Conditions: Schizophrenia Schizophreniform Disorder Bipolar I Disorder
Keywords: Alkermes ALKS 3831 Olanzapine Samidorphan Schizophrenia Schizophreniform Bipolar I
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 523
Healthy volunteers: no

Brief summary:
This study will evaluate the long-term safety, tolerability, and durability of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform disorder, or bipolar I disorder

Detailed description:

Arms:
arm 1: Coated bilayer tablet

Interventions: intervention 1: ALKS 3831
Intervention descriptions: intervention 1: Olanzapine + samidorphan, daily oral dosing

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
ALK3831-A308 
EudraCT 2017-000918-36 
 
Study Title: 
A Phase 3 Study to Assess the Long-Term Safety, 
Tolerability, and Durability of Treatment Effect of 
ALKS 3831 in Subjects with Schizophrenia, 
Schizophreniform Disorder, or Bipolar I Disorder 
Document Date: 
Amendment 3.0: 09 May 2019 
Amendment 2.0: 10 Jan 2018 
Amendment 1.0: 12 Sep 2017 
Original Protocol: 01 Feb 2017 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 
 
 
 




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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 Assess the Long-Term Safety, Tolerability, and Durability of 
Treatment Effect of ALKS 3831 in Subjects with Schizophrenia, Schizophreniform Disorder, or 
Bipolar I Disorder 
Investigator(s): This is a multinational multicenter study. 
Study Period: 
Estimated date of first subject’s consent: Q2 2017 
Estimated date of last subject’s last visit: Q4 2022 
Phase of Development: 3 
Objective: The primary objective of this study is to evaluate the long-term safety, tolerability, and 
durability of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform disorder, 
or bipolar I disorder. 
Methodology: This is a multicenter, open-label study to evaluate the long-term safety, tolerability, and 
durability of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform disorder, 
or bipolar I disorder. Subjects that have completed the antecedent studies (ALK3831-A304, 
ALK3831-A306, or ALK3831-A307) within the past 7 days will be eligible to enroll in this study. 
Subjects enrolled in the study will be started on the same olanzapine dose that they had maintained at 
the end of the antecedent study. Available doses of ALKS 3831 will be 5, 10, 15, and 20 mg olanzapine 
combined with 10 mg samidorphan (henceforth to be referred to as 5/10, 10/10, 15/10, and 20/10 mg). 
Subjects may be titrated to a different dose after the start of the study at the Investigator’s discretion. 
Dosing will be flexible throughout the study; however, frequent adjustments are discouraged. Dose 
adjustments will only be performed on-site at the study center. Subjects requiring dose adjustments 
between scheduled visits will need to arrange an unscheduled visit. 
Safety assessments will include adverse event (AE) monitoring, clinical laboratory testing, vital signs, 
body weight, electrocardiograms (ECGs), and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
Psychiatric symptoms will be evaluated using the Clinical Global Impressions-Severity (CGI-S) scale. 
Additional assessments will include Impact of Weight on Quality of Life-Lite Questionnaire 
(IWQOL-Lite). A schematic summarizing study design is presented below. 
Study Design Schematic: 


 
 
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Number of Subjects Planned: Approximately 500 subjects 
Main Criteria for Inclusion: Subjects will have completed the treatment period in one of the 
following antecedent studies within 7 days: ALK3831-A304, ALK3831-A306, or ALK3831-A307. 
Subjects will have potential to benefit from ALKS 3831 in the opinion of the investigator, and agree to 
use an acceptable method of contraception during the study and until 30 days after any study drug 
administration, unless surgically sterile or post-menopausal. 
Main Criteria for Exclusion: Subjects may be excluded based on positive tests for drugs of abuse at 
study entry, any finding that would compromise the subject’s safety or their ability to fulfill the study 
requirements, pregnancy or breastfeeding, or employment by (or relationship to an employee of) the 
study sponsor, clinical research organization, or study site. 
Investigational Product, Dosage, Duration, and Mode of Administration: ALKS 3831 refers to the 
fixed dose combination of olanzapine and samidorphan. ALKS 3831 will be supplied as a coated 
bilayer tablet containing 5, 10, 15, or 20 mg olanzapine and 10 mg samidorphan. The tablet will be 
taken by mouth once daily, preferably at bedtime, for at least 24 but not more than 48 months. The 
study is planned to be open until approximately the 4th quarter 2022 or until regulatory action. 
Therefore, depending on when a subject is enrolled, the duration of participation in this study will vary. 
Reference Therapy, Dosage, Duration, and Mode of Administration: None 
Duration of Study: The total study duration will be up to 49 months, including a treatment period of 
24 to 48 months and a 4-week safety Follow-up period. 
Criteria for Evaluation: 
Safety and Tolerability: The following parameters will be collected to measure safety and tolerability 
throughout the study: 
• 
AEs (including clinically significant abnormal ECG findings) 
• 
Vital signs (oral temperature, respiratory rate, blood pressure, and heart rate) 
• 
Weight and waist circumference 
• 
Clinical laboratory parameters (biochemistry, hematology, and urinalysis) 
• 
C-SSRS 
Efficacy: Throughout the study, CGI-S scores will be collected to measure the durability of treatment 
effect. 
Other: Throughout the study, IWQOL-Lite scores will be collected to obtain information regarding 
subject experience. 
Endpoints: 
Safety and Tolerability Endpoints: 
• 
Incidence of AEs 
• 
Percent change from baseline in body weight by visit 
• 
Absolute change from baseline in body weight by visit 
• 
Change from baseline in waist circumference by visit 
Efficacy Endpoints: 
• 
Change from baseline in CGI-S by visit 
• 
Time to discontinuation 
• 
Change from baseline in IWQOL-Lite score by visit 
Statistical Methods: In general, summary statistics (n, mean, standard deviation, median, minimum 


 
 
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and maximum for continuous variables, and number [%] of subjects in each category for categorical 
variables) will be provided for all variables. Source data for the summary tables and statistical analyses 
will be presented as subject data listings. 
Study Populations: The Safety Population will include all enrolled subjects who receive at least 
1 dose of study drug. All analyses will be conducted using the Safety Population. 
Efficacy Analyses: Changes from baseline in CGI-S and IWQOL-Lite scores will be summarized 
using descriptive statistics. The time to discontinuation will be estimated using the Kaplan-Meier (KM) 
method and the KM plot will be provided. 
Safety Analyses: All safety assessments will be summarized using descriptive statistics. All safety 
analyses will be based on observed data only, and no missing values will be imputed. Reported AE 
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized by preferred term and system organ class categories. Serious adverse events (SAEs) and 
AEs leading to study discontinuation will also be summarized. 
Observed values and change from baseline in laboratory parameters and vital signs will be summarized 
by study visit. The number and percentage of subjects who have met potentially clinically significant 
criteria at any post baseline visit will be summarized for laboratory and vital signs. The number and 
percentage of subjects with shifts in laboratory parameters will be summarized. Supporting listings will 
be provided. The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will also be summarized. 
Concomitant medication use will be summarized by World Health Organization Anatomical 
Therapeutic Chemical (WHO ATC) classification system. Listings will be provided for all concomitant 
medications. 
Sample Size Considerations: No formal sample size calculation will be performed for this extension 
study. A sample size of approximately 500 is based on the estimated number of subjects who are 
expected to roll over from the antecedent Phase 3 studies (ALK3831-A304, ALK3831-A306, and 
ALK3831-A307). 
 


 
 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................6 
4. 
LIST OF ABBREVIATIONS.....................................................................................10 
5. 
INTRODUCTION ......................................................................................................11 
5.1. 
Background .................................................................................................................11 
5.2. 
Study Drugs ................................................................................................................11 
5.2.1. 
Samidorphan ...............................................................................................................12 
5.2.2. 
Olanzapine ..................................................................................................................12 
5.3. 
Study Rationale ...........................................................................................................12 
5.4. 
Dose Rationale ............................................................................................................13 
5.5. 
Benefit-Risk Assessment ............................................................................................13 
6. 
OBJECTIVES .............................................................................................................14 
6.1. 
Primary Objective .......................................................................................................14 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................15 
7.1. 
Subject Inclusion Criteria ...........................................................................................15 
7.2. 
Subject Exclusion Criteria ..........................................................................................15 
7.3. 
Subject Withdrawal ....................................................................................................16 
7.4. 
Replacement of Subjects .............................................................................................16 
8. 
STUDY DESIGN .......................................................................................................17 
8.1. 
Overall Study Design and Plan ...................................................................................17 
8.2. 
Schedule of Visits and Assessments ...........................................................................18 
8.3. 
Study Procedures Descriptions ...................................................................................21 
8.3.1. 
Informed Consent .......................................................................................................21 
8.3.2. 
Eligibility Review .......................................................................................................21 
8.3.3. 
Demographics and Medical / Psychiatric History ......................................................21 
8.3.4. 
Concomitant Medication Review ...............................................................................21 
8.3.5. 
Vital Signs ..................................................................................................................21 
8.3.6. 
Physical Examination .................................................................................................21 
8.3.7. 
Weight and Waist Circumference ...............................................................................22 
8.3.8. 
Structured Interviews and Questionnaires ..................................................................22 


 
 
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8.3.8.1. 
Safety Assessments .....................................................................................................22 
8.3.8.2. 
Psychiatric/Quality of Life Assessments ....................................................................22 
8.3.9. 
Laboratory Assessments .............................................................................................22 
8.3.9.1. 
Drug Testing ...............................................................................................................22 
8.3.9.2. 
Hematology, Biochemistry, and Urinalysis ................................................................23 
8.3.9.3. 
Urine Pregnancy Testing ............................................................................................24 
8.3.10. 
Drug Dispensation and Reconciliation .......................................................................25 
8.3.11. 
Emergency Treatment Card ........................................................................................25 
8.3.12. 
Adverse Event Monitoring .........................................................................................25 
8.4. 
Study Requirements and Restrictions .........................................................................25 
8.4.1. 
Contraception and Pregnancy .....................................................................................25 
8.4.2. 
Prohibited Medications ...............................................................................................26 
8.4.3. 
Permitted Medications ................................................................................................26 
8.4.4. 
Pain Management .......................................................................................................27 
8.4.5. 
Fasting.........................................................................................................................27 
8.4.6. 
Other Restrictions and Requirements .........................................................................27 
9. 
TREATMENT OF SUBJECTS ..................................................................................29 
9.1. 
Study Drug Dose and Administration .........................................................................29 
9.2. 
Treatment Adherence ..................................................................................................29 
9.3. 
Randomization/Method of Assigning Subjects to Treatment .....................................29 
9.4. 
Blinding ......................................................................................................................29 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................30 
10.1. 
Study Drug ..................................................................................................................30 
10.2. 
Packaging and Labeling ..............................................................................................30 
10.3. 
Storage ........................................................................................................................30 
10.4. 
Accountability .............................................................................................................30 
10.5. 
Handling and Disposal ................................................................................................30 
11. 
ASSESSMENT OF EFFICACY ................................................................................32 
11.1. 
Efficacy Endpoints ......................................................................................................32 
12. 
ASSESSMENT OF PHARMACOKINETICS ...........................................................33 
13. 
ASSESSMENT OF SAFETY .....................................................................................34 
13.1. 
Safety Endpoints .........................................................................................................34 
13.2. 
Definition of Adverse Event .......................................................................................34 


 
 
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13.3. 
Definition of Serious Adverse Event ..........................................................................34 
13.4. 
Relationship to Study Drug ........................................................................................35 
13.5. 
Monitoring and Recording of Adverse Events ...........................................................36 
13.6. 
Reporting of Serious Adverse Events and Pregnancy ................................................37 
14. 
STATISTICS ..............................................................................................................38 
14.1. 
Sample Size Considerations .......................................................................................38 
14.2. 
General Statistical Methodology ................................................................................38 
14.2.1. 
Study Population .........................................................................................................38 
14.2.1.1. 
Safety Population ........................................................................................................38 
14.3. 
Demographics and Baseline Data ...............................................................................38 
14.4. 
Efficacy Analyses .......................................................................................................38 
14.5. 
Pharmacokinetic Analyses ..........................................................................................38 
14.6. 
Safety and Tolerability Analyses ................................................................................38 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................40 
15.1. 
Study Monitoring ........................................................................................................40 
15.2. 
Audits and Inspections ................................................................................................40 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................40 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................41 
16.1. 
Case Report Forms .....................................................................................................41 
16.2. 
Confidentiality of Data ...............................................................................................41 
17. 
ETHICAL CONSIDERATIONS................................................................................42 
17.1. 
Ethics Review .............................................................................................................42 
17.2. 
Ethical Conduct of the Study ......................................................................................42 
17.3. 
Written Informed Consent ..........................................................................................42 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................44 
18.1. 
Data Capture ...............................................................................................................44 
18.2. 
Inspection of Records .................................................................................................44 
18.3. 
Retention of Records ..................................................................................................44 
18.4. 
Use of Information and Publication Policy ................................................................45 
19. 
REFERENCES ...........................................................................................................46 
20. 
APPENDIX A: PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A INHIBITORS AND INDUCERS ..............................................................47 


 
 
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21. 
APPENDIX B: PARTIAL LIST OF CYP1A2 MODERATE-TO-STRONG 
INHIBITORS AND MODERATE INDUCERS ........................................................48 
22. 
APPENDIX C: PARTIAL LIST OF MEDICATIONS KNOWN TO BE 
ASSOCIATED WITH PROLONGED QTC INTERVAL AND TORSADE 
DE POINTES ..............................................................................................................49 
 
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ..........................................................10 
Table 3: 
Schedule of Assessments ............................................................................................19 
Table 4: 
Clinical Laboratory Assessments ...............................................................................24 
Table 5: 
Adverse Event Causality Guidelines ..........................................................................36 
Table 6: 
Partial List of CYP3A Inhibitors and Inducers ...........................................................47 
Table 7: 
Partial List of CYP1A2 Inhibitors and Inducers .........................................................48 
Table 8: 
Partial List of Medications Known to Be Associated with Prolonged QTc 
Interval and Torsade de Pointes ..................................................................................49 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................17 
 


 
 
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4. 
LIST OF ABBREVIATIONS 
Table 2: List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Full Form or Definition 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
ATC 
Anatomical Therapeutic Chemical [classification system] 
CGI-S 
Clinical Global Impressions-Severity 
CRO 
Clinical Research Organization 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IWQOL-Lite 
Impact of Weight on Quality of Life-Lite 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
PI 
Principal Investigator 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 


 
 
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5. 
INTRODUCTION 
5.1. 
Background 
Olanzapine has been commercially available for over 20 years as a treatment for schizophrenia 
and bipolar I disorder (see local olanzapine label) and is regarded as a highly effective treatment 
with demonstrated antipsychotic efficacy and decreased incidence of extrapyramidal symptoms. 
However, the greater antipsychotic efficacy of olanzapine is undermined by its propensity to 
cause significant weight gain and increased cardio metabolic risk compared to other atypical 
antipsychotic drugs (Allison et al, 1999; Leucht et al, 2013; Lieberman et al, 2005; Meyer et al, 
2008; Wirshing et al, 1999). Olanzapine is also recommended as a second-line treatment in 
patients early in illness according to the Schizophrenia Patient Outcomes Research Team 
(PORT) treatment guidelines (Buchanan et al, 2010). This is largely due to the fact that 
olanzapine-induced weight gain and metabolic risk is especially pronounced in patients who are 
early in illness for both schizophrenia and bipolar disorder (Correll et al, 2014). 
Alkermes is developing ALKS 3831 as a fixed-dose combination of olanzapine and samidorphan 
(a µ-opioid receptor antagonist), for the treatment of schizophrenia designed to combine the 
antipsychotic efficacy of olanzapine with a reduced risk of weight gain and associated metabolic 
deficits. The novel combination of olanzapine and samidorphan in ALKS 3831 has the potential 
to deliver the therapeutic benefits of olanzapine to patients while avoiding the harmful weight 
gain and associated metabolic risks. 
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 and 
safety. Four Phase 3 studies (ALK3831-A303, ALK3831-A304, ALK3831-A305, and 
ALK3831-A306) are ongoing to assess the efficacy, associated weight changes, and safety of 
ALKS 3831 in subjects with schizophrenia. One Phase 3 study (ALK3831-A307) is planned to 
begin enrollment in 2017 and will evaluate the effect of ALKS 3831 compared to olanzapine on 
body weight in young adults with schizophrenia, schizophreniform, or bipolar I disorder with a 
recent onset of symptoms and early in medical treatment. 
5.2. 
Study Drugs 
In this study a fixed dose combination of olanzapine and samidorphan will be administered in a 
single bilayer tablet. The following sections provide an overview of samidorphan and 
olanzapine. Detailed information about the study drugs can be found in the current 
ALKS 3831 Investigator’s Brochure. 
 
 


 
 
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5.2.1. 
Samidorphan 
Samidorphan is a new molecular entity in clinical development by Alkermes. Samidorphan is a 
µ-opioid receptor antagonist. It is currently being investigated in combination with olanzapine 
for the treatment of schizophrenia (ALKS 3831) and in combination with buprenorphine for the 
treatment of major depressive disorder (ALKS 5461). Based on its chemical structure, 
samidorphan is considered a Schedule II controlled substance according to the US Drug 
Enforcement Agency and will require proper handling (see Section 10.5). At least 10 clinical 
studies of samidorphan have been conducted to date, eight of which included subjects that 
received samidorphan alone (not in combination with another product). Overall, over 
2000 subjects have been exposed to samidorphan as a single agent or in combination with 
olanzapine or buprenorphine in completed and ongoing clinical studies. Commonly reported 
adverse events (AEs) observed across all studies included nausea, fatigue, and somnolence. 
Overall, no trends or clinically meaningful changes have been observed in clinical laboratory 
analytes, vital sign parameters, or electrocardiogram (ECG) data. 
5.2.2. 
Olanzapine 
Olanzapine has been commercially available for over 20 years as a treatment for schizophrenia 
and bipolar I disorder (see local olanzapine label). The safety and tolerability profile of 
olanzapine is well documented, and AE labeling is supported by an extensive safety database 
with over 20 years of post-marketing experience (see local olanzapine label). Commonly 
reported AEs consistent across all or most dosage forms in short-term, placebo controlled trials 
include somnolence, constipation, dry mouth, accidental injury, weight gain, postural 
hypotension, dizziness, asthenia, fever, and abnormal gait. 
5.3. 
Study Rationale 
This Phase 3 study is an extension study (for antecedent studies ALK3831-A304, 
ALK3831-A306, and ALK3831-A307) that will evaluate the long-term safety, tolerability, and 
durability of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform 
disorder, or bipolar I disorder. This study will extend subject exposure by up to 4 years, and 
provide valuable safety and tolerability data over the longest treatment durations evaluated so far 
(up to 5.5 years). Information regarding non-clinical and clinical studies completed to date with 
ALKS 3831 is available in the current version of the Investigator’s Brochure. 
 
 


 
 
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5.4. 
Dose Rationale 
All subjects will receive ALKS 3831. The doses of ALKS 3831 will be 5, 10, 15, and 20 mg 
olanzapine combined with 10 mg samidorphan (henceforth to be referred to as 5/10, 10/10, 
15/10, and 20/10 mg). These doses represent the intended therapeutic doses of ALKS 3831 and 
include the full range of doses used in all antecedent studies. The 10 mg samidorphan dose was 
identified as the minimal effective dose based on the efficacy and optimal safety profile observed 
in Study ALK3831-302. A fixed dose of samidorphan was selected due to the fact that data from 
Study ALK3831-302 demonstrated no correlation between the ratio of samidorphan/olanzapine 
dose and percent change from baseline in body weight after 12 weeks of treatment, indicating 
that even with higher olanzapine doses, a fixed dose of samidorphan is sufficient to achieve 
maximal effect in reducing olanzapine-induced weight gain. 
5.5. 
Benefit-Risk Assessment 
As stated in the background section, first- and early-episode schizophrenia and bipolar I disorder 
are critical phases of the diseases, where optimal antipsychotic efficacy is crucial. Treatment 
with ALKS 3831 combines the advantages of the antipsychotic efficacy of olanzapine in treating 
both schizophrenia and bipolar disorder, with the potential to mitigate the known effect of 
olanzapine treatment of excessive weight gain. The antipsychotic efficacy seen in stable subjects 
treated in study ALK3831-302 was similar between ALKS 3831 and olanzapine as measured by 
Total PANSS and CGI scores. Based on the available data from the completed studies in healthy 
volunteers (ALK33-301) and in subjects with schizophrenia (ALK3831-302), subjects treated 
with ALKS 3831 have been shown to gain less weight compared to subjects treated with 
olanzapine alone. In ALK3831-302, the prevention of weight gain persisted during the 3 month 
ALKS 3831 treatment period. 
The important identified risks associated with the use of olanzapine include weight gain, glucose 
dysregulation, and dyslipidemia. For additional information on the known risks of olanzapine, 
see the local label. The safety profile of ALKS 3831 is consistent with that of olanzapine (see 
local label). In study ALK3831-302, the only adverse events reported with ALKS 3831 treatment 
occurring in ≥5% of subjects and at ≥2 times the rate of olanzapine alone were somnolence, 
sedation, dizziness, and constipation. Notably, these are all labeled events for olanzapine. The 
most common adverse events noted in clinical studies in >2% of subjects with ALKS 3831 to 
date have been somnolence, dizziness, weight increased, sedation, increased appetite, headache, 
orthostatic hypotension, and liver function test abnormal (see current ALKS 3831 Investigator’s 
Brochure). In summary, data from the completed ALKS 3831 studies have demonstrated a 
favorable benefit-risk profile for further investigating ALKS 3831 in subjects with 
schizophrenia, schizophreniform disorder, or bipolar I disorder. 


 
 
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6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the long term safety, tolerability, and durability 
of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform disorder, or 
bipolar I disorder. 


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7.
SELECTION AND WITHDRAWAL OF SUBJECTS
Each subject must meet all of the inclusion and none of the exclusion criteria to be qualified to 
participate in this study. 
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
1. Subject is willing and able to give informed consent/assent as per local requirements
2. Subject agrees to use an acceptable method of contraception during the study and until
30 days after any study drug administration, unless surgically sterile or post-menopausal
3. Subject has the potential to benefit from the administration of ALKS 3831, in the opinion
of the Investigator
4. Subject met the eligibility criteria of the antecedent study at the time of enrollment in the
antecedent study and completed the treatment period in one of the following antecedent
studies within 7 days: ALK3831-A304, ALK3831-A306, or ALK3831-A307
7.2. 
Subject Exclusion Criteria 
Each subject must not meet any of the following criteria to be qualified to participate in this 
study. 
1. Subject has any finding that in the view of the investigator or medical monitor would
compromise the safety of the subject or affect his/her ability to fulfill the protocol visit
schedule or visit requirements
2. Subject has a positive test for drugs of abuse (see Section 8.3.9.1) at study entry
3. Subject is currently pregnant. breastfeeding or is planning to become pregnant during the
study or within 30 days of the last study drug administration
4. Subject is employed by Alkermes, the Investigator or study site (permanent, temporary
contract worker, or designee responsible for the conduct of the study) or is immediate
family1 of an Alkermes, clinical research organization, or study site employee
5. If in the opinion of the Investigator (and/or Sponsor) is unsuitable for enrollment in the
study
1 Immediate family is defined as a spouse, parent, sibling, or child, whether biological or legally 
adopted. 


 
 
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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 absolute neutrophil count (ANC) < 1.0 × 103 per µL or Hemoglobin A1c (HbA1c) ≥6.5% 
at any time, the PI (or designee) should discontinue the subject from participation immediately. 
Reasons for discontinuation include: 
• Adverse Event 
• Lack of Efficacy 
• Lost to Follow-up 
• Withdrawal by Subject 
• Protocol Deviation (including non-compliance with study drug or study procedures) 
• Pregnancy 
• Study Terminated by Sponsor 
• Other 
If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the Investigator, or until the subject is deemed by the 
Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is necessary to 
monitor a subject beyond the safety follow-up visit, the follow-up period may be extended as 
necessary. In such instances, the Sponsor and Investigator will agree to an acceptable follow-up 
schedule. 
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Subjects who terminate the treatment early (prior to Visit 25) will complete an early 
termination (ET) visit and the 4-week Safety Follow-up period. The ET visit should be scheduled 
as close as possible to the subject’s last dose and will mimic the assessments scheduled to be 
conducted at the EOT Visit. If the subject fails or refuses to return to the study center, an attempt 
must be made to contact the subject by telephone in order to assess as many safety and efficacy 
parameters as possible. All data collected over the telephone must be documented and kept in the 
subject’s record. 
The Investigator must maintain a record of all subjects who fail to complete the study. The 
reason for study discontinuation will be documented and made on the appropriate electronic case 
report form (eCRF). If a subject is lost to follow-up, a reasonable attempt to contact the subject 
must be made and documented. 
7.4. 
Replacement of Subjects 
Subjects who withdraw from the study will not be replaced. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a multicenter, open-label study to evaluate the long term safety, tolerability, and 
durability of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform 
disorder, or bipolar I disorder. Subjects that have completed the antecedent studies 
(ALK3831-A304, ALK3831-A306, or ALK3831-A307) within the past 7 days will be eligible to 
enroll in this study. 
Subjects enrolled in the study will be started on the same olanzapine dose that they had 
maintained at the end of the antecedent study. Available doses of ALKS 3831 will be 5/10, 
10/10, 15/10, and 20/10 mg. Subjects may be titrated to a different dose after the start of the 
study at the Investigator’s discretion. Dosing will be flexible throughout the study; however, 
frequent adjustments are discouraged. Dose adjustments will only be performed on-site at the 
study center. Subjects requiring dose adjustments between scheduled visits will need to arrange 
an unscheduled visit. 
Safety assessments will include AE monitoring, clinical laboratory testing, vital signs, body 
weight, ECGs, and the Columbia-Suicide Severity Rating Scale (C-SSRS). Psychiatric 
symptoms will be evaluated using the CGI-S scale. Additional assessments will include Impact 
of Weight on Quality of Life-Lite Questionnaire (IWQOL-Lite).  
The duration of the treatment period will vary by subject, between 24 and 48 months, or until 
regulatory action; duration will vary by subject. The study completion is targeted for the 4th 
quarter of 2022. After the last subject is enrolled, the end date of the study will be set to occur 24 
months later (approximately the 4th quarter of 2022), and subjects will be informed of the target 
completion date. The total study duration will be up to 49 months including a treatment period of 
24 to 48 months and a 4-week safety Follow-up period and return to their normal standard of 
care once their participation has ended. A schematic of the study design is provided in Figure 1. 
The end of trial is defined as the date of the last subject’s last visit. 
Figure 1: 
Study Design Schematic 
 


 
 
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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. 


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Table 3: 
Schedule of Assessments 
Visits 1-25b 
Treatment Perioda 
Follow-up 
Perioda 
Transition 
from 
Previous 
Studyc 
Monthly 
Visitsd 
Quarterly 
Visits 
EOT/ 
ET 
Safety 
Follow-up 
Visite 
1 
2, 3, 5, 6, 8, 
9, 11, 12, 
14, 15, 17, 
18, 20, 21, 
23, 24 
4, 7, 10, 13, 
16, 19, 22, 
25  
No later than 
Visit 49 
No later 
than Visit 
50 
Visits 26-50b 
— 
26, 27, 29, 
30, 32, 33, 
35, 36, 38, 
39, 41, 42, 
44, 45, 47, 
48 
28, 31, 34, 
37, 40, 43, 
46 
Qualification/ Safety Assessments 
Informed Consent 
X 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
Urine Pregnancy Testing (all 
women) 
X 
X 
X 
X 
X 
Urine Drug Screen 
Xf 
 
X 
 
 
Physical Examination and ECG 
 
 
X 
X 
 
Vital Signs 
 
 
X 
X 
 
Biochemistry, Hematology, and 
Urinalysis Samples 
 
 
X 
X 
 
Weight and Waist Circumference 
 
X 
X 
X 
X 
Adverse Event Monitoring 
 
X 
X 
X 
X 
Concomitant Medication Review 
 
X 
X 
X 
X 
C-SSRSg 
 
X 
X 
X 
X 
Psychiatric/ Quality of Life Assessments 
CGI-S 
 
X 
X 
X 
X 
IWQOL-Lite 
 
 
X 
X 
 
Other/ General Procedures 
Study Drug Dispensation 
X 
X 
X 
 
 
Study Drug Return Review 
 
X 
X 
X 
 
Abbreviations: CGI-S=Clinical Global Impressions-Severity; C-SSRS=Columbia-Suicide Severity Scale; 
ECG=electrocardiogram; EOT=end of treatment; ET=early termination; IWQOL-Lite=Impact of Weight on 
Quality of Life-Lite 
a A visit window of ±4 days is allowed throughout the treatment period and the Follow-up period. 


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b Subjects may be treated with study drug for 24 to 48 months, or until regulatory action; duration will vary by 
subject. 
c Visit 1 must occur within 7 days of the EOT visit of the antecedent studies (ALK3831-A304, ALK3831-A306, or 
ALK3831-A307) and may occur on the same day. Subsequent visits are to be conducted every month (every 
28 days [±4 days]). 
d Except for every 3rd visit from Visit 1 (Quarterly Visits). 
e To be performed one month (28 days [±4 days]) after the EOT/ET visit.  
f The urine drug screen will be performed at Visit 1; however if Visit 1 is the same as EOT visit of the antecedent 
study and a urine drug screen was already performed during that visit, it doesn’t need to be repeated. 
g ‘Since Last Visit’ version to be used at all indicated visits. 


 
 
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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 (PI) or designated study personnel as outlined in Section 17.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent/assent as per local requirements from each potential subject as 
specified in Table 3. 
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 / Psychiatric History 
Subject’s demographic data and medical / psychiatric history (including primary psychiatric 
diagnosis) will be carried over from the antecedent studies (ALK3831-A304, ALK3831-A306, 
or ALK3831-A307). 
8.3.4. 
Concomitant Medication Review 
At the timepoints specified in Table 3, subjects will be asked about the medications they have 
taken since their last visit, including prescription and nonprescription medications, vitamins, and 
supplements. 
The investigator will record the following data on all medications used by the subject: name, 
dose, regimen, route of administration, start and stop dates, and the indication for use. 
8.3.5. 
Vital Signs 
Vital signs (ie, blood pressure, pulse, 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. Automated measurement is preferred, but if performed manually, heart rate will be 
measured in the brachial artery for at least 30 seconds. 
Blood pressure, heart, and respiratory rate will be measured after the subject has been in the 
supine position for at least 5 minutes. Vital signs may be collected at any time during a 
scheduled visit, unless otherwise noted. 
8.3.6. 
Physical Examination 
A brief physical examination and an ECG (local) will be performed at the timepoints specified in 
Table 3. 


 
 
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8.3.7. 
Weight and Waist Circumference 
Weight and waist circumference will be measured at all the timepoints specified in 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 (including shoes, 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. 
Structured Interviews and Questionnaires 
Brief descriptions of each of the interviews and questionnaires to be distributed are available 
below. All interviews and questionnaires will be administered by trained and qualified study 
personnel. 
For assessments performed at multiple visits, every effort should be made to pair the same 
clinician / rater with the same subject across visits. 
Table 3 provides information on the timepoints at which each assessment should be 
administered. 
8.3.8.1. 
Safety Assessments 
8.3.8.1.1. Columbia-Suicide Severity Rating Scale 
The PI or designee will administer C-SSRS according to the timepoints in Table 3. The “Since 
Last Visit” version of the C-SSRS will be used at all indicated visits. The C-SSRS should be 
administered by a qualified clinician trained in assessing and managing suicidal ideation and 
behavior (Posner et al, 2011). 
8.3.8.2. 
Psychiatric/Quality of Life Assessments 
8.3.8.2.1. Clinical Global Impressions-Severity 
The PI or designee will complete the CGI-S scale at the timepoints specified in Table 3. The 
CGI-S measures mental illness severity. Clinicians are asked to rate subjects based on their prior 
experience working with individuals in a similar patient population (Guy 1976). 
8.3.8.2.2. Impact of Weight on Quality of Life-Lite 
Subjects will complete the IWQOL-Lite questionnaire (Kolotkin et al, 2001) at the timepoints 
specified in Table 3. 
8.3.9. 
Laboratory Assessments 
8.3.9.1. 
Drug Testing 
A urine drug test for opioids and drugs of abuse, including amphetamine/methamphetamine, 
phencyclidine, and cocaine, will be performed at the timepoints specified in Table 3. Results 
must be negative for the subject to be eligible for the study. The urine drug screen will be 


 
 
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performed at Visit 1; however if Visit 1 is the same as the end of treatment visit of the antecedent 
study and a urine drug screen was already performed during that visit, it doesn’t need to be 
repeated. The urine drug screen may be repeated at any point during the study based on the 
investigator’s discretion. 
8.3.9.2. 
Hematology, Biochemistry, and Urinalysis 
Blood and urine samples for laboratory assessments will be collected at the timepoints specified 
in Table 3. Specific hematology, biochemistry, and urinalysis assessments are listed in Table 4. 
Subjects will be instructed not to eat or drink anything (except water) for 8 hours before each 
visit where blood samples for biochemistry and hematology assessments will be collected. 
Samples will be collected in accordance with the site’s usual procedures and analyzed by a 
central laboratory. Laboratory assessments may be repeated at the Investigator’s discretion. 


 
 
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Table 4: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
Total and differential (absolute) 
white blood cell count 
General Chemistry 
Albumin 
Bicarbonate 
Calcium 
Chloride 
Creatine phosphokinase 
Glucose 
Lactic dehydrogenase 
Potassium 
Sodium 
Total protein 
Uric acid 
Endocrine Function Test 
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 
 
 
8.3.9.3. 
Urine Pregnancy Testing 
A urine pregnancy test will be administered to all women at the timepoints specified in Table 3. 
At Visit 1, 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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8.3.10. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
dispensed/administered at the timepoints specified in Table 3. The study drug use and storage 
information will be explained to/reviewed with the subject. 
8.3.11. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject at Visit 1 and collected at the 
EOT/ET Visit. The card will indicate that the subject is receiving an opioid antagonist and 
olanzapine and will include the PI’s contact information, a suggested pain management plan and 
information regarding opiate blockade. Subjects will be instructed to keep the card with them at 
all times. Study personnel will confirm that subjects have the card in their possession at each 
study visit. 
8.3.12. 
Adverse Event Monitoring 
All AEs will be monitored continuously from the time a subject signs the informed consent 
document until the completion of the final study visit (see Table 3). All AEs ongoing at the end 
of trial or concomitant medications continuing from the antecedent study will be carried over and 
followed until resolution. All AEs and serious adverse events (SAEs) are defined in Section 13.2 
and Section 13.3, respectively. Section 13.5 provides guidance on the monitoring and recording 
requirements for AEs. Section 13.6 provides guidance on the reporting requirements for SAEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study. All female subjects must agree to use an acceptable method for 30 days 
after the last dose of study drug, unless they are surgically sterile or postmenopausal (see below). 
The following are considered acceptable methods of contraception: 
1. Intrauterine device 
2. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, contraceptive implant) 
3. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
4. Abstinence (see below) 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. Abstinence is defined as “true abstinence” in which 
subjects must refrain from heterosexual intercourse for the full duration of the study and must be 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), declaration of abstinence for the duration of 
exposure to the study drug, and withdrawal are not acceptable methods of contraception. 
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 


 
 
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salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
are considered surgically sterile. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female subject. 
Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to Screening in women who are 45 years of age or older. 
If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The ET and safety follow-up visits will be scheduled and the pregnancy 
will be reported to Alkermes. Additional follow-up may be required.  Pregnancies in female 
partners of male subjects should also be reported and will be followed in the same manner. If a 
male subject has a partner who becomes pregnant, the partner may need to provide written 
informed consent to obtain pregnancy follow-up information, as per local requirements. 
A Pregnancy Report Form must be submitted to Alkermes via 
 
(per Section 13.6) immediately, within 24 hours of awareness of the pregnancy, irrespective of 
whether an AE has occurred. The pregnancy will be followed until completion or termination. If 
the outcome of the pregnancy meets the criteria for classification as an SAE, it should be 
reported following the SAE procedure (see Section 13.6). 
8.4.2. 
Prohibited Medications 
In this study, the medications listed below are prohibited: 
• Antipsychotic medications for any indication 
• Diabetes treatments and hypoglycemic agents including Metformin and Insulin 
• Moderate to strong inhibitors or inducers of cytochrome P450 (CYP) 3A (prescription 
medications, OTC medications, or dietary supplements) within 30 days before 
enrollment through Follow-up (refer to Section 20 for a list of CYP3A inhibitors and 
inducers) 
• Use of opioid antagonists, including naltrexone (any formulations) and naloxone 
• Opioid agonists should be avoided as they may be rendered ineffective by 
samidorphan 
The CRO Medical Monitor should be consulted for any questions about use of any psychotropic 
medications during a subject’s participation in this study. 
8.4.3. 
Permitted Medications 
In this study, the medications listed below are permitted: 
• Medications that exhibit drug interaction potential with olanzapine, including known 
inhibitors and inducers of CYP1A2 (Section 21), may affect olanzapine 
concentrations. Hence, investigators must use caution with inhibitors and inducers of 
CYP1A2 and monitor for need for study drug dose adjustment 
• Medicinal products known to be associated with increase in QTc interval should be 
used with caution given the increased risk of torsade de pointes (Section 22) 


 
 
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• Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, 
contraceptive patch, contraceptive implant) will be permitted 
• Permissible medications to treat extrapyramidal symptoms may include 
benzodiazepines, antihistamines, and anticholinergics. Benzodiazepines should be 
utilized for treatment-emergent akathisia 
• Treatment of agitation and/or anxiety with benzodiazepines is permissible 
8.4.4. 
Pain Management 
Because ALKS 3831 contains samidorphan, a μ-opioid 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 functions as a μ-opioid 
antagonist and could interfere with opioid-mediated pain management. 
8.4.5. 
Fasting 
Subjects are required to fast for at least 8 hours (no food or drink except water) prior to 
laboratory blood draws. 
8.4.6. 
Other Restrictions and Requirements 
Additional restrictions and requirements include: 
• Prohibited substances include opioids, amphetamines (including methamphetamine), 
cocaine, and phencyclidine 
• Subjects will be required to abstain from blood or blood product donation during the 
study and for 30 days following the follow-up visit 
• Subjects will be instructed to maintain their normal caffeine intake and/or tobacco use 
as well as normal activity/exercise throughout the study. Subjects will be asked to 
abstain from strenuous physical activity for 48 hours prior to each study visit 


 
 
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• 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 


 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
The study drug, ALKS 3831 will be available in the following doses: 
• ALKS 3831 5/10, 10/10, 15/10, and 20/10 administered as a coated bilayer tablet 
Subjects enrolled in the study will be started on the same olanzapine dose that they had 
maintained at the end of the antecedent study. Subjects may be titrated to a different dose after 
the start of the study at the Investigator’s discretion. Dosing will be flexible throughout the 
study; however, frequent adjustments are discouraged. Dose adjustments will only be performed 
on-site at the study center. 
Subjects will be given study drug to take home and instructed to take one tablet orally preferably 
at bedtime. If there are tolerability problems, dosing may be switched to another time based on 
the judgment of the Investigator; frequent switching is discouraged. 
Subjects will be instructed to keep all unused tablets in their blister card and to return unused 
tablets to the study site at their next visit. If dosing is to occur at that visit, the dose should be 
taken from the subject’s next blister card, not from the card they are returning. 
If a dose is missed or forgotten, subjects will be instructed to resume regular dosing the 
following night. Subjects will be instructed not to take a double dose to try to “make up” for the 
missed dose. 
9.2. 
Treatment Adherence 
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 
Not applicable. 
9.4. 
Blinding 
Not applicable.  


 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The ALKS 3831 drug product will be supplied as a coated bilayer tablet in four fixed-dose 
combinations: 
• ALKS 3831 5/10 (5 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 15/10 (15 mg olanzapine/10 mg samidorphan) 
• ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) 
The tablets contain olanzapine and samidorphan L-malate (RDC-0313-02), and the following 
excipients commonly used in pharmaceutical drug products: microcrystalline cellulose, lactose 
monohydrate, crospovidone, colloidal silica dioxide, and magnesium stearate. 
The tablet coating contains hydroxypropyl methylcellulose 2910 (HPMC 2910), titanium 
dioxide, lactose monohydrate, and triacetin as well as one or more of the following dye 
components; iron oxide yellow, iron oxide red, and/or FD&C blue #2/indigo carmine AL. 
10.2. 
Packaging and Labeling 
ALKS 3831 will be supplied in blister packs. Blister cards will be in biweekly configurations. 
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 no 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, ALKS 3831 must be stored in accordance 
with restrictions related to Schedule II substances. The site will take adequate precautions, 
including storage of the investigational drug in a securely locked, substantially constructed 
cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, 
to prevent theft or diversion of the substance. 
10.4. 
Accountability 
The clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Refer to Section 8.3.10 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 


 
 
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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 
Throughout the study, CGI-S scores will be collected to measure the durability of treatment 
effect. Time to discontinuation will also be estimated. Throughout the study, IWQOL-Lite scores 
will be collected to obtain information regarding subject experience. 
11.1. 
Efficacy Endpoints 
• Change from baseline in CGI-S by visit 
• Time to discontinuation 
• Change from baseline in IWQOL-Lite score by visit 


 
 
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12. 
ASSESSMENT OF PHARMACOKINETICS 
Not applicable. 


 
 
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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• AEs (including clinically significant abnormal ECG findings) 
• Vital signs (oral temperature, respiratory rate, blood pressure, and heart rate) 
• Weight and waist circumference 
• Clinical laboratory parameters (biochemistry, hematology, and urinalysis) 
• C-SSRS results 
13.1. 
Safety Endpoints 
• Incidence of AEs 
• Percent change from baseline in body weight by visit 
• Absolute change from baseline in body weight by visit 
• Change from baseline in waist circumference by visit 
13.2. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been administered a pharmaceutical product. The occurrence, which may or may not have a 
causal relationship with the investigational treatment, may include any clinical or laboratory 
change that does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the 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 will be 
recorded as such on the eCRFs. 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy, including a partner’s pregnancy, 
must be reported to Alkermes, and additional follow-up may be required.  
Transition from schizophreniform to schizophrenia is not considered an AE unless deemed so by 
the Investigator. 
13.3. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• Results in death 


 
 
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• 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 
• Results in persistent or significant 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. Admission to an inpatient unit or hospital for a nonmedical or 
nonbehavioral reason (ie, social stay admission) during the study in the absence of untoward 
medical occurrence will not be considered an SAE, but will be reported as an AE. 
Hospitalization due to worsening of behavioral health related issues should be reported as 
an SAE. 
13.4. 
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. 
Abbreviations: AE=adverse event 
13.5. 
Monitoring and Recording of Adverse Events 
All AE data collection will begin after a subject signs the ICF and will continue until completion 
of the safety follow-up visit. Any AE or SAE having an onset after the safety follow-up visit will 


 
 
Al ker mes, I nc.  
Pr ot oc ol A L K 3 8 3 1- A 3 0 8 A me n d me nt 3. 0  
 
C O N FI D E N TI A L  
Pa ge 3 7 of 4 9 
n ot be c ollecte d or re p ort e d u nless t he I n vesti gat or feels t hat t he e v e nt ma y be relate d t o t he 
st u d y dr u g. 
S u bjects will be i nstr ucte d b y t he I n vesti gat or or d esi g nee t o re p ort t he occ urre nce of a n y A E. 
All v ol u nteere d, elicite d, a n d o bser ve d A Es are t o be rec or de d o n t he A E e C R Fs. 
T he I n vesti gat or will ass ess all A Es re gar di n g a n y ca usal relati o ns hi p t o t he st u d y dr u g (s ee 
Secti o n  1 3. 4 ), t he i nte nsit y (se v erit y) of t he e ve nt, acti o n ta ke n, a n d s u bject o utc o me. 
T he f oll o wi n g criteri a s h o ul d be use d t o g ui de t h e assess me nt of i nte nsit y (se verit y): 
•  Mil d:  Ca uses a ware ness of si g n or s y m pt o m, b ut is easil y t olerate d; d oes n ot i nterfere 
wit h us ual acti vities  
•  M o der ate:  Ca uses disc o mf ort e n o u g h t o i nterfere wit h us ual acti vities  
•  Se vere:  Is i nca p acitati n g; res ults i n i na bilit y t o w or k or perf or m us ual acti vities 
All A Es will be f oll o we d u ntil res ol uti o n, u ntil dee me d sta ble b y t he I n v esti gat or, or u ntil t he 
s u bject is dee me d b y t he I n v esti gat or t o be l ost t o f oll o w- u p. 
F or cli nical st u d y safet y r e p orti n g p ur p oses, t he m ost rece nt versi o n of t he I n vesti gat or’s 
Br oc h ure will be use d as t he ref ere n ce d oc u m e nt t o desi g nat e e ve nt e x pecte d ness.  
Wit h dra wal fr o m t he st u d y as a res ult of a n A E, a n d a n y t h era p e utic meas ures t hat are ta ke n , 
s hall be at t he discreti o n of t he I n vesti gat or. If a s u bject wit h dra ws fr o m t he st u d y f or a n y reas o n, 
a n y on g oi n g A Es will be f oll o we d u ntil res ol uti o n, u ntil dee me d sta ble b y t he I n vesti gat or, or 
u ntil t he s u bject is dee me d b y t he I n vesti gat or t o b e l ost t o f oll o w- u p. 
1 3. 6.  
Re p orti n g of Seri o us A d verse E ve nts  a n d Pre g n a nc y  
All S A Es a n d pre g n a ncies m ust be re p orte d t o 
 
i m me di atel y, wit hi n 2 4 h o urs of disc o ver y, b y e m aili n g or f a xi n g t he re p ort t o t he 
f oll o wi n g: 
Atte nti o n:  
 Me dical M o nit or 
U S E m ail:
 
R O W E m ail:
 
U S F a x N u m ber:  
 
R O W F a x N u m ber:  
 
T he writte n re p ort s h o ul d be s u b mitte d o n t he S A E f or m pr o vi de d f or t his p ur p ose. T he re p ort 
m ust i ncl u de t he I n v esti gat or ’s o pi ni o n as t o w het her t he e v e nt is st u d y dr u g -relate d. If t his 
relati o ns hi p is deter mi ne d t o be p ossi bl y, pr o ba bl y, or d efi nitel y relat e d t o st u d y dr u g, e vi d e nce 
t o s u p p ort t his assess me nt m ust als o be pr o vi de d.  
T he writte n re p ort f or pr e g na n cies i n fe m ale s u bjects a n d i n fe male p art ners of male  s u bjects 
s h o ul d be s u b mitte d o n t he Pre g na nc y R e p ort F or m pr o vi de d f or t his p ur p ose. 
P P D
P P D


 
 
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Page 38 of 49 
14. 
STATISTICS 
14.1. 
Sample Size Considerations 
No formal sample size calculation will be performed for this extension study. A sample size of 
approximately 500 subjects is based on the estimated number of subjects who are expected to 
roll over from the antecedent Phase 3 studies within 7 days (ALK3831-A304, ALK3831-A306, 
and ALK3831-A307). 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan (SAP) to be finalized before database lock. 
In general, summary statistics (n, mean, standard deviation, median, minimum and maximum for 
continuous variables, and number [%] of subjects in each category for categorical variables) will 
be provided for all variables. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
14.2.1. 
Study Population 
14.2.1.1. Safety Population 
The safety population will include all enrolled subjects who receive at least one dose of study 
drug. All analyses will be conducted using the safety population. 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, weight, and body mass 
index will be summarized. 
14.4. 
Efficacy Analyses 
Changes from baseline in CGI-S and IWQOL-Lite scores will be summarized using descriptive 
statistics. The time to discontinuation will be estimated using the Kaplan-Meier (KM) method 
and the KM plot will be provided. 
14.5. 
Pharmacokinetic Analyses 
Not applicable. 
14.6. 
Safety and Tolerability Analyses 
All safety assessments will be summarized using descriptive statistics. All safety analyses will be 
based on observed data only, and no missing values will be imputed. Safety will be evaluated 
based on the occurrence of AEs (including clinically significant abnormal ECG findings), vital 
signs, and results of clinical laboratory tests. Reported AE terms will be coded using the 
MedDRA preferred terms and system organ classes. 


 
 
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Page 39 of 49 
Treatment-emergent AEs (TEAEs) are defined as AEs that occur or worsen after the first dose of 
study drug. 
The summary tables will include the number and percent of subjects with TEAEs by system 
organ class, and by preferred terms within each system organ class. All SAEs, TEAEs leading to 
discontinuation, as well as additional categories of AEs as defined in the SAP will be 
summarized. The number and percentage of subjects with TEAEs will also be summarized by 
severity and by relationship to the study drug. 
Observed values and change from baseline in laboratory parameters and vital signs will be 
summarized by visit. 
The number and percentage of subjects who have met potentially clinically significant criteria at 
any postbaseline visit will be summarized for laboratory and vital signs. Supporting listings will 
be provided. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will also be summarized. 
Concomitant medications will be summarized by World Health Organization (WHO) 
Anatomical Therapeutic Chemical (ATC) classification system. Listings will be provided for all 
concomitant medications. 


 
 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by an Alkermes monitor or designee. 
15.2. 
Audits and Inspections 
By signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of Alkermes, a regulatory 
authority, and/or an institutional review board (IRB)/independent ethics committee (IEC) may 
visit the site to perform audits or inspections, including the drug storage area, study drug stocks, 
drug accountability records, subject charts, 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 Council 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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CONFIDENTIAL 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness and compliance, the study site should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 15.2 for details regarding the audit process. 
16.1. 
Case Report Forms 
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data (ie, data directly reported on the eCRF). All eCRFs will be completed by the 
clinic staff prior to review by the Alkermes monitor or designated representative. 
The Alkermes monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF. 
16.2. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to Alkermes that he or she will maintain in 
confidence information furnished to him or her by Alkermes and will divulge such information 
to his or her respective IRB or IEC under an appropriate understanding of confidentiality with 
such board. All data will be considered the sole property of Alkermes. Please refer to the Clinical 
Study Agreement (CSA) for details. 


 
 
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17. 
ETHICAL CONSIDERATIONS 
17.1. 
Ethics Review 
The clinical site’s IRB/IEC must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB/IEC prior to enrolling subjects into the study; written 
approval from the committee must be received by Alkermes before drug will be released to 
the investigator. The protocol must be re-approved by the IRB/IEC upon receipt of amendments 
and annually, as local regulatory requirements require.  
The Investigator is responsible for submitting all protocol changes and SAE reports to the 
IRB/IEC according to local procedures. At a minimum, all SAEs requiring an investigational 
new drug safety report must be immediately reported. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. Good Clinical Practice (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 and 
parent/caregiver (as per local requirements or the subject’s legal representative) is given full and 
adequate oral and written information about the nature, purpose, potential and possible risks and 
benefits of the study. Each prospective subject and parent/caregiver (as per local requirements) 
will receive an IRB-approved ICF that summarizes the pertinent study information and will be 
given ample time to read the form and ask questions about the study. All information is to be 
provided in a language understandable to the subject and must not include any language that 
waives the subject’s legal rights. Prospective subjects must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the subject chooses to 
participate, he/she must sign the ICF/assent form (as per local requirements) and if required, the 
parent/caregiver must sign the parent/caregiver ICF before any study-specific procedures are 
conducted. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB, 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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Page 43 of 49 
Significant changes to the protocol or product safety information may require a revision of the 
ICF/assent form, 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/assent form in the subject’s source documents. A copy of the signed 
ICF/assent form must be given to the subject. 


 
 
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Protocol ALK3831-A308 Amendment 3.0 
 
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Page 44 of 49 
18. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the Investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail. 
A paper copy of all laboratory reports will remain with the source documents at the study site. 
All electronic source data collected outside of the eCRF, such as e-diaries, central laboratory, or 
central MRI data, will be transferred directly to EDC or directly to Alkermes for incorporation 
into the final datasets. All out-of-range laboratory values will be deemed as clinically significant 
or not clinically significant by the Investigator. Clinically significant values will be considered 
AEs and will be recorded as such on the eCRFs. 
All AEs will be coded using MedDRA. Concomitant medications will be categorized using the 
WHO-ATC classification system. 
18.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and source documents, and other records relative to study conduct. 
18.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the Sponsor to inform the Investigator/Institution as to when 
these documents no longer need to be retained. 
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. 


 
 
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Page 45 of 49 
18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that are the sole property of Alkermes. 
Results of the study are to be held in confidence by both the Investigators and the Sponsor. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 


 
 
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Protocol ALK3831-A308 Amendment 3.0 
 
CONFIDENTIAL 
Page 46 of 49 
19. 
REFERENCES 
Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive 
research synthesis. Am J Psychiatry. 1999;156(11):1686-1696. 
Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT 
psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 
2010;36(1):71-93. doi: 10.1093/schbul/sbp116. 
Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic risk in patients with first-episode 
schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA 
Psychiatry. 2014;71(12):1350-1363. doi: 10.1001/jamapsychiatry.2014.1314. 
Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. 2016; 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm. Accessed on 08 Sep 2017. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Department of 
Health, Education, and Welfare; 1976. 
Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief measure to assess 
quality of life in obesity. Obes Res. 2001;9(2):102-111. doi: 10.1038/oby.2001.13. 
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic 
drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951-962. 
doi: 10.1016/S0140-6736(13)60733-3. 
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
Meyer JM, Davis VG, McEvoy JP, et al. Impact of antipsychotic treatment on nonfasting 
triglycerides in the CATIE Schizophrenia Trial phase 1. Schizophr Res. 2008;103(1-3):104-109. 
doi: 10.1016/j.schres.2008.04.023. 
Posner K, 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. 
University of Washington: School of Pharmacy. In Vivo CYP3A Inducers. Seattle, WA: M and 
T Drug Interaction Database; 2017a. 
University of Washington: School of Pharmacy. In Vivo Inhibitors of CYP3A Probes. Seattle, 
WA: M and T Drug Interaction Database; 2017b. 
Wirshing DA, Wirshing WC, Kysar L, et al. Novel Antipsychotics: Comparison of Weight Gain 
Liabilities. J Clin Psychiatry. 1999;60(6):358-363. 


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


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


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

SAP_001.pdf: 
 
FINAL STATISTICAL ANALYSIS PLAN 
 
ALKS 3831-A308 
NCT03201757 
 
Study Title: 
A Phase 3 Study to Assess the Long Term Safety, Tolerability and 
Durability of Treatment Effect of ALKS 3831 in Subjects with 
Schizophrenia, Schizophreniform Disorder, or Bipolar I Disorder 
Document Status: 
Version 1.0 
Document Date: 
13 Jun 2023 
Based on: 
ALKS 3831-A308 Protocol Amendment 3.0 Date: 09 May 2019 and 
ALKS 3831-A308 Interim Statistical Analysis Plan 1.0 Date: 
06 Jun 2019 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in compliance 
with good clinical practice, including the archiving of essential documents. 


Alkermes, Inc. 
Statistical Analysis Plan – ALKS 3831-A308 
Version 1.0 
 
 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................3 
LIST OF FIGURES .........................................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
1.1. 
Study Objectives ...........................................................................................................6 
1.1.1. 
Primary Objective .........................................................................................................6 
1.2. 
Summary of the Study Design ......................................................................................6 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................7 
3. 
DATA ANALYSIS ......................................................................................................7 
3.1. 
General Statistical Methodology ..................................................................................7 
3.2. 
Definitions of Analysis Populations .............................................................................7 
3.2.1. 
Safety Population ..........................................................................................................7 
3.2.2. 
Follow-up Safety Population ........................................................................................8 
3.2.3. 
Post-discontinuation Safety Population ........................................................................8 
3.3. 
Disposition ....................................................................................................................9 
3.4. 
Demographics and Baseline Characteristics .................................................................9 
3.5. 
Prior and Concomitant Medication ...............................................................................9 
3.6. 
Treatment Adherence Rate and Extent of Exposure to Study Drug .............................9 
3.6.1. 
Treatment Adherence Rate ...........................................................................................9 
3.6.2. 
Extent of Exposure to Study Drug ................................................................................9 
3.7. 
Efficacy Analyses .......................................................................................................10 
3.7.1. 
Efficacy Analysis ........................................................................................................10 
3.7.2. 
Multiple Comparison / Multiplicity ............................................................................11 
3.7.3. 
Subgroup Analysis ......................................................................................................11 
3.7.4. 
Other Endpoints ..........................................................................................................12 
3.8. 
Safety Analysis ...........................................................................................................12 
3.8.1. 
Adverse Events ...........................................................................................................12 
3.8.1.1. 
Deaths, Serious and Other Significant AEs ................................................................13 
3.8.1.2. 
AEs of Special Interest ...............................................................................................13 
3.8.2. 
Clinical Laboratory Parameters ..................................................................................13 


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3.8.3. 
Vital Signs and Body Weight .....................................................................................16 
3.8.3.1. 
Vital Signs ..................................................................................................................16 
3.8.3.2. 
Weight and Body Mass Index .....................................................................................17 
3.8.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................17 
3.9. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................18 
4. 
INTERIM ANALYSES ..............................................................................................18 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................18 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........18 
6.1. 
Analysis Visit Windows .............................................................................................19 
6.2. 
Handling of Partial Dates of Concomitant Medication and Adverse Events .............21 
6.3. 
Handling of Safety Data .............................................................................................21 
7. 
GENERAL STATISTICAL METHODOLOGY (AND REPORTING OF 
RESULTS) ..................................................................................................................22 
7.1. 
Reporting Precision ....................................................................................................22 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................22 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................22 
10. 
REFERENCES ...........................................................................................................23 
APPENDIX 1. AESI - MOVEMENT DISORDERS (INCLUDING 
EXTRAPYRAMIDAL SYNDROME AND TARDIVE DYSKINESIA; 
STANDARDIZED MEDDRA QUERY) ...................................................................24 
APPENDIX 2. AESI - SUICIDAL IDEATION AND BEHAVIOR (CUSTOM 
MEDDRA QUERY) ...................................................................................................28 
APPENDIX 3. AE TERMS - ABUSE POTENTIAL (CUSTOM MEDDRA QUERY)............29 
APPENDIX 4. AE TERMS – DEPENDENCE (CUSTOM MEDDRA QUERY) .....................32 
APPENDIX 5. AE TERMS – WITHDRAWAL (CUSTOM MEDDRA QUERY) ...................33 
APPENDIX 6. COVID-19 ANALYSIS .....................................................................................35 
 
LIST OF TABLES 
Table 1: 
Definition of Shift CGI-S Categories .........................................................................10 
Table 2: 
Shift Categories for CGI-S response ..........................................................................11 
Table 3: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................14 


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Table 4: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters ...................................................................................................................15 
Table 5: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c ...............16 
Table 6: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test ...............16 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate .............................................................................................................................17 
Table 8: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight ...........................................................................................................17 
Table 9: 
C-SSRS Categories for Analysis ................................................................................18 
Table 10: Visit Window Definition for Weight, Waist Circumference and CGI-S Data ...........19 
Table 11: Visit Window Definition for Vital Signs, Lab and IWQOL-Lite Data ......................21 
Table 12: Degree of Precision .....................................................................................................22 
 
LIST OF FIGURES 
Figure 1: Study Design Schematic ...................................................................................................7 


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ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
BMI 
Body mass index 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence interval 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CMQ 
Customized MedDRA queries 
eCRF 
Electronic case report form 
EPS 
Extra pyramidal symptoms 
HbA1C 
Hemoglobin A1c 
SAP 
statistical analysis plan 
IWQOL 
Impact of Weight on Quality of Life 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
OLZ 
Olanzapine 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for analyses and 
presentation of safety and efficacy data for study ALK3831-A308 to support the clinical study 
report (CSR) development. This document has been prepared based on Alkermes 
ALKS 3831-A308 Study Protocol Amendment 3.0 (dated 09 May 2019) and Alkermes 
ALKS 3831-A308 Interim Statistical Analysis Plan to Support New Drug Application (NDA) 
Submission (dated 09 Jun 2019). 
Subjects who have completed or prematurely discontinued ALKS 3831 will be included in the 
analysis described in this document. 
1.1. 
Study Objectives 
1.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety, tolerability, and durability 
of treatment effect of ALKS 3831 in subjects with schizophrenia, schizophreniform disorder, or 
bipolar I disorder. 
1.2. 
Summary of the Study Design 
Subjects are eligible to be enrolled in the study within 7 days after completing the antecedent 
studies (ALK3831-A304, ALK3831-A306, or ALK3831-A307). 
Subjects enrolled in the study will be started on the same olanzapine dose that they had 
maintained at the end of the antecedent study. Available doses of ALKS 3831 will be 5, 10, 15, 
and 20 mg olanzapine combined with 10 mg samidorphan (henceforth to be referred to as 5/10, 
10/10, 15/10, and 20/10 mg). Subjects may be titrated to a different dose after the start of the 
study at the Investigator’s discretion. Dosing will be flexible throughout the study; however, 
frequent adjustments are discouraged. Dose adjustments will only be performed on-site at the 
study center. Subjects requiring dose adjustments between scheduled visits will need to arrange 
an unscheduled visit. 
Safety assessments will include adverse event (AE) monitoring, clinical laboratory testing, vital 
signs, body weight and the Columbia-Suicide Severity Rating Scale (C-SSRS). Psychiatric 
symptoms will be evaluated using the Clinical Global Impressions-Severity (CGI-S) scale. 
Additional assessments will include Impact of Weight on Quality of Life-Lite Questionnaire 
(IWQOL-Lite). 
A schematic of the study design is provided in Figure 1. 


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Figure 1: Study Design Schematic  
 
2. 
SAMPLE SIZE CONSIDERATION 
No formal sample size calculation is performed for this extension study. A sample size of 
approximately 500 is based on the estimated maximum number of subjects who might be 
expected to continue from the antecedent Phase 3 studies within 7 days (ALK3831-A304, 
ALK3831-A306, or ALK3831-A307). 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for efficacy or safety analyses is defined as the last non-missing assessment before the 
first dose of ALKS 3831 in the ALK3831-A308 study, and it will be used for all efficacy and 
safety analyses, unless specified otherwise. 
All results from this analysis will be presented for the overall group, ie all subjects as a single 
group, and not by previous treatment sequence in antecedent studies of ALK3831-A303 and 
ALK3831-A305. 
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. 
All source data will be presented as subject data listings. 
3.2. 
Definitions of Analysis Populations 
3.2.1. 
Safety Population 
The Safety Population will include all subjects who enrolled and received at least one dose of 
ALKS 3831 in the ALK3831-A308 study. All analyses will be conducted using the Safety 
Population except for AEs in the safety follow-up period and AE to evaluate the potential for 


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drug withdrawal and dependence. The populations used for the analyses of these events are 
specified below. 
3.2.2. 
Follow-up Safety Population 
Follow-up Safety Population will be defined as subjects in the Safety Population and met any of 
the following criteria: 
• Completed at least one follow-up visit after >7 days of the last dose of ALKS 3831 
• Reported at least one AE after >7 days of the last dose of ALKS 3831 
• Follow-up Safety Population will be used to analyze the AEs in the safety follow-up 
period 
3.2.3. 
Post-discontinuation Safety Population 
Post-discontinuation Safety Population will be defined as subjects in the Safety Population and 
met any of the following criteria: 
• Completed at least one follow-up visit >2 days after the last dose of ALKS 3831 
• Reported at least one AE >2 days after the last dose of ALKS 3831 
AEs to evaluate potential for drug withdrawal and dependence emerging following 
discontinuation of ALKS 3831 will be assessed for this population, during the period of >2 days 
to 16 days after the last dose of drug for subjects with at least 4 weeks ALKS 3831 exposure.


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3.3. 
Disposition 
The number and percentage of subjects completing or prematurely discontinuing the study 
including reasons for discontinuation will be summarized for the following: 
• Subjects who enrolled in the study 
• Subjects in the Safety Population 
• Subjects who completed the treatment period 
• Subjects who discontinued treatment along with reason for discontinuation 
• Subjects who are ongoing in the treatment period 
3.4. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as sex, age, race, ethnicity, weight, and body 
mass index (BMI) will be summarized for the Safety Population. 
3.5. 
Prior and Concomitant Medication 
Prior medications will be defined as medications taken prior to the first dose of study drug in 
ALK3831-A308 study. Concomitant medications will be defined as medications taken on or 
after the first dose of study drug in ALK3831-A308 study. All medications will be coded using 
the World Health Organization WHO-DD Enhanced + Herbal (version: March 2016). 
Concomitant medications taken during the treatment period will be summarized by the preferred 
name, for the Safety Population. All reported medications (including those initiated after the last 
dose of study medication) will be included in the listing. For the summary table, if a subject has 
taken a concomitant medication more than once, the subject will be counted only once for that 
medication. 
3.6. 
Treatment Adherence Rate and Extent of Exposure to Study Drug 
3.6.1. 
Treatment Adherence Rate 
Treatment adherence to the daily dosing schedule during treatment period will be summarized. 
Treatment adherence will be calculated as follows: 
100 × Total tablets dispensed −total tablets returned −total tablets lost
Total tablets scheduled to be taken
 
3.6.2. 
Extent of Exposure to Study Drug 
Duration of exposure to study drug (ALKS 3831) is defined as the number of days from the date 
of the first dose of study drug in this study (ALK3831-A308) to the date of the last dose of study 
drug, inclusive (ie, last dose date – first dose date + 1 day). Duration of exposure to study drug 
will be summarized for the Safety Population. 
The overall mean and modal dose of olanzapine will be summarized. Number and percentage of 
subjects will be summarized by their modal dose level and final dose level. Summary of the 


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extent of exposure will also be presented by demographic subgroups: Age, Sex, Race, Region, 
weight, and body mass index (BMI). Dose level will be summarized by visit at 12 months, 
18 months, 24 months, and 48 months. 
Dose level at12 months, 18 months 24 months, and 48 months will be summarized by antecedent 
study. 
3.7. 
Efficacy Analyses 
3.7.1. 
Efficacy Analysis 
The following efficacy endpoints will be analyzed: 
• Change from baseline in CGI-S score by visit 
• Shift analysis in CGI-S 
• Change from baseline in IWQOL-Lite scales (total score, physical function, 
self-esteem, sexual life, public distress, and work) by visit 
• Time to treatment discontinuation 
Value and change from baseline in CGI-S and IWQOL-Lite scores by visit will be summarized 
using descriptive statistics. 
The IWQOL-Lite scale is a 31-item self-report measure of obesity-specific quality of life. 
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 scores will be 
transformed as follows (Tessier et al, 2012): the transformed scores range from 0 to 100, with 
100 representing the best, and 0 representing the most impaired quality of life. 
𝑇𝑟𝑎𝑛𝑠𝑓𝑜𝑟𝑚𝑒𝑑 𝑆𝑐𝑜𝑟𝑒= 𝑚𝑎𝑥𝑖𝑚𝑢𝑚 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑠𝑐𝑜𝑟𝑒−𝑎𝑐𝑡𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒
𝑡𝑒𝑠𝑡 𝑠𝑐𝑜𝑟𝑒 𝑟𝑎𝑛𝑔𝑒
𝑋100 
CGI-S response will be categorized into the categories summarized in Table 1. The number and 
percentage of subjects in each category and with shifts from baseline will be summarized based 
on the observed data by descriptive statistics at 1, 3, 6, and 12 months. The shift categories are 
summarized in Table 2. 
Table 1: 
Definition of Shift CGI-S Categories 
Response Category 
CGI-S Score 
Markedly to Extremely Ill 
≥5 
Moderately Ill 
4 
Normal to Mildly Ill 
≤3 


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Table 2: 
Shift Categories for CGI-S response 
Shift from Baseline Category for CGI-S Response 
Baseline Category 
Shift Category 
Markedly to Extremely Ill 
No change 
≥1 level improvement 
2 level improvement 
Moderately Ill 
No change 
1 level improvement 
1 level worsening 
Normal to Mildly Ill 
No change 
≥1 level worsening 
2 level worsening 
Time to treatment discontinuation will be analyzed using the Kaplan-Meier method and the KM 
plot will be provided. Both all-cause discontinuation and discontinuation due to AE will be 
summarized. For prematurely discontinued subjects (all cause or due to AE), time to event is 
defined as time from the date of first dose of study drug in study ALK3831-A308 to the date of 
last dose of study drug. Other subjects will be censored at the last dose of the study drug. 
3.7.2. 
Multiple Comparison / Multiplicity 
Not applicable. 
3.7.3. 
Subgroup Analysis 
Subgroup analyses of efficacy endpoints will be performed for each of the 
following categories: 
• Bipolar disorder 
− Change from baseline in IWQOL-Lite score by visit 
− Weight, metabolic responses, waist circumference, safety AEs and shift in CGI 
score in 2 points or 5 compared to those hospitalized due to AEs will be presented 
by visit. 
• Sex (male, female) 
• Age (<18 years, ≥18 years) 
• Age (<30 years, ≥30 years) 
• Race (Black or African American, Non-Black or Non-African American) 


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• Baseline BMI (<25 kg/m2, ≥25 kg/m2) 
• Region (US, Non-US) 
• Among those who completed study at 24 months, 36 months, and 48 months, change 
in weight, waist circumference and metabolic responses will be summarized. 
• For those who switched from ALKS3831-A307 to ALKS3831-A308 change from 
baseline in CGI, weight, waist circumference and lipid levels by visit will be 
summarized. 
Descriptive statistics will be provided for the subgroups listed above. 
3.7.4. 
Other Endpoints 
Other endpoints include: 
• Absolute change from baseline in fasting lipids (triglycerides, LDL, HDL, total 
cholesterol, fasting glucose, hemoglobin A1c (HbA1c), insulin) by subgroups 
• Absolute change from baseline in fasting lipids (triglycerides, LDL, HDL, total 
cholesterol, fasting glucose, hemoglobin A1c (HbA1c), insulin) by antecedent study 
at End of the treatment 
• Absolute change from baseline in BMI by visit 
• BMI shift: 
− Proportion of subjects shifting from BMI <25 kg/m2 at baseline to BMI ≥25 
kg/m2 by visit 
− Proportion of subjects shifting from BMI <30 kg/m2 at baseline to BMI ≥30 by 
visit 
3.8. 
Safety Analysis 
All safety endpoints will be summarized for the Safety Population. 
3.8.1. 
Adverse Events 
Incidence of treatment-emergent AEs (TEAEs) will be analyzed as a safety endpoint. Adverse 
events will be coded by System Organ Class and Preferred Term using the Medical Dictionary 
for Regulatory Activities (MedDRA®) Version 21.0 or higher. The verbatim term will be 
included in the AE listings. 
An AE (coded by preferred term) will be considered a TEAE if the event is newly occurring or 
worsening on or after the date of first dose of study drug and within 7 days after the last dose of 
study drug in this study. 
An overview table, including number of subjects with TEAEs, AEs leading to treatment 
discontinuation, study drug related TEAEs, and SAEs will be provided. 
The number and percentage of subjects reporting TEAEs during the treatment period will be 
presented for the following categories: 


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• System organ class and preferred term 
• Preferred term, and including the following subset: 
− TEAEs experienced by ≥2% of subjects 
• 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 study drug related TEAEs 
If the same preferred term occurred more than once for the same subject, 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 the 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 and preferred term. 
Subgroup analysis by age (<40 years vs ≥40 years), sex (Female vs Male) and race (Black or 
African American, White, and Other) will be performed for TEAEs during the treatment period 
by preferred term. 
3.8.1.1. 
Deaths, Serious and Other Significant AEs 
The number and percentage of subjects who have serious adverse events (SAE) and AEs leading 
to discontinuation from the treatment will be summarized by system organ class and preferred 
term. And the number and percentage of subjects reporting SAEs will be summarized by system 
organ class, preferred term, and relationship to study drug. 
By-subject listings will be provided for SAEs, AEs leading to treatment discontinuation and AEs 
leading to death. 
3.8.1.2. 
AEs of Special Interest 
In addition, incidence of a selected subset of relevant AEs in this class of drugs (eg, TEAE to 
evaluate potential of movement disorders, TEAE to evaluate potential of suicidal ideation and 
behavior, etc.) will be summarized by preferred term. The selection of AEs per subset will be 
based on the preferred terms from Standardized MedDRA queries (SMQs) or Customized 
MedDRA queries (CMQs). 
3.8.2. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Only scheduled 
laboratory parameters will be included in the summaries, unless specified otherwise. All 
laboratory data, including those collected at unscheduled visits, will be included in the listings. 
Laboratory results including baseline and change from baseline for the Safety Population during 
the treatment period for chemistry and hematology parameters will be summarized by visit. 
Clinical laboratory test values, scheduled or unscheduled, will be considered potentially 
clinically significant (PCS) if they meet PCS criteria listed in Table 3. The number and 


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percentage of subjects who have postbaseline PCS clinical laboratory values will be summarized. 
The percentages will be calculated based on the number of subjects with abnormal baseline value 
and have at least one postbaseline assessment. All PCS values including baseline PCS values 
will be included in supportive listings. 
Shift tables for selected fasting metabolic parameters (glucose, total cholesterol, low density 
lipoprotein [LDL], high density lipoprotein [HDL], triglycerides, and hemoglobin A1c [HbA1c]) 
and liver function tests will be presented. The criteria are summarized in Table 4, Table 5, and 
Table 6. 
Table 3: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameter 
Criteria 
Chemistry 
Albumin 
<2 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 
>400 mg/dL 
Cholesterol, Fastinga 
≥240 mg/dL 
Cholesterol, Fasting 
Increase ≥40 mg/dL 
Cholesterol, HDL Fasting 
<40 mg/dL 
Cholesterol, HDL Fasting 
Decrease ≥20 mg/dL 
Cholesterol, LDL Fasting 
≥160 mg/dL 
Cholesterol, LDL Fasting 
Increase ≥30 mg/dL 
Creatine Kinase (U/L) 
≥3 × ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<40 mg/dL or 
≥250 mg/dL 
Glucose, Fasting 
<50 mg/dL or 
≥126 mg/dL 
Glucose, Fasting 
Increase ≥10 mg/dL 
HbA1c  
≥5.7% 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
Lactate Dehydrogenase (U/L) 
>3 × ULN 


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Parameter 
Criteria 
Prolactin (Female) 
≥ 1 X ULNb 
Prolactin (Male) 
≥ 1 X ULNb 
Prolactin (Female) 
≥ 3 X ULNb 
Prolactin (Male) 
≥ 3 X ULNb 
Sodium 
<130 mmol/L or 
>150 mmol/L 
Triglycerides, Fasting  
≥200 mg/dL 
Triglycerides, Fasting 
Increase ≥50 mg/dL 
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 
a Reported fasting 
b ULN is 30 ng/mL for females and 20 ng/mL for males 
Table 4: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters 
Total Cholesterol (fasting) mg/dL 
Normal (<200) to High (≥240) 
Borderline (≥200 and < 240) to High (≥240) 
Normal (<200) to Borderline (≥200 and <240) 
LDL Cholesterol (fasting) mg/dL 
Normal (<100) to High (≥160) 
Borderline (≥100 and <160) to High (≥160) 
Normal (<100) to Borderline (≥100 and <160) 
HDL Cholesterol (fasting) mg/dL 
Normal (≥40) to Low (<40) 
Triglycerides (fasting) mg/dL 
Normal (<150) to High (≥200) 


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Borderline (≥150 and <200) to High (≥200) 
Normal (<150) to Borderline (≥150 and <200) 
Table 5: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c 
Glucose (fasting) mg/dL 
Normal (<100) to Impaired (≥100 and <126) 
Normal (<100) to High (≥126) 
Impaired (≥100 and <126) to High (≥126) 
HbA1c % 
Normal (<5.7%) to Borderline (≥5.7% and <6.5%) 
Borderline (≥5.7% and <6.5%) to High (≥6.5%) 
Normal (<5.7%) to High (≥6.5%) 
Table 6: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test 
Alanine Aminotransferase (ALT) (U/L)  
Shift from Normal to ≥3 x ULN   
Shift from Normal to ≥5 x ULN   
Shift from Normal to ≥10 x ULN   
Aspartate Aminotransferase (AST) (U/L) 
Shift from Normal to ≥3 x ULN   
Shift from Normal to ≥5 x ULN   
Shift from Normal to ≥10 x ULN   
Bilirubin, Total (mg/dL) 
Shift from Normal to >1 x ULN   
Shift from Normal to ≥2 x ULN   
3.8.3. 
Vital Signs and Body Weight 
3.8.3.1. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values at each scheduled time 
point will be presented for the treatment 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 7. The number and percentage of subjects with PCS 
postbaseline values will be tabulated. The percentages will be calculated based on the number of 
subjects with abnormal baseline values and at least one postbaseline assessment. The numerator 
will be the number of subjects with abnormal baseline values and at least one postbaseline PCS 
value. A supportive listing of subjects with PCS postbaseline values will be provided. 


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All vital signs will be presented in the subject data listing. 
Table 7: 
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 
3.8.3.2. 
Weight and Body Mass Index 
Weight (kg), BMI (kg/m2) and waist circumferences (cm) (baseline and change from baseline) 
will be summarized using observed data. Absolute and percent change from baseline in body 
weight will be summarized. 
Number and percentage of subjects with ≥7% or ≥10% weight gain from baseline based on the 
observed data will be summarized by visit. Subgroup analysis by region (US vs non-US) will be 
performed. In addition, number and percentage of subjects with weight change values considered 
as PCS occurring at any post-baseline visit will be summarized. Criteria for PCS are presented 
below in Table 8. The percentages will be calculated relative to the number of subjects in the 
Safety Population with at least one post-baseline value. A supportive listing will be provided for 
subjects with PCS values. 
Table 8: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight 
Parameter 
Criteria 
Body Weight 
Decrease from Baseline ≥7% 
Increase from Baseline ≥7% 
3.8.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used to measure the presence and intensity of suicidal ideation 
and behavior (Table 9). 
Suicidal behavior and suicidal ideation will be summarized for the Safety Population. The 
number of subjects with suicidal ideation and suicidal behavior will be summarized when 
applicable. 
Supportive tabular display of subjects with all values will be provided. 


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Table 9: 
C-SSRS Categories for Analysis 
Category 
C-SSRS Item response is “YES” 
Suicidal behaviora 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideationa 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without 
intent to act 
Active suicidal ideation with some intent to act, without specific 
plan 
Active suicidal ideation with specific plan and intent 
Non-Suicidal Self-Injurious 
Behavior 
Non-Suicidal Self-Injurious 
Behavior 
a Derived based on responses to individual items listed within the category 
3.9. 
Pharmacokinetic/ Pharmacodynamic Data Analysis 
Not applicable. 
4. 
INTERIM ANALYSES 
As described in Section 1, this SAP document is an update of the interim analysis that was 
conducted to support the ALKS 3831 New Drug Application (NDA). The full study population 
will be analyzed once the study is completed. 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
To further assess the long-term durability, the following analysis was added in ISAP but was not 
specified in protocol: 
• Shift analysis in CGI-S 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 


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6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits at scheduled timepoints as specified in the protocol 
(Table 1). 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in eCRF. There will be one valid value of assessment kept for each scheduled analysis visit 
in summary/analysis statistics. 
Unscheduled visits are visits with data not collected on the scheduled time point. Unscheduled 
visits will not be used for by-visit summary/analysis statistics, unless specified otherwise. 
All unscheduled visits as collected in eCRF will be included in listings. 
Last postbaseline values are defined as the last valid postbaseline values collected for each 
subject during the treatment period. 
An early termination (ET) visit during the on-treatment period can be mapped to a scheduled 
visit, if there is no valid value already at that visit. Visit window as defined in Table 10 for 
weight, waist circumference and CGI-S data and Table 11 for vital signs, lab and IWQOL-Lite 
data will be used to map the assessments collected after premature discontinuation of the study 
drug. An ET visit that is not mapped will not be summarized in the tables or figures but will be 
included in the listing. 
Table 10: 
Visit Window Definition for Weight, Waist Circumference and CGI-S Data 
Analysis Visit to be 
Mapped to 
Target Study Month 
Target Visit Date 
Visit Window 
Visit 2 
Month 1 
Day 29 
[2, 42] 
Visit 3 
Month 2 
Day 57 
[43, 70] 
Visit 4 
Month 3 
Day 85 
[71, 98] 
Visit 5 
Month 4 
Day 113 
[99, 126] 
Visit 6 
Month 5 
Day 141 
[127, 154] 
Visit 7 
Month 6 
Day 169 
[155, 182] 
Visit 8 
Month 7 
Day 197 
[183, 210] 
Visit 9 
Month 8 
Day 225 
[211, 238] 
Visit 10 
Month 9 
Day 253 
[239, 266] 
Visit 11 
Month 10 
Day 281 
[267, 294] 
Visit 12 
Month 11 
Day 309 
[295, 322] 
Visit 13 
Month 12 
Day 337 
[323, 350] 
Visit 14 
Month 13 
Day 365 
[351, 378] 
Visit 15 
Month 14 
Day 393 
[379, 406] 
Visit 16 
Month 15 
Day 421 
[407, 434] 
Visit 17 
Month 16 
Day 449 
[435, 462] 


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Analysis Visit to be 
Mapped to 
Target Study Month 
Target Visit Date 
Visit Window 
Visit 18 
Month 17 
Day 477 
[463, 490] 
Visit 19 
Month 18 
Day 505 
[491, 518] 
Visit 20 
Month 19 
Day 533 
[519, 546] 
Visit 21 
Month 20 
Day 561 
[547, 574] 
Visit 22 
Month 21 
Day 589 
[575, 602] 
Visit 23 
Month 22 
Day 617 
[603, 630] 
Visit 24 
Month 23 
Day 645 
[631, 658] 
Visit 25 
Month 24 
Day 673 
[659, 686] 
Visit 26 
Month 25 
Day 701 
[687, 714] 
Visit 27 
Month 26 
Day 729 
[715, 742] 
Visit 28 
Month 27 
Day 757 
[743, 770] 
Visit 29 
Month 28 
Day 785 
[771, 798] 
Visit 30 
Month 29 
Day 813 
[799, 826] 
Visit 31 
Month 30 
Day 841 
[827, 854] 
Visit 32 
Month 31 
Day 869 
[855, 882] 
Visit 33 
Month 32 
Day 897 
[883, 910] 
Visit 34 
Month 33 
Day 925 
[911, 938] 
Visit 35 
Month 34 
Day 953 
[939, 966] 
Visit 36 
Month 35 
Day 981 
[967, 994] 
Visit 37 
Month 36 
Day 1009 
[995, 1022] 
Visit 38 
Month 37 
Day 1037 
[1023, 1050] 
Visit 39 
Month 38 
Day 1065 
[1051, 1078] 
Visit 40 
Month 39 
Day 1093 
[1079, 1106] 
Visit 41 
Month 40 
Day 1121 
[1107, 1134] 
Visit 42 
Month 41 
Day 1149 
[1135, 1162] 
Visit 43 
Month 42 
Day 1177 
[1163, 1190] 
Visit 44 
Month 43 
Day 1205 
[1191, 1218] 
Visit 45 
Month 44 
Day 1233 
[1219, 1246] 
Visit 46 
Month 45 
Day 1261 
[1247, 1274] 
Visit 47 
Month 46 
Day 1289 
[1275, 1302] 
Visit 48 
Month 47 
Day 1317 
[1303, 1330] 


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Analysis Visit to be 
Mapped to 
Target Study Month 
Target Visit Date 
Visit Window 
Visit 49 
Month 48 
Day 1345 
[1331, 1351] 
Visit Day is calculated as visit date – date of the first dose of study drug + 1. 1 month=28 days 
Table 11: 
Visit Window Definition for Vital Signs, Lab and IWQOL-Lite Data 
Analysis Visit to be 
Mapped to 
Target Study Month 
Target Visit Day 
Visit Window 
Visit 4 
Month 3 
Day 85 
[2, 126] 
Visit 7 
Month 6 
Day 169 
[127, 210] 
Visit 10 
Month 9 
Day 253 
[211, 294] 
Visit 13 
Month 12 
Day 337 
[295, 378] 
Visit 16 
Month 15 
Day 421 
[379, 462] 
Visit 19 
Month 18 
Day 505 
[463, 546] 
Visit 22 
Month 21 
Day 589 
[547,630] 
Visit 25 
Month 24 
Day 673 
[631,714] 
Visit 28 
Month 27 
Day 757 
[715,798] 
Visit 31 
Month 30 
Day 841 
[799, 882] 
Visit 34 
Month 33 
Day 925 
[883,966] 
Visit 37 
Month 36 
Day 1009 
[967,1050] 
Visit 40 
Month 39 
Day 1093 
[1051,1134] 
Visit 43 
Month 42 
Day 1177 
[1135,1218] 
Visit 46 
Month 45 
Day 1261 
[1219,1302] 
Visit 49 
Month 48 
Day 1345 
[1303,1351] 
Visit Day is calculated as visit date – date of the first dose of study drug + 1. 1 month=28 days 
6.2. 
Handling of Partial Dates of Concomitant Medication and Adverse 
Events 
Partial start dates of prior, concomitant medications, and adverse events will be assumed to 
be the earliest possible date consistent with the partial date. Partial stop dates of prior, 
concomitant medications, and adverse events will be assumed to be the latest possible date 
consistent with the partial date. In the case of completely missing stop date, medication will be 
assumed to be ongoing. 
6.3. 
Handling of Safety Data 
All efforts should be made to obtain the missing information from the investigator. For C-SSRS, 
vital signs and laboratory testing (chemistry, hematology, urinalysis), only observed data will be 
used for analyses, and missing data will not be imputed. 


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7. 
GENERAL STATISTICAL METHODOLOGY (AND REPORTING 
OF RESULTS) 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of subjects in each category for categorical variables) will 
be provided. 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 but will be 
included in the analyses for the PCS postbaseline values, and subject listings. Source data for the 
summary tables will be presented as subject data listings. 
7.1. 
Reporting Precision 
Summary statistics will be presented to the following degree of precision (Table 12), unless 
otherwise specified: 
Table 12: 
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 body mass index (BMI), one decimal place will be used for summary 
statistics, unless otherwise specified. 
8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) 
Mock-up tables and listings will be provided in a separate document. 


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10. 
REFERENCES 
Tessier A, Zavorsky GS, Kim dJ, Carli F, Christou N, Mayo NE. Understanding the 
Determinants of Weight-Related Quality of Life among Bariatric Surgery Candidates. J Obes. 
2012;2012:713426. doi: 10.1155/2012/713426. 
 


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APPENDIX 1. AESI - MOVEMENT DISORDERS (INCLUDING 
EXTRAPYRAMIDAL SYNDROME AND TARDIVE 
DYSKINESIA; STANDARDIZED MEDDRA QUERY) 
Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Abnormal involuntary movement scale 
10075002 
Action tremor 
10072413 
Akathisia 
10001540 
Akinesia 
10001541 
Athetosis 
10003620 
Ballismus 
10058504 
Blepharospasm 
10005159 
Bradykinesia 
10006100 
Bradyphrenia 
10050012 
Buccoglossal syndrome 
10006532 
Chorea 
10008748 
Choreoathetosis 
10008754 
Chronic tic disorder 
10076661 
Cogwheel rigidity 
10009848 
Complex tic 
10076663 
Dopamine dysregulation syndrome 
10067468 
Drooling 
10013642 
Dyskinesia 
10013916 
Dyskinesia hyperpyrexia syndrome 
10071302 
Dyskinesia neonatal 
10013922 
Dyskinesia oesophageal 
10013924 
Dysphonia 
10013952 
Dystonia 
10013983 
Dystonic tremor 
10073210 
Emprosthotonus 
10014566 
Extrapyramidal disorder 
10015832 
Facial spasm 
10063006 
Fine motor skill dysfunction 
10076288 
Freezing phenomenon 
10060904 


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Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Gait disturbance 
10017577 
Gait inability 
10017581 
Grimacing 
10061991 
Hyperkinesia 
10020651 
Hyperkinesia neonatal 
10020652 
Hypertonia 
10020852 
Hypertonia neonatal 
10048615 
Hypokinesia 
10021021 
Hypokinesia neonatal 
10021022 
Hypokinetic dysarthria 
10082243 
Laryngeal tremor 
10078751 
Laryngospasm 
10023891 
Meige’s syndrome 
10027138 
Micrographia 
10057333 
Mobility decreased 
10048334 
Motor dysfunction 
10061296 
Movement disorder 
10028035 
Muscle contractions involuntary 
10028293 
Muscle rigidity 
10028330 
Muscle spasms 
10028334 
Muscle spasticity 
10028335 
Muscle tightness 
10049816 
Muscle tone disorder 
10072889 
Muscle twitching 
10028347 
Musculoskeletal stiffness 
10052904 
Oculogyric crisis 
10030071 
Oesophageal spasm 
10030184 
On and off phenomenon 
10030312 
Opisthotonus 
10030899 
Oromandibular dystonia 
10067954 
Oropharyngeal spasm 
10031111 
Parkinsonian crisis 
10048868 


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Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Parkinsonian gait 
10056242 
Parkinsonian rest tremor 
10056437 
Parkinsonism 
10034010 
Parkinsonism hyperpyrexia syndrome 
10071243 
Parkinson's disease 
10061536 
Parkinson's disease psychosis 
10074835 
Pharyngeal dyskinesia 
10070912 
Pharyngeal dystonia 
10081226 
Pleurothotonus 
10035628 
Postural reflex impairment 
10067206 
Postural tremor 
10073211 
Posture abnormal 
10036436 
Posturing 
10036437 
Propulsive gait 
10082328 
Protrusion tongue 
10037076 
Provisional tic disorder 
10076694 
Psychomotor hyperactivity 
10037211 
Rabbit syndrome 
10068395 
Reduced facial expression 
10078576 
Respiratory dyskinesia 
10057570 
Resting tremor 
10071390 
Restlessness 
10038743 
Risus sardonicus 
10039198 
Secondary tic 
10076702 
Spasmodic dysphonia 
10067672 
Status dystonicus 
10088053 
Tardive dyskinesia 
10043118 
Tic 
10043833 
Tongue spasm 
10043981 
Torticollis 
10044074 
Torticollis psychogenic 
10044076 
Tremor 
10044565 


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Preferred Term (SMQ [#20000095] of Extrapyramidal syndrome) 
PT Code 
Tremor neonatal 
10044575 
Trismus 
10044684 
Uvular spasm 
10050908 
Walking disability 
10053204 
Writer's cramp 
10072249 
 


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APPENDIX 2. AESI - SUICIDAL IDEATION AND BEHAVIOR 
(CUSTOM MedDRA QUERY) 
Preferred Term 
PT Code 
Assisted suicide 
10079105 
Columbia suicide severity rating scale abnormal 
10075616 
Completed suicide 
10010144 
Depression suicidal 
10012397 
Intentional overdose 
10022523 
Intentional self-injury 
10022524 
Overdose 
10033295 
Poisoning deliberate 
10036000 
Self-injurious ideation 
10051154 
Suicidal behaviour 
10065604 
Suicidal ideation 
10042458 
Suicide attempt 
10042464 
Suicide threat 
10077417 
Suspected suicide 
10082458 
Suspected suicide attempt 
10081704 


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APPENDIX 3. AE TERMS - ABUSE POTENTIAL (CUSTOM MedDRA 
QUERY) 
Category 
Preferred Term 
PT Code 
Abuse behavior 
Accidental overdose 
10000381 
Drug abuse 
10013654 
Drug abuser 
10061111 
Drug detoxification 
10052237 
Drug diversion 
10066053 
Drug level above therapeutic 
10061132 
Drug level increased 
10013722 
Drug screen 
10050837 
Drug screen positive 
10049177 
Drug use disorder 
10079381 
Drug use disorder, antepartum 
10079382 
Drug use disorder, postpartum 
10079383 
Intentional overdose 
10022523 
Intentional product misuse 
10074903 
Intentional product use issue 
10076308 
Maternal use of illicit drugs 
10026938 
Needle track marks 
10028896 
Neonatal complications of substance abuse 
10061862 
Overdose 
10033295 
Prescription drug used without a prescription 10076639 
Prescription form tampering 
10067669 
Product tampering 
10069330 
Reversal of opiate activity 
10039004 
Substance abuse 
10066169 
Substance abuser 
10067688 
Substance use 
10070964 
Substance use disorder 
10079384 
Substance-induced mood disorder 
10072387 
Substance-induced psychotic disorder 
10072388 
Toxicity to various agents 
10070863 


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Category 
Preferred Term 
PT Code 
Euphoria related 
Euphoric mood 
10015535 
Feeling abnormal 
10016322 
Feeling drunk 
10016330 
Feeling of relaxation 
10016352 
Hallucination 
10019063 
Hallucination, auditory 
10019070 
Hallucination, gustatory 
10019071 
Hallucination, olfactory 
10019072 
Hallucination, synaesthetic 
10062824 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
Inappropriate affect 
10021588 
Mood altered 
10027940 
Mood swings 
10027951 
Thinking abnormal 
10043431 
Non-specific 
Acute psychosis 
10001022 
Aggression 
10001488 
Cognitive disorder 
10057668 
Confusional state 
10010305 
Delirium 
10012218 
Delusional disorder, unspecified type 
10012255 
Depersonalisation/derealisation disorder 
10077805 
Disorientation 
10013395 
Dissociation 
10013457 
Disturbance in attention 
10013496 
Disturbance in social behaviour 
10061108 
Dopamine dysregulation syndrome 
10067468 
Emotional disorder 
10014551 
Flight of ideas 
10016777 
Medication overuse headache 
10072720 


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Category 
Preferred Term 
PT Code 
Mental impairment 
10027374 
Narcotic bowel syndrome 
10072286 
Paranoia 
10033864 
Psychotic behaviour 
10037249 
Psychotic disorder 
10061920 
Sedation 
10039897 
 
 
Stupor 
10042264 


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APPENDIX 4. AE TERMS – DEPENDENCE (CUSTOM MedDRA 
QUERY) 
Preferred Term  
PT Code 
Dependence 
10012335 
Drug dependence 
10013663 
Drug dependence, antepartum 
10013675 
Drug dependence, postpartum 
10013676 
Drug tolerance 
10052804 
Drug tolerance decreased 
10052805 
Drug tolerance increased 
10052806 
Substance dependence 
10076595 
 


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APPENDIX 5. AE TERMS – WITHDRAWAL (CUSTOM MedDRA 
QUERY) 
Preferred Term  
PT Code 
Abdominal pain 
10000081 
Agitation 
10001497 
Anhedonia 
10002511 
Anxiety 
10002855 
Arthralgia 
10003239 
Chills 
10008531 
Depressed mood 
10012374 
Depression 
10012378 
Diarrhoea 
10012735 
Drug detoxification 
10052237 
Drug rehabilitation 
10064773 
Drug withdrawal convulsions 
10013752 
Drug withdrawal headache 
10013753 
Drug withdrawal maintenance therapy 
10052970 
Drug withdrawal syndrome 
10013754 
Drug withdrawal syndrome neonatal 
10013756 
Dysphoria 
10013954 
Dyssomnia 
10061827 
Feeling of despair 
10016344 
Headache 
10019211 
Hyperhidrosis 
10020642 
Insomnia 
10022437 
Irritability 
10022998 
Morose 
10027977 
Mydriasis 
10028521 
Nausea 
10028813 
Negative thoughts 
10058672 
Nervousness 
10029216 
Obsessive thoughts 
10029897 
Pain 
10033371 


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Preferred Term  
PT Code 
Persistent depressive disorder 
10077804 
Piloerection 
10035039 
Poor quality sleep 
10062519 
Rebound effect 
10038001 
Restlessness 
10038743 
Reversal of opiate activity 
10039004 
Rhinorrhoea 
10039101 
Steroid withdrawal syndrome 
10042028 
Syncope 
10042772 
Tachycardia 
10043071 
Terminal insomnia 
10068932 
Tremor 
10044565 
Vomiting 
10047700 
Withdrawal arrhythmia 
10047997 
Withdrawal syndrome 
10048010 
Yawning 
10048232 
 


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APPENDIX 6. COVID-19 ANALYSIS 
Pandemic has resulted in certain disruptions in the study conduct since early 2020, including site 
closure, delayed study drug supply, subjects discontinuation and missing assessments. These 
impacts were limited in scope upon review of the protocol deviations, and also confounded by 
the initiation of new regions. Sites in Ukraine and Russia were first initiated in March 2020 and 
July 2020. Therefore, only descriptive statistics will be provided to explore the potential impact 
of the pandemic on the primary and secondary objectives of the study. The following subgroup 
analysis (before vs during pandemic) will be conducted: 
• Disposition 
• Demographics and Baseline Characteristics 
• Protocol Deviation 
• Primary Efficacy Endpoint 
• Key Secondary Endpoints 
• TEAE 
• SAE 
Subjects enrolled before 01 Mar 2020 will be grouped as before pandemic, and subjects enrolled 
after this date will be grouped as during pandemic. While the pandemic has started in various 
regions a few weeks apart, a single cutoff date will be applied. 
 
 


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