Clinical trial NCT02694328
Conditions: Schizophrenia
Keywords: Alkermes ALKS 3831 Samidorphan Schizophrenia Olanzapine Weight
Sponsor: Alkermes, Inc.
Start date: 2016-03-02; Completion date: 2018-11-07
Enrollment: 561 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate weight gain of ALKS 3831 compared to olanzapine in adult subjects with schizophrenia.

Detailed description:

Arms: arm 1: Administered as a coated bilayer tablet arm 2: Administered as a coated bilayer tablet
Interventions: intervention 1: ALKS 3831 intervention 2: Olanzapine
Intervention descriptions: intervention 1: Daily dosing intervention 2: Daily dosing

Protocol documents:
Prot_000.pdf: 
A Phase 3 Study to Evaluate Weight Gain of ALKS 3831 
Compared to Olanzapine in Adults with Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A303 
NCT Number: 
NCT02694328 
Date of Protocol:  
18 Sep 2018 
 


 
1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK3831-A303 
 
Study Title: 
A Phase 3 Study to Evaluate Weight Gain of ALKS 3831 
Compared to Olanzapine in Adults with Schizophrenia 
Document Date: 
Amendment 5.0:       18 Sep 2018 
Amendment 4.0:       04 May 2017 
Amendment 3.0:       10 Jan 2017 
Amendment 2.0:       11 Aug 2016 
Amendment 1.0:       15 Dec 2015 
Original Protocol:     17 Sep 2015 
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. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
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CONTACT INFORMATION 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone 
Alkermes Clinical Program 
Manager 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
Phone: 
 
Alkermes Medical Monitor 
 
Alkermes Pharma Ireland, Ltd 
Connaught House 
1 Burlington Road 
Dublin 4, Ireland 
Phone: 
 
Alkermes Global Safety 
Officer 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
Phone: 
 
Clinical Research 
Organization (CRO) Medical 
Monitor and 24-Hour 
Emergency Contact 
 
 
 
 
Del Mar, CA 92014 
Mobile: 
 
Office: 
 
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
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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 Phase 3 Study to Evaluate Weight Gain of ALKS 3831 Compared to Olanzapine in 
Adults with Schizophrenia 
Investigators: This is a multicenter study. 
Study Period:  
Estimated date of first subject’s consent: Q1 2016 
Estimated date of last subject’s last visit: Q1 2018 
Phase of Development: 3 
Objectives:  
Primary: To evaluate weight gain of ALKS 3831 (a fixed-dose combination of olanzapine and 
samidorphan) compared to olanzapine in adults with schizophrenia 
Secondary: To evaluate the safety and tolerability of ALKS 3831 in adults with schizophrenia 
Methodology: This is a Phase 3, multicenter, randomized, double-blind, study in adults with 
schizophrenia.  
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 (olanzapine/10 mg samidorphan) or olanzapine treatment groups 
and receive study drug for up to 24 weeks. Subjects are not excluded from the study if they are taking 
other antipsychotic medication. However they must be tapered off this medication and switched onto 
ALKS 3831 or olanzapine by the end of Week 2, Visit 4. This is an outpatient study in which subjects 
will visit the study site weekly for the first 6 weeks, then biweekly for the remaining 18 weeks. Study 
drug will be provided as coated bilayer tablets dispensed to the subjects in blister packs at each visit to 
be taken at home, one tablet by mouth each day, preferably at bedtime. For the first week, subjects will 
receive 10 mg olanzapine per dose: either ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
or OLZ 10 (10 mg olanzapine), according to treatment assignment. At the end of Week 1, the dose will 
escalate to 20 mg: ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) or OLZ 20. Following 
this increase, the dose may be decreased back to 10 mg at the end of Week 2, 3, or 4 according to 
investigator discretion. No further dose adjustments will be allowed beyond Week 4 and the dose will 
remain fixed for the remaining 20 weeks of the study. Body weight and metabolic parameters 
(including fasting triglycerides, cholesterol, and glucose) will be measured throughout the 24-week 
treatment period. Psychiatric symptoms will also be evaluated using PANSS and CGI. A schematic 
summarizing study design is presented below. 
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Subjects completing this study will be eligible to enroll in a long-term safety study (ALK3831-A304). 
Subjects not continuing in the long-term safety study or subjects prematurely discontinuing from the 
study will enter the 4-week safety follow-up period. 
Number of Subjects Planned: Approximately 400 or 540 randomized (200 or 270 per treatment 
group) 
Main Criteria for Inclusion: Men and women 18 through 55 years of age (inclusive), with a body 
mass index (BMI) of 18.0 to 30.0 kg/m2 (inclusive) and with a Diagnostic and Statistical Manual of 
Mental Disorders (DSM-5) diagnosis of schizophrenia who meet sponsor criteria for symptom 
stability. 
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 or CRO. 
Investigational Product, Dosage, Duration, and Mode of Administration: ALKS 3831 will be 
supplied as a coated bilayer tablet containing either 10 mg or 20 mg olanzapine and 10 mg 
samidorphan. The tablet is to be taken by mouth once daily, preferably at bedtime. 
Reference Therapy, Dosage, Duration, and Mode of Administration: Olanzapine will be supplied 
as an identical bilayer tablet manufactured by Alkermes, Inc., containing either 10 mg or 20 mg of 
olanzapine only and no additional active ingredients. Olanzapine tablets will be taken by mouth once 
daily, preferably at bedtime. 
Duration of Study: The total duration of this study is approximately 32 weeks (8 months) including a 
4 week (1 month) screening period, a 24-week (6 month) treatment period, and a 4 week (1 month) 
follow-up period. 
Criteria for Evaluation: 
Efficacy:  
• 
Body Weight (Primary Endpoint) 
Antipsychotic Efficacy: 
• 
Positive and Negative Symptom Scale (PANSS) 
• 
Clinical Global Impression – Severity (CGI-S) 
ALKS 3831
20/10 mg or 10/10 mg
Screening
Safety 
Follow-up
Long Term 
Safety Study
24-Week Double-Blind Treatment Period
Randomization 1:1
(Visit 2)
Up to 4 
weeks
4 weeks
Olanzapine
20 mg or 10 mg
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• 
Clinical Global Impression – Improvement (CGI-I) 
Other Assessments: 
• 
Cigarette Use Questionnaire 
• 
Impact of Weight on Quality of Life – Lite Questionnaire (IWQOL-Lite) 
• 
EuroQol-5D (EQ-5D) 
• 
Substudy: an exploratory substudy will measure body composition (using Bioelectrical 
Impedance Analysis [BIA]) in subjects at a subset of sites participating in the main 
ALK3831-A303 study; see Addendum A for substudy details 
Safety: The following assessments will be collected to measure safety and tolerability throughout the 
study: 
• 
Adverse events (AEs) 
• 
Waist Circumference 
• 
Clinical laboratory parameters including chemistry, hematology, and urinalysis 
• 
Vital signs (oral temperature, respiratory rate, orthostatic blood pressure, and heart rate) 
• 
Electrocardiogram parameters (Uncorrected QT, QTcF, QTcB, PR, RR, and QRS 
intervals) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Simpson-Angus Scale (SAS) 
• 
Barnes Akathisia Rating Scale (BARS) 
Pharmacokinetics/Pharmacodynamics: Concentrations of olanzapine, samidorphan, and metabolites 
of interest will be determined from plasma samples collected according to the schedule in Table 3. 
Pharmacokinetic (PK) data from these samples may be included in a subsequent population PK 
analysis or other post-hoc analyses conducted outside of this study. 
Statistical Methods: 
Study Populations: 
Safety Population: The safety population includes all randomized subjects who receive at least one 
dose of study drug (ALKS 3831 or olanzapine). 
Efficacy Population: The efficacy population includes: 
• 
Full analysis set (FAS) population: all subjects in the safety population who have at least 
one postbaseline weight assessment 
• 
Early weight gain population: all subjects in the FAS population who gain weight (>0 kg) 
at Week 1 
Efficacy: 
Primary Endpoints: The primary endpoints are: 
• 
Percent change from baseline in body weight at Week 24 in the FAS population 
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• 
Proportion of subjects with ≥10% weight gain at Week 24 in the FAS population 
For percent change from baseline in body weight at Week 24, the primary analysis will be carried out 
using an analysis of covariance (ANCOVA) method based on multiple imputation for missing data. 
The model will include treatment group, race, and baseline age as factors, and baseline weight as a 
covariate. 
For proportion of subjects with ≥10% weight gain at Week 24, the primary analyses will be carried out 
using a logistic regression model based on multiple imputation for missing data. The model will 
include treatment group, race, and baseline age as factors, and baseline weight as a covariate. 
Key Secondary Endpoint: The key secondary endpoint is: 
• 
Proportion of subjects with ≥7% weight gain at Week 24 
The key secondary endpoint will be analyzed similarly to the primary endpoints. 
A fixed sequence approach will be used to control overall Type I error rate. First, both primary 
endpoints will be tested at an alpha level of 0.05. If both primary endpoints are statistically significant, 
the key secondary endpoint will be tested at an alpha level of 0.05.  
Other Endpoints: Other endpoints are: 
• 
Percent change from baseline in body weight at Week 24 in the early weight gain 
population 
• 
Proportion of subjects with ≥10% weight gain at Week 24 in the early weight gain 
population 
• 
Change from baseline in fasting lipids (fasting triglycerides, LDL, HDL, total cholesterol), 
fasting glucose, fasting insulin, and HbA1c by visit 
• 
Absolute change in body weight by visit 
• 
Change from baseline in waist circumference by visit 
• 
Change from baseline in PANSS total score and subscales by visit 
• 
Change from baseline in CGI-S by visit 
• 
CGI-I score by visit 
• 
Change from baseline in IWQOL-Lite total score and subscales by visit 
• 
Change from baseline in EQ-5D score by visit 
Safety: All safety analyses will be based on observed data only, and no missing values will be 
imputed. 
Reported adverse event 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 BMI, waist circumference, 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 Drug 
Dictionary Anatomical Therapeutic Class code and treatment group. 
Pharmacokinetics/Pharmacodynamics: Concentrations of olanzapine, samidorphan, and metabolites 
of interest will be provided as by-subject listings. 
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Sample Size Considerations: The target sample size is 400 randomized subjects (200 per treatment 
group). This sample size will provide at least 90% power to detect a significant difference in mean 
percent change in body weight at Week 24 of 4% or more (3% on ALKS 3831 vs 7% on olanzapine 
group with standard deviation of 9%) and a 13% difference in proportion of subjects with ≥10% weight 
gain at Week 24 (14% on ALKS 3831 vs 27% on olanzapine group). 
One unblinded interim analysis will be conducted by an independent statistical center (ISC) when 50% 
of subjects (N=200) have completed the double-blind treatment period or have discontinued from the 
study to determine if the final sample size will be increased to 540 (270 subjects per treatment group). 
Interim Analysis: The details regarding the conduct of unblinded interim analyses will be specified in 
the interim analysis operational plan and the statistical testing methodology will be specified in the 
interim analysis plan (IAP). There will be no early stopping for efficacy or futility. The sponsor will 
not be informed with any unblinded interim analysis results except for a recommendation to either 
increase the sample size or to leave the sample size unchanged. 
 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................8 
4. 
LIST OF ABBREVIATIONS.....................................................................................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Background .................................................................................................................15 
5.2. 
Study Drugs ................................................................................................................16 
5.2.1. 
Samidorphan ...............................................................................................................16 
5.2.2. 
Olanzapine ..................................................................................................................16 
5.3. 
Study Rationale ...........................................................................................................16 
5.4. 
Dose Rationale ............................................................................................................17 
6. 
OBJECTIVES .............................................................................................................18 
6.1. 
Primary Objective .......................................................................................................18 
6.2. 
Secondary Objective ...................................................................................................18 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................19 
7.1. 
Subject Inclusion Criteria ...........................................................................................19 
7.2. 
Subject Exclusion Criteria ..........................................................................................19 
7.2.1. 
Psychiatric Criteria .....................................................................................................19 
7.2.2. 
Criteria Based on Treatment History ..........................................................................20 
7.2.3. 
Criteria Based on Drug/Alcohol Use and Concomitant Meds ....................................20 
7.2.4. 
Criteria Based on Medical Conditions/Medical History ............................................21 
7.2.5. 
Criteria Based on Laboratory Assessments ................................................................22 
7.2.6. 
General Criteria ..........................................................................................................22 
7.3. 
Subject Withdrawal ....................................................................................................23 
7.4. 
Replacement of Subjects .............................................................................................24 
8. 
STUDY DESIGN .......................................................................................................25 
8.1. 
Overall Study Design and Plan ...................................................................................25 
8.2. 
Schedule of Visits and Assessments ...........................................................................26 
8.3. 
Study Procedures Descriptions ...................................................................................31 
8.3.1. 
Informed Consent .......................................................................................................31 
8.3.2. 
Eligibility Review .......................................................................................................31 
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8.3.3. 
Demographics and Medical History ...........................................................................31 
8.3.4. 
Concomitant Medication Review ...............................................................................31 
8.3.5. 
Vital Signs ..................................................................................................................31 
8.3.6. 
Physical Examination .................................................................................................32 
8.3.7. 
Height, Body Weight, and Waist Circumference .......................................................32 
8.3.8. 
12-Lead Electrocardiogram ........................................................................................32 
8.3.9. 
Structured Interviews and Questionnaires ..................................................................32 
8.3.9.1. 
Diagnostic Assessments ..............................................................................................32 
8.3.9.2. 
Antipsychotic Efficacy Assessments ..........................................................................33 
8.3.9.3. 
Safety Assessments .....................................................................................................33 
8.3.9.4. 
Other Assessments ......................................................................................................33 
8.3.10. 
Rater Review ..............................................................................................................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. 
Pregnancy Testing ......................................................................................................35 
8.3.11.4. 
Serology Testing .........................................................................................................36 
8.3.12. 
Pharmacokinetic Assessments ....................................................................................36 
8.3.13. 
Genotype Sampling ....................................................................................................36 
8.3.14. 
Randomization ............................................................................................................36 
8.3.15. 
Drug Dispensation and Reconciliation .......................................................................36 
8.3.16. 
Emergency Treatment Card ........................................................................................36 
8.3.17. 
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 Therapy ......................................................................................................39 
8.4.4. 
Pain Management .......................................................................................................39 
8.4.5. 
Other Restrictions and Requirements .........................................................................39 
9. 
TREATMENT OF SUBJECTS ..................................................................................41 
9.1. 
Study Drug Dose and Administration .........................................................................41 
9.2. 
Study Drug Return and Adherence Review................................................................41 
9.3. 
Randomization/Method of Assigning Subjects to Treatment .....................................41 
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9.4. 
Blinding ......................................................................................................................41 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 
10.1. 
Study Drug ..................................................................................................................43 
10.2. 
Packaging and Labeling ..............................................................................................43 
10.3. 
Storage ........................................................................................................................43 
10.4. 
Accountability .............................................................................................................43 
10.5. 
Handling and Disposal ................................................................................................44 
11. 
ASSESSMENT OF EFFICACY ................................................................................45 
12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................46 
13. 
ASSESSMENT OF SAFETY .....................................................................................47 
13.1. 
Definition of Adverse Event .......................................................................................47 
13.2. 
Definition of Serious Adverse Event ..........................................................................47 
13.3. 
Relationship to Study Drug ........................................................................................48 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................50 
13.5. 
Reporting of Serious Adverse Events .........................................................................50 
14. 
STATISTICS ..............................................................................................................51 
14.1. 
Sample Size Considerations .......................................................................................51 
14.2. 
General Statistical Methodology ................................................................................51 
14.2.1. 
Study Populations .......................................................................................................51 
14.2.1.1. 
Safety Population ........................................................................................................51 
14.2.1.2. 
Efficacy Population ....................................................................................................51 
14.3. 
Demographics and Baseline Data ...............................................................................51 
14.4. 
Efficacy Analyses .......................................................................................................52 
14.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................53 
14.6. 
Safety and Tolerability Analyses ................................................................................54 
14.7. 
Interim Analysis ..........................................................................................................54 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................56 
15.1. 
Study Monitoring ........................................................................................................56 
15.2. 
Audits and Inspections ................................................................................................56 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................56 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................57 
16.1. 
Case Report Forms .....................................................................................................57 
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16.2. 
Confidentiality of Data ...............................................................................................57 
17.
ETHICAL CONSIDERATIONS................................................................................58
17.1. 
Ethics Review .............................................................................................................58 
17.2. 
Ethical Conduct of the Study ......................................................................................58 
17.3. 
Written Informed Consent ..........................................................................................58 
18.
DATA HANDLING AND RECORDKEEPING .......................................................60
18.1. 
Data Capture ...............................................................................................................60 
18.2. 
Inspection of Records .................................................................................................60 
18.3. 
Retention of Records ..................................................................................................60 
18.4. 
Use of Information and Publication Policy ................................................................60 
19.
REFERENCES ...........................................................................................................61
20.
LIST OF APPENDICES.............................................................................................63
21.
ADDENDUM ...........................................................................................................107
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definitions of Terms .........................................................13 
Table 3: 
Schedule of Assessments ............................................................................................27 
Table 4: 
Clinical Laboratory Assessments ...............................................................................35 
Table 5: 
Adverse Event Causality Guidelines ..........................................................................49 
LIST OF FIGURES 
Figure 1: 
ALK3831-A303 Study Design Schematic..................................................................25 
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LIST OF APPENDICES 
Appendix A 
Partial list of prohibited cytochrome P450 (CYP) 3A4 inducers and moderate-to-strong 
inhibitors 
Appendix B 
Clinical Global Impression 
• 
Severity 
• 
Improvement 
Appendix C 
Positive and Negative Syndrome Scale 
Appendix D 
Abnormal Involuntary Movement Scale 
Appendix E 
Barnes Akathisia Rating Scale 
Appendix F 
Simpson-Angus Scale 
Appendix G 
Columbia-Suicide Severity Rating Scale 
• 
Baseline/Screening 
• 
Since Last Visit 
Appendix H 
Impact of Weight on Quality of Life - Lite 
Appendix I 
 
EuroQol - 5D 
 
 
 
ADDENDUM 
Addendum A 
 
Substudy 
 
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4. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Table 2: 
List of Abbreviations and Definitions of Terms 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CNS 
Central nervous system 
CP 
Conditional power 
CRO 
Contract research organization 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
IEC 
Independent Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECT 
Electroconvulsive therapy 
EQ-5D 
EuroQol five dimensions questionnaire 
EOT 
End of treatment 
EPS 
Extra pyramidal symptoms 
ET 
Early termination 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
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Table 2: 
List of Abbreviations and Definitions of Terms (Continued) 
Abbreviation or Term 
Explanation or Definition 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HbA1C 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
IAP 
Interim analysis plan 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ISC 
Independent statistical center 
IUD 
Intrauterine device 
IWQOL 
Impact of Weight on Quality of Life 
IRB 
Institutional Review Board 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed model with repeated measurements 
OLZ 
Olanzapine 
PANSS 
Positive and Negative Syndrome Scale 
PCP 
Phencyclidine 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
QTcB 
QT corrected with Bazett formula 
QTcF 
QT corrected with Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson-Angus Scale 
SCI-PANSS 
Structured Clinical Interview for the PANSS 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
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5. 
INTRODUCTION 
5.1. 
Background 
Schizophrenia is a chronic, severe disease with debilitating psychotic symptoms, physical and 
psychiatric comorbidities and increased mortality. Despite the availability of a range of 
FDA-approved medicines, the disease is still inadequately treated and associated with enormous 
human and economic cost. Life expectancy is reduced by 19 years in men and 16 years in 
women with schizophrenia compared to the general population (Harris and Barraclough 1998; 
Lambert et al, 2010; Tiihonen et al, 2009). The decreased life expectancy is due to a combination 
of direct effects of the disease, eg increased rates of suicide and violence (Hodgins 2008; Kuo et 
al, 2005), as well as indirect causes including increased incidence of obesity and cardiovascular 
disease (Nasrallah et al, 2006; Saha et al, 2007). 
The goal of treatment in schizophrenia is to achieve the maximal reduction in positive and 
negative symptoms and increase functionality. Unfortunately, even with regular administration 
of currently available antipsychotic medications at full therapeutic dose levels, the overwhelming 
majority of patients continue to exhibit residual active symptomatology. For physicians and 
patients, in many cases the current treatment paradigm involves an efficacy/tolerability trade-off, 
where use of the most efficacious agents is avoided or delayed in order to avoid known safety 
issues. As such, there is a need for more efficacious therapies with better tolerability. 
Olanzapine is regarded as one of the most effective antipsychotic agents with well-recognized 
efficacy and decreased incidence of extrapyramidal symptoms. However, its efficacy is 
compromised by safety and tolerability limitations that affect compliance and retention of 
patients on olanzapine therapy (Lieberman et al, 2005). In particular, results of the Clinical 
Antipsychotic Trials of Intervention Effectiveness (CATIE), identify olanzapine as an effective 
atypical antipsychotic associated with the highest weight gain (9.4 kg over a treatment period up 
to 18 months and ≥7% body weight in 30% of subjects) and a comparatively higher 
discontinuation rate compared to other antipsychotic agents due to weight gain and metabolic 
effects. As a result of these limitations surrounding safety, tolerability, adherence and retention, 
the risk of olanzapine therapy can outweigh the benefit and patients are often switched to 
alternative antipsychotic agents even if they are less effective. 
ALKS 3831 is a fixed-dose combination product of olanzapine and samidorphan (also referred to 
as ALKS 33 or RDC-0313, see Section 5.2.1 for more information on samidorphan) under 
investigation for the treatment of schizophrenia. Phase 1 and Phase 2 studies demonstrated that 
coadministration of samidorphan with olanzapine attenuates the weight gain experienced with 
olanzapine alone. Results from these studies are described in more detail in Section 5.3. In 
addition, ALKS 3831 may have the further benefit of controlling substance abuse in patients 
with schizophrenia. Comorbid substance use disorder is a well-recognized obstacle to patient 
care. An estimated 1 out of every 3 patients with schizophrenia (33.7%) meet or have met criteria 
for alcohol use disorder (Regier et al, 1990). Patients with both schizophrenia and alcohol use 
disorder represent a common variant of the schizophrenia spectrum that is difficult to treat and is 
associated with an extremely poor prognosis (Dixon 1999; Koekkoek et al, 2006). In clinical 
studies, samidorphan has been shown to block both the subjective and physiological effects of 
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the opioid agonist remifentanil (ALK33-004) and it is correlated with reduced drinking behavior 
in adults with alcohol dependence (ALK33-005). ALK3831-401 is an ongoing clinical study 
designed to evaluate the effect of ALKS 3831 on drinking behavior in adult subjects with 
schizophrenia and alcohol use disorder. 
In summary, ALKS 3831 is being explored as a therapeutic agent for the treatment of 
schizophrenia designed to combine the antipsychotic efficacy of olanzapine with a reduced risk 
of weight gain and associated metabolic deficits. Development of ALKS 3831 as a fixed-dose 
combination of olanzapine and samidorphan has the potential to improve upon the benefit/risk 
profile of olanzapine alone and address a significant clinical need for patients that are currently 
forced to choose between treatment efficacy vs safety. 
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 (IB). 
5.2.1. 
Samidorphan 
Samidorphan is a new molecular entity in clinical development by Alkermes. It is an opioid 
modulator that functions as an antagonist at μ-opioid receptors and as a low intrinsic activity 
agonist at κ- and δ-opioid receptors. It is currently being investigated in combination with 
buprenorphine for the treatment of major depressive disorder (ALKS 5461) and in combination 
with olanzapine for the treatment of schizophrenia. 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 10.5). At least ten clinical studies of samidorphan 
have been conducted to date, 8 of which included subjects that received samidorphan alone (not 
in combination with another product). 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 available in the US since 1996 (Zyprexa®) and was originally approved for 
the treatment of schizophrenia, but has since been approved for other indications including the 
treatment of schizophrenia in adolescents and bipolar disorder. The safety and tolerability profile 
of olanzapine is well documented, and adverse event labeling is supported by an extensive safety 
database that includes over 8,500 adult patients (Eli Lilly and Company 2016). 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 
The rationale for this Phase 3 study is based on the promising efficacy and safety results from 
prior Phase 1 and Phase 2 studies of ALKS 3831. 
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A Phase 1 study conducted in healthy males (Study ALK33-301), demonstrated that 3 weeks of 
treatment with ALKS 3831 resulted in 29% less weight gain compared with subjects who 
received olanzapine alone. Based on the results of this study, a two-part (Part A and Part B), 
Phase 2 study (ALK3831-302) was conducted to evaluate the antipsychotic efficacy and body 
weight effect of ALKS 3831 in subjects with schizophrenia. In Part A (a 12-week, double-blind, 
randomized, olanzapine-controlled phase), ALKS 3831 demonstrated similar antipsychotic 
efficacy compared with olanzapine based on Positive and Negative Syndrome Scale (PANSS) 
total score. ALKS 3831 also led to clinically and statistically significant less body weight gain 
compared to olanzapine. Specifically, treatment with ALKS 3831 led to a 37% lower mean 
percent weight gain from baseline compared with olanzapine, and a 2.7-fold reduction in the risk 
of gaining 10% or more of baseline body weight in the full study population. Moreover, in the 
population of subjects (63% of total) that gained weight during the 1-week olanzapine lead-in 
period (referred to as the early weight gain population), ALKS 3831 treatment led to a 51% 
lower mean percent weight gain compared with olanzapine, and a 4.1-fold reduction in the risk 
of gaining 10% or more of baseline body weight. Data from Part B (a 12-week all-active, 
extension) indicated maintenance of the beneficial effect on weight observed in Part A, while 
maintaining stable PANSS scores over the 12 week extension period. 
The current Phase 3 study will further evaluate weight gain of ALKS 3831 compared to 
olanzapine in adults with schizophrenia over a 24 week period. 
5.4. 
Dose Rationale 
The selected doses of ALKS 3831 (20/10 [20 mg olanzapine/10 mg samidorphan] and 10/10 
[10 mg olanzapine/10 mg samidorphan]) are within the approved olanzapine therapeutic dose 
range for the treatment of schizophrenia (Eli Lilly and Company 2016). Olanzapine doses of 
10 and 20 mg will bracket the lowest and highest approved maintenance doses for the treatment 
of schizophrenia and provide adequate coverage for the intended commercial maintenance dose 
range of ALKS 3831, 10 to 20 mg. 
The 10 mg samidorphan dose was identified as the minimally effective dose based on the robust 
efficacy, with optimal safety profile observed in ALK3831-302 at this dose. A fixed dose of 
samidorphan was selected due to the fact that data from this study demonstrated no correlation 
between the ratio of samidorphan/olanzapine dose and percent change from baseline in body 
weight, indicating that even with higher olanzapine doses, a fixed dose of samidorphan is 
sufficient to achieve maximal effect on reducing olanzapine-induced weight gain. 
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Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate weight gain of ALKS 3831 (a fixed-dose 
combination of olanzapine and samidorphan) compared to olanzapine in adults with 
schizophrenia. 
6.2. 
Secondary Objective 
The secondary objective is to evaluate the safety and tolerability of ALKS 3831 in adults with 
schizophrenia. 
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CONFIDENTIAL 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
1. Subject is willing and able to provide written informed consent 
2. Subject is age 18 to 55 years, inclusive, at screening (Visit 1) 
3. Subject has a body mass index (BMI) of 18.0 to 30.0 kg/m2, inclusive, at Visit 1 and 
Visit 2 
4. Subject meets the DSM-5 criteria for a primary diagnosis of schizophrenia, confirmed 
with the Mini International Neuropsychiatric Interview (MINI) at Visit 1 
5. Subject is outpatient at Visits 1 and 2 
6. Subject is appropriate for outpatient treatment as evidenced by the following: 
• No hospitalizations for acute exacerbations of schizophrenia within 6 months before 
Visit 1 
• PANSS total score of 50 to 90 (inclusive) at Visits 1 and 2 
• Clinical Global Impression of Severity (CGI-S) score of ≤4 at Visits 1 and 2 
7. Subject has maintained a stable body weight (change ≤5%) for at least 3 months prior to 
Visit 1 based on self-report 
8. Subject agrees to abide by the contraception requirements specified in the protocol 
9. Subject is willing and able to provide government-issued identification 
7.2. 
Subject Exclusion Criteria 
Each subject must not meet any of the following criteria to be qualified to participate in this 
study. 
7.2.1. 
Psychiatric Criteria 
1. Subject does not meet antipsychotic treatment or duration of illness eligibility 
requirements for one or more of the following reasons: 
• Subject initiated first antipsychotic treatment within the past 12 months 
• <1 year has elapsed since the initial onset of active-phase of schizophrenia symptoms  
• Subject is antipsychotic naïve 
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Alkermes, Inc. 
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CONFIDENTIAL 
2. Subject has any of the following psychiatric conditions per DSM-5 criteria, as assessed 
by the MINI. Conditions not assessable by the MINI should be assessed by clinical 
judgment: 
• Diagnosis of schizoaffective disorder or bipolar I or II disorder, or current, untreated 
or unstable major depressive disorder (according to DSM-5 criteria) 
• Clinically significant cognitive difficulties including dementia, delirium, or amnestic 
syndromes, or any other cognitive disorder present within the past 2 years that could 
interfere with participation in the study 
• Drug-induced or toxic psychosis 
• Any other psychiatric condition that could interfere with participation in the study 
3. 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. 
Criteria Based on Treatment History 
4. Subject has a history of treatment resistance, defined as failure to respond to 2 adequate 
trials of different antipsychotic medications (a minimum of 4 week at the subject’s 
maximum tolerated dose) 
5. Subject has a history of poor or inadequate response to treatment with olanzapine 
6. Subject has used clozapine within 6 months prior to Visit 1 and has any history of 
clozapine use for treatment-resistant schizophrenia 
7. Subject has used olanzapine, chlorpromazine, or thioridazine at any time during the 
6 months prior to Visit 1 or long-acting injectable antipsychotic medication in the last 
6 months with the exception of 3-month paliperidone which must not have been received 
within the past 12 months 
8. Subject requires or has had electroconvulsive therapy (ECT) treatment in the 6-month 
period prior to Visit 1 
7.2.3. 
Criteria Based on Drug/Alcohol Use and Concomitant Meds 
9. Subject has a diagnosis (based on DSM-5 criteria, as assessed by the MINI) of 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 
10. Subject has a positive drug screen for opioids, phencyclidine (PCP), amphetamine/ 
methamphetamine, or cocaine at Visit 1 or Visit 2 
11. 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 
study period (eg, planned surgery), or has taken opioid antagonists including naltrexone 
(any formulations) and naloxone within 60 days prior to Visit 1 
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
12. Subject is currently taking any contraindicated medications as per the approved labeling 
for olanzapine 
13. Subject is currently on a statin medication (an HMG-CoA reductase inhibitor) that was 
initiated or has had a dose adjustment within the 3 months prior to Visit 1 
14. Subject is taking any weight loss agents or hypoglycemic agents at Visit 1 
7.2.4. 
Criteria Based on Medical Conditions/Medical History 
15. Subject has a known or suspected intolerance, allergy or hypersensitivity to olanzapine or 
opioid antagonists at Visit 1 
16. 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, including (but not necessarily limited to) the following: 
• Clinically significant hypotension or hypertension not stabilized by medical therapy 
• Unstable thyroid dysfunction in the past 6 months (eg, hypothyroidism, 
hyperthyroidism, or thyroiditis that was untreated, or discovered and treatment was 
initiated within the 6 months prior to screening) 
• Personal or family history of neuroleptic malignant syndrome, has a history of 
clinically significant extrapyramidal symptoms when taking olanzapine, or has had 
clinically significant tardive dyskinesia 
• Neurologic conditions including the following: 
− History of seizure disorder or a condition associated with seizures (exception: 
history of febrile seizures) 
− History of brain tumor, subdural hematoma, stroke, or other clinically significant 
neurological condition within the 12 months prior to Visit 1 
− Head trauma with loss of consciousness within the 12 months prior to Visit 1 
− Active acute or chronic central nervous system (CNS) infection 
• A cardiac condition that might confound the results of the study or pose additional 
risk when administering the investigational agents to the subject or preclude 
successful completion of the study including the following: 
− Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction 
defect, a history of myocardial infarction or unstable angina within 6 months prior 
to Visit 1 
17. Subject has inflammatory bowel disease or any other gastrointestinal (GI) disorder 
associated with weight loss, anorexia nervosa, bulimia nervosa, or binge eating disorder 
18. Subject has had any GI surgical procedures within 1 year prior to Visit 1 
19. Subject has had a surgical procedure for weight loss or is planning to have liposuction 
during the study 
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
20. 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 
21. Subject has started a smoking cessation program within the 6 months prior to Visit 1 or 
anticipates quitting smoking during the study 
22. Subject has a history of diabetes 
23. Subject has had a significant blood loss (>500 mL) or blood 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 
7.2.5. 
Criteria Based on Laboratory Assessments 
24. 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) ≤1.5 × 103 μL 
• Platelet count ≤75 × 103 μL 
• Serum creatinine >2.5 mg/dL 
• Positive pregnancy test result 
25. Subject has a positive serology test for hepatitis B surface antigen, hepatitis C antibody 
confirmed by RNA testing, or human immunodeficiency virus (HIV) antibody at Visit 1 
26. Subject has dyslipidemia, defined for this study as total fasting cholesterol >280 mg/dL 
or fasting triglycerides >500 mg/dL, at Visit 1 
27. Subject has a Hemoglobin A1c (HbA1c) ≥6.0% at Visit 1 
28. Subject has a fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) at Visit 1 
29. Subject has a clinically significant ECG abnormality at Visits 1 or 2 
− Subject has a QT interval >450 msec for men and >470 msec for women, as 
corrected by the Fridericia formula (QTcF), observed at Visits 1 or 2 
7.2.6. 
General Criteria 
30. Subject is currently pregnant or breastfeeding or is planning to become pregnant within 
60 days of the last study drug administration 
31. Subject has any finding that, in the view of the investigator, would compromise the 
subject’s ability to fulfill the protocol visit schedule or study requirements 
32. 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 an clinical trial subject registry 
33. Subject has participated in a prior clinical study of ALKS 3831 or samidorphan 
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Alkermes, Inc. 
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CONFIDENTIAL 
34. Subject is employed by Alkermes, CRO, or study site (permanent, temporary contract 
worker, or designee responsible for the conduct of the study) or is immediate family1 of 
an Alkermes, CRO, 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 µL or HbA1c ≥6.5% at any time from Visit 2 to Visit 17, the PI (or 
designee) should discontinue the subject from participation immediately. Other reasons for 
discontinuation include:  
• Adverse Event 
• Lack of Efficacy 
• Lost to Follow-up 
• Withdrawal by Subject 
• Protocol Deviation (non-compliance with study drug or study procedures) 
• Pregnancy 
• Study Terminated by Sponsor 
• Other 
Following premature discontinuation, subjects can be started on another antipsychotic at the 
discretion of their prescribing physician. 
If a subject withdraws from the study for any reason, they will be asked to return to the clinic for 
an early termination (ET) visit. The early termination visit should be scheduled as close as 
possible to the subject’s last dose and will mimic the assessments scheduled to be conducted at 
the EOT visit (Visit 17). Randomized subjects who discontinue study drug but are willing to 
come in for further assessments will be asked to complete the ET visit followed by 2 safety 
follow-up visits 2 and 4 weeks after the ET visit (same assessments as Visits 18 and 19 in 
Table 3. They will then be asked to return to the study center for monthly visits until end of 
planned treatment, to collect the following information: weight, adverse events, and new 
antipsychotics. 
Any ongoing AEs at the time of discontinuation 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.  
 
1 Immediate family is defined as a spouse, parent, sibling or child, whether biological or legally adopted. 
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Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
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. 
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. A full 
explanation of the reason for study discontinuation will be documented and made on the 
appropriate electronic case report form (eCRF). In addition, the eCRF will also record if weight 
gain contributed to premature discontinuation from the study. If a subject is lost to follow-up, a 
reasonable attempt to contact the subject must be made and documented. 
Randomized subjects completing all scheduled visits through Visit 17 will be considered study 
completers. 
7.4. 
Replacement of Subjects 
Subjects prematurely discontinued from the study post-randomization will not be replaced. 
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a Phase 3, multicenter, randomized, double-blind, study in adults with schizophrenia. 
Subjects will be screened at Visit 1, up to 30 days prior to randomization. Eligible subjects will 
be randomized at Visit 2 in a 1:1 fashion to the following 2 treatment groups: ALKS 3831 
(olanzapine/10 mg samidorphan) or olanzapine. For all subjects, the initial olanzapine dose will 
be 10 mg given as either ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) or OLZ 10 
(10 mg olanzapine), according to treatment assignment. Subjects will be titrated up to 20 mg 
(ALKS 3831 20/10 [20 mg olanzapine/10 mg samidorphan] or OLZ 20 [20 mg olanzapine]) at 
the end of Week 1 of treatment. Following this dose increase, the dose may be decreased to 
ALKS 3831 10/10 or OLZ 10 at the end of Week 2, 3, or 4 if there are tolerability issues based 
on the judgment of the investigator. Reasons for down-titration will be documented in the 
electronic case report form (eCRF). No further dose adjustments will be allowed beyond week 4 
and the dose will remain fixed for the remaining 20 weeks of the study.  
This is an outpatient study. Subjects will be seen weekly for the first 6 weeks (Visits 3-8), then 
biweekly for the remaining 18 weeks (Visits 9-17/end of treatment [EOT]). Body weight and 
metabolic parameters (including fasting triglycerides, cholesterol, and glucose) will be measured 
throughout the 24-week treatment period. Psychiatric symptoms will also be evaluated using the 
assessments listed in Section 11. A schematic summarizing study design is presented in Figure 1. 
The details of study visits and assessments are provided in Table 3. 
Figure 1: 
ALK3831-A303 Study Design Schematic 
 
Subjects completing this study will be eligible to enroll in a long-term safety study 
(ALK3831-A304). Subjects not continuing in the long-term safety study or subjects prematurely 
discontinuing from the study will enter the 4-week safety follow-up period. 
Subjects taking antipsychotic medication at study entry must be tapered off their medication and 
titrated onto ALKS 3831 or olanzapine (in accordance with the randomized allocation) within 
2 weeks after randomization (by Visit 4). This cross-taper from prior antipsychotic treatment to 
ALKS 3831
20/10 mg or 10/10 mg
Screening
Safety 
Follow-up
Long Term 
Safety Study
24-Week Double-Blind Treatment Period
Randomization 1:1
(Visit 2)
Up to 4 
weeks
4 weeks
Olanzapine
20 mg or 10 mg
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Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
double-blind study medication will be conducted under the care and discretion of the principal 
investigator and consistent with current clinical practice. 
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. Any subject that prematurely 
discontinues study drug but agrees to return for further assessments must first complete an ET 
visit (same assessments as Visit 17) and two safety follow-up visits 2 and 4 weeks following the 
ET visit (same assessments as Visits 18 and 19 respectively). Following completion of these 
follow-up visits, subjects will be asked to return to the study center for monthly visits until the 
end of planned treatment, to collect the following information: weight, adverse events, and new 
antipsychotics.
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
 
CONFIDENTIAL 
Table 3: 
Schedule of Assessments 
  
Visit  
Screening 
Day -30  
to -1 
24-Week Double-Blind Treatment 
Safety 
Follow-
upa 
Monthly 
Visitsb 
1 
2c 
3  
4  
5  
6  
7 
8 
9 
10  
11  
12  
13  
14  
15  
16  
17/ET  18  19  
20 to 24 
Study Week 
(Visit Window of ±2 Days for Visits 3-24) 
 
 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
 
Qualification/ Diagnostic Assessments 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical/ 
Psychiatric History Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mini International 
Neuropsychiatric Interview (MINI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualification/ Safety Assessments 
 
Serology Testingd 
X 
 
 
Pregnancy Teste 
X 
X 
 
X 
 
Drug Screenf 
X 
X 
 
 
Physical Examg 
X 
X 
 
 
X 
 
12-lead Electrocardiogram 
X 
X 
 
X 
X 
 
Abnormal Involuntary Movement 
Scale (AIMS) 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Simpson-Angus Scale (SAS) 
X 
X 
X 
 
X 
X 
 
Barnes Akathisia Rating Scale 
(BARS) 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
 
CONFIDENTIAL 
Table 3: 
Schedule of Visits and Assessments (Continued) 
  
Visit  
Screening 
Day -30  
to -1 
24-Week Double-Blind Treatment 
Safety 
Follow-
upa 
Monthly 
Visitsb 
1 
2c 
3  
4  
5  
6  
7 
8 
9 
10  
11  
12  
13  
14  
15  
16  
17/ET  18  19  
20 to 24 
Study Week 
(Visit Window of ±2 Days for Visits 3-24) 
 
 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
 
Biochemistry, Urinalysis, and 
Hematology Samplesh 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Vital Signsi 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Body Weight and Waist 
Circumferencej 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Xj 
AE Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
Concomitant Medication Reviewl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
C-SSRSn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Psychiatric Efficacy/ Lifestyle/ Quality of Life Assessments 
 
PANSSo 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
CGI-S 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
CGI-I  
 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Cigarette Use Questionnaire  
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
IWQOL-Lite 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
EQ-5D 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
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Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
 
CONFIDENTIAL 
Table 3: 
Schedule of Visits and Assessments (Continued) 
  
Visit  
Screening 
Day -30 
 to -1 
24-Week Double-Blind Treatment 
Safety 
Follow-
upa 
Monthly 
Visitsb 
1 
2c 
3 
4 
5  
6  
7 
8 
9 
10  
11  
12  
13  
14  
15  
16  
17/ET  18  19  
20 to 24 
Study Week 
(Visit Window of ±2 Days for Visits 3-24) 
 
 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
 
Other/ General Procedures 
 
Randomization  
X 
 
 
Genotype Sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Labsp 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Study Drug Dispensation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Return and Adherence 
Review  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Emergency Treatment Cardq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: AE=adverse event; CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; C-SSRS=Columbia-Suicide 
Severity Rating Scale; ET=early termination; EQ-5D=EuroQol five dimensions questionnaire; IWQOL-Lite=Impact of Weight on Quality of Life – Lite 
Questionnaire; PANSS=Positive and Negative Syndrome Scale; PK=pharmacokinetics 
a The Safety Follow-up Period is not required for subjects entering ALK3831-A304. 
b Up to 5 additional weight assessments following premature discontinuation. 
c All assessments conducted at Visit 2 are to be done predose. 
d Serology testing to include hepatitis B surface antigen, anti-hepatitis C antibodies, and anti-human immunodeficiency virus (HIV) antibodies. A positive 
hepatitis C antibody test must be confirmed by RNA testing. 
e Serum pregnancy test at screening; urine pregnancy test at subsequent specified visits. The urine pregnancy test may be repeated at any time during the study 
based on the investigator’s judgment. 
f Centralized drug testing at screening; local drug testing (via dipstick) at other timepoints. The drug panel includes opiates, amphetamine/methamphetamine, 
phenylcyclidine (PCP), and cocaine. The urine drug screen may be repeated at any point during the study based on the investigator’s discretion. 
g Full physical exam at screening; brief physical at all other indicated visits 
h Blood samples to be collected after an overnight (at least 8 hour) fast with no food or drink except water. 
i Vital signs include orthostatic blood pressure and heart rate, respiratory rate, and oral body temperature. Blood pressure, pulse rate, and respiratory rate will be 
taken after the subject has been supine for 5 minutes and once again after the subject has stood for 2 minutes. 
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Protocol ALK3831-A303 Amendment 5.0 
 
CONFIDENTIAL 
j Body weight and waist circumference to be measured in triplicate at all indicated visits. Body weight will also be measured in subjects prematurely 
discontinuing study drug and returning for weight assessments for the additional follow-up visits 20 through 24.  
k Adverse events will be recorded for subjects prematurely discontinuing study drug and returning for weight assessments for additional follow-up visits 20 
through 24. 
l All medications (prescription and over the counter, including vitamins and herbal supplements) taken within 60 days will be recorded at screening. Any 
changes will be recorded at subsequent visits. 
m Only new antipsychotic medications are to be recorded at visits 20 through 24 for subjects prematurely discontinuing study drug and returning for weight 
assessments for additional follow-up visits. 
n "Baseline/Screening" version to be completed at screening. "Since Last Visit" version to be completed at subsequent timepoints. 
o To be completed by the PI or designee using the Structured Clinical Interview for the PANSS (SCI-PANSS). The PANSS should be administered before any 
other psychiatric assessment or questionnaire. 
p 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. 
q Dispense card at Visit 2; confirm possession of card and redispense another card as necessary at all subsequent visits. Collect card at Visit 17/ET or Visit 19 as 
applicable.
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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 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. 
8.3.3. 
Demographics and Medical History 
Subject’s demographic data and medical history will be reviewed and documented at the 
timepoints specified in Table 3. 
8.3.4. 
Concomitant Medication Review 
All medications (prescription and non-prescription, including vitamins and herbal supplements) 
taken by a given subject within 60 days of screening through follow-up will be recorded. 
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. Note: for subjects prematurely discontinuing study drug and 
returning for weight assessments for additional follow-up visits 20 to 24, only new antipsychotic 
medications will be recorded. 
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. Orthostatic blood pressure and 
heart rate will be collected in the following manner: 
• Allow subject to be in a supine position for at least 5 minutes 
• Measure blood pressure and heart rate 
• Have subject stand for 2 minutes 
• Measure blood pressure and heart rate 
Vital signs may be collected at any time during a scheduled visit, unless otherwise noted. 
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8.3.6. 
Physical Examination 
A physical examination will be performed at the timepoints specified in Table 3. A full physical 
will be performed at screening and a brief physical at subsequent visits. 
8.3.7. 
Height, Body Weight, and Waist Circumference 
Height will be measured at screening only and body weight and waist circumference will be 
measured at all the timepoints specified in Table 3. Subjects who discontinue prematurely will be 
asked to return to the clinic for weight measurements as outlined in Section 7.3 and Table 3. 
For weight 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 such as watches and jewelry and they should be 
weighed on the same scale for each measurement under the same conditions.  
Both weight and waist circumference will be measured three consecutive times at each 
assessment and all measurements will be recorded in the eCRF. 
8.3.8. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (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 standard operating procedures. The following ECG parameters 
will be collected: pulse, RR, PR, QRS, QT, QT interval corrected using the Fridericia formula 
(QTcF), and QT interval corrected using the Bazett formula (QTcB). 
The ECGs will also 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. 
Table 3 provides information on the timepoints at which each assessment should be 
administered. 
At screening the medical and psychiatric history and MINI diagnostic interview must be 
conducted prior to the PANSS. For all other visits where assessments overlap, the PANSS should 
be administered first before any other psychiatric assessment. 
8.3.9.1. 
Diagnostic Assessments 
8.3.9.1.1. Mini International Neuropsychiatric Interview 
The MINI is a short, clinician-administered, structured diagnostic interview, with an 
administration time of approximately 15 minutes (Sheehan et al, 1998). The MINI has been 
validated against the much longer Structured Clinical Interview for DSM Diagnoses (SCID). The 
MINI will be used at screening only as indicated in Table 3. 
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8.3.9.2. 
Antipsychotic Efficacy Assessments 
For assessments performed at multiple visits, every effort should be made to pair the same 
clinician/rater with the same subject across visits.  
8.3.9.2.1. Clinical Global Impression-Severity 
The PI or designee will complete the CGI-Severity (CGI-S, Appendix B) 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). 
8.3.9.2.2. Clinical Global Impression-Improvement 
The PI or designee will complete the CGI-Improvement (CGI-I, Appendix B) at the timepoints 
specified in Table 3. The CGI-I measures improvement from the first assessment (Guy 1976). 
8.3.9.2.3. Positive and Negative Syndrome Scale 
The PI or designee will complete the PANSS (Appendix C) (Kay et al, 1987) according to the 
schedule in Table 3. The Structured Clinical Interview for the PANSS (SCI-PANSS) will be 
used to administer the PANSS.  
8.3.9.3. 
Safety Assessments 
8.3.9.3.1. Abnormal Movement Rating Scales 
The PI or designee will complete the following abnormal movement rating scales: The Abnormal 
Involuntary Movement Scale (AIMS, Appendix D) (Guy 1976), the Barnes Akathisia Rating 
Scale (BARS, Appendix E) (Barnes 1989), and the Simpson-Angus Scale (SAS, Appendix F) 
(Simpson and Angus 1970) at the timepoints specified in Table 3. 
After administration of the first dose of study drug, if a subject complains of extrapyramidal 
symptoms on a day when abnormal movement scale assessments are not scheduled, an 
unscheduled abnormal movement assessment should be performed. 
8.3.9.3.2. Columbia-Suicide Severity Rating Scale 
The PI or designee will administer the C-SSRS (Appendix G) according to the schedule in 
Table 3. The “Baseline/Screening” version is to be completed at Visit 1 and the “Since Last 
Visit” version is to be completed at all subsequent scheduled timepoints. The C-SSRS should be 
administered by a qualified clinician trained in assessing and managing suicidal ideation and 
behavior (Posner et al, 2011). 
8.3.9.4. 
Other Assessments 
8.3.9.4.1. Cigarette Use Questionnaire 
Data on cigarette use will be collected using the question: “How many packs of cigarettes did 
you smoke over the past 7 days?” at the timepoints specified in Table 3. 
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8.3.9.4.2. Impact of Weight on Quality of Life – Lite  
Subjects will complete the IWQOL-Lite questionnaire (Appendix H) at the timepoints specified 
in Table 3. 
8.3.9.4.3. EuroQol-5D 
Subjects will complete the EQ-5D (Appendix I) at the timepoints specified in Table 3. This scale 
provides an indication of health status based on self-rating in the following five categories: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Additionally, it asks 
subjects to rank their health status on a visual analogue scale (VAS) from “worst imaginable 
health state” to “best imaginable health state.” 
8.3.10. 
Rater Review 
Rater (ie, study staff) accuracy at screening on pre-specified study measures (ie, PANSS) will be 
reviewed by central raters.  
Later reviews will take place according to a pre-specified schedule (subject to change based on 
rater accuracy) after the measure has been administered using an audio recording of the 
screening interview. Rater review is necessary for mitigating inaccurate inclusion/exclusion 
assessments and inaccurate efficacy 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. 
8.3.11. 
Laboratory Assessments 
8.3.11.1. Drug Testing 
A drug screen for opioids (including codeine, hydrocodone, hydromorphone, methadone, 
morphine, oxycodone, and oxymorphone) and drugs of abuse (including amphetamine/ 
methamphetamine, phencyclidine, and cocaine) will be performed at the timepoints specified in 
Table 3. Urine drug screens may be repeated based on investigator judgment. The test may also 
be repeated at any time during the study, should the investigator feel it is warranted. Subjects are 
not eligible for participation if the results are positive at screening. If a subject is determined to 
be using any of these substances during the treatment period, the investigator should contact the 
medical monitor to discuss the course of action. 
8.3.11.2. Hematology, Biochemistry, and Urinalysis 
Fasting blood and urine samples 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 standard 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 
Platelet count 
Red blood cell count 
Total and differential 
(absolute) white blood cell 
count 
General Chemistry 
Albumin 
Bicarbonate 
Calcium 
Chloride 
Creatine phosphokinase 
Glucose  
Lactic dehydrogenase 
Potassium 
Sodium 
Total protein 
Uric acid 
Endocrine Function Test 
Thyroid-stimulating hormonea 
HbA1c 
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 
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 
a At screening only 
8.3.11.3. Pregnancy Testing 
A urine/serum pregnancy test will be administered to all women at the timepoints specified in 
Table 3. At the screening visit, results must be negative for the subject to be eligible for the 
study. 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 
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8.3.11.4. Serology Testing 
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C 
antibodies, and human immunodeficiency virus (HIV) will be performed at screening only 
(Table 3). A positive hepatitis C antibody test must be confirmed by RNA testing to be 
exclusionary. 
8.3.12. 
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 PK blood draw must be documented in the 
subject’s source documents. Samples for PK analysis will be stored at -20°C ±10°C. The PK data 
from these samples may be included in a subsequent population PK analysis or other post-hoc 
analyses conducted outside of this study. 
8.3.13. 
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. 
Randomization 
At the timepoint specified in Table 3, subjects will be randomized as outlined in Section 9.3. 
8.3.15. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
dispensed at the timepoints specified in Table 3. The study drug use and storage information will 
be explained to/reviewed with the subject. 
Whether or not samidorphan is classified as a controlled substance varies from country to 
country; some countries have classified samidorphan as a controlled substance, while others have 
not. Sites will be given storage, handling, and reconciliation instructions applicable to their 
country to ensure compliance with local regulations for controlled substances. 
8.3.16. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject and collected from each subject 
at the timepoints indicated in Table 3. The card will indicate that the subject may be 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 as indicated in Table 3. 
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8.3.17. 
Adverse Event Monitoring 
Adverse events 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 adverse events (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 unless they are surgically sterile or post-menopausal (see below). The 
following are considered acceptable methods of contraception:  
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device (IUD) 
3. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, contraceptive implant) 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
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. Pregnancies in female subjects and female partners of male subjects 
should be handled in the same manner. The investigator must fill out a Pregnancy Report Form 
and submit the information to the sponsor within 24 hours of awareness of the pregnancy, 
irrespective of whether an adverse event has occurred. The early termination and safety 
follow-up visits will be scheduled. The investigator will follow the pregnancy until completion 
or until pregnancy termination and notify the outcome to the sponsor. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE the investigator should 
follow the procedure of reporting SAEs (see Section 13.5). Additional follow-up may be 
required. 
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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). Prohibited medications include the 
following: 
• Monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline, or 
moclobemide) 
• Long-acting formulations of any antipsychotic agent 
• Antipsychotic agents (with the exception of cross-tapering of previous antipsychotic 
during first 2-weeks post randomization) 
• Use of antipsychotic sleep aids (eg, Seroquel®) is prohibited. However, use of 
benzodiazepines to treat some symptoms is permissible (see Section 8.4.3) 
• In general, the use of psychotropic medications other than study drug is prohibited 
with the exception of the following (these medications should only be administered 
after all assessments have been completed for that visit): 
− Beta-blockers (eg, propranolol or pinodolol), antihistamines, and anticholinergics 
may be used for treatment-emergent akathisia 
− Anticholinergics may be used for extrapyramidal symptoms 
• Chantix® (varenicline) is prohibited. 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 
• Antidepressants that have been started within 30 days of screening are prohibited. An 
antidepressant should not be started during a subject’s participation in the study. 
Subjects who have been on a stable dose of an antidepressant for at least 30 days 
before screening may be allowed to participate in the study if it is anticipated that the 
dose will not change during the subject’s participation in the study 
Medications that are contraindicated with olanzapine use or exhibit drug-interaction potential 
with olanzapine are prohibited. 
Use of moderate to strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 (prescription 
medications, OTC medications, or dietary supplements) within 30 days before randomization 
through follow-up is prohibited. Refer to Appendix A for a list of CYP3A4 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. 
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Use of opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) within 14 days before 
screening is prohibited. Use of opioid antagonists, including naltrexone (any formulations) and 
naloxone within 60 days before screening and throughout the study period is prohibited. Note: 
during the study period, opioid agonists should be avoided as they may be rendered ineffective 
by samidorphan. 
8.4.3. 
Permitted Therapy 
Permissible potential medications to treat extrapyramidal symptoms may include 
benzodiazepines, antihistamines, and anticholinergics. Benzodiazepines should be utilized for 
treatment-emergent akathisia. While insomnia may be treated with a variety of agents, short 
half-life benzodiazepines should be utilized to avoid the potential for lingering effects on 
daytime functioning and study assessments (eg, triazolam). Non-benzodiazepine medication may 
be used to treat insomnia (eg, zolpidem, eszopiclone). Treatment of agitation and/or anxiety with 
benzodiazepines is permissible. However, doses should be restricted to no more than a 2 mg 
lorazepam equivalent per day and should be kept as stable as possible throughout study so as not 
to interfere with daytime functioning and study assessments.  
8.4.4. 
Pain Management 
Because ALKS 3831 contains samidorphan, a μ-opioid receptor antagonist, patients 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 
• 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 is an opioid antagonist and 
could interfere with opioid-mediated pain management. 
8.4.5. 
Other Restrictions and Requirements 
Additional restrictions and requirements include: 
• Prohibited substances include amphetamines (including methamphetamine), cocaine, 
barbiturates, methadone, opioids (including morphine, oxycodone, methadone, and 
buprenorphine), and phencyclidine 
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• 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 10/10 (10 mg olanzapine/10 mg samidorphan) or 20/10 (20 mg 
olanzapine/10 mg samidorphan) administered as a coated bilayer tablet 
• Olanzapine 10 mg or 20 mg administered as a coated bilayer tablet 
At Visit 2 and all subsequent visits until Visit 17 (EOT), subjects will be given blister cards 
containing study drug to take at home. Subjects will be instructed to take one tablet by mouth 
each day, preferably at bedtime. Dosing may be switched to another time at the investigator’s 
discretion if there are tolerability problems; however, 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. 
Study Drug Return and Adherence Review 
Subjects will undergo a study drug adherence review at the timepoints indicated in Table 3. 
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 non-adherence with the subject 
9.3. 
Randomization/Method of Assigning Subjects to Treatment 
Subjects meeting eligibility criteria at baseline (Day 1) will be randomized in a 1:1 ratio to 
ALKS 3831 or olanzapine. 
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, clinical staff, and subjects will be blinded to treatment assignment until 
database lock. 
The principal investigator 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 
must make every effort to contact the CRO/sponsor medical monitor before the blind is broken. 
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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. 
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 two fixed-dose 
combinations: 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) 
Samidorphan is a Schedule II controlled substance. Thus, ALKS 3831 should be treated as a 
Schedule II controlled substance in the US and any other country in which it is controlled. 
Matching olanzapine-only drug will be manufactured by Alkermes, Inc and will be supplied as a 
coated bilayer tablet in two dose strengths: 
• OLZ 10 (10 mg olanzapine) 
• OLZ 20 (20 mg olanzapine) 
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 2 additional once daily doses. Biweekly blister cards will contain 
16 tablets, enough for 2 weeks of dosing plus sufficient overage for 2 additional once daily 
doses. 
10.3. 
Storage 
Product should be stored at not more than 25°C. 
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 investigator will be responsible for the oversight of recording the receipt and administration 
of study drug, and for insuring the supervision of the storage and allocation of these supplies. 
The investigator is required to maintain current drug dispensing and accountability logs 
throughout the study. The investigator may delegate accountability duties to an appropriate and 
qualified pharmacist or staff member who is under the supervision of the investigator. The 
investigator or designee must allow the Clinical Research Associate or equivalent to perform 
drug reconciliation during each study monitoring visit. All unused supplies will be checked 
against the study drug movement records before investigational drug is returned or destroyed. 
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Refer to Section 8.3.15 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 
The following assessments will be used to collect efficacy throughout the study: 
• Weight (Primary Endpoint) 
Antipsychotic efficacy measures include the following: 
• Positive and Negative Symptom Scale (PANSS) 
• Clinical Global Impression – Severity (CGI-S) 
• Clinical Global Impression – Improvement (CGI-I) 
See Section 8.3.7 and Section 8.3.9.2 for more details on weight measurement and antipsychotic 
efficacy assessments. 
Other Assessments 
• Cigarette Use Questionnaire 
• Impact of Weight on Quality of Life – Lite (IWQOL-Lite) Questionnaire 
• EuroQol-5D (EQ-5D) 
• Substudy: an exploratory substudy will measure body composition (using 
Bioelectrical Impedance Analysis [BIA]) in subjects at a subset of sites participating 
in the main ALK3831-A303 study  
See Section 8.3.9.4 for more details on the questionnaires and quality of life assessments. See 
Addendum A for substudy details. 
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12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
Concentrations of olanzapine, samidorphan, and metabolites of interest will be determined from 
plasma samples collected according to the schedule in Table 3. Pharmacokinetic (PK) data from 
these 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 
The following assessments will be collected to measure safety and tolerability throughout the 
study: 
• Adverse events (AEs) 
• Waist Circumference 
• Clinical laboratory parameters including chemistry, hematology, and urinalysis 
• Vital signs (oral temperature, respiratory rate, orthostatic blood pressure, and heart 
rate) 
• Electrocardiogram parameters (Uncorrected QT, QTcF, QTcB, PR, RR, and QRS 
intervals) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
See Section 8.3.9.3 for more details regarding safety assessment questionnaires. 
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
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 informed consent form (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 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 must be reported to Alkermes 
and additional follow-up may be required. 
13.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality that meets one or more of 
the following criteria: 
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• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization. Hospital 
admission for elective surgery scheduled prior to study entry is not considered an 
SAE 
• Results in disability/incapacity (eg, a substantial disruption of a person’s ability to 
conduct normal life functions) 
• Is a congenital anomaly/birth defect 
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. 
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 
sub-investigator) 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. 
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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 final study visit (Visit 19 for subjects completing the study or the final 
monthly visit for subjects discontinuing study drug, but returning for monthly visits). Any AE or 
SAE having an onset after the final study visit will not be 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 
All SAEs must be reported to 
 within 1 business day of 
discovery, by emailing: 
 or faxing the report to the 
following: 
Attention: 
 Medical Monitor 
US Fax Number: 
 
EU Fax Number: 
 
The written report should be submitted on the SAE form provided for this purpose. The 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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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
The initial target sample size is 200 randomized subjects per treatment group (400 in total). This 
sample size will provide at least 90% power to detect a significant difference in mean percent 
change in body weight at Week 24 of 4% or more (3.0% on ALKS 3831 vs 7% on olanzapine 
group with standard deviation of 9%) and a 13% difference in proportion of subjects with ≥10% 
weight gain at Week 24 (14% on ALKS 3831 vs 27% on olanzapine group). 
An unblinded interim analysis is planned to be conducted to determine if the final sample size 
will be increased to 540 (270 subjects per treatment group Section 14.7). 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan (SAP). 
In general, summary statistics (n, mean, standard deviation [SD], 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 2-sided and will be 
set at α=0.05. 
14.2.1. 
Study Populations 
14.2.1.1. Safety Population 
The safety population includes all randomized subjects who receive at least one dose of study 
drug (ALKS 3831 or olanzapine). 
14.2.1.2. Efficacy Population 
The efficacy population includes: 
• Full analysis set (FAS) population: all subjects in the safety population who have at 
least one postbaseline weight assessment 
• Early weight gain population: all subjects in the FAS population who gain weight 
(>0 kg) at Week 1 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, weight, BMI, and 
psychiatric history will be summarized by treatment group. If there are heterogeneities between 
study groups in any of the subject characteristics that are of clinical importance or could affect 
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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 summarized for the safety population using the number of observations 
and percentage of subjects reporting each category. 
14.4. 
Efficacy Analyses 
Efficacy analyses will be based on the relevant efficacy population. Baseline for the primary 
efficacy analysis is defined as the last non-missing assessment before the first dose of the 
double-blind study drug. All statistical tests will be two-sided hypothesis tests performed at the 
5% significance level. All confidence intervals will be two-sided 95% confidence intervals, 
unless specified otherwise. 
Primary Endpoints 
The primary endpoints are: 
• Percent change from baseline in body weight at Week 24 in the FAS population 
• Proportion of subjects with ≥10% weight gain at Week 24 in the FAS population 
For percent change from baseline in body weight at Week 24, the primary analysis will be 
carried out using an analysis of covariance (ANCOVA) method. The ANCOVA model will 
include treatment group, race (Black or African American, non-Black or African American), and 
age (<30, ≥30) as factors, and baseline weight as a covariate. Missing values will be addressed 
using a multiple imputation (MI) approach, as described in the SAP. The variables in the MI 
model will at least include the same variables as used in the ANCOVA model. Additional 
sensitivity analyses will be carried out to explore the impact of missing data. 
For proportion of subjects with ≥10% weight gain at Week 24, the primary analyses will be 
carried out using a logistic regression model. The model will include treatment group, race 
(Black or African American, non-Black or African American), and age (<30, ≥30) as factors, and 
baseline weight as a covariate. Missing values will be addressed using the MI approach, as 
described above. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• Proportion of subjects with ≥7% weight gain at Week 24 
The key secondary endpoint will be analyzed using the same approach as the analysis for the 
proportion of subjects with ≥10% weight gain at Week 24 in the FAS population. 
A fixed sequence approach will be used to control overall Type I error rate. First, both primary 
endpoints will be tested at an alpha level of 0.05. If both primary endpoints are statistically 
significant, the key secondary endpoint will be tested at an alpha level of 0.05. 
 
 
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Other Endpoints 
Other endpoints are: 
• Percent change from baseline in body weight at Week 24 in the early weight gain 
population 
• Proportion of subjects with ≥10% weight gain at Week 24 in the early weight gain 
population  
• Change from baseline in fasting lipids (fasting triglycerides, low-density lipoprotein 
[LDL], high-density lipoprotein [HDL], total cholesterol), fasting glucose, fasting 
insulin, and HbA1c by visit 
• Absolute change in body weight by visit 
• Change from baseline in waist circumference by visit 
• Change from baseline in PANSS total score and subscales by visit 
• Change from baseline in CGI-S by visit 
• CGI-I score by visit 
• Change from baseline in IWQOL-Lite total score and subscales by visit 
• Change from baseline in EQ-5D score by visit 
The body weight- and waist circumference-related endpoints will be analyzed in the same 
manner as the co-primary endpoints. An ANCOVA model will be used for continuous endpoints. 
The model will include treatment group, race (Black or African American, non-Black or African 
American), and age (<30, ≥30) as factors, and baseline value as a covariate. A logistic regression 
model will be used for categorical endpoint, adjusting for the same covariates. Missing values 
will be addressed by an MI approach.  
Change from baseline in fasting lipids (fasting triglycerides, LDL, HDL, total cholesterol) and 
fasting glucose, fasting insulin, and HbA1c will be analyzed by a mixed model with repeated 
measurements (MMRM) model. The model will include treatment, visit, treatment-by-visit 
interaction term, race (Black or African American, non-Black or African American) and age 
(<30, ≥30) as categorical fixed effects; the baseline value will be included as a covariate.   
Change from baseline in PANSS, CGI-S, IWQOL-Lite and EQ-5D will be analyzed by MMRM 
model. The model will include treatment, visit, and treatment-by-visit interaction term as 
categorical fixed effects; the baseline value will be included as a covariate.  
PANSS responder status (<20%, ≥20% improvement over baseline PANSS), CGI-I score, and 
CGI-I responder status (≤2 vs >2) will be presented by summary statistics.  
14.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Listings will be provided for concentrations of olanzapine, samidorphan, and metabolites of 
interest. 
 
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14.6. 
Safety and Tolerability Analyses 
The safety analysis will be carried out using the Safety Population. For each safety parameter, 
the last assessment of the parameter before the first dose of randomized study drug will be used 
as the baseline for all analyses of that safety parameter. All safety analyses will be based on 
observed data only, and no missing values will be imputed. 
Reported adverse event terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by preferred term and system organ class categories. 
The number and percentage of treatment emergent adverse events (TEAEs) will be summarized 
by treatment group by system organ class, and preferred terms within each system organ class. 
Subjects with SAEs, and AEs contributing to discontinuation will also be summarized. 
Observed values and change from baseline in BMI, waist circumference, 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 postbaseline visit will be summarized by treatment group for laboratory, vital 
signs, weight, and ECG parameters. Supporting listings will be provided.  
The number and percentage of subjects with shifts in laboratory and extra pyramidal symptoms 
(EPS) parameters (AIMS, BARS, and SAS) will also be summarized by treatment group. 
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 medication use will be summarized by World Health Organization 
(WHO) Drug Dictionary Anatomical Therapeutic Class (ATC) code and by treatment group. 
Listings will be provided for all safety endpoints. 
14.7. 
Interim Analysis 
 One unblinded interim analysis will be conducted by an independent statistical center (ISC) 
when 50% of subjects (N=200) have completed the double-blind treatment period or have 
discontinued from the study. The details regarding the conduct of the unblinded interim analysis 
will be specified in the interim analysis operational plan and the statistical testing methodology 
will be specified in the interim analysis plan (IAP). 
The conditional power (CP) will be computed for both primary endpoints. Based on the 
conditional power, it will be assigned into one of 3 zones: favorable (CP ≥90%), promising 
(30% ≤ CP <90%), or unfavorable (CP <30%). The target sample size of 200 per arm will be 
increased to 270 subjects per arm when the conditional power for either primary endpoint is in 
the promising zone and neither of the primary endpoints is in the unfavorable zone. Otherwise, 
the target sample size will be maintained at 200 subjects per arm. Overall Type 1 error rate for 
the final analysis are maintained using CHW method (Cui et al, 1999) by combining the Z test 
statistics from two independent stages (before and after the interim analysis) with a fixed weight 
based on the original sample size. There will be no early stopping for efficacy or futility. The 
sponsor will not be informed with any unblinded interim analysis results except for a 
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recommendation to either increase the sample size to 540 subjects (270 per arm) or to leave the 
sample size unchanged. 
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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, subjects’ medical records) to determine whether these activities were conducted, and 
data recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of the 
International Conference on Harmonisation (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. GCP 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 (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 
will receive an IRB-approved informed consent form (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 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, the contract research organization (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. 
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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, 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. 
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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. 
All electronic source data collected outside of the eCRF such as central laboratory data will be 
transferred directly to Alkermes for incorporation into the final datasets. A paper copy of all 
laboratory reports will remain with the source documents at the study site. 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 recorded as such on the 
eCRFs. 
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. 
Subjects’ 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. 
18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that is 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. 
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19. 
REFERENCES 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-857. 
Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on 
outcomes. Schizophr Res. 1999;35 Suppl:S93-100. 
Zyprexa (olanzapine) [package insert]. Indianapolis, IN: Eli Lilly and Company; Oct 2016. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Department of 
Health, Education, and Welfare; 1976. 
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-
53. 
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. 
Kay S, Fiszbein A, Opler L. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
Koekkoek B, van MB, Hutschemaekers G. "Difficult patients" in mental health care: a review. 
Psychiatr Serv. 2006;57(6):795-802. doi: 10.1176/appi.ps.57.6.795. 
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. 
Lambert M, Conus P, Cotton S, Robinson J, McGorry PD, Schimmelmann BG. Prevalence, 
Predictors, and Consequences of Long-Term Refusal of Antipsychotic Treatment in First-
Episode Psychosis. J Clin Psychopharmacol. 2010;30(5):565-572. doi: 
10.1097/JCP.0b013e3181f058a0. 
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. 
Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia 
and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. 
Schizophr Res. 2006;86(1-3):15-22. doi: 10.1016/j.schres.2006.06.026. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704. 
Page 61 of 111


 
 
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Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other 
drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 
1990;264(19):2511-2518. 
Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the 
differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123-1131. 
doi: 10.1001/archpsyc.64.10.1123. 
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. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-19. 
Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with 
schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620-627. 
doi: 10.1016/S0140-6736(09)60742-X. 
 
Page 62 of 111


 
 
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20. 
LIST OF APPENDICES 
Appendix A 
Partial list of prohibited cytochrome P450 (CYP) 3A4 inducers and moderate-to-strong 
inhibitors 
Appendix B 
Clinical Global Impression 
• 
Severity 
• 
Improvement 
Appendix C 
Positive and Negative Syndrome Scale 
Appendix D 
Abnormal Involuntary Movement Scale 
Appendix E 
Barnes Akathisia Rating Scale 
Appendix F 
Simpson-Angus Scale 
Appendix G 
Columbia-Suicide Severity Rating Scale 
• 
Baseline/Screening 
• 
Since Last Visit 
Appendix H 
Impact of Weight on Quality of Life - Lite 
Appendix I 
 
EuroQol – 5D 
 
Page 63 of 111


 
 
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APPENDIX A. PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INDUCERS AND MODERATE-TO-STRONG 
INHIBITORS  
Partial List of CYP3A4 Inhibitors and Inducers (This is not an all-inclusive list.) 
 
 
Moderate to Strong CYP3A4 inhibitors: 
 
Amprenavir 
Aprepitant 
Atazanavir 
Boceprevir 
Ciprofloxacin 
Clarithromycin 
Conivaptan 
Crizotinib 
Darunavir/ ritonavir 
Diltiazem 
Erythromycin 
Fosamprenavir 
Fluconazole 
Imatinib 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir/ ritonavir 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprenavir 
Telithromycin 
Troleandomycin  
 
Verapamil  
 
 
 
Voriconazole 
Partial List of Moderate to Strong 
CYP3A4 inducers: 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
Nevirapine 
Phenobarbital 
Phenytoin 
Rifampin 
Rifabutin 
St. John’s Wort 


 
 
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APPENDIX B. CLINICAL GLOBAL IMPRESSION  
• Severity 
• Improvement 
 


Clinical Global Impression – Severity of Illness and Improvement of 
Illness (CGI-S and CGI-I)
Severity of Illness (CGI-S)
Considering your total clinical experience with this particular population, how 
mentally ill is the patient at this time?
0 = Not assessed
1 = Normal, not at all ill
2 = Borderline mentally ill
3 = Mildly ill
4 = Moderately ill
5 = Markedly ill
6 = Severely ill
7 = Among the most extremely ill 
patients
Global Improvement (CGI-I)
Rate total improvement whether or not in your judgment it is due entirely to drug 
treatment.  Compared to his/her condition at admission, how much has he/she 
changed?
0 = Not assessed
1 = Very much improved
2 = Much improved
3 = Minimally improved
4 = No change
5 = Minimally worse
6 = Much worse
7 = Very much worse
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 
1976. Rockville, MD, U.S. Department of Health, Education, and Welfare
SAMPLE
n, how
n, ho
ill
erely ill
rely
= Among the most extremely ill 
Among the most extremely 
patients
patients
E
MP E
ether or not in your judgment i
not in your judgmen
t
his/her condition at admission
his/her condition at admission
MP
MP
MP
d
much improved
h improved
Much improved
ved
3 = Minimally improved
3 = Minimally improve
S
4 = 
4
AM
S M
d f


 
 
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APPENDIX C. POSITIVE AND NEGATIVE SYNDROME SCALE 


PPD
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PPD


 
 
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APPENDIX D. ABNORMAL INVOLUNTARY MOVEMENT SCALE 


Guy, W. ed. ECDEU Assessment Manual for Psychopharmacology. US Dept 
of HEW, Publication No. (Adm): 76-338, 1976 
Clintara Version 1.6 June, 2011 
Page 1 of 1
Abnormal Involuntary Movement Scale (AIMS)
Movement ratings: Rate highest severity observed. Rate movements that occur upon activation 
one less than those observed spontaneously.
Code:
0 = None
1 = Minimal, may be extreme normal
2 = Mild
3 = Moderate
4 = Severe
(Circle One)
FACIAL AND 
ORAL 
MOVEMENTS: 
1.
MUSCLES OF FACIAL EXPRESSION e.g movements of forehead, eyebrows,
periorbital area, cheeks, including frowning, blinking, smiling, grimacing
0 
1 
2 
3 
4 
2.
LIPS AND PERIORAL AREA e.g. puckering, pouting, smacking
0
1
2
3
4
3.
JAW e.g. biting, clenching, chewing, mouth opening, lateral movement
0
1
2
3
4
4.
TONGUE Rate only increases in movement both in and out of mouth. NOT
inability to sustain movement
0 
1 
2 
3 
4 
EXTREMITY 
MOVEMENTS:
5.
UPPER (ARMS, WRISTS, HANDS, FINGERS) Include choreic movements (i.e.
rapid, objectively purposeless, irregular, spontaneous), athetoid movements (i.e.
slow, irregular, complex, serpentine). Do NOT include tremor (i.e. repetitive,
regular, rhythmic)
0 
1 
2 
3 
4 
6.
LOWER (LEGS, KNEES, ANKLES, TOES) e.g. lateral knee movement, foot
tapping, heel dropping, foot squirming, inversion and eversion of foot
0 
1 
2 
3 
4 
TRUNK 
MOVEMENTS:
7.
NECK, SHOULDERS, HIPS e.g.rocking, twisting, squirming, pelvic gyrations
0 
1 
2 
3 
4 
GLOBAL 
JUDGMENT:
8.
SEVERITY OF ABNORMAL MOVEMENTS
None, normal     0 
Minimal     1 
Mild     2 
Moderate     3 
Severe     4 
9.
INCAPACITATION DUE TO ABNORMAL MOVEMENTS
None, normal     0 
Minimal     1 
Mild     2 
Moderate     3 
Severe     4 
10. PATIENT’S AWARENESS OF ABNORMAL MOVEMENTS. RATE ONLY
PATIENT’S REPORT
No awareness     0 
Aware, no distress     1 
Aware, mild distress     2 
Aware, moderate distress     3 
Aware, severe distress     4 
DENTAL 
STATUS:
11. Current problems with teeth and/or dentures?
No     0 
Yes    1 
12. Does patient usually wear dentures?
No     0 
Yes    1 
Rater Signature: _______________________
Date: _________________________
SAMPLE
1
E
0 
0 
1
E
.e.
e.
s (i.e.
e
ive,
0 
0 
1
2
E
LE
ement, foot
of foot
f foo
0 
1
2
LE
LE
LE
LE
LE
LE
, pelvic gyrations
elvic gyr
0 
1 
1
LE
LE
LE
LE
LE
LE
PL
RMAL MOVEMENTS
MAL MOVEMENTS
MP
RENESS OF ABNORMAL MOVEMENTS
SS OF ABNORMAL MOVEMENTS
PORT
M
. Current problems with teeth and/or d
ems with teeth and/or d
SA
S
12. Does patient usually wear de
tient usually w
SA
SA
Signature:
gnatu
_________
___


 
 
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APPENDIX E. BARNES AKATHISIA SCALE 


Reproduced from: Barnes TR: A Rating Scale for Drug-Induced Akathisia. 
British Journal of Psychiatry 154:672-676, 1989.  
Clintara Version 1.6 June, 2011 
Page 1 of 1
Barnes Akathisia Rating Scale (BARS)
Instructions: Patient should be observed while they are seated, and then standing while engaged in neutral conversation (for a 
minimum of two minutes in each position). Symptoms observed in other situations, for example, while engaged in activity on the 
ward, may also be rated. Subsequently, the subjective phenomena should be elicited by direct questioning.  
Please circle the appropriate scores. 
Objective
0
Normal, occasional fidgety movements of the limbs
1
Presence of characteristic restless movements: shuffling or tramping movements of the legs/feet, or swinging of 
one leg while sitting, and/or rocking from foot to foot or “walking on the spot” when standing, but movements
present for less than half the time observed 
2
Observed phenomena, as described in (1) above, which are present for at least half the observation period 
3
Patient is constantly engaged in characteristic restless movements, and/or has the inability to remain seated or
standing without walking or pacing, during the time observed 
Subjective 
Awareness of restlessness
0
Absence of inner restlessness
1
Non-specific sense of inner restlessness 
2
The patient is aware of an inability to keep the legs still, or a desire to move the legs, and/or complains of inner
restlessness aggravated specifically by being required to stand still 
3
Awareness of an intense compulsion to move most of the time and/or reports strong desire to walk or pace most
of the time 
Distress related to restlessness
0
No distress 
1
Mild 
2
Moderate 
3
Severe 
Global Clinical Assessment of Akathisia
0
Absent. No evidence of awareness of restlessness. Observation of characteristic movements of akathisia in the
absence of a subjective report of inner restlessness or compulsive desire to move the legs should be classified 
as pseudoakathisia 
1
Questionable. Non-specific inner tension and fidgety movements
2
Mild akathisia. Awareness of restlessness in the legs and/or inner restlessness worse when required to stand
still. Fidgety movements present, but characteristic restless movements of akathisia not necessarily observed. 
Condition causes little or no distress 
3
Moderate akathisia. Awareness of restlessness as described for mild akathisia above, combined with
characteristic restless movements such as rocking from foot to foot when standing. Patient finds the condition 
distressing 
4
Marked akathisia. Subjective experience of restlessness includes a compulsive desire to walk or pace.
However, the patient is able to remain seated for at least five minutes. The condition is obviously distressing.
5
Severe akathisia. The patient reports a strong compulsion to pace up and down most of the time. Unable to sit
or lie down for more than a few minutes. Constant restlessness which is associated with intense distress and 
insomnia. 
Rater Signature: _______________________
Date: _________________________
Scoring the Barnes Akathisia Rating Scale (BARS) 
The Barnes Akathisia Rating Scale is scored as follows:  
Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are rated on a 
4-point scale from 0 – 3 and are summed yielding a total score ranging from 0 to 9.  
The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0 – 4. 
SAMPLE
ervation pe
ervation
ty to remain seate
y to re
o move the legs, 
ove the
and/or complains of i
ins of 
ll
and/or 
and/or reports strong desire to walk o
reports strong desire to walk o
of restlessness. Observation of chara
of restlessness. Observation of chara
inner restlessness or compulsive desi
ner restlessness or compulsive de
 inner tension and fidgety movements
n and fidgety moveme
ss of restlessness in the legs 
ss of restlessness in the l
and/or 
nd/or ini
ts present, but characteristic restless 
present, but characteristic re
le or no distress
no distress
sia. Awareness of restlessness as de
reness of restlessness as de
restless movements such as rocking f
ments such as rocking 
akathisia
akathisia. Subjective experience of re
Subjective expe
ver, the patient is able to remain seate
er, the patient is able to rema
vere akathisia
e ak
. The patient reports a s
The patient reports
ie down for more than a few minute
down for more than a few minute
mnia.
ia.
ure: ___________
__________
Ak


 
 
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APPENDIX F. SIMPSON-ANGUS SCALE 


Modified from: Simpson GM, Angus JWS: A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica 212:11-19, 
1970. Revised
Clintara Version 1.5 June, 2011
Page 1 of 3
SIMPSON ANGUS RATING SCALE 
Circle the appropriate score for each item:
1.
GAIT
The patient is examined as he walks into the examining room: his gait, the swing of arms, his 
general posture; all form the basis for an overall score for this item. This is rated as follows:
0 
Normal
1
Mild diminution in swing while the patient is walking
2
Obvious diminution in swing suggesting shoulder rigidity
3
Stiff gait with little or no arm swing noticeable
4 
Rigid gait with arms slightly pronated; or stopped-shuffling gait with propulsion and retropulsion
2.
ARM DROPPING
The patient and the examiner both raise their arms to shoulder height and let them fall to their 
sides. In a normal subject a stout slap is heard as the arms hit the sides. In the patient with 
extreme Parkinson’s syndrome, the arms fall very slowly.
0 
Normal, free fall with loud slap and rebound
1
Fall slowed slightly with less audible contact and little rebound
2
Fall slowed, no rebound
3 
Marked slowing, no slap at all
4
Arms fall as though against resistance; as though through glue
3.
SHOULDER SHAKING
The subject’s arms are bent at a right angle at the elbow and are taken one at a time by the
examiner who grabs one hand and also clasps the other around the patient’s elbow. The subject’s 
upper arm is pushed to and fro and the humerus is externally rotated. The degree of resistance 
from normal to extreme rigidity is scored as follows:
0
Normal
1
Slight stiffness and resistance
2 
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
SAMP
nt at a right angle at the elbow and
nt at a right angle at the elbow and
e hand and also clasps the other
hand and also clasps the othe a
to and fro and the humerus is exte
d fro and the humerus is exte
MPLE
h propulsion and retropulsion
pulsion and retropulsion
der height and let them fall to their
them fall to thei
ms hit the sides. In the patient with
ms hit the sides. In the patient with
wly.
LE
PL
nd little
nd little rebound
ound
tance; as though
; as thou
through glue
hrough
reme rigidity is
y is scored as follows:
cored as follow
MP
AM
ness and resistance
and resistance
ate stiffness and resistance
s and resistance
arked rigidity with dif
arked rigidity with difficulty in pass
ficu
f
Extreme stiffness and rigidity wi
Extreme stiffness and rigid
SA


Subject ID No.________    Visit No.________
Modified from: Simpson GM, Angus JWS: A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica 212:11-19, 
1970. Revised
Clintara Version 1.6 June, 2011
Page 2 of 3 
4.
ELBOW RIGIDITY
The elbow joints are separately bent at right angles and passively extended and flexed, with the
subject’s biceps observed and simultaneously palpated. The resistance to this procedure is rated. 
(The presence of cogwheel rigidity is noted separately.)
0 
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3 
Marked rigidity with difficulty in passive movement 
4
Extreme stiffness and rigidity with almost a frozen joint
5.
WRIST RIGIDITY OR FIXATION OF POSITION
The wrist is held in one hand and then the fingers held by the examiner’s other hand with the wrist 
moved to extension, and both ulnar and radial deviation. The resistance to this procedure is rated:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3 
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
6.
LEG PENDULOUSNESS
The patient sits on a table with his legs hanging down and swinging free. The ankle is grasped by 
the examiner and raised until the knee is partially extended. It is then allowed to fall. The
resistance to falling and the lack of swinging form the basis for the score on this item:
0 
The legs swing freely
1
Slight diminution in the swing of the legs
2
Moderate resistance to swing
3
Marked resistance and damping of swing
4
Complete absence of swing
7.
HEAD ROTATION
The patient sits or stands and is told that you are going to move his head side to side, that it will 
not hurt and that he should try and relax. (Questions about pain in the cervical area or difficulty in 
moving his head should be obtained to avoid causing any pain.) Clasp the patient’s head between 
the two hands with fingers on back of the neck. Gently rotate the head in a circular motion 3 times 
and evaluate the muscular resistance to the movement.
0
Loose, no resistance
1 
Slight resistance to movement although the time to rotate may be normal
2
Resistance is apparent and time of rotation is slowed
3
Resistance is obvious and rotation is slowed
4
Head appears stiff and rotation is difficult to carry out
SAMPLE
er’s other hand
r’s other hand with th
with
ance to this procedure is rat
ce to this procedu
E
LE
zen
en joint
join
hanging down and swinging free. T
ging down and swinging free. 
e is
e is partially extended. It is then
partially extended
al
f swinging fo
winging f rm the
the basis for the sc
ba
PL
MP
ing of the legs
ng of
o swing
wing
e and damping of swing
ng of swing
sence of swing
nce of swin
OTATION
ON
tient sits or stands and is told that 
r stands and is told tha
hurt and that he should try and rela
rt and that he should try and rela
oving his head should be obtained
oving his head should be
the two hands with fingers on bac
the two hands with fingers
and evaluate the muscular resi
and evaluate the muscular
AM
Loose, no resistance
Loose, no resistance
SA
Slight resistance to mo
to m
stance is appa
ance is appa
ce is 


Subject ID No.________    Visit No.________
Modified from: Simpson GM, Angus JWS: A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica 212:11-19, 
1970. Revised
Clintara Version 1.6 June, 2011
Page 3 of 3 
8.
GLABELLA TAP
Subject is told to open his eyes and not to blink. The glabella region is tapped at a steady, rapid 
speed. The number of times patient blinks in succession is noted:
0
0-5 blinks
1 
6-10 blinks
2
11-15 blinks
3
16-20 blinks
4
21 and more blinks
9.
TREMOR
Patient is observed walking into examining room and then is examined for this item:
0
Normal
1
Mild finger tremor, obvious to sight and touch
2
Tremor of hand or arm occurring spasmodically
3
Persistent tremor of one or more limbs
4
Whole body tremor
10.
SALIVATION
Patient is observed while talking and then asked to open his mouth and elevate his tongue. The
following ratings are given:
0
Normal
1
Excess salivation so that pooling takes place if the mouth is open and the tongue raised
2 
Excess salivation is present and might occasionally result in difficulty in speaking
3
Speaking with difficulty because of excess salivation
4
Frank drooling
Rater Signature: _______________________
Date: _________________________
SAMPLE
or this item:
r this 
E
ked to
ked to open his mouth and elevate
his mouth and elevate
PL
PL
akes place if the mouth is open an
es place if the mout
nd might occasionally result in diffi
occasionally result in 
ecause of excess salivation
cause of excess salivation
AM
______________________
___________________
D


 
 
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APPENDIX G. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
• Baseline/Screening Version 
• Since Last Visit Version 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes,” ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
Yes 
  No 
Ƒ
Ƒ
Yes     No 
Ƒ   Ƒ
2. Non-Specific Active Suicidal Thoughts
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) without thoughts 
of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 Yes 
 No 
Ƒ
Ƒ
Yes     No 
Ƒ   Ƒ
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…..and I would never go through with it”.  
Have you been thinking about how you might do this? 
If yes, describe: 
 Yes   No 
Ƒ
Ƒ
Yes     No 
Ƒ   Ƒ
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
 Yes   No 
Ƒ
Ƒ
Yes     No 
Ƒ   Ƒ
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
 Yes    No 
Ƒ
Ƒ
Yes     No 
Ƒ   Ƒ
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being 
the least severe and 5 being the most severe ). For prior to study entry, ask about time he/she was feeling the most 
suicidal.  
Lifetime - 
 Most Severe Ideation:  _______  
 ________________________________________ 
     Type # (1-5)  
  Description of  Ideation 
Past X Months - Most Severe Ideation:  _______ 
 ________________________________________ 
     Type # (1-5)  
  Description of  Ideation
Most 
Severe
Most 
Severe
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
____ 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes  
 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time  
  (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts     
 (4) Can control thoughts  with a lot of difficulty 
(2) Can control thoughts with little difficulty   
 (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty  
  (0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide  
  (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you     
 (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you     
  (0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others. 
 (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.     
     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others     
 (5) Completely to end or stop the pain (you couldn’t go on  
  and to end/stop the pain. 
 living with the pain or  how you were feeling). 
 (0)  Does not apply 
____ 
____ 
Version 1/14/09 
S
p thinking about ki
inking about k
SAM
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on:  _______  
 ____________
 __________
     Type # (1-5)  
    
 D
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ation:  _______ 
 ____
     Type # (1-5)  
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
Ƒ   Ƒ
Total # of 
Attempts 
______ 
Yes     No 
Ƒ   Ƒ
Yes     No 
Ƒ   Ƒ
Total # of 
Attempts 
______ 
Yes     No 
Ƒ   Ƒ
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
Yes 
 No 
Ƒ   Ƒ
Total # of 
interrupted 
______ 
Yes     No 
Ƒ   Ƒ
Total # of 
interrupted 
______ 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
 No 
Ƒ   Ƒ
Total # of 
aborted 
______ 
Yes     No 
Ƒ   Ƒ
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes 
 No 
Ƒ   Ƒ
Yes     No 
Ƒ   Ƒ
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
 No 
Ƒ   Ƒ
Yes     No 
Ƒ   Ƒ
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal  
  
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:  
0. No physical damage or very minor physical damage (e.g. surface scratches).
1. Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5. Death
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
S
amage: 
e: 
minor physical da
minor physical da
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hargic spee
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stress, feel better,
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Yes     N
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themselves before they ac
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the individual stops him/her
mething to try to end your life but you s
mething to try to end your life but you 
MP
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ls, purchasing a gun) or preparing fo
wards making a suicide attempt or prep
ing a suicide attempt or p
uables away or writing a suicide note
writing a suicide note)?
AM
r:
was present during the assessment period? 
present during the assessment period?
SA
SA
tual Attempts Only
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes,” 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
Since Last 
Visit 
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
Yes 
  No 
Ƒ
Ƒ
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 Yes   No 
Ƒ
Ƒ
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it”.  
Have you been thinking about how you might do this? 
If yes, describe: 
 Yes   No 
Ƒ
Ƒ
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
Yes 
  No 
Ƒ
Ƒ
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
 Yes   No 
Ƒ
Ƒ
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the least severe 
and 5 being the most severe ).  
Most Severe Ideation: 
 _____ 
 _________________________________________________ 
 Type # (1-5) 
 Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes  
 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time  
  (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time     
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts     
 (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty   
 (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty  
  (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide  
  (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you     
 (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you     
  (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others. 
 (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.     
     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others     
 (5) Completely to end or stop the pain (you couldn’t go on  
  and to end/stop the pain. 
     living with the pain or  how you were feeling). 
 (0)  Does not apply 
____ 
Version 1/14/09 
thinking about killin
ing about killi
rol thoughts     
ol thoughts     
with little dif
with little di
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SAMPLE
ent than a specific plan w
nt than a specific plan
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yourself? Do you intend to carry out this plan
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MP
spect to the most severe type of ideation (
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__
__________________
______________
pe # (1-5)
(1-5)
Desc
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thoughts?
week    (2) Once a week   (3)  2-5 times in wee
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AM
the thoughts, how long do they last?
the thoughts, how long do the
g - few seconds or minutes 
few seconds or minutes  
than 1 hour/some of the time  
1 hour/some of the time  
urs/a lot of time    
a lot of time     
SA
S


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes 
 No 
Ƒ   Ƒ
Total # of 
Attempts 
______ 
Yes     No 
Ƒ   Ƒ
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
Yes 
 No 
Ƒ   Ƒ
Total # of 
interrupted 
______ 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
 No 
Ƒ   Ƒ
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes 
 No 
Ƒ   Ƒ
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
 No 
Ƒ   Ƒ
Completed Suicide: 
 Yes    No
Ƒ   Ƒ
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g. surface scratches).
1. Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes intact; third-degree burns less
than 20% of body; extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree burns over 20% of body;
extensive blood loss with unstable vital signs; major damage to a vital area). 
5. Death
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
Enter Code 
______ 
S
am
S
Attempts On
SAM
ntly making a suicide attempt. This can include
aking a suicide attempt. This can inc
purchasing a gun) or preparing for one’s death
ng a gun) or preparing for one’s deat
AMPLE
ve stress, feel better, get 
ve stress, feel better, g
injurious act
act (if not for t
(if n
hat, actual attempt wou
t wo
t
pills, this becomes an attempt rather than an int
ills, this becomes an attempt rather than an in
is somehow prevented from pulling trigger. On
s somehow prevented from pulling trigger. O
grabbed and taken down from ledge. Hanging: 
rabbed and taken down from ledge. Hanging:
d your life but someone or something st
ur life but someone or something s
LE
ttempt, but stops themselves before they actual
s themselves before they actu
the individual stops him/herself, instead of bein
he individual stops him/herself, instead of bei
 do something to try to end your life b
do something to try to end your lif
MP
s towards making a suicide attempt or p
aking a suicide attempt o
or writing a suicide note
writing a suicide note)?
AM
vior:
or:
ior was present during the assessment period?
was present during the assessment perio
SA
icide:
ide:
SA
S


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
 
 
APPENDIX H. IMPACT OF WEIGHT ON QUALITY OF LIFE-LITE 


© Copyright 2000. Duke University Medical Center. Direct all correspondence to 
 Obesity 
and Quality of Life Consulting, 1004 Norwood Avenue, Durham, NC 27707, USA; 
 Fax: 
 (email address: 
 
IWQOL-Lite – English (US). 
Impact of Weight on Quality of Life Questionnaire—Lite Version (IWQOL-Lite) 
Please answer the following statements by circling the number that best applies 
to you in the past week. Be as open as possible. There are no right or wrong 
answers.
Physical Function 
ALWAYS 
TRUE
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I have trouble
picking up objects.
5 
4 
3 
2 
1 
2.
Because of my weight I have trouble tying
my shoes.
5 
4 
3 
2 
1 
3.
Because of my weight I have difficulty
getting up from chairs.
5 
4 
3 
2 
1 
4.
Because of my weight I have trouble using
stairs.
5 
4 
3 
2 
1 
5.
Because of my weight I have difficulty
putting on or taking off my clothing.
5 
4 
3 
2 
1 
6.
Because of my weight I have trouble with
mobility.
5 
4 
3 
2 
1 
7.
Because of my weight I have trouble
crossing my legs.
5 
4 
3 
2 
1 
8.
I feel short of breath with only mild exertion.
5 
4 
3 
2 
1 
9.
I am troubled by painful or stiff joints.
5 
4 
3 
2 
1 
10.
My ankles and lower legs are swollen at
the end of the day.
5 
4 
3 
2 
1 
11.
I am worried about my health.
5 
4 
3 
2 
1 
Self-esteem 
ALWAYS 
TRUE
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I am self-conscious.
5 
4 
3 
2 
1 
2.
Because of my weight my self-esteem is
not what it could be.
5 
4 
3 
2 
1 
3.
Because of my weight I feel unsure of
myself.
5 
4 
3 
2 
1 
4.
Because of my weight I don’t like myself.
5
4
3
2
1
5.
Because of my weight I am afraid of being
rejected.
5 
4 
3 
2 
1 
6.
Because of my weight I avoid looking in
mirrors or seeing myself in photographs.
5 
4 
3 
2 
1 
7.
Because of my weight I am embarrassed to
be seen in public places.
5 
4 
3 
2 
1 
PPD
PPD
PPD
PPD


© Copyright 2000. Duke University Medical Center. Direct all correspondence to 
 Obesity 
and Quality of Life Consulting, 1004 Norwood Avenue, Durham, NC 27707, USA; 
 Fax: 
 (email address: 
 
IWQOL-Lite – English (US). 
Sexual Life 
ALWAYS 
TRUE
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I do not enjoy sexual
activity.
5 
4 
3 
2 
1 
2.
Because of my weight I have little or no
sexual desire.
5 
4 
3 
2 
1 
3.
Because of my weight I have difficulty with
sexual performance.
5 
4 
3 
2 
1 
4.
Because of my weight I avoid sexual
encounters whenever possible.
5 
4 
3 
2 
1 
Public Distress 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I experience ridicule,
teasing, or unwanted attention.
5 
4 
3 
2 
1 
2.
Because of my weight I worry about fitting
into seats in public places (e.g. theaters,
restaurants, cars, or airplanes).
5 
4 
3 
2 
1 
3.
Because of my weight I worry about fitting
through aisles or turnstiles.
5 
4 
3 
2 
1 
4.
Because of my weight I worry about finding
chairs that are strong enough to hold my
weight.
5 
4 
3 
2 
1 
5.
Because of my weight I experience
discrimination by others.
5 
4 
3 
2 
1 
Work  (Note: For homemakers and 
retirees, answer with respect 
to your daily activities.) 
ALWAYS 
TRUE 
USUALLY 
TRUE 
SOMETIMES 
TRUE 
RARELY 
TRUE 
NEVER 
TRUE 
1.
Because of my weight I have trouble getting
things accomplished or meeting my
responsibilities.
5 
4 
3 
2 
1 
2.
Because of my weight I am less productive
than I could be.
5 
4 
3 
2 
1 
3.
Because of my weight I don’t receive
appropriate raises, promotions or
recognition at work.
5 
4 
3 
2 
1 
4.
Because of my weight I am afraid to go on
job interviews.
5 
4 
3 
2 
1 
PPD
PPD
PPD
PPD


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
 
 
APPENDIX I. EUROQOL-5D 


USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
Health Questionnaire
English version for the USA
SAMPLE
tionnaire
tionnaire
version for the USA
version for the


2
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

SAMPLE





sework, family or 
sework, family
activities
ctivities
usual activities
al activiti
oing my usual activities
ual activit
doing my usual activities
ing my usual activities
y usual activities
ctivities
FORT
ORT
in or discomfort
scomfort
ight pain or discomfort
ight pain or discomfo
ve moderate pain or discomfo
e moderate pain or dis
have severe pain or discomf
ve severe pain or discom
e extreme pain or dis
extreme pain or 
/ DEPRES
/ DEPRES
us


3
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
The worst health 
you can imagine
•
We would like to know how good or bad your health is TODAY.
•
This scale is numbered from 0 to 100.
•
100 means the best health you can imagine.
0 means the worst health you can imagine.
•
Mark an X on the scale to indicate how your health is TODAY.
•
Now, please write the number you marked on the scale in the box
below.
The best health 
you can imagine
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
SAMPLE
DAY.
DAY.
cale in the box
he box
P
MP
H TODAY =
E


Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
21.
ADDENDUM
Addendum A 
Substudy 
Page 106 of 111


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
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Page 1 of 5 
 
ADDENDUM A. SUBSTUDY TO PROTOCOL ALK3831-A303 (FOR 
SELECTED SITES ONLY) 
Introduction and Rationale 
Weight gain is a well-documented side effect associated with olanzapine use (Eli Lilly and 
Company 2016) and thus is the primary efficacy measure in ALK3831-A303 (see Section 5.1 of 
the protocol). In addition to weight gain, changes to body composition (ie, increases in total fat 
mass and in visceral fat accumulation) have also been observed with olanzapine use in subjects 
with schizophrenia (Ader et al, 2008; Graham et al, 2005). 
Bioelectrical Impedance Analysis (BIA) is a method of measuring body composition in which an 
electrical current is passed through the body and an impedance value is generated based on body 
height and the measured electrical conductance. Because fat mass and lean mass conduct 
electricity differently, the relative proportion of each tissue type can be derived from the 
impedance value (Ellis 2000).  
Advancements in bioelectrical impedance technology allow for body composition measurements 
that can be collected uniformly across clinical trial sites without additional burden to the subjects 
in contrast to other methods such as dual-energy X-ray absorptiometry (DEXA) and magnetic 
resonance imaging (MRI). Using BIA, this substudy will evaluate body composition in a subset 
of subjects at a select number of sites participating in ALK3831-A303. As this is an exploratory 
substudy, body composition will be measured at two timepoints to provide data which may 
inform future studies. 
Objective 
The objective of this exploratory substudy is to determine body composition during Visit 2 and 
at the end of treatment (Visit 17/ early termination [ET]) of subjects who are participating in 
study ALK3831-A303. 
Selection of Subjects 
Eligible subjects who are at an ALK3831-A303 site participating in the substudy and who sign a 
separate consent will have these additional assessments collected if they meet the inclusion and 
exclusion criteria below. 
Subject Inclusion Criteria 
Each subject must meet both of the following inclusion criteria to be qualified to participate in 
this substudy. 
1. Enrolled in study ALK3831-A303 at a site equipped with a body composition analyzer 
2. Consented to have body composition analysis conducted on or prior to Visit 2 


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
 
Page 2 of 5 
 
Subject Exclusion Criteria 
Each subject must not meet the following criteria to be qualified to participate in this substudy. 
1. Subjects with an electronic implant or devices of any kind (eg, pacemaker, infusion 
pump) or any active or powered prostheses. 
Subject Withdrawal 
Subjects may withdraw consent from participation in this substudy at any time. If they do so, 
they may continue full participation in the main ALK3831-A303 study. 
Substudy Design 
The substudy will be conducted in up to 200 subjects participating in the main ALK3831-A303 
study. The substudy will be completed in conjunction with the main study protocol. Subjects 
who enroll in the substudy will complete all the study procedures described in the main study 
protocol (see Table 1). Additionally, subjects in the substudy will have a body composition 
assessment done prior to dosing at Visit 2 (confirmation of eligibility and randomization visit) 
and then again upon completion of the study at Visit 17/ET (see Table 1).  


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
 
Page 3 of 5 
 
Table 1: 
Substudy Schedule of Assessments 
Visit  
Screening 
Day -30  
to -1 
24-Week Double-Blind Treatment 
Safety 
Follow-
up 
Monthly 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17/ 
ET 
18 
19 
20 to 24 
Study Week (Visit 
Window of ±2 Days for 
Visits 3-24) 
 
 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
 
Consent for Substudy 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Composition 
Assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviation: ET=early termination 
a If not consented at Visit 1, subjects may be consented at Visit 2 prior to any assessments. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
Page 4 of 5 
 
Body Impedance Analysis Procedure 
Body composition will be assessed using the Seca Medical Body Composition Analyzer 
(mBCA 514). For the body composition 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 standing on the same scale for each measurement 
under the same condition. At timepoints when body composition is measured, subjects will be 
asked to stand on the two separate study-supplied scales. The body composition analysis should 
not be performed when the subject is attached to any portable electronic equipment (eg, a 
portable electrocardiogram machine). 
Substudy Exploratory Endpoints 
This substudy will assess the following exploratory endpoints: 
• Absolute change from baseline in lean mass 
• Absolute change from baseline in fat mass 
• Change from baseline in percent body fat 
Statistical Analysis 
The analysis will be carried out using ANCOVA (analysis of covariance) model with treatment 
group, race (Black or African American, Non-Black or African American), and baseline age 
(<30, ≥30 years) as factors, and the baseline value as the covariate. Please refer to the statistical 
analysis plan (SAP) for analysis details. Results from the substudy will be provided in an 
addendum, which will be included as an appendix of the main ALK3831-A303 clinical study 
report. 
Safety Reporting 
Adverse events and serious adverse events will be captured and reported in accordance with the 
main ALK3831-A303 study (Section 13 of the protocol).  
Informed Consent 
A separate informed consent will be obtained from subjects who voluntarily agree to participate 
in the BIA substudy. The Informed Consent Form reflecting this substudy will be submitted for 
review and approval to the responsible Institutional Review Board (IRB). 
Institutional Review Board 
The Informed Consent Form for this substudy will be submitted for review and approval to the 
IRB charged with this responsibility. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A303 Amendment 5.0 
CONFIDENTIAL 
Page 5 of 5 
 
REFERENCES 
Ader M, Garvey WT, Phillips LS, et al. Ethnic heterogeneity in glucoregulatory function during 
treatment with atypical antipsychotics in patients with schizophrenia. J Psychiatr Res. 
2008;42(13):1076-1085. doi: 10.1016/j.jpsychires.2008.01.004. 
Zyprexa (olanzapine) [package insert]. Indianapolis, IN: Eli Lilly and Company; Oct 2016. 
Ellis KJ. Human body composition: in vivo methods. Physiol Rev. 2000;80(2):649-680. 
Graham KA, Perkins DO, Edwards LJ, Barrier RC, Jr., Lieberman JA, Harp J. Effect of 
olanzapine on body composition and energy expenditure in adults with first-episode psychosis. 
Am J Psychiatry. 2005;162(1):118-123. doi: 10.1176/appi.ajp.162.1.118. 
 

SAP_001.pdf: 
A Phase 3 Study to Evaluate Weight Gain of ALKS 3831 
Compared to Olanzapine in Adults with Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A303 
NCT Number: 
NCT02694328 
Date of Statistical Analysis 
Plan:  
18 Sep 2018 
 


STATISTICAL ANALYSIS PLAN 
ALK3831-A303 
NCT02694328 
Study Title: 
A Phase 3 Study to Evaluate Weight Gain of ALKS 3831 Compared to 
Olanzapine in Adults with Schizophrenia 
Document Status: 
Final Version 3.0 
Document Date: 
18 Sep 2018 
Based on: 
ALK3831-A303 Protocol Amendment 5.0 Date: 18 Sep 2018 
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. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
Page 2 of 28 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.2 
Summary of the Study Design ......................................................................................7 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................8 
3. 
DATA ANALYSIS ......................................................................................................8 
3.1. 
General Statistical Methodology ..................................................................................8 
3.2. 
Definitions of Analysis Populations .............................................................................9 
3.2.1. 
Safety Population ..........................................................................................................9 
3.2.2. 
Efficacy Population ......................................................................................................9 
3.3. 
Disposition ....................................................................................................................9 
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. 
Duration of study drug administration ........................................................................11 
3.8. 
Efficacy Analyses .......................................................................................................11 
3.8.1. 
General Considerations ...............................................................................................11 
3.8.2. 
Primary Efficacy Endpoints ........................................................................................11 
3.8.2.1. 
Primary Efficacy Endpoint: Percent Change from Baseline in Body Weight 
at Week 24 in the FAS population ..............................................................................11 
3.8.2.2. 
Primary Efficacy Endpoint: Proportion of Subjects with ≥10% Weight Gain 
at Week 24 in the FAS Population .............................................................................14 
3.8.3. 
Key Secondary Endpoint ............................................................................................15 
3.8.4. 
Multiple Comparison/ Multiplicity .............................................................................15 
3.8.5. 
Examination of Subgroups .........................................................................................16 
3.8.6. 
Other Efficacy Endpoints ...........................................................................................16 
3.8.7. 
Exploratory Endpoints ................................................................................................18 


Alkermes, Inc. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
Page 3 of 28 
3.9. 
Safety Analysis ...........................................................................................................18 
3.9.1. 
Adverse Events ...........................................................................................................18 
3.9.1.1. 
Other significant AEs .................................................................................................19 
3.9.2. 
Clinical Laboratory Parameters ..................................................................................19 
3.9.3. 
Vital signs, and Electrocardiograms ...........................................................................23 
3.9.3.1. 
Vital Signs ..................................................................................................................23 
3.9.3.2. 
Electrocardiograms .....................................................................................................23 
3.9.4. 
Abnormal Movement Scales .......................................................................................24 
3.9.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................24 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................25 
4. 
INTERIM ANALYSIS ...............................................................................................25 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................26 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........26 
6.1. 
Analysis Visit Windows .............................................................................................26 
6.2. 
Handling of Partial Dates of Concomitant Medication ..............................................26 
6.3. 
Handling of Safety Data .............................................................................................26 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................27 
7.1. 
Reporting Precision ....................................................................................................27 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................27 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) ............................................27 
10. 
REFERENCES ...........................................................................................................28 
 


Alkermes, Inc. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
Page 4 of 28 
LIST OF TABLES 
Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................20 
Table 2: 
Shifts Category from Baseline to Any Post-Baseline for Selected Lipid 
Parameters ...................................................................................................................21 
Table 3: 
Shift Category from Baseline to Any Post-baseline in Glucose and HbA1c .............22 
Table 4: 
Shift Category from Baseline to Any Post-Baseline in Liver Function Test .............22 
Table 5: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate .............................................................................................................................23 
Table 6: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF ......................24 
Table 7: 
C-SSRS Categories for Analysis ................................................................................25 
Table 8: 
Degree of Precision .....................................................................................................27 
 
LIST OF FIGURES 
Figure 1: 
ALK3831-A303 Study Design Schematic....................................................................8 


Alkermes, Inc. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
Page 5 of 28 
ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
BPM 
Beats per minute 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CI 
confidence interval 
CP 
conditional power 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
EPS 
extra pyramidal symptoms 
ESAP 
Exploratory Statistical Analysis Plan 
ET 
early termination 
FAS 
full analysis set 
GLMM 
generalized linear mixed effect model 
HbA1C 
Hemoglobin A1c 
IA 
Interim Analysis 
IAP 
Interim Analysis Plan 
IWQOL 
Impact of Weight on Quality of Life 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model with repeated measurements 
OLZ 
olanzapine 


Alkermes, Inc. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
Page 6 of 28 
Abbreviation or Term 
Explanation or Definition 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
potentially clinically significant 
PK 
pharmacokinetic 
QTcB 
QT corrected with Bazett formula 
QTcF 
QT corrected with Fridericia formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Scale 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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18 Sep 2018 
 
 
Page 7 of 28 
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-A303. This 
document has been prepared based on Alkermes ALK3831-A303 Study Protocol. 
1.1. 
Study Objectives 
Primary objective: 
• To evaluate weight gain of ALKS 3831 (a fixed-dose combination of olanzapine and 
samidorphan) compared to olanzapine in adults with schizophrenia 
Secondary objective: 
• To evaluate the safety and tolerability of ALKS 3831 in adults with schizophrenia 
1.2 
Summary of the Study Design 
This is a Phase 3, multicenter, randomized, double-blind, study in adults with schizophrenia. 
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 (olanzapine/10 mg samidorphan) or olanzapine 
treatment groups and receive study drug for up to 24 weeks. Subjects are not excluded from the 
study if they are taking other antipsychotic medication. However, they must be tapered off this 
medication and switched onto ALKS 3831 or olanzapine by the end of Week 2, Visit 4. This is 
an outpatient study in which subjects will visit the study site weekly for the first 6 weeks, then 
biweekly for the remaining 18 weeks. Study drug will be provided as coated bilayer tablets 
dispensed to the subjects in blister packs at each visit to be taken at home, one tablet by mouth 
each day, preferably at bedtime. For the first week, subjects will receive 10 mg olanzapine per 
dose: either ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) or OLZ 10 (10 mg 
olanzapine), according to treatment assignment. At the end of Week 1, the dose will escalate to 
20 mg: ALKS 3831 20/10 [20 mg olanzapine/10 mg samidorphan] or OLZ 20). Following this 
increase, the dose may be decreased back to 10 mg at the end of Week 2, 3, or 4 according to 
investigator discretion. No further dose adjustments will be allowed beyond Week 4 and the dose 
will remain fixed for the remaining 20 weeks of the study. Body weight and metabolic 
parameters (including fasting triglycerides, cholesterol, and glucose) will be measured 
throughout the 24-week treatment period. Psychiatric symptoms will also be evaluated using 
Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI). 
A schematic summarizing study design is presented below. 


Alkermes, Inc. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
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Figure 1: 
ALK3831-A303 Study Design Schematic 
 
Subjects completing this study will be eligible to enroll in a long-term safety study 
(ALK3831-A304). Subjects not continuing in the long-term safety study or subjects prematurely 
discontinuing from the study will enter the 4-week safety follow-up period. 
Premature discontinuation procedures are provided in Protocol Section 7.3. Randomized subjects 
who discontinue study drug but are willing to come in for further assessments will be asked to 
complete the early termination (ET) visit followed by 2 safety follow-up visits 2 and 4 weeks 
after the ET visit. They will then be asked to return to the study center for monthly visits until 
end of planned treatment, to collect the following information: weight, adverse events, and new 
antipsychotics. 
2. 
SAMPLE SIZE CONSIDERATION 
The initial target sample size is 200 randomized subjects per treatment group (400 in total). This 
sample size will provide at least 90% power to detect a significant difference in mean percent 
change in body weight at Week 24 of 4% or more (3.0% on ALKS 3831 versus 7% on 
olanzapine group with standard deviation of 9%) and a 13% difference in proportion of subjects 
with ≥10% weight gain at Week 24 (14% on ALKS 3831 versus 27% on olanzapine group). 
An unblinded interim analysis is planned to be conducted to determine if the final sample size 
will be increased to 540 (270 subjects per treatment group), details in ALK3831-A303 Interim 
Analysis Plan. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for the primary efficacy or safety analysis is defined as the last non-missing efficacy or 
safety assessment 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 variables. 


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Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
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The fasting lipids and fasting glucose laboratory parameters will be analyzed on a linear and 
log-transformed scale. 
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. 
To adjust for the unblinded interim analysis for sample size re-estimation, the CHW method will 
be applied to the primary analysis of the two primary endpoints only, with details in 
Section 3.8.2.1.1 and Section 3.8.2.2.1. It will not be applied to the sensitivity or additional 
analysis of the two primary endpoints, analysis of the key secondary, other, exploratory 
endpoints, or subgroup analyses.  
All source data will be presented as subject data listings. 
Body weight is measured 3 times at every visit. The median weight will be used in summary 
tables or figures. 
3.2. 
Definitions of Analysis Populations 
3.2.1. 
Safety Population 
The Safety Population includes 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 Full Analysis Set (FAS) includes 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 Early Weight Gain population includes all subjects in the FAS population who gain weight 
(>0 kg) at Week 1. 
Stage 1 Subjects are defined as first 200 FAS subjects who have completed or prematurely 
discontinued before the interim analysis. 
Stage 2 Subjects are defined as FAS subjects who completed or prematurely discontinued after 
the interim analysis. 
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 in the Early Weight Gain Population 
• Subjects who completed the double-blind treatment period 


Alkermes, Inc. 
Statistical Analysis Plan - ALK3831-A303 
18 Sep 2018 
 
 
Page 10 of 28 
• Subjects who discontinued the study during the double-blind treatment period along 
with reasons for discontinuation 
3.4. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as sex, age, race, ethnicity, weight, and body 
mass index (BMI) and psychiatric history will be summarized overall and by treatment group for 
the Safety Population, the FAS Population, and the Early Weight Gain Population. 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 summarized for the Safety Population by treatment group and overall 
using the number of observations and percentage of subjects reporting each category. 
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 the inclusion/exclusion 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 WHODRUG_C / 161E+H. 
Prior and concomitant medications will be summarized by the preferred drug name for the Safety 
Population. Concomitant medications that are taken during the double-blind treatment period 
will be included in the summary table. For subjects who discontinue study drug prematurely and 
return for monthly visits, 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. 


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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. 
Duration of study drug administration 
Duration of study drug administration (ALKS 3831 and OLZ) is 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 study drug administration will be summarized 
for the Safety Population by treatment group. 
The overall mean and modal dose of olanzapine will be summarized by treatment group. Number 
and percentage of subjects will be summarized by their Visit 6 (Week 4) dose level and by final 
dose level. 
3.8. 
Efficacy Analyses 
3.8.1. 
 General Considerations 
All statistical tests will be 2-sided hypothesis tests performed at the 5% significance level. All 
confidence intervals will be 2-sided 95% confidence intervals. 
Baseline for the primary efficacy analysis is defined as the last non-missing observation on or 
before the first dose of study drug in the double-blind treatment period.  
Only the on-treatment weight assessments will be included in the analyses, unless specified 
otherwise. 
3.8.2. 
Primary Efficacy Endpoints 
The primary efficacy endpoints are 
− percent change from baseline in body weight at Week 24 in FAS population  
− proportion of subjects with ≥10% weight gain at Week 24 in FAS population 
3.8.2.1. 
Primary Efficacy Endpoint: Percent Change from Baseline in Body Weight at 
Week 24 in the FAS population 
3.8.2.1.1. Primary Analysis 
The primary endpoint will be analyzed by analysis of covariance (ANCOVA) with the multiple 
imputation (MI) method for handling of missing values. Only the on-treatment measurements 
will be included in the analysis. The following steps will be performed:  


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1. The missing data on body weight in Stage 1 subjects 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, race (Black or 
African American, Non-Black or African American) and baseline age (<30, ≥30 years) as 
factors, and body weight at all previous visits (including baseline weight) as covariates. 
At least five hundred 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 1104078.  
2. Percent change from baseline in weight at Week 24 of each of these multiply imputed 
datasets will be analyzed by the ANCOVA model with treatment group, race (Black or 
African American, Non-Black or African American), and baseline age (<30, ≥30 years) 
as factors, and the baseline weight as covariate. 
3. Results from Step 2 will be combined using Rubin’s method to get the Stage 1 results, 
including estimated treatment effect, standard error and test statistic 𝑧1.  
4. Repeat Steps 1 to 3 for Stage 2 Subjects. Estimated treatment effect, standard error  and 
test statistic 𝑧2 will be obtained. 
5. To adjust for the IA for sample size re-estimation, the independent test statistic from two 
stages will be combined using the CHW method with a fixed weight of √0.5 based on the 
original sample size (Cui et al, 1999): 
𝑍𝑐ℎ𝑤
∗
= ඥ𝑡1𝑧1 + ඥ1 −𝑡1𝑧2 
where 𝑡1 = 200/400, 
In addition, to estimate the treatment effect, the same MI procedure will be performed based on 
the entire dataset including all FAS subjects. Five hundred imputations will be carried out. The 
results will be analyzed by the same ANCOVA model and combined using Rubin’s method. 
Estimated treatment effect, standard error (SE), and 95% CIs 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-imputed data. 
3.8.2.1.2. Sensitivity Analysis 
To assess the robustness of the primary analysis, the following sensitivity analyses will be 
performed: 


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• 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 OLZ 
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 OLZ 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 include the measurement at the current time point as the 
response variable, and the measurements at the previous time points, the baseline, 
race (Black or African American, Non-Black or African American), and age (<30, 
≥30 years) as covariates. Five hundred imputations will be carried out. For each of the 
500 imputed data sets, the same ANCOVA model as in the primary analysis will be 
fitted to the percent change from baseline at Week 24 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 OLZ and ALKS 3831 from the primary analysis of the percent change from 
baseline in body weight at Week 24 in FAS population. 
• To further assess the potential impact of missing data due to missing not at random 
(MNAR), the primary analysis will be repeated including both on-treatment and 
off-treatment weight assessments after premature discontinuation of study drug. 
• The ANCOVA and MI approach may adjust for additional covariates and/or factors, 
including but not limited to study region or study sites. 
• Average treatment difference across visits through Week 24 between ALKS 3831 and 
OLZ will be analyzed using mixed model with repeated measurements (MMRM) 
model. The MMRM model will include treatment, visit, treatment-by-visit interaction 
term, race (Black or African American, Non-Black or African American) and age 
(<30, ≥30 years) 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. 
3.8.2.1.3. Additional Analyses 
To explore the time point (visit) at which the percent change in body weight from baseline has 
stabilized and is constant during the 24-week double blind treatment period, two methods will be 
performed. 


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• Stepwise tests of linear trend (Maganti et al, 2008) will be performed using a linear 
mixed model (LMM) approach. The LMM model includes treatment, race (Black or 
African American, Non-Black or African American), and age (<30, ≥30 years) as 
fixed effects; visit and treatment-by-visit interaction as random effects; and baseline 
weight as the covariate. In this model, visit will be treated as a continuous variable. 
The slope of each treatment group will be estimated from the model. Denominator 
degrees of freedom will be estimated using the Kenward–Roger approximation 
(Kenward and Roger 1997). The null hypothesis is that there is no linear trend, ie, the 
slope of the regression line equals zero. The alternative is that there is a linear trend. 
The first test of the slope uses the entire range of time points. If the slope is 
significantly different from zero, the second test excludes the earliest time point. The 
testing continues, successively excluding the next earliest time point from the start of 
the study, until the slope is no longer significantly different from zero or until only 
three time points remain in the model. If the final test is not statistically significant, 
then the first time point included in that test is considered to be the time point over 
which a constant weight is attained. If the final test includes three time points and is 
still statistically significant, then no stable weight is considered to have been attained 
by the end of the study. 
• Helmert contrast (Maganti et al, 2008) will be performed using a similar MMRM 
approach as outlined in Section 3.8.2.1.2. The first contrast compares the mean 
change in body weight at the first time point to the pooled mean change in body 
weight over all remaining time points. The second contrast compares the mean at the 
second time point to the pooled mean over all remaining time points. Testing 
continues until the contrast is not statistically significant. The first time point included 
in this last contrast is concluded to be the time interval on which a stable weight is 
attained. If the final test is still statistically significant, then no stable weight is 
considered to have been attained by the end of the study. 
3.8.2.2. 
Primary Efficacy Endpoint: Proportion of Subjects with ≥10% Weight Gain at 
Week 24 in the FAS Population 
3.8.2.2.1. Primary Analysis 
The primary analyses will be carried out using a logistic regression model based on MI for 
missing data as described in Section 3.8.2.1.1 . Proportion of subjects with ≥10% Weight Gain at 
Week 24 will be derived based on the same complete datasets obtained from the multiple 
imputation procedure. The logistic regression model will include the treatment group, race 
(Black or African American, Non-Black or African American), and age (<30, ≥30 years) as 
factors; and the baseline weight as the covariate. 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 primary analyses. 
Similarly to the primary efficacy endpoint of percent change from baseline body weight at Week 
24, the independent test statistic before and after the interim analysis will be combined using the 
CHW method with a fixed weight of √0.5 based on the original sample size. The treatment 
effects and 95% CIs will be reported as described in Section 3.8.2.1.1. 


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3.8.2.2.2. Sensitivity analysis 
To assess the robustness of the primary analysis of the primary endpoint, the following 
sensitivity analyses will be performed: 
• To assess the potential impact of missing data due to missing not at random (MNAR), the 
delta-adjusted Pattern Mixture Model in Section 3.8.2.1.2  will be conducted to assess the 
impact of missing data. Proportion of subjects with ≥10% Weight Gain at Week 24 will 
be derived based on the same complete datasets obtained from the multiple imputation 
procedure in Section 3.8.2.1.2. The logistic regression model as in the primary analysis 
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. 
• To further assess the potential impact of missing data due to missing not at random 
(MNAR), the approach described in Section 3.8.2.2.1 will be repeated including both on-
treatment and off-treatment weight assessments after premature discontinuation of study 
drug. 
• The logistic regression model may also adjust for additional covariates and/or factors, 
including but not limited to, study region or study sites. 
• Average treatment difference across visits through Week 24 between ALKS 3831 and 
OLZ will be analyzed. 
3.8.2.2.3. Additional Analyses 
To assess the impact of different cutoffs for weight gain (ie, 5%, 7%, 10%, etc), a plot of 
cumulative responder distribution at Week 24 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 weight gain. The analysis will be based on MI imputation for missing data. 
3.8.3. 
Key Secondary Endpoint 
The key secondary endpoint is the proportion of subjects with ≥7% weight gain at Week 24. The 
primary analysis will be carried out using a logistic regression model based on MI without CHW 
adjustment as described in Section 3.8.2.2.1. The sensitivity analysis will be the same as 
Section 3.8.2.2.2.  
3.8.4. 
Multiple Comparison/ Multiplicity 
The study will be claimed positive when the primary analyses of both co-primary efficacy 
endpoints are statistically significant based on the CHW method to adjust for the unblinded 
interim analysis for sample size re-estimation; therefore, both co-primary endpoints will be 
tested at a full α level of 0.05. A fixed sequence approach will be used to control overall Type I 
error rate for the primary and key secondary endpoints. Only if both primary endpoints are 
statistically significant based on the CHW method will the key secondary endpoint be further 
tested at an alpha level of 0.05. 


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3.8.5. 
Examination of Subgroups 
Subgroup analyses of the primary endpoints will be performed for each of the following 
categories: 
• Sex (male, female) 
• Age (<30 years, ≥30 years) 
• Race (Black or African American, Non-Black or African American) 
• BMI (<27 kg/m2, ≥27 kg/m2) 
The forest plot of the least squares mean difference along with 95% CIs in percent change in 
body weight from baseline at Week 24 between ALKS 3831 and OLZ will be provided by the 
subgroup factors listed above. 
3.8.6. 
Other Efficacy Endpoints 
• Percent change from baseline in body weight at Week 24 in the Early Weight Gain 
population  
• Proportion of subjects with ≥10% weight gain at Week 24 in the Early Weight Gain 
population 
• Change from baseline in fasting lipids (fasting triglycerides, LDL, HDL, total 
cholesterol), fasting glucose, fasting insulin and HbA1c by visit 
• Absolute change in body weight by visit 
• Change from baseline in waist circumference by visit 
• Change from baseline in PANSS total score and subscales by visit 
• Change from baseline in Clinical Global Impression-Severity (CGI-S) by visit 
• CGI-I score by visit 
• Change from baseline in Impact of Weight on Quality of Life (IWQOL)-Lite total 
score and subscales by visit 
• Change from baseline in EuroQol five dimensions questionnaire (EQ-5D)-5L score 
by visit 
The following endpoints will be analyzed similarly by ANCOVA model and MI for missing data 
as noted in Section 3.8.2.1.1, without CHW adjustment: 
• Percent change from baseline in body weight at Week 24 in the Early Weight Gain 
population 
• Absolute change in body weight by visit 
• Change from baseline in waist circumference by visit 
Proportion of subjects with ≥10% weight gain at Week 24 in the Early Weight Gain population 
will be analyzed similarly by logistic regression model and MI for missing data as described in 
Section 3.8.2.2.1, without CHW adjustment. 


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Change from baseline in fasting lipids (fasting triglycerides, LDL, HDL, total cholesterol), 
fasting glucose, fasting insulin and HbA1c will be analyzed by the same MMRM model as 
described in Section 3.8.2.1.2. The model will include treatment, visit, treatment-by-visit 
interaction term, race (Black or African American, Non-Black or African American) and age 
(<30, ≥30 years) as categorical fixed effects; the baseline value will be included as the covariate. 
MMRM model will also be applied to the following endpoints: 
• Change from baseline in PANSS total score and subscales by visit 
• Change from baseline in Clinical Global Impression-Severity (CGI-S) by visit 
• Change from baseline in Impact of Weight on Quality of Life (IWQOL)-Lite total 
score and subscales by visit 
• Change from baseline in EuroQol five dimensions questionnaire (EQ-5D)-5L score 
by visit 
The model will include treatment, visit, treatment-by-visit interaction term as categorical fixed 
effects; the baseline value will be included as a covariate. 
PANSS responder status (<20%, ≥20% improvement over baseline PANSS), CGI-I score, and 
CGI-I responder status (≤2 versus >2) at each visit will be summarized by descriptive statistics. 
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 
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 
The EQ-5D-5L is a validated quality of life questionnaire developed by the EuroQol Group in 
order to provide a simple, generic utility measure for characterizing current health states of 
patients. EQ-5D-5L is designed for self-completion by subjects. It consists of 2 parts – the EQ-
5D-5L descriptive system and the visual analogue scale (VAS). 
The EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels. 
The 5 dimensional 5-level systems are converted into an index value. Values for theoretically 
possible health states are calculated using a regression model and weighted according to the 
social preferences of the U.S. population (Van Hout et al, 2012). The VAS records the 
respondent’s self-rated health on a vertical visual analogue scale. The VAS ‘thermometer’ has 
100 (Best imaginable health state) at the top and 0 (Worst imaginable health state) at the bottom. 
This information can be used as a quantitative measure of health outcomes as judged by the 
individual respondents. EQ-5D-5L self-reported VAS data generates information on the self-
perceived overall health-related quality of life. 


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Additional analyses of metabolic laboratory parameters, body weight, and PANSS total score are 
included in the Exploratory Statistical Analysis Plan (ESAP) conducted outside the scope of this 
SAP. 
3.8.7. 
Exploratory Endpoints 
Body composition is assessed in the substudy at Visit 2 (Week 1) and Visit 17/ 
ET (Week 24) for a subset of subjects by the following exploratory endpoints: 
• Absolute change from baseline in lean mass 
• Absolute change from baseline in fat mass 
• Change from baseline in percent body fat 
These endpoints will be analyzed by the ANCOVA method adjusting for race (Black or African 
American, Non-Black or African American), and baseline age (<30, ≥30 years) as factors and 
corresponding baseline value as covariate for the subset of subjects with baseline and post-
baseline body composition assessments.  
3.9. 
Safety Analysis 
3.9.1. 
Adverse Events 
Adverse events will be coded by System Organ Class and Preferred Term using the Medical 
Dictionary for Regulatory Activities (MedDRA®) Version 21.0. The verbatim term will be 
included in the AE listings. 
An AE (classified by preferred term) will be considered as treatment-emergent AE (TEAE) if the 
event is newly occurring or worsening on or after the date of first dose of study drug. 
The number and percentage of subjects reporting TEAEs during the double-blind treatment 
period in each treatment group 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 OLZ 
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 
The number and percentage of subjects reporting TEAEs during the double-blind treatment 
period between Visit 6 (Week 4) to Visit 17 (Week 24) will be presented by treatment group, 
OLZ dose levels at Visit 6 and preferred terms. 


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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 during the Safety Follow-up 
Period will be tabulated by the system organ class, preferred term and treatment group. 
For the subjects who prematurely discontinue the study drug and return for the monthly visits, all 
AEs collected after discontinuation of the study drug will be summarized by system organ class, 
preferred term and treatment group. 
The number and percentage of subjects who have serious adverse events (SAE) and AEs leading 
to premature discontinuation from the treatment will be summarized by preferred term and 
treatment group and will be sorted by decreasing frequency for ALKS 3831 group. 
3.9.1.1. 
Other significant AEs 
In addition, incidence of a selected subset of relevant AEs in this class of drugs 
(eg, Extrapyramidal symptom (EPS) TEAEs, AEs associated with abuse potential, AEs 
associated with drug withdrawal, and suicide related events, etc.) 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). 
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. 
Number (percentage) of subjects with potentially clinically significant (PCS) values at any post-
baseline visit, will be summarized by treatment group. PCS criteria are presented in Table 1. 
The denominator is all subjects with non-PCS baseline and at least one post-baseline assessment 
in the Safety Population and the numerator is the number of subjects with non-PCS baseline and 
PCS at post-baseline. All PCS values including baseline PCS values will be included in 
supportive listings. 
Shift tables for metabolic parameters (fasting glucose, total cholesterol, LDL, HDL, 
Triglycerides, and HbA1c) and liver function tests will be presented. The criteria are summarized 
in Table 2, Table 3 and Table 4. 


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameters 
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 
≤30 mg/dL 
Cholesterol, LDL Fasting 
≥160 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 
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 
Sodium 
<130 mmol/L or 
>150 mmol/L 
Triglycerides, Fasting (Female) 
≥120 mg/dL 
Triglycerides, Fasting (Male) 
≥160 mg/dL 


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes (Continued) 
Parameters 
Criteria 
Hematology 
Eosinophils 
>1.0 × 103/μL 
Hematocrit (Female) 
≤32% 
Hematocrit (Male) 
≤37% 
Neutrophils, Absolute 
<1.5 × 103/μL 
Platelets 
<75.0 × 103 cells/μL or 
≥ 700.0 × 103 cells/μL 
Leukocytes 
≤ 2.8 × 103/μL or 
≥ 16.0 ×103/μL 
Table 2: 
Shifts Category from Baseline to Any Post-Baseline for Selected Lipid 
Parameters 
Total cholesterol (fasting) mg/dL 
  Normal (<200) to high (≥240) 
  Borderline (≥200 and < 240) to high (≥240) 
  Normal/Borderline (<240) to high (≥240) 
  Normal (<200) to borderline/high (≥200) 
  Increase ≥40 mg/dL 
LDL Cholesterol (fasting) mg/dL 
  Normal (<100) to high (≥160) 
  Borderline (≥100 and <160) to high (≥160) 
  Normal/borderline (<160) to high (≥160) 
  Normal (<100) to borderline/high (≥100) 
  Increase ≥30 mg/dL 
HDL Cholesterol (fasting) mg/dL 
  Normal (≥40) to low (<40) 
  Decrease ≥20 mg/dL 
Triglycerides (fasting) mg/dL 
  Normal (<150) to high (≥200) 
  Normal (<150) to very high (≥500) 
  Borderline (≥150 and <200) to high (≥200) 


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Table 2: 
Shifts Category from Baseline to Any Post-Baseline for Selected Lipid 
Parameters (Continued) 
 
Table 3: 
Shift Category from Baseline to Any Post-baseline in Glucose and HbA1c 
Serum glucose (fasting) mg/dL 
  Normal (<100) to high (≥126) 
  Impaired (≥100 and <126) to high (≥126) 
  Normal/Impaired (<126) to high (≥126) 
  Increase ≥10 mg/dL 
HbA1c% 
  Shift from baseline (<5.7%) to post-baseline ≥5.7% 
  Shift from baseline (<5.7%) to post-baseline ≥5.7% and <6.5% 
  Shift from baseline (<5.7%) to post-baseline ≥6.5% 
Table 4: 
Shift Category from Baseline to Any Post-Baseline in Liver Function Test 
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 
Triglycerides (fasting) mg/dL 
  Borderline (≥150 and <200) to very high (≥500) 
  Normal/borderline (<200) to high (≥200) 
  Normal/borderline (<200) to very high (≥500) 
  Normal (<150) to borderline/high/very high (≥150) 
  Increase ≥50 mg/dL 


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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 5. The number and percentage of subjects with PCS 
post-baseline 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 post-baseline assessment for the double-blind period. The 
numerator will be the total number of subjects with available baseline values and at least 1 PCS 
post-baseline value for double-blind period. A supportive tabular display of subjects with PCS 
post-baseline values will be provided, including the subject ID number, and baseline and all post-
baseline (including non-PCS) values. 
All vital signs will be presented in the subject data listing. 
Orthostatic hypotension (20/10) is defined as a fall in systolic blood pressure of at least 
20 mmHg and a fall in the diastolic blood pressure of at least 10 mmHg upon standing from 
supine. Orthostatic hypotension (30) is defined as a fall in systolic blood pressure of at least 
30 mmHg upon standing from supine. 
Orthostatic tachycardia is defined as a heart rate increase of 30 beats per minute (bpm) or more 
upon standing from supine, or over 120 bpm upon standing. 
The number and percentage of subjects with orthostatic hypotension or orthostatic tachycardia 
occurring at any post-baseline visit will also be summarized by treatment group for the 
double-blind period. 
Table 5: 
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 each assessment 
time point and at the end of the double-blind treatment period will be presented by treatment 
group for the double-blind period. QTc interval will be calculated using both Bazett 


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(QTcB = QT/(RR)½) and 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 6. The number and percentage of subjects with PCS post-baseline 
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 post-baseline 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 post-baseline value 
for the double-blind treatment period. A supportive tabular display of subjects with PCS post-
baseline values will be provided, including the subject ID number, study center number, the 
baseline value, all post-baseline (including non-PCS) values, and change from baseline. 
Table 6: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF 
Parameter 
Criteria 
QTcB and 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. 
Abnormal Movement Scales 
Extra pyramidal symptoms (EPS) will be evaluated as AEs and also as assessed by abnormal 
movement scales. Abnormal movement scales will include the following: Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale 
(SAS). 
For all abnormal movement scales, total scores and subscale scores will be summarized by 
treatment group at each visit for the absolute value and for changes from baseline. 
Number and percentage of subjects meeting the criteria for treatment-emergent Parkinsonism 
(SAS total score>3), for treatment-emergent akathisia (BARS global clinical assessment of 
akathisia score ≥2), for treatment-emergent dyskinesia (AIMS score ≥3 on any of the first 7 
items, or a score ≥2 on two or more of any of the first 7 items) at any post-baseline visit will be 
summarized by treatment group. 
A listing will be provided for every abnormal movement scale. Listing for treatment-emergent 
EPS will be provided. 
3.9.5. 
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. 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 7: 
C-SSRS Categories for Analysis 
Category 
C-SSRS Item response is “YES” 
Suicidal behavior 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideation 
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 
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. 
4. 
INTERIM ANALYSIS 
One unblinded interim analysis will be conducted by an independent statistical center (ISC) 
when 50% of subjects (N=200) have completed the double-blind treatment period or have 
discontinued from the study. The details regarding the conduct of the unblinded interim analysis 
will be specified in the interim analysis operational plan and the statistical testing methodology 
will be specified in the interim analysis plan (IAP). 
The conditional power (CP) will be computed for both primary endpoints. Based on the 
conditional power, it will be assigned into one of 3 zones: favorable (CP ≥90%), promising (30%  
≤ CP <90%), or unfavorable (CP< 30%). The target sample size of 200 per arm will be increased 
to 270 subjects per arm when the conditional power for at least one primary endpoint is in the 
promising zone and neither of the primary endpoints are in the unfavorable zone. Otherwise, the 
target sample size will be maintained at 200 subjects per arm. Overall Type 1 error for the final 
analysis are maintained using CHW method (Cui et al, 1999) by combining the Z test statistics 
from two indpendent stages (before and after the interim analysis) with a fixed weight based on 
the original sample size. The weighted CHW statistics always controls type I error, as it does not 
depend on the design specifications, such as the sample size adaptation algorithm, the maximum 


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number to be increased, and the final sample size (Hung et al, 2014).There will be no early 
stopping for efficacy or futility. The sponsor will not be informed of any unblinded interim 
analysis results except for a recommendation to either increase the sample size to 540 subjects 
(270 per arm) or to leave the sample size unchanged. 
5.
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM
THE PROTOCOL
There are no major deviations from the protocol-specified analysis. 
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 collected outside of 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. 
Visit Day is calculated as (visit date) – (date of the first dose of study drug) + 1. 
Last post-baseline values are defined as the last valid post-baseline values collected for each 
subject during the double-blind treatment period. 
Any post-baseline values are defined as any valid values collected from scheduled visits if 
applicable. 
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. 


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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 post-baseline values, and subject listings. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
7.1. 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Table 8: 
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
Alkermes ALK3831-A303 Study Protocol Amendment 5.0 Date: 18 Sep 2018 
Alkermes ALK3831-A303 Interim Analysis Plan Final Version 2.0 Date: 05 May 2017 
Alkermes ALK3831-A303 Interim Operational Plan Final Version 2.0 Date: 05 May 2017 
Alkermes ALK3831-A303 Exploratory Statistical Analysis Plan Final Version 1.0 Date: 18 Sep 
2018 
Cui L, Hung H, Wang S. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55:853-857. 
Hung HM, Wang SJ, Yang P. Some challenges with statistical inference in adaptive designs. J 
Biopharm Stat. 2014;24(5):1059-1072. doi: 10.1080/10543406.2014.925911. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-997. 
Maganti L, Panebianco DL, Maes AL. Evaluation of methods for estimating time to steady state 
with examples from phase 1 studies. AAPS J. 2008;10(1):141-147. 
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. 
van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping the EQ-
5D-5L to EQ-5D-3L value sets. Value Health. 2012;15(5):708-715. doi: 
10.1016/j.jval.2012.02.008.