
Percentage 
One decimal place. A percentage of 100% will be reported as 
100%. Percentages of zero will be reported as 0 
Fractional numeric values will be presented with a zero to the left of the decimal point 
(for example, 0.12 – 0.30). 
For weight, height, and BMI, one decimal place will be used for summary statistics. 
8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
Mock-up tables and listings will be provided in a separate document. 


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10. 
REFERENCES 
 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-997. 
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-347. doi: 
10.1002/pst.1549. 
Tessier A, Zavorsky GS, Kim dJ, Carli F, Christou N, Mayo NE. Understanding the 
Determinants of Weight-Related Quality of Life among Bariatric Surgery Candidates. J Obes. 
2012;2012:713426. doi: 10.1155/2012/713426. 
 


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APPENDIX 1. COVID-19 ANALYSIS 
Pandemic has resulted in certain disruptions in the study conduct since early 2020, including site 
closure, delayed study drug supply, subjects discontinuation and missing assessments. These 
impacts were limited in scope upon review of the protocol deviations, and also confounded by 
the initiation of new regions. Sites in Ukraine and Russia were first initiated in March 2020 and 
July 2020. Therefore, only descriptive statistics will be provided to explore the potential impact 
of the pandemic on the primary and secondary objectives of the study. The following subgroup 
analysis (before vs during pandemic) will be conducted: 
• Disposition 
• Demographics and Baseline Characteristics 
• Protocol Deviation 
• Primary Efficacy Endpoint 
• Key Secondary Endpoints 
• TEAE 
• SAE 
Subjects enrolled before March 1, 2020 will be grouped as before pandemic, and subjects 
enrolled after this date will be grouped as during pandemic. While the pandemic has started in 
various regions a few weeks apart, a single cutoff date will be applied, due to the relatively slow 
enrollment at the time (about 4 subjects/month) and short treatment duration.  


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APPENDIX 2. ADVERSE EVENTS ASSOCIATED WITH MOVEMENT 
DISORDERS (INCLUDING EXTRAPYRAMIDAL 
SYNDROME AND TARDIVE DYSKINESIA) 
Preferred Term (SMQ [#20000095] of Extrapyramidal Syndrome) 
Preferred Term Code 
Abnormal involuntary movement scale 
10075002 
Action tremor 
10072413 
Akathisia 
10001540 
Akinesia 
10001541 
Athetosis 
10003620 
Ballismus 
10058504 
Blepharospasm 
10005159 
Bradykinesia 
10006100 
Bradyphrenia 
10050012 
Buccoglossal syndrome 
10006532 
Chorea 
10008748 
Choreoathetosis 
10008754 
Chronic tic disorder 
10076661 
Cogwheel rigidity 
10009848 
Complex tic 
10076663 
Dopamine dysregulation syndrome 
10067468 
Drooling 
10013642 
Dyskinesia 
10013916 
Dyskinesia neonatal 
10013922 
Dyskinesia oesophageal 
10013924 
Dysphonia 
10013952 
Dystonia 
10013983 
Dystonic tremor 
10073210 
Emprosthotonus 
10014566 
Extrapyramidal disorder 
10015832 
Facial spasm 
10063006 
Fine motor skill dysfunction 
10076288 
Freezing phenomenon 
10060904 
Gait disturbance 
10017577 
Gait inability 
10017581 
Grimacing 
10061991 


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Preferred Term (SMQ [#20000095] of Extrapyramidal Syndrome) 
Preferred Term Code 
Hyperkinesia 
10020651 
Hyperkinesia neonatal 
10020652 
Hypertonia 
10020852 
Hypertonia neonatal 
10048615 
Hypokinesia 
10021021 
Hypokinesia neonatal 
10021022 
Hypokinetic dysarthria 
10082243 
Laryngeal tremor 
10078751 
Laryngospasm 
10023891 
Meige's syndrome 
10027138 
Micrographia 
10057333 
Mobility decreased 
10048334 
Motor dysfunction 
10061296 
Movement disorder 
10028035 
Muscle contractions involuntary 
10028293 
Muscle rigidity 
10028330 
Muscle spasms 
10028334 
Muscle spasticity 
10028335 
Muscle tightness 
10049816 
Muscle tone disorder 
10072889 
Muscle twitching 
10028347 
Musculoskeletal stiffness 
10052904 
Oculogyric crisis 
10030071 
Oesophageal spasm 
10030184 
On and off phenomenon 
10030312 
Opisthotonus 
10030899 
Oromandibular dystonia 
10067954 
Oropharyngeal spasm 
10031111 
Parkinsonian crisis 
10048868 


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Preferred Term (SMQ [#20000095] of Extrapyramidal Syndrome) 
Preferred Term Code 
Parkinsonian gait 
10056242 
Parkinsonian rest tremor 
10056437 
Parkinsonism 
10034010 
Parkinsonism hyperpyrexia syndrome 
10071243 
Parkinson's disease 
10061536 
Parkinson's disease psychosis 
10074835 
Pharyngeal dyskinesia 
10070912 
Pharyngeal dystonia 
10081226 
Pleurothotonus 
10035628 
Postural reflex impairment 
10067206 
Postural tremor 
10073211 
Posture abnormal 
10036436 
Posturing 
10036437 
Propulsive gait 
10082328 
Protrusion tongue 
10037076 
Provisional tic disorder 
10076694 
Psychomotor hyperactivity 
10037211 
Rabbit syndrome 
10068395 
Reduced facial expression 
10078576 
Respiratory dyskinesia 
10057570 
Resting tremor 
10071390 
Restlessness 
10038743 
Risus sardonicus 
10039198 
Secondary tic 
10076702 
Spasmodic dysphonia 
10067672 
Tardive dyskinesia 
10043118 
Tic 
10043833 
Tongue spasm 
10043981 
Torticollis 
10044074 
Torticollis psychogenic 
10044076 
Tremor 
10044565 
Tremor neonatal 
10044575 
Trismus 
10044684 
Uvular spasm 
10050908 


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Preferred Term (SMQ [#20000095] of Extrapyramidal Syndrome) 
Preferred Term Code 
Walking disability 
10053204 
Writer's cramp 
10072249 
Note: The list is based on MedDRA version 24.0 and will be updated based on the dictionary or relevant SMQ 
updates at the time of the analysis. 


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APPENDIX 3. ADVERSE EVENTS ASSOCIATED WITH SUICIDAL 
IDEATION AND BEHAVIOR 
Preferred Term 
Preferred Term Code 
Assisted suicide 
10079105 
Columbia suicide severity rating scale abnormal 
10075616 
Completed suicide 
10010144 
Depression suicidal 
10012397 
Intentional overdose 
10022523 
Intentional self-injury 
10022524 
Overdose 
10033295 
Poisoning deliberate 
10036000 
Self-injurious ideation 
10051154 
Suicidal behaviour 
10065604 
Suicidal ideation 
10042458 
Suicide attempt 
10042464 
Suicide threat 
10077417 
Suspected suicide 
10082458 
Suspected suicide attempt 
10081704 
Note: The list is based on MedDRA version 24.0 and will be updated based on the dictionary or relevant SMQ 
updates at the time of the analysis.