Clinical trial NCT02669758
Conditions: Schizophrenia
Keywords: Alkermes ALKS 3831 Samidorphan Schizophrenia Safety
Sponsor: Alkermes, Inc.
Start date: 2016-01-20; Completion date: 2018-06-29
Enrollment: 281 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the long term safety and tolerability of ALKS 3831 in subjects with schizophrenia.

Detailed description:

Arms: arm 1: Olanzapine + samidorphan; administered as a coated bilayer tablet.
Interventions: intervention 1: ALKS 3831
Intervention descriptions: intervention 1: Tablets were administered for daily dosing

Protocol documents:
Prot_000.pdf: 
A Phase 3, Multicenter Study to Assess the Long Term 
Safety and Tolerability of ALKS 3831 in Subjects with 
Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A306 
NCT Number: 
NCT02669758 
EudraCT Number:  
2015-003880-13 
Date of Protocol:  
25 April 2017 
 


1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK3831-A306 
EudraCT Number: 2015-003880-13 
 
Study title: 
A Phase 3, Multicenter Study to Assess the Long Term 
Safety and Tolerability of ALKS 3831 in Subjects with 
Schizophrenia 
Document date: 
v 3.0 (incorporates Amendment 2.0): 25 Apr 2017 
v 2.0 (incorporates Amendment 1.0): 28 Mar 2016 
Original Protocol: 24 Sep 2015 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


 
 
Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
CONTACT INFORMATION 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone 
Alkermes Medical Monitor  
 
Alkermes Pharma Ireland, Ltd. 
Connaught House 
1 Burlington Road 
Dublin 4, Ireland 
Phone: 
 
CRO Medical Monitor and 
24-Hour Emergency Contact 
 
 
 
02-785 Warsaw, Poland 
Mobile: 
 
Fax: 
 
SAE and Pregnancy Reporting 
 Safety Medical Monitor 
US Email:
EU/Rest of World (ROW) Email: 
 
US Fax Number: 
 
EU/ROW Fax Number: 
 
 
Abbreviations: CRO=contract research organization; SAE=serious adverse event 
 
 
 
 
 
 
 
 
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
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, Multicenter Study to Assess the Long Term Safety and Tolerability of 
ALKS 3831 in Subjects with Schizophrenia 
Investigators: This is a multinational, multicenter study. 
Study Period: 
Estimated date of first subject’s consent: Q1 2016 
Estimated date of last subject’s last visit: Q4 2018 
Phase of Development: 3 
Objectives: 
Primary: The primary objective of this study is to evaluate the long-term safety and tolerability of 
ALKS 3831 in subjects with schizophrenia. 
Methodology: Subjects that have completed the 4-week Treatment Period of the antecedent study, 
ALK3831-A305, within the past 7 days are eligible to be enrolled in this study. Subjects completing 
the antecedent study as inpatients may continue as inpatients for up to 1 week in this extension study. 
These subjects may be discharged from the inpatient unit at any time during this week based on 
Investigator’s judgment. 
Subjects enrolled in the study will be started on ALKS 3831 10/10 (10 mg olanzapine/10 mg 
samidorphan). The dose may be increased to ALKS 3831 15/10 (15 mg olanzapine/10 mg 
samidorphan) and up to ALKS 3831 20/10 (20 mg olanzapine/10 mg samidorphan) during the first 
week or thereafter, based on Investigator discretion. For subjects entering this study as outpatients, 
study staff will check in with them by phone on Day 3 to assess tolerability and determine if a dose 
increase is needed. An Unscheduled Visit will be arranged mid-Week 1 for subjects requiring a dose 
increase to ALKS 3831 15/10 or ALKS 3831 20/10. Following a dose increase, the dose may be 
decreased back to 10/10 or 15/10 if there are tolerability issues. Thus, dosing is flexible and subjects 
will receive ALKS 3831 10/10, 15/10, or 20/10 throughout the duration of the study, based on 
Investigator discretion. Dose adjustments can only be performed on-site at the study center. Subjects 
requiring dose adjustments between visits should arrange an Unscheduled Visit where the following 
procedures will be performed: study drug return, adherence review, and study drug dispensation. 
Safety assessments will include adverse event (AE) monitoring, clinical laboratory testing, vital signs, 
weight and waist circumference assessments, 12-lead electrocardiograms (ECGs), movement disorder 
assessments, including the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating 
Scale (BARS), and Simpson Angus Scale (SAS), and the Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
Antipsychotic efficacy assessments to evaluate durability of treatment effect include Positive and 
Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S). 
Additional assessments include the Impact of Weight on Quality of Life–Lite Questionnaire 
(IWQOL-Lite), Cigarette Use, and EuroQOL-5D (EQ-5D). 
Subjects completing 52 weeks of treatment with study drug will be eligible to continue in the 
open-label, long-term safety study (ALK3831-A308) and will continue to receive ALKS 3831. 
Subjects not continuing in the ALK3831-A308 long-term safety study will enter a 4-week Safety 
Follow-up Period. A schematic summarizing the study design is shown below. 
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
Within 7 days of 
ALK3831-A305 
Study Completion
ALKS 3831 10/10, 15/10, or 20/10 mg
All subjects start on 
ALKS 3831 10/10 mg
Day 3
 Phone Call*
52-week open-label Treatment Period*
Safety 
Follow-up 
4 weeks
*Visits will occur weekly for the first 2 weeks, then biweekly thereafter. Outpatient subjects will be contacted 
by phone on Day 3 to determine if a dose increase is needed, and, if so, an unscheduled visit will be arranged 
mid-Week 1. The dose may be adjusted to either 10/10, 15/10, or 20/10 mg throughout the study period, 
based on Investigator discretion, and such dose adjustments will require subjects to visit the study site
Long Term 
Safety Study
 
Number of Subjects Planned: Approximately 390 subjects are planned to be enrolled in this study. 
Main Criteria for Inclusion: 
1. Subject is willing and able to provide informed consent; subject has signed the informed 
consent form before initiation of any study specific procedures 
2. Subject agrees to use an acceptable method of contraception for the duration of the study 
3. Subject is willing and able to follow the study procedures as outlined in the protocol 
4. Subject has the potential to benefit from the administration of ALKS 3831, in the opinion of 
the Investigator 
5. Subject has completed the antecedent study, ALK3831-A305, within 7 days 
Main Criteria for Exclusion: 
1. Subject has any finding that, in the view of the Investigator or Medical Monitor, would 
compromise the safety of the subject or affect their ability to fulfill the protocol visit schedule 
or visit requirement 
2. Subject is currently taking medications that are contraindicated with olanzapine use or exhibit 
drug-interaction potential with olanzapine will be defined and prohibited at the discretion of 
the Principal Investigator (PI) 
3. Subject has a positive test for drugs of abuse at study entry 
4. Subject is pregnant, planning to become pregnant, or breastfeeding during the study 
Investigational Product, Dosage, Duration, and Mode of Administration: ALKS 3831 will be 
supplied as a coated bilayer tablet containing either 10, 15, or 20 mg olanzapine and 10 mg 
samidorphan. The tablet is to be taken by mouth once daily, preferably at bedtime. 
Reference Therapy, Dosage, Duration, and Mode of Administration: Not applicable. 
Duration of Study: The study duration will be up to 56 weeks, which includes a 52-week Treatment 
Period and a 4-week Safety Follow-up Period. 
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Criteria for Evaluation: 
Safety: 
The safety assessments include: 
• 
Adverse events (AEs) 
• 
Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• 
Vital signs (oral temperature, respiratory rate, orthostatic blood pressure, and pulse) 
• 
Weight and waist circumference 
• 
ECG parameters (heart rate, RR, PR, QRS, and QT) 
• 
C-SSRS 
• 
AIMS 
• 
BARS 
• 
SAS 
Efficacy: 
The efficacy assessments include: 
• 
PANSS 
• 
CGI-S 
Other: 
Other assessments include: 
• 
IWQOL-Lite 
• 
Cigarette Use 
• 
EQ-5D 
Statistical Methods: 
The Safety Population is defined as all enrolled subjects who receive at least one dose of ALKS 3831 
in this study. The Full Analysis Set (FAS) Population is defined as all subjects that receive at least one 
dose of ALKS 3831 and at least one postdose PANSS assessment in this study. 
Safety analyses will be carried out using the Safety Population. Incidence of AEs will be analyzed as a 
safety endpoint. Reported AE terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®) and will be summarized by system organ class and preferred term categories. 
Serious AEs and AEs leading to study discontinuation (AEDCs) will also be summarized. 
Observed values and changes from Baseline in weight, body mass index (BMI), waist circumference, 
laboratory parameters, vital signs, and ECG parameters will be summarized by study visit. Prior and 
concomitant medication use will be summarized by World Health Organization (WHO) Drug 
Dictionary Anatomical Therapeutic Class (ATC) code. 
Efficacy analyses will be carried out using the FAS Population. The following efficacy endpoints will 
be analyzed to evaluate the durability of treatment effect for ALKS 3831: 
• 
Change from Baseline in PANSS total score and subscales by visit 
• 
Change from Baseline in CGI-S by visit 
• 
PANSS response 
• 
Relapse 
• 
Remission 
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• 
Time to discontinuation 
The PANSS (total and subscale scores) and CGI-S scores, and appropriate changes from Baseline, will 
be summarized using descriptive statistics. Positive and Negative Syndrome Scale response and 
remission at each visit will be summarized as number and percentage. 
The discontinuation rate and the relapse rate will be estimated using the Kaplan-Meier (KM) Method 
and the KM plot will be provided. 
Sample Size Considerations: Approximately 390 subjects are planned to be enrolled in this study. 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................7 
4. 
LIST OF ABBREVIATIONS.....................................................................................11 
5. 
INTRODUCTION ......................................................................................................13 
5.1. 
Background .................................................................................................................13 
5.2. 
Study Drugs ................................................................................................................14 
5.2.1. 
Samidorphan ...............................................................................................................14 
5.2.2. 
Olanzapine ..................................................................................................................14 
5.3. 
Study Rationale ...........................................................................................................15 
5.4. 
Dose Rationale ............................................................................................................15 
6. 
OBJECTIVES .............................................................................................................16 
6.1. 
Primary Objective .......................................................................................................16 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................17 
7.1. 
Subject Inclusion Criteria ...........................................................................................17 
7.2. 
Subject Exclusion Criteria ..........................................................................................17 
7.3. 
Subject Withdrawal ....................................................................................................17 
7.4. 
Replacement of Subjects .............................................................................................18 
8. 
STUDY DESIGN .......................................................................................................19 
8.1. 
Overall Study Design and Plan ...................................................................................19 
8.2. 
Schedule of Visits and Assessments ...........................................................................20 
8.3. 
Study Procedures Descriptions ...................................................................................24 
8.3.1. 
Informed Consent .......................................................................................................24 
8.3.2. 
Eligibility Review .......................................................................................................24 
8.3.3. 
Demographics and Medical History ...........................................................................24 
8.3.4. 
Concomitant Medication Review ...............................................................................24 
8.3.5. 
Vital Signs ..................................................................................................................24 
8.3.6. 
Physical Examination .................................................................................................25 
8.3.7. 
Body Weight and Waist Circumference .....................................................................25 
8.3.8. 
12-Lead Electrocardiogram ........................................................................................25 
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8.3.9. 
Structured Interviews and Questionnaires ..................................................................25 
8.3.9.1. 
Antipsychotic Efficacy Assessments ..........................................................................25 
8.3.9.2. 
Safety Assessments .....................................................................................................26 
8.3.9.3. 
Other Assessments ......................................................................................................26 
8.3.10. 
Laboratory Assessments .............................................................................................27 
8.3.10.1. 
Drug Testing ...............................................................................................................27 
8.3.10.2. 
Hematology, Biochemistry, and Urinalysis ................................................................27 
8.3.10.3. 
Pregnancy Testing ......................................................................................................28 
8.3.11. 
Drug Dispensation and Reconciliation .......................................................................29 
8.3.12. 
Emergency Treatment Card ........................................................................................29 
8.3.13. 
Adverse Event Monitoring .........................................................................................29 
8.4. 
Study Requirements and Restrictions .........................................................................29 
8.4.1. 
Contraception and Pregnancy .....................................................................................29 
8.4.2. 
Prohibited Medications ...............................................................................................30 
8.4.3. 
Permitted Therapy ......................................................................................................31 
8.4.4. 
Pain Management .......................................................................................................31 
8.4.5. 
Other Restrictions and Requirements .........................................................................32 
9. 
TREATMENT OF SUBJECTS ..................................................................................33 
9.1. 
Study Drug Dose and Administration .........................................................................33 
9.2. 
Treatment Adherence ..................................................................................................33 
9.3. 
Randomization/Method of Assigning Subjects to Treatment .....................................33 
9.4. 
Blinding ......................................................................................................................33 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................34 
10.1. 
Study Drug ..................................................................................................................34 
10.2. 
Packaging and Labeling ..............................................................................................34 
10.3. 
Storage ........................................................................................................................34 
10.4. 
Accountability .............................................................................................................34 
10.5. 
Handling and Disposal ................................................................................................35 
11. 
ASSESSMENT OF EFFICACY ................................................................................36 
12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................37 
13. 
ASSESSMENT OF SAFETY .....................................................................................38 
13.1. 
Definition of Adverse Event .......................................................................................38 
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13.2. 
Definition of Serious Adverse Event ..........................................................................38 
13.3. 
Relationship to Study Drug ........................................................................................39 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................41 
13.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................41 
14. 
STATISTICS ..............................................................................................................43 
14.1. 
Sample Size Considerations .......................................................................................43 
14.2. 
General Statistical Methodology ................................................................................43 
14.2.1. 
Study Population .........................................................................................................43 
14.2.1.1. 
Safety Population ........................................................................................................43 
14.2.1.2. 
Full Analysis Set .........................................................................................................43 
14.3. 
Demographics and Baseline Data ...............................................................................43 
14.4. 
Safety and Tolerability Analyses ................................................................................43 
14.5. 
Efficacy Analysis ........................................................................................................44 
14.6. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................44 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................45 
15.1. 
Study Monitoring ........................................................................................................45 
15.2. 
Audits and Inspections ................................................................................................45 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................45 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................46 
16.1. 
Case Report Forms .....................................................................................................46 
16.2. 
Confidentiality of Data ...............................................................................................46 
17. 
ETHICAL CONSIDERATIONS................................................................................47 
17.1. 
Ethics Review .............................................................................................................47 
17.2. 
Ethical Conduct of the Study ......................................................................................47 
17.3. 
Written Informed Consent ..........................................................................................47 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................49 
18.1. 
Data Capture ...............................................................................................................49 
18.2. 
Inspection of Records .................................................................................................49 
18.3. 
Retention of Records ..................................................................................................49 
18.4. 
Use of Information and Publication Policy ................................................................50 
19. 
REFERENCES ...........................................................................................................51 
20. 
APPENDICES ............................................................................................................53 
 
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LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definitions of Terms .........................................................11 
Table 3: 
Schedule of Assessments ............................................................................................21 
Table 4: 
Clinical Laboratory Assessments ...............................................................................28 
Table 5: 
Adverse Event Causality Guidelines ..........................................................................40 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................20 
 
LIST OF APPENDICES 
Appendix A: 
Partial List of Prohibited Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers 
Appendix B: 
Positive and Negative Syndrome Scale 
Appendix C: 
Clinical Global Impression 
• Severity 
Appendix D: 
Abnormal Involuntary Movement Scale 
Appendix E: 
Barnes Akathisia Rating Scale 
Appendix F: 
Simpson-Angus Scale 
Appendix G: 
Columbia-Suicide Severity Rating Scale 
• Since Last Visit 
Appendix H: 
Impact of Weight on Quality of Life-Lite 
Appendix I: 
EuroQOL–5D 
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4. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Table 2: 
List of Abbreviations and Definitions of Terms 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-S 
Clinical Global Impression-Severity 
CRO 
Contract research organization 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Eectronic case report form 
EOT 
End of treatment 
EQ-5D 
EuroQOL-5D 
ET 
Early termination 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HbA1C 
Hemoglobin A1c 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IWQOL 
Impact of Weight on Quality of Life 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
PANSS 
Positive and Negative Syndrome Scale 
PCP 
Phencyclidine 
PI 
Principal Investigator 
SAE 
Serious adverse event 
SAS 
Simpson-Angus Scale 
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Table 2: 
List of Abbreviations and Definitions of Terms (Continued) 
Abbreviation or Term 
Explanation or Definition 
WHO 
World Health Organization 
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5. 
INTRODUCTION 
5.1. 
Background 
Schizophrenia is a chronic, severe disease with debilitating psychotic symptoms, physical and 
psychiatric comorbidities, and increased mortality. Despite the availability of a range of 
FDA-approved medicines, the disease is still inadequately treated, and is associated with 
enormous human and economic cost. Life expectancy is reduced by 19 years in men and 
16 years in women with schizophrenia compared to the general population (Harris and 
Barraclough 1998; Lambert et al, 2010; Tiihonen et al, 2009). The decreased life expectancy is 
due to a combination of direct effects of the disease, eg, increased rates of suicide and violence 
(Hodgins 2008; Kuo et al, 2005), as well as indirect causes, including increased incidence of 
obesity and cardiovascular disease (Nasrallah et al, 2006; Saha et al, 2007). 
The goal of treatment in schizophrenia is to achieve the maximal reduction in positive and 
negative symptoms and increase functionality. Unfortunately, even with regular administration 
of currently available antipsychotic medications at full therapeutic dose levels, the overwhelming 
majority of patients continue to exhibit residual active symptomatology. For physicians and 
patients, in many cases the current treatment paradigm involves an efficacy/tolerability trade-off, 
where use of the most efficacious agents is avoided or delayed in order to avoid known safety 
issues. As such, there is a need for more efficacious therapies with better tolerability. 
Olanzapine is regarded as one of the most effective antipsychotic agents with well-recognized 
efficacy and decreased incidence of extrapyramidal symptoms. However, its efficacy is 
compromised by safety and tolerability limitations that affect compliance and retention of 
patients on olanzapine therapy (Lieberman et al, 2005). In particular, results of the Clinical 
Antipsychotic Trials of Intervention Effectiveness (CATIE), identify olanzapine as an effective 
atypical antipsychotic associated with the highest weight gain (9.4 kg increase over a treatment 
period up to 18 months and ≥7% body weight in 30% of subjects) and a comparatively higher 
discontinuation rate relative to other antipsychotic agents due to weight gain and metabolic 
effects. As a result of these limitations surrounding safety, tolerability, adherence, and retention, 
the risk of olanzapine therapy can outweigh the benefit, and patients are often switched to 
alternative antipsychotic agents even if they are less effective. 
ALKS 3831 is a fixed-dose combination product of olanzapine and samidorphan (a μ-opioid 
antagonist) under investigation for the treatment of schizophrenia. Phase 1 and Phase 2 studies 
demonstrated that coadministration of samidorphan with olanzapine attenuates the weight gain 
experienced with olanzapine alone. Results from these studies are described in more detail in 
Section 5.3. ALKS 3831 may have the further benefit of controlling substance abuse in patients 
with schizophrenia. Comorbid substance use disorder is a well-recognized obstacle to patient 
care. An estimated 1 out of every 3 patients with schizophrenia (33.7%) meet or have met criteria 
for alcohol use disorder (Regier et al, 1990). Patients with both schizophrenia and alcohol use 
disorder represent a common variant within the schizophrenia spectrum that is difficult to treat 
and is associated with an extremely poor prognosis (Dixon 1999; Koekkoek et al, 2006). 
Samidorphan (also referred to as ALKS 33 or RDC-0313), is structurally derived from 
naltrexone and is a potent μ-opioid antagonist. In clinical studies, it has been shown to block 
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both the subjective and physiological effects of the opioid agonist remifentanil (ALK33-004) and 
it is correlated with reduced drinking behavior in adults with alcohol dependence (ALK33-005). 
ALK3831-401 is an ongoing clinical study designed to evaluate the effect of ALKS 3831 on 
drinking behavior in adult subjects with schizophrenia and alcohol use disorder. 
In summary, ALKS 3831 is being explored as a therapeutic agent for the treatment of 
schizophrenia designed to combine the antipsychotic efficacy of olanzapine with a reduced risk 
of weight gain and associated metabolic deficits. Development of ALKS 3831 as a fixed-dose 
combination of olanzapine and samidorphan has the potential to improve upon the benefit/risk 
profile of olanzapine alone and address a significant clinical need for patients that are currently 
forced to choose between treatment efficacy and safety. 
5.2. Study Drugs 
In this study, a fixed-dose combination of olanzapine and samidorphan will be administered in a 
single bilayer tablet. The following sections provide an overview of samidorphan and 
olanzapine. Detailed information about the study drugs can be found in the current ALKS 3831 
Investigator’s Brochure. 
5.2.1. 
Samidorphan 
Samidorphan is a new chemical entity in clinical development by Alkermes. It is an opioid 
modulator which acts primarily as an antagonist at μ opioid receptors, with mixed 
agonist/antagonist activity at δ and κ receptors. It is currently being investigated in combination 
with buprenorphine for the treatment of major depressive disorder (ALKS 5461) and in 
combination with olanzapine for the treatment of schizophrenia. Based on its chemical structure, 
samidorphan is considered a Schedule II controlled substance according to the US Drug 
Enforcement Agency and will require proper handling (see Section 10). At least ten clinical 
studies of samidorphan have been conducted to date, eight of which included subjects that 
received samidorphan alone (not in combination with another product). Commonly reported 
adverse events (AEs) observed across all studies included nausea, fatigue, and somnolence. 
Overall, no trends or clinically meaningful changes have been observed in clinical laboratory 
analytes, vital sign parameters, or electrocardiogram (ECG) data. 
5.2.2. 
Olanzapine 
Olanzapine has been available in the US since 1996 (Zyprexa®) and was originally approved for 
the treatment of schizophrenia. It has since been approved for other indications, including the 
treatment of schizophrenia in adolescents and bipolar disorder. The safety and tolerability profile 
of olanzapine is well documented, and AE labeling is supported by an extensive safety database 
that includes over 8,500 adult patients (Eli Lilly and Company 2017). 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. 
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5.3. Study Rationale 
Phase 1 and Phase 2 studies (ALK33-301 and ALK3831-302, respectively) have demonstrated 
that ALKS 3831 significantly attenuates olanzapine-induced weight gain while providing similar 
antipsychotic efficacy for stabilization of schizophrenia symptoms. Safety and tolerability data 
from these studies indicate that ALKS 3831 is safe and generally well-tolerated. However, the 
longest treatment period assessed to date is 24 weeks. The proposed study will extend these 
findings and evaluate the safety and tolerability of ALKS 3831 over a 52-week period. 
5.4. 
Dose Rationale 
The selected doses of ALKS 3831 (10/10 [10 mg olanzapine/10 mg samidorphan], 15/10 [15 mg 
olanzapine/10 mg samidorphan], and 20/10 [20 mg olanzapine/10 mg samidorphan]) are within 
the approved olanzapine therapeutic dose range for the treatment of schizophrenia (Eli Lilly and 
Company 2017) and represent the intended commercial doses of ALKS 3831. 
The 10 mg samidorphan dose was identified as the minimally effective dose based on the robust 
efficacy and optimal safety profile observed in a previous Phase 2 study (ALK3831-302) with 
that dose. A fixed dose of samidorphan was selected due to the fact that data from this study 
demonstrated no correlation between the ratio of samidorphan/olanzapine dose and percent 
change from Baseline in body weight, indicating that even with higher olanzapine doses, a fixed 
dose of samidorphan is sufficient to achieve maximal effect on reducing olanzapine-induced 
weight gain. 
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6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
ALKS 3831 in subjects with schizophrenia. 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
1. Subject is willing and able to provide informed consent; subject has signed the informed 
consent form before initiation of any study specific procedures 
2. Subject agrees to use an acceptable method of contraception for the duration of the study 
(please refer to Section 8.4.1 for additional details regarding contraception) 
3. Subject is willing and able to follow the study procedures as outlined in the protocol 
4. Subject has the potential to benefit from the administration of ALKS 3831, in the opinion 
of the Investigator 
5. Subject has completed the 4-week Treatment Period (all visits up to and including 
Visit 6, End of Treatment) in the antecedent study, ALK3831-A305, within 7 days 
7.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions 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 their ability to fulfill the protocol visit 
schedule or visit requirement 
2. Subject is currently taking medications that are contraindicated with olanzapine use or 
exhibit drug-interaction potential with olanzapine will be defined and prohibited at the 
discretion of the Principal Investigator (PI) 
3. Subject has a positive test for drugs of abuse at study entry 
4. Subject is pregnant, planning to become pregnant, or breastfeeding during the study 
7.3. 
Subject Withdrawal 
A subject may be discontinued from the study at any time if the subject, Investigator, or the 
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 HbA1c ≥6.5% at any time 
during this extension study, the subject will be discontinued from the study. Other reasons for 
discontinuation include the following: 
• AEs 
• Lack of Efficacy 
• Lost to follow-up 
• Withdrawal by subject  
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• Protocol Deviation (noncompliance with study drug or study procedures) 
• Pregnancy 
• Study terminated by Sponsor 
• Other 
If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the Investigator, or until the subject is deemed by the 
Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is necessary to 
monitor a subject beyond the Safety Follow-up Visit, the Follow-up Period may be extended, as 
necessary. In such instances, the Sponsor and the Investigator will agree to an acceptable 
follow-up schedule. 
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Enrolled subjects are to be asked to return to the clinic for an Early Termination (ET) 
Visit and to complete a subsequent 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 End of Treatment (EOT) Visit (Visit 28, Table 3). 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 entered 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 prematurely discontinued from the study will not be replaced. 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
Subjects that have completed the 4-week Treatment Period of the antecedent study, 
ALK3831-A305, within the past 7 days are eligible to be enrolled in the study. Subjects 
completing the 4-week Treatment Period of the antecedent study, ALK3831-A305, as inpatients 
may continue as inpatients for up to 1 week in this extension study. These subjects may be 
discharged from the inpatient unit at any time during this week based on Investigator’s judgment. 
Subjects enrolled in the study will be started on ALKS 3831 10/10 (10 mg olanzapine/10 mg 
samidorphan). The ALKS 3831 dose may be increased to 15/10 (15 mg olanzapine/10 mg 
samidorphan) or 20/10 (20 mg olanzapine/10 mg samidorphan) during the first week of 
treatment or thereafter, based on Investigator discretion. For subjects entering this study as 
outpatients, study staff will check in with them by phone on Day 3 to assess tolerability and 
determine if a dose increase to ALKS 3831 15/10 or 20/10 is needed. An Unscheduled Visit will 
be arranged mid-Week 1 for subjects requiring a dose increase. Following a dose increase, the 
dose may be decreased back to 15/10 or 10/10 if there are tolerability issues. Thus, dosing is 
flexible and subjects will receive ALKS 3831 10/10, 15/10, or 20/10 throughout the duration of 
the study, based on Investigator discretion. Dose adjustments can only be performed on-site at 
the study center. Subjects requiring dose adjustments between scheduled visits should arrange an 
Unscheduled Visit for the following procedures: study drug return, adherence review, and study 
drug dispensation. 
Safety assessments will include AE monitoring, clinical laboratory testing, vital signs, weight 
and waist circumference assessments, 12-lead ECGs, movement disorder assessments, including 
the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), 
and Simpson Angus Scale (SAS), and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
Efficacy assessments to evaluate the durability of treatment effect will include Positive and 
Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S). 
Additional assessments include Impact of Weight on Quality of Life–Lite Questionnaire 
(IWQOL-Lite), Cigarette Use, and EuroQOL-5D (EQ-5D). 
Subjects completing 52 weeks of treatment with study drug will be eligible to continue in the 
open-label, long-term safety study (ALK3831-A308) and will continue to receive ALKS 3831. 
Subjects not continuing in the ALK3831-A308 long-term safety study will enter a 4-week Safety 
Follow-up Period. The overall schedule of visits and assessments for each Treatment Group is 
provided in Table 3. 
A schematic of the study design is provided in Figure 1. 
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Figure 1: 
Study Design Schematic 
Within 7 days of 
ALK3831-A305 
Study Completion
ALKS 3831 10/10, 15/10, or 20/10 mg
All subjects start on 
ALKS 3831 10/10 mg
Day 3
 Phone Call*
52-week open-label Treatment Period*
Safety 
Follow-up 
4 weeks
*Visits will occur weekly for the first 2 weeks, then biweekly thereafter. Outpatient subjects will be contacted 
by phone on Day 3 to determine if a dose increase is needed, and, if so, an unscheduled visit will be arranged 
mid-Week 1. The dose may be adjusted to either 10/10, 15/10, or 20/10 mg throughout the study period, 
based on Investigator discretion, and such dose adjustments will require subjects to visit the study site
Long Term 
Safety Study
 
8.2. 
Schedule of Visits and Assessments 
The schedule of assessments is shown in Table 3. 
A visit window of ±2 days is permitted throughout the Treatment Period and the Follow-up 
Period (Visits 2-30). For a missed visit, the site should attempt to contact the subject to 
reschedule. 
Premature discontinuation procedures are provided in Section 7.3. 
On Day 3, study staff will check in with outpatient subjects by phone to determine if a dose 
increase to ALKS 3831 15/10 or 20/10 is needed. If, in the opinion of the Investigator, a dose 
increase is warranted, an Unscheduled Visit will be arranged mid-Week 1. The following 
procedures will be performed during the Unscheduled Visit: study drug return, adherence review, 
and study drug dispensation. 
Dose adjustments can only occur on-site and require subjects to come to the study center. 
Throughout the study, subjects requiring dose adjustments between scheduled visits may arrange 
an Unscheduled Visit (same procedures as mid-Week 1 Unscheduled Visit described above). 
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P
 
Table 3: 
Schedule of Assessments 
Visit
a 
Open Label Treatment Period 
Follow-
up 
Period 
1
b 
2
c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28/ 
ET/ 
EOT 
29
d 
30 
Study week 
- 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
56 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Testing
e 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug 
Screen
f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Waist 
Circum-
ference 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital 
Signs
g 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Laboratory 
Samples
h 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
ECG 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Physical 
Exam 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PANSS
i 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
CGI-S 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
AE
j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMedj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS
k 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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P
 
Table 3: 
Schedule of Assessments (Continued) 
Visita 
Open Label Treatment Period 
Follow-
up 
Period 
1b 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28/ 
ET/ 
EOT 
29d 
30 
Study week 
- 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
54 
56 
Abnormal 
Movement 
Scales
l 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
IWQOL 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
EQ-5D 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Cigarette 
Use 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Emergency 
Treatment 
Card
m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Drug 
Dispensation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug 
Adherence 
Review
n 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations: AE=adverse event; CGI-S=Clinical Global Impression-Severity; ConMed=concomitant medication; C-SSRS=Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; EOT=End of Treatment; EQ-5D=EuroQOL-5D; IWQOL=Impact of Weight on Quality of Life; PANSS=Positive and 
Negative Syndrome Scale 
a A visit window of ±2 days is permitted throughout the Treatment Period and the Follow-up Period (Visits 2-30) 
b Visit 1 must occur within 7 days of the EOT Visit (Visit 6) of the antecedent study, ALK3831-A305, and may occur on the same day. Assessments from 
ALK3831-A305 Visit 6 will constitute the Baseline/Screening assessments for this extension study 
c On Day 3, study staff will contact outpatient subjects by phone to determine if a dose increase to ALKS 3831 15/10 or 20/10 is needed. An Unscheduled 
Interim Visit will be arranged for subjects requiring a dose adjustment for study drug return and adherence review and study drug dispensation. Any subsequent 
dose adjustments throughout the study require subjects to come to the site for either a scheduled or unscheduled visit 
d Follow-up Visits (Visits 29 and 30) are not required for subjects who enroll in ALK3831-A308 
e Urine pregnancy test prior to dosing at Visit 1 and at all subsequent specified visits 
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f Urine drug screen via dipstick prior to dosing on Day 1 for subjects who did not receive a urine drug screen at Visit 6 of the ALK3831-A305 study, or for 
subjects for whom Visit 1 of this study is not the same day as Visit 6 of the ALK3831-A305 study. Urine drug screen includes opiates, phencyclidine (PCP), 
amphetamine/methamphetamine, and cocaine 
g Vital signs include orthostatic blood pressure and heart rate, respiratory rate, and oral body temperature. Blood pressure, pulse rate, and respiratory rate will be 
taken after the subject has been supine for 5 minutes and once again after the subject has stood for 2 minutes 
h Subjects must fast (no food or drink except water) for at least 8 hours before laboratory draws. Laboratory draws are to be conducted in the morning for all 
specified visits 
i PANSS should be administered before other psychiatric assessments at each specified study visit 
j AEs ongoing at the end of the antecedent study or concomitant medications continuing from the antecedent study will be carried over and followed through 
until resolution 
k The “Since Last Visit” version to be used at all visits 
l Abnormal movement scales include the following: Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and 
Simpson-Angus Scale (SAS) 
m Emergency treatment card to be dispensed at Visit 1, confirmed at subsequent timepoints, and collected at Visit 28, EOT 
n Calls should be made in weeks between in-person study visits to ensure subjects are continuing to stay adherent with medication. An Unscheduled Visit will be 
arranged for any dose adjustments required between planned visits when subjects will come to the site for study drug return and new drug dispensation 
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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. Information collected with the following assessments will be carried 
forward from the antecedent study, ALK3831-A305, for Screening/Baseline: demographics and 
medical history, vital signs, physical exam, height, body weight and waist circumference, 
12-lead ECG, CGI-S, PANSS, and Abnormal Movement Scales. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the 
Investigator or designated study personnel as outlined in Section 17.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential subject. 
8.3.2. 
Eligibility Review 
An eligibility review will be conducted by the Investigator at the visit specified in Table 3 using 
the subject inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. 
8.3.3. 
Demographics and Medical History 
Subjects’ demographic data and medical history will be carried over from the antecedent study, 
ALK3831-A305. 
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, heart rate, respiratory rate, and oral body temperature) will be 
assessed at the timepoints specified in Table 3. An effort will be made to consistently use the 
same arm (preferably the subject’s dominant arm) to measure blood pressure and heart rate 
throughout the study. The blood pressure cuff will be calibrated per study site standard operating 
procedures (SOP). Automated measurement is preferred, but if performed manually, heart rate 
will be measured in the brachial artery for at least 30 seconds. Orthostatic blood pressure and 
heart rate will be collected in the following manner: 
• Allow subject to be in a supine position for at least 5 minutes 
• Measure blood pressure and heart rate 
• Have subject stand for 2 minutes 
• Measure blood pressure and heart rate 
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Vital signs may be collected at any time during a scheduled visit, unless otherwise noted. 
8.3.6. 
Physical Examination 
A physical examination will be performed at the timepoints specified in Table 3.  
8.3.7. 
Body Weight and Waist Circumference 
Body 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, such as watches and jewelry, and they should be 
weighed on the same scale for each measurement under the same conditions. 
Both weight and waist circumference will be measured three consecutive times at each 
assessment and all measurements will be recorded in the eCRF. 
8.3.8. 
12-Lead Electrocardiogram 
A 12-lead ECG will be conducted at the timepoints specified in Table 3. All scheduled ECGs 
must be performed after the subject has rested quietly for at least 5 minutes in the supine 
position. 
A qualified clinician will conduct ECGs and assess ECG results using equipment that has been 
calibrated according to the site’s SOP. The following ECG parameters will be collected: pulse, 
RR, PR, QRS, QT, QT interval corrected using the Fridericia formula (QTcF), and QT interval 
corrected using the Bazett formula (QTcB). 
Electrocardiograms will also be evaluated by a central reader. 
8.3.9. 
Structured Interviews and Questionnaires 
Brief descriptions of each of the interviews and questionnaires to be distributed are available 
below. All interviews and questionnaires will be administered by trained and qualified study 
personnel. 
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. For all visits where assessments overlap, the PANSS should be administered first 
before any other psychiatric assessment. 
8.3.9.1. 
Antipsychotic Efficacy Assessments 
8.3.9.1.1. Positive and Negative Syndrome Scale 
The PI or designee will complete the PANSS (Appendix B) (Kay et al, 1987) according to the 
schedule in Table 3. The Structured Clinical Interview for the PANSS (SCI-PANSS) will be 
used to administer the PANSS. 
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8.3.9.1.2. Clinical Global Impression-Severity 
The PI or designee will complete the CGI-Severity (CGI-S, Appendix C) scale at the timepoints 
specified in Table 3. The CGI-S measures mental illness severity. Clinicians are asked to rate 
subjects based on their prior experience working with individuals in a similar patient population 
(Guy 1976). 
8.3.9.2. 
Safety Assessments 
8.3.9.2.1. Abnormal Movement Rating Scales 
The PI or designee will complete the following abnormal movement rating scales: The AIMS 
(Appendix D) (Guy 1976), the BARS (Appendix E) (Barnes 1989), and the SAS (Appendix F) 
(Simpson and Angus 1970) at the timepoints specified in Table 3. 
After administration of the first dose of study drug, if a subject complains of extrapyramidal 
symptoms on a day when abnormal movement scale assessments are not scheduled, an 
unscheduled abnormal movement assessment should be performed. 
8.3.9.2.2. Columbia-Suicide Severity Rating Scale 
The PI or designee will administer the C-SSRS (Appendix G) according to the schedule in 
Table 3. The “Since Last Visit” version is to be completed at all scheduled timepoints. The 
C-SSRS should be administered by a qualified clinician trained in assessing and managing 
suicidal ideation and behavior (Posner et al, 2011). 
8.3.9.3. 
Other Assessments 
8.3.9.3.1. Cigarette Use 
Data on cigarette use will be collected using the question: “How many packs of cigarettes did 
you smoke over the past 7 days?” at the timepoints specified in Table 3. 
8.3.9.3.2. Impact of Weight on Quality of Life–Lite 
Subjects will complete the IWQOL-Lite questionnaire (Appendix H) at the timepoints specified 
in Table 3. 
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8.3.9.3.3. EuroQOL-5D 
Subjects will complete the EQ-5D (Appendix I) at the timepoints specified in Table 3. This scale 
provides an indication of health status based on self-rating in the following five categories: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Additionally, it asks 
subjects to rank their health status on a visual analogue scale (VAS) from “worst imaginable 
health state” to “best imaginable health state.” 
8.3.10. 
Laboratory Assessments 
8.3.10.1. Drug Testing 
A drug screen for opiates (including codeine, hydrocodone, hydromorphone, methadone, 
morphine, oxycodone, and oxymorphone) and drugs of abuse (including amphetamine/ 
methamphetamine, phencyclidine [PCP], and cocaine) will be performed at the timepoints 
specified in Table 3. Urine drug screens may be repeated based on Investigator judgment. The 
test may also be repeated at any time during the study, should the Investigator feel it is 
warranted. Subjects are not eligible for participation if the results are positive at Screening. If a 
subject is determined to be using any of these substances during the Treatment Period, the 
Investigator should contact the Medical Monitor to discuss the course of action. 
8.3.10.2. Hematology, Biochemistry, and Urinalysis 
Fasting blood and urine samples will be collected at the timepoints specified in Table 3 for 
specific hematology, biochemistry, and urinalysis assessments listed in Table 4. Subjects will be 
instructed not to eat or drink anything (except water) for 8 hours before each visit where blood 
samples for biochemistry and hematology assessments will be collected. Samples will be 
collected in accordance with the site’s standard procedures and analyzed by a central laboratory. 
Laboratory assessments may be repeated at the Investigator’s discretion. 
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Table 4: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
Total and differential 
(absolute) white blood cell 
count 
General Chemistry 
Albumin 
Bicarbonate 
Calcium 
Chloride 
Creatine phosphokinase 
Glucose  
Lactic dehydrogenase 
Potassium 
Sodium 
Total protein 
Uric acid 
Endocrine Function Test 
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 
 
8.3.10.3. 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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8.3.11. 
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. 
Whether or not samidorphan is classified as a controlled substance varies from country to 
country; some countries have classified samidorphan as a controlled substance, while others have 
not. Sites will be given storage, handling, and reconciliation instructions applicable to their 
country to ensure compliance with local regulations for controlled substances. 
8.3.12. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject and collected from each subject 
at the timepoints indicated in Table 3. The card will indicate that the subject 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, as indicated in Table 3. 
8.3.13. 
Adverse Event Monitoring 
Adverse events will be monitored continuously from the time a subject signs the informed 
consent document until the completion of the final study visit (see Table 3). Adverse events and 
serious AEs (SAEs) are defined in Section 13.1 and 13.2, respectively. Section 13.4 provides 
guidance on the monitoring and recording requirements for AEs. Section 13.5 provides guidance 
on the reporting requirements for SAEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study unless they are surgically sterile or postmenopausal (see below). The 
following are considered acceptable methods of contraception: 
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device (IUD) 
3. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, contraceptive implant); oral contraceptives should be initiated at least 30 days 
prior to Screening 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
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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. Additional follow-up may be required. Pregnancies in female subjects 
and female partners of male subjects should also be reported and will be followed in the same 
manner. A Pregnancy Report Form must be submitted to Alkermes via 
 
(fax number in Section 13.5) immediately, within 24 hours of awareness of the pregnancy, 
irrespective of whether an AE has occurred. The pregnancy will be followed until completion or 
termination. If the outcome of the pregnancy meets the criteria for classification as a SAE it 
should be reported following the SAE procedure (see Section 13.5). 
8.4.2. 
Prohibited Medications 
The prohibited medications include the following: 
• Monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline, or 
moclobemide) 
• Long-acting formulations of any antipsychotic agent 
• Use of antipsychotic sleep aids (eg, Seroquel) is prohibited. However, use of 
benzodiazepines to treat some symptoms is permissible 
• In general, the use of psychotropic medications other than study drug is prohibited, 
with the exception of the following (these medications should only be administered 
after all assessments have been completed for that visit): 
− Beta-blockers (eg, propranolol or pinodolol), antihistamines, and anticholinergics 
may be used for treatment-emergent akathisia 
− Anticholinergics may be used for extrapyramidal symptoms 
• Chantix® (varenicline) is not permitted. However, nicotine replacement therapy, 
including nicotine replacement patch and oral nicotine gum, is permitted 
• All prescription or over-the-counter (OTC) agents taken for the purpose of weight 
reduction 
• Systemic steroids administered by oral, intravenous, or intramuscular route 
• Topiramate (Topamax®) and combination products containing topiramate; calcitonin 
(eg, Miacalcin®) 
• Diabetes treatments and hypoglycemic agents including Metformin and Insulin 
Medications that are contraindicated with olanzapine use or exhibit drug-interaction potential 
with olanzapine are prohibited. 
Use of moderate-to-strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 (prescription 
medications, OTC medications, or dietary supplements) is prohibited in the antecedent study and 
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is prohibited in this study throughout the Treatment Period and throughout Follow-up. Refer to 
Appendix A for a list of CYP3A4 inhibitors and inducers (Food and Drug Administration 2016; 
University of Washington: School of Pharmacy 2017a; University of Washington: School of 
Pharmacy 2017b). 
The contract research organization (CRO) Medical Monitor should be consulted for any 
questions about use of any psychotropic medications during a subject’s participation in this 
study. 
Use of opioid antagonists, including naltrexone (any formulations) and naloxone throughout the 
study period is prohibited. Note: during the study period, opioid agonists should be avoided as 
they may be rendered ineffective by samidorphan. 
8.4.3. 
Permitted Therapy 
Permissible potential medications to treat extrapyramidal symptoms may include 
benzodiazepines, antihistamines, and anticholinergics. Benzodiazepines should be utilized for 
treatment-emergent akathisia. While insomnia may be treated with a variety of agents, short 
half-life benzodiazepines should be utilized due to the potential for lingering effects on daytime 
functioning and study assessments (eg, triazolam). Nonbenzodiazepine medication may be used 
to treat insomnia (eg, zolpidem, eszopiclone). Treatment of agitation and/or anxiety with 
benzodiazepines is permissible. 
8.4.4. 
Pain Management 
Because ALKS 3831 contains samidorphan, a μ-opioid receptor antagonist, patients may 
experience reduced or ineffective analgesia when taking an opioid analgesic agent concurrently 
with ALKS 3831, including several days after last dosing of ALKS 3831. 
In the event of an emergency, pain management of the subject should include the following: 
• Regional analgesia or use of non-opioid analgesics 
• If opiate anesthesia or analgesia is required, the subject should be continuously 
monitored, in an anesthesia care setting, by persons not involved in the conduct of the 
surgical or diagnostic procedure. The opioid therapy must be provided by individuals 
specifically trained in the use of anesthetic drugs and the management of the 
respiratory effects of potent opioids, specifically the establishment and the 
maintenance of a patent airway and assisted ventilation 
• Close monitoring by appropriately trained personnel in a setting equipped and staffed 
for cardiopulmonary resuscitation 
For subjects requiring emergency opioid analgesics prior to dosing, the study drug should not be 
administered. If opioid analgesics are required after the study drug has been dosed, it may take 
several days for opiate sensitivity to be restored, since samidorphan is an opioid antagonist and 
could interfere with opioid-mediated pain management. 
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8.4.5. 
Other Restrictions and Requirements 
Additional restrictions and requirements include: 
• Prohibited substances include amphetamines (including methamphetamine), cocaine, 
barbiturates, methadone, opiates (including morphine, oxycodone, methadone, and 
buprenorphine), and PCP 
• Subjects will be required to abstain from blood or blood product donation during the 
study and for 30 days following the Follow-up Visit 
• Subjects will be instructed to maintain their normal caffeine intake and/or tobacco 
use, as well as normal activity/exercise throughout the study. Subjects will be asked 
to abstain from strenuous physical activity for 48 hours prior to each study visit 
• Subjects 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 
Study drugs include: 
• ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan), 15/10 (15 mg 
olanzapine/10 mg samidorphan), or 20/10 (20 mg olanzapine/10 mg samidorphan) 
administered as a coated bilayer tablet 
At Visit 1 and all subsequent visits until EOT, subjects will be given blister cards containing 
study drug to take at home. Subjects will be instructed to take one tablet by mouth each day, 
preferably at bedtime. Dosing may be switched to another time, at the Investigator’s discretion, if 
there are tolerability problems; however, frequent switching is discouraged. 
Subjects will be instructed to keep all unused tablets in their blister card and to return unused 
tablets to the study site at their next visit. If dosing is to occur at that visit, the dose should be 
taken from the subject’s next blister card, not from the card they are returning. 
If a dose is missed or forgotten, subjects will be instructed to resume regular dosing the 
following night. Subjects will be instructed not to take a double dose to try to “make up” for the 
missed dose. 
9.2. 
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 nonadherence with the subject. 
9.3. 
Randomization/Method of Assigning Subjects to Treatment 
Not applicable. 
9.4. 
Blinding 
Not applicable. Study is open-label. 
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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 three fixed-dose 
combinations: 
• 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) 
Samidorphan is a Schedule II controlled substance. Thus, ALKS 3831 should be treated as a 
Schedule II controlled substance in the US and any other country in which it is controlled. 
10.2. 
Packaging and Labeling 
ALKS 3831 will be supplied in blister packs. Blister cards will be in weekly and biweekly 
configurations. Weekly blister cards will contain 9 tablets, enough for 1 week of dosing, plus 
sufficient overage for two additional once daily doses. Biweekly blister cards will contain 
16 tablets, enough for 2 weeks of dosing, plus sufficient overage for two additional once daily 
doses. 
10.3. 
Storage 
Product should be stored 15-25°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 Investigator will be responsible for the oversight of recording the receipt and administration 
of study drug, and for insuring the supervision of the storage and allocation of these supplies. 
The Investigator is required to maintain current drug dispensing and accountability logs 
throughout the study. The Investigator may delegate accountability duties to an appropriate and 
qualified pharmacist or staff member who is under the supervision of the Investigator. The 
Investigator or designee must allow the Clinical Research Associate or equivalent to perform 
drug reconciliation during each study monitoring visit. All unused supplies will be checked 
against the study drug movement records before investigational drug is returned or destroyed. 
Refer to Section 8.3.11 for additional study drug reconciliation procedures. 
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10.5. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. Packages may be destroyed on site according to Good Clinical Practice (GCP) and 
site practice. Alternatively, the Sponsor may arrange for destruction with a third party vendor 
operating in accordance with GCP and/or Good Manufacturing Practice (GMP), as applicable. 
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11. 
ASSESSMENT OF EFFICACY 
The following efficacy assessments will be used to analyze the durability of treatment effect: 
• PANSS 
• CGI-S 
Other Assessments: 
The following assessments will be used to obtain information regarding subject experience 
throughout the study: 
• IWQOL-Lite 
• Cigarette Use 
• EQ-5D 
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12. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
Not applicable. 
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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• AEs 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• Vital signs (oral temperature, respiratory rate, orthostatic blood pressure, and pulse) 
• Weight and waist circumference 
• ECG parameters (heart rate, RR, PR, QRS, and QT) 
• C-SSRS 
• AIMS 
• BARS 
• SAS 
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product. The occurrence, which may or may not have a causal 
relationship with the investigational treatment, may include any clinical or laboratory change that 
does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the informed consent form (ICF) are considered to 
be pre-existing conditions and are documented on the medical history eCRF. Pre-existing 
conditions that worsen during the study are entered on the AE eCRF. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the Investigator. Clinically significant values will be considered AEs and recorded 
as such on the eCRFs. 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy must be reported to Alkermes 
and additional follow-up may be required. 
13.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality that meets one or more of 
the following criteria: 
• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include a reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
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• 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 a hospital or an inpatient unit for a nonmedical reason (ie, social stay admission) 
during the study in the absence of untoward medical occurrence will not be considered an SAE, 
but will be captured as an AE. 
Hospitalization due to worsening of behavioral health-related issues should be reported as an 
SAE. 
13.3. 
Relationship to Study Drug 
The assessment of study drug relationship to each AE will be reported on the appropriate source 
document (and SAE form, in the event of an SAE) by the Investigator (or designated 
Subinvestigator) according to his/her best clinical judgment. The criteria listed in Table 5 should 
be used to guide this assessment. Please note that not all criteria must be present to be indicative 
of a particular drug relationship. All study drugs are considered “test drugs” for the purposes of 
the definitions listed in the table. 
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Table 5: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for Assessment 
Definitely related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Rechallenge (if feasible) is positive. 
The AE shows a pattern consistent with previous knowledge of the test drug or test drug 
class. 
Probably related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Possibly related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE could have been due to another equally likely cause. 
Dechallenge (if performed) is positive. 
Probably not 
related 
There is evidence of exposure to the test drug. 
AND 
There is another more likely cause of the AE. 
Dechallenge (if performed) is negative or ambiguous. 
Rechallenge (if performed) is negative or ambiguous. 
Definitely not 
related 
The subject did not receive the test drug. 
OR 
Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable.  
OR 
There is another obvious cause of the AE. 
Abbreviation: AE=adverse event 
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13.4. 
Monitoring and Recording of Adverse Events 
Adverse event data collection will begin after a subject signs the ICF and will continue until 
completion of the Safety Follow-up Visit (Visit 30) or 28 days after the final dose of study drug. 
Any AE or SAE having an onset after the Safety Follow-up Visit will not be collected or 
reported unless the Investigator feels that the event may be related to the study drug. 
Subjects will be instructed by the Investigator or Designee to report the occurrence of any AE. 
All volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The Investigator will assess all AEs regarding any causal relationship to the study drug (see 
Section 13.3), the intensity (severity) of the event, action taken, and subject outcome. 
The following criteria should be used to guide the assessment of intensity (severity): 
• Mild: Causes awareness of sign or symptom, but is easily tolerated; does not interfere 
with usual activities 
• Moderate: Causes discomfort enough to interfere with usual activities 
• Severe: Is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE and any therapeutic measures that are taken shall 
be at the discretion of the Investigator. If a subject withdraws from the study for any reason, any 
ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or until 
the subject is deemed by the Investigator to be lost to follow-up. 
13.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported to Alkermes via 
 
Limited immediately, within 24 hours of discovery, by emailing or faxing the report to the 
following: 
Attention: Safety 
 Medical Monitor 
US Email: 
 
EU/Rest of World (ROW) Email: 
 
US Fax Number: 
 
EU/ROW Fax Number: 
 
The written report for SAEs should be submitted on the SAE form provided for this purpose. The 
SAE report must include the Investigator’s opinion as to whether the event is study drug-related. 
If this relationship is determined to be possibly, probably, or definitely related to study drug, 
evidence to support this assessment must also be provided. 
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The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 
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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
No formal sample size calculation was performed for this extension study. A sample size of 
approximately 390 subjects is based on the estimated maximum number of subjects who might 
be expected to continue from the ALK3831-A305 study. 
14.2. 
General Statistical Methodology 
In general, summary statistics (n, mean, standard deviation, median, minimum and maximum 
values for continuous variables, and number and percentage of subjects in each category for 
categorical variables) will be provided for evaluated variables. All individual subject level data 
will be presented as data listings. 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan to be finalized before database lock. 
14.2.1. 
Study Population 
14.2.1.1. Safety Population 
The Safety Population includes all enrolled subjects who received at least one dose of 
ALKS 3831. 
14.2.1.2. Full Analysis Set 
The Full Analysis Set (FAS) Population includes all enrolled subjects who received at least 
one dose of ALKS 3831 and underwent at least one postdose PANSS assessment. 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics, such as gender, age, race, weight, and BMI, will be 
summarized with descriptive statistics. 
14.4. 
Safety and Tolerability Analyses 
Safety analyses will be carried out using the Safety Population. Incidence of AEs will be 
analyzed as a safety endpoint. Reported AE terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarized by system organ class and preferred 
term categories. 
Serious AEs and AEs leading to study discontinuation (AEDCs) will also be summarized. 
Observed values and changes from Baseline in weight, BMI, waist circumference, laboratory 
parameters, vital signs, and ECG parameters will be summarized by study visit. 
The number and percentage of subjects who have met potentially clinically significant (PCS) 
criteria at any post-Baseline visit will be summarized for laboratory, vital signs, weight, and 
ECG parameters. Supporting listings will be provided. 
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The number and percentage of subjects with shifts in laboratory and extrapyramidal symptom 
(EPS) parameters (AIMS, BARS, and SAS) will be summarized. Supporting listings will be 
provided. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will be summarized. 
Prior and concomitant medication use will be summarized by World Health Organization 
(WHO) Drug Dictionary Anatomical Therapeutic Class (ATC) code. 
Listings will be provided for all safety endpoints. 
14.5. 
Efficacy Analysis 
Efficacy analyses will be carried out using the FAS Population. The following endpoints will be 
used to evaluate durability of treatment effect: 
• Change from Baseline in PANSS total score and subscales by visit 
• Change from Baseline in CGI-S by visit 
• PANSS response 
• Relapse 
• Remission 
• Time to discontinuation 
The PANSS (total and subscale scores) and CGI-S scores, and appropriate changes from 
Baseline, will be summarized using descriptive statistics. Positive and Negative Syndrome Scale 
response and remission at each visit will be summarized as number and percentage. 
The discontinuation rate and the relapse rate will be estimated using the Kaplan-Meier (KM) 
Method and the KM plot will be provided. 
14.6. 
Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable. 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by an Alkermes monitor or designee. 
15.2. 
Audits and Inspections 
By signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of Alkermes, a regulatory 
authority, and/or an institutional review board (IRB)/independent ethics committee (IEC) may 
visit the site to perform audits or inspections, including the drug storage area, study drug stocks, 
drug accountability records, subject charts and source documents, and other records relative to 
study conduct. The purpose of an Alkermes audit or inspection is to systematically and 
independently examine all study-related activities and documents (eg, laboratory reports, x-rays, 
workbooks, subject medical records) to determine whether these activities were conducted, and 
whether data were recorded, analyzed, and accurately reported according to the protocol, GCP 
guidelines of the International Council on Harmonisation (ICH), and any applicable regulatory 
requirements. 
The Investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
15.3. 
Institutional Review Board/Independent Ethics Committee 
The Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, 
as well as all materials approved by the IRB/IEC for this study, including the subject consent 
form and recruitment materials, must be maintained by the Investigator and made available for 
inspection. 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness, and compliance, the study site should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 15.2 for details regarding the audit process. 
16.1. 
Case Report Forms 
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data (ie, data directly reported on the eCRF). All eCRFs will be completed by the 
clinic staff prior to review by the Alkermes monitor or designated representative. 
The Alkermes monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF. 
16.2. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to Alkermes that he or she will maintain in 
confidence information furnished to him or her by Alkermes and will divulge such information 
to his or her respective IRB or IEC under an appropriate understanding of confidentiality with 
such board. All data will be considered the sole property of Alkermes. Please refer to the Clinical 
Study Agreement (CSA) for details. 
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17. 
ETHICAL CONSIDERATIONS 
17.1. 
Ethics Review 
The clinical site’s IRB/IEC must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB/IEC prior to enrolling subjects into the study; written 
approval from the committee must be received by Alkermes before drug will be released to the 
Investigator. The protocol must be re-approved by the IRB/IEC upon receipt of amendments and 
annually, as local regulatory requirements require. 
The Investigator is responsible for submitting all protocol changes and SAE reports to the 
IRB/IEC according to local procedures. At a minimum, all SAEs requiring an investigational 
new drug safety report must be immediately reported. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. Good Clinical Practice is an international ethical and 
scientific quality standard used for designing, conducting, recording, and reporting studies 
involving the participation of human subjects. Alkermes is committed to complying with this 
standard to provide assurance that the rights, safety, and well-being of study subjects will be 
protected, consistent with the principles having their origin in the Declaration of Helsinki. 
17.3. 
Written Informed Consent 
The Investigator (or authorized designee) at each center will ensure that the subject (or the 
subject’s legal representative) is given full and adequate oral and written information about the 
nature, purpose, potential and possible risks and benefits of the study. Each prospective subject 
will receive an IRB/IEC-approved ICF that summarizes the pertinent study information and will 
be given ample time to read the form and ask questions about the study. All information is to be 
provided in a language understandable to the subject and must not include any language that 
waives the subject’s legal rights. Prospective subjects must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the subject chooses to 
participate, he/she must sign the ICF before any study-specific procedures are conducted. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB/IEC, the CRO, if applicable, and to regulatory authorities 
for review and evaluation for the duration of the study and until the project has been approved 
for marketing, or is withdrawn from investigation. They will also be informed that the Study 
Monitor may inspect their medical records to verify the accuracy and completeness of the study 
records and results. 
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB/IEC, and then signed by all applicable 
study participants. 
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The time that informed consent is obtained must be documented. The Investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 
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18. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the Investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail. 
All electronic source data collected outside of the eCRF, such as central laboratory data, will be 
transferred directly to Alkermes for incorporation into the final datasets. A paper copy of all 
laboratory reports will remain with the source documents at the study site. All out-of-range 
laboratory values will be deemed as clinically significant or not clinically significant by the 
Investigator. Clinically significant values will be considered AEs and recorded as such on the 
eCRFs. 
Adverse events will be coded using the MedDRA. Concomitant medications will be categorized 
using the WHO-ATC classification system. 
18.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and source documents, and other records relative to study conduct. 
18.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the Sponsor to inform the Investigator/institution as to when 
these documents no longer need to be retained. 
Subject medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
Page 49 of 92


 
 
Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that is the sole property of Alkermes. 
Results of the study are to be held in confidence by both the investigators and the Sponsor. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 
Page 50 of 92


 
 
Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
19. 
REFERENCES 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on 
outcomes. Schizophr Res. 1999;35 Suppl:S93-100. 
Zyprexa (olanzapine) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017. 
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: 18 Apr 2017. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Department of 
Health, Education, and Welfare; 1976. 
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-
53. 
Hodgins S. Violent behaviour among people with schizophrenia: a framework for investigations 
of causes, and effective treatment, and prevention. Philos Trans R Soc Lond B Biol Sci. 
2008;363(1503):2505-2518. doi: 10.1098/rstb.2008.0034. 
Kay S, Fiszbein A, Opler L. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
Koekkoek B, van MB, Hutschemaekers G. "Difficult patients" in mental health care: a review. 
Psychiatr Serv. 2006;57(6):795-802. doi: 10.1176/appi.ps.57.6.795. 
Kuo CJ, Tsai SY, Lo CH, Wang YP, Chen CC. Risk factors for completed suicide in 
schizophrenia. J Clin Psychiatry. 2005;66(5):579-585. 
Lambert M, Conus P, Cotton S, Robinson J, McGorry PD, Schimmelmann BG. Prevalence, 
Predictors, and Consequences of Long-Term Refusal of Antipsychotic Treatment in First-
Episode Psychosis. J Clin Psychopharmacol. 2010;30(5):565-572. doi: 
10.1097/JCP.0b013e3181f058a0. 
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia 
and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. 
Schizophr Res. 2006;86(1-3):15-22. doi: 10.1016/j.schres.2006.06.026. 
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Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
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. 
Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other 
drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 
1990;264(19):2511-2518. 
Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the 
differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123-1131. 
doi: 10.1001/archpsyc.64.10.1123. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-19. 
Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with 
schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620-627. 
doi: 10.1016/S0140-6736(09)60742-X. 
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. 
 
 
 
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
20. 
APPENDICES 
Appendix A: 
Partial List of Prohibited Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers 
Appendix B: 
Positive and Negative Syndrome Scale 
Appendix C: 
Clinical Global Impression 
• Severity 
Appendix D: 
Abnormal Involuntary Movement Scale 
Appendix E: 
Barnes Akathisia Rating Scale 
Appendix F: 
Simpson-Angus Scale 
Appendix G: 
Columbia-Suicide Severity Rating Scale 
• Since Last Visit 
Appendix H: 
Impact of Weight on Quality of Life-Lite 
Appendix I: 
EuroQOL–5D 
 
 
 
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX A. PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INHIBITORS AND INDUCERS 
The following is a list of CYP3A4 inhibitors and inducers that subjects are to avoid within 
30 days of Screening and throughout the study. This list is not comprehensive. 
Table 1: 
Partial List of CYP3A4 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-human immunodeficiency virus (HIV) or anti-hepatitis C 
virus (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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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX B. POSITIVE AND NEGATIVE SYNDROME SCALE  
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX C. CLINICAL GLOBAL IMPRESSION 
• Severity 
Page 72 of 92


Clinical Global Impressions- Severity
Instructions: Circle the appropriate number after the following item.
This document is provided by Wyeth Pharmaceuticals Inc.
244260-01
SEVERITY OF ILLNESS 
Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? 
Not assessed
Normal, not at all ill
Borderline mentally ill
Mildly ill
Moderately ill
Markedly ill
Severely ill
Among the most extremely ill patients
0
1
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5
6
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Name or ID: 
Date:
This tool should be used to supplement, not to replace, clinical judgement.
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX D. ABNORMAL INVOLUNTARY MOVEMENT SCALE 
Page 74 of 92


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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX E. BARNES AKATHISIA RATING SCALE 
Page 76 of 92


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APPENDIX F. SIMPSON-ANGUS SCALE 
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX G. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
• Since Last Visit Version 
Page 82 of 92


 
 
 
 
 
 
 
 
 
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Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes,” 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 Ƒ    Ƒ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 Ƒ    Ƒ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it”.  
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 Ƒ    Ƒ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 Ƒ    Ƒ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 Ƒ    Ƒ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the least severe 
and 5 being the most severe ).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others.       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.                     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                         living with the pain or  how you were feeling). 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
Version 1/14/09 
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__                      ____________________
_                      ___________________
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
Ƒ   Ƒ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
Ƒ   Ƒ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
Ƒ   Ƒ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
Ƒ   Ƒ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
Ƒ   Ƒ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
Ƒ   Ƒ 
Completed Suicide: 
   Yes    No 
Ƒ   Ƒ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g. surface scratches). 
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes intact; third-degree burns less 
than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX H. IMPACT OF WEIGHT ON QUALITY OF LIFE - LITE 
Page 86 of 92


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Alkermes, Inc. 
Protocol ALK3831-A306 v 3.0 (Amendment 2.0) 
CONFIDENTIAL 
 
APPENDIX I. EUROQOL-5D 
Page 89 of 92


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3DJHRI

SAP_001.pdf: 
A Phase 3, Multicenter Study to Assess the Long Term 
Safety and Tolerability of ALKS 3831 in Subjects with 
Schizophrenia 
 
 
Unique Protocol ID: 
ALK3831-A306 
NCT Number: 
NCT02669758 
EudraCT Number:  
2015-003880-13 
Date of Statistical Analysis 
Plan:  
5 October 2017 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
ALK3831-A306 
 
Study Title: 
A Phase 3, Multicenter Study to Assess the Long Term Safety and 
Tolerability of ALKS 3831 in Subjects with Schizophrenia 
Document Status: 
Final Version 1.0 
Document Date: 
5 October 2017 
Based on: 
ALK3831-A306 Protocol Amendment 2.0 Date: 25 Apr 2017 
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. 
 


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TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.1.1. 
Primary objective ..........................................................................................................7 
1.2 
Summary of the Study Design ......................................................................................7 
2. 
SAMPLE SIZE CONSIDERATION ............................................................................8 
3. 
DATA ANALYSIS ......................................................................................................9 
3.1. 
General Statistical Methodology ..................................................................................9 
3.2. 
Definitions of Analysis Populations .............................................................................9 
3.2.1. 
Safety Population ..........................................................................................................9 
3.2.2. 
Efficacy Population ......................................................................................................9 
3.3. 
Disposition ....................................................................................................................9 
3.4. 
Protocol Deviation ......................................................................................................10 
3.5. 
Demographics and Baseline Characteristics ...............................................................10 
3.6. 
Prior and Concomitant Medication .............................................................................10 
3.7. 
Treatment Adherence Rate and Duration of Study Drug Administration ..................10 
3.7.1. 
Treatment Adherence Rate .........................................................................................10 
3.7.2. 
Duration of Study Drug Administration .....................................................................11 
3.8. 
Efficacy Analyses .......................................................................................................11 
3.8.1. 
General Considerations ...............................................................................................11 
3.8.2. 
Efficacy Analysis ........................................................................................................11 
3.8.3. 
Other Assessments ......................................................................................................14 
3.8.3.1. 
Examination of Subgroups .........................................................................................15 
3.8.4. 
Multiple Comparison / Multiplicity ............................................................................15 
3.9. 
Safety Analysis ...........................................................................................................15 
3.9.1. 
Adverse Events ...........................................................................................................15 
3.9.1.1. 
Other significants AEs ................................................................................................16 
3.9.2. 
Clinical Laboratory Parameters ..................................................................................16 
3.9.3. 
Vital Signs, Body Weight, and ECG ..........................................................................20 


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3.9.3.1. 
Vital Signs ..................................................................................................................20 
3.9.3.2. 
Weight and Body Mass Index .....................................................................................20 
3.9.3.3. 
Electrocardiograms .....................................................................................................21 
3.9.4. 
Abnormal Movement Scales .......................................................................................22 
3.9.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................22 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................23 
4. 
INTERIM ANALYSES ..............................................................................................23 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................23 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........23 
6.1. 
Analysis Visit Windows .............................................................................................23 
6.2. 
Handling of Partial Dates of Concomitant Medication ..............................................24 
6.3. 
Handling of Safety Data .............................................................................................24 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................24 
7.1. 
Reporting Precision ....................................................................................................24 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................25 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................25 
10. 
REFERENCES ...........................................................................................................25 
 
LIST OF TABLES 
Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes ......................................................................................................................17 
Table 2: 
Shifts Category from Baseline to Any Postbaseline for Selected Lipid 
Parameters ...................................................................................................................18 
Table 3: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c ...............19 
Table 4: 
Shift Category from Baseline to Any Postbaseline in Liver Function Test ...............19 
Table 5: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate .............................................................................................................................20 
Table 6: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight ...........................................................................................................21 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF ......................21 
Table 8: 
C-SSRS Categories for Analysis ................................................................................22 


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Table 9: 
Degree of Precision .....................................................................................................24 
 
LIST OF FIGURES 
Figure 1: Study Design Schematic ...................................................................................................8 


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ABBREVIATIONS 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence interval 
C-SSRS 
Columbia Suicide Severity Rating Scale 
EC 
Excited Component 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of treatment 
EPS 
Extra pyramidal symptoms 
EQ-5D 
EuroQOL-5D 
ET 
Early termination 
FAS 
Full analysis set 
HbA1C 
Hemoglobin A1c 
IWQOL 
Impact of Weight on Quality of Life 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLZ 
Olanzapine 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
PT 
Preferred term 
KM 
Kaplan-Meier 
QTcB 
QT corrected with Bazett formula 


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Abbreviation or Term 
Explanation or Definition 
QTcF 
QT corrected with Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson-Angus Scale 
SD 
Standard deviation 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
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 the study ALK3831-A306. This document has been 
prepared based on Alkermes ALK3831-A306 Study Protocol Amendment 2.0 (dated 25 Apr 
2017)1. 
1.1. 
Study Objectives 
1.1.1. 
Primary objective 
The primary objective of this study is to evaluate the long term safety and tolerability of 
ALKS 3831 in subjects with schizophrenia.  
1.2 
Summary of the Study Design 
Subjects that have completed the 4-week Treatment Period of the antecedent study, 
ALK3831-A305, within the past 7 days are eligible to be enrolled in the study. Subjects 
completing the 4-week Treatment Period of the antecedent study, ALK3831-A305, as inpatients 
may continue as inpatients for up to 1 week in this extension study. These subjects may be 
discharged from the inpatient unit at any time during this week based on Investigator’s judgment. 
Subjects enrolled in the study will be started on ALKS 3831 10/10 (10 mg olanzapine/10 mg 
samidorphan). The ALKS 3831 dose may be increased to 15/10 (15 mg olanzapine/10 mg 
samidorphan) or 20/10 (20 mg olanzapine/10 mg samidorphan) during the first week of 
treatment or thereafter, based on Investigator discretion. For subjects entering this study as 
outpatients, study staff will check in with them by phone on Day 3 to assess tolerability and 
determine if a dose increase to ALKS 3831 15/10 or 20/10 is needed. An Unscheduled Visit will 
be arranged mid-Week 1 for subjects requiring a dose increase. Following a dose increase, the 
dose may be decreased back to 15/10 or 10/10 if there are tolerability issues. Thus, dosing is 
flexible and subjects will receive ALKS 3831 10/10, 15/10, or 20/10 throughout the duration of 
the study, based on Investigator discretion. Dose adjustments can only be performed on-site at 
the study center. Subjects requiring dose adjustments between scheduled visits should arrange an 
Unscheduled Visit for the following procedures: study drug return, adherence review, and study 
drug dispensation. 
Safety assessments will include AE monitoring, clinical laboratory testing, vital signs, weight 
and waist circumference assessments, 12-lead ECGs, movement disorder assessments, including 
the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), 
Simpson Angus Scale (SAS), and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
Efficacy assessments to evaluate the durability of treatment effect will include Positive and 
Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S). 


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Additional assessments include Impact of Weight on Quality of Life–Lite Questionnaire 
(IWQOL-Lite), Cigarette Use, and EuroQOL-5D (EQ-5D). 
Subjects completing 52 weeks of treatment with study drug will be eligible to continue in the 
open-label, long-term safety study (ALK3831-A308) and will continue to receive ALKS 3831. 
Subjects not continuing in the ALK3831-A308 long-term safety study will enter a 4-week Safety 
Follow-up Period. 
A schematic of the study design is provided in Figure 1. 
Figure 1: Study Design Schematic  
 
 
*Visits will occur weekly for the first 2 weeks, then biweekly thereafter. Outpatient subjects will be 
contacted by phone on Day 3 to determine if a dose increase is needed, and, if so, an unscheduled visit 
will be arranged mid-Week 1. The dose may be adjusted to either 10/10, 15/10, or 20/10 mg throughout 
the study period, based on Investigator discretion, and such dose adjustments will require subjects to visit 
the study site 
 
2. 
SAMPLE SIZE CONSIDERATION 
No formal sample size calculation is performed for this extension study. A sample size of 
approximately 390 is based on the estimated maximum number of subjects who might be 
expected to continue from the ALK3831-A305 study. 


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3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for efficacy or safety analysis is defined as the last non-missing assessment before the 
first dose of ALKS 3831 in ALK3831-A306 study, and it will be used for all efficacy and safety 
analysis unless specified otherwise.  
Antecedent study baseline, defined as the last non-missing assessment on or before the first dose 
of study drug during double-blind treatment period in ALK3831-A305 study, may be explored as 
applicable. 
Treatment sequence is defined according to the treatment assignment in antecedent and current 
studies as ALKS 3831/ALKS 3831 (ALKS 3831 in both ALK3831-A305 study and ALK3831-
A306 study), OLZ/ALKS 3831 (olanzapine in ALK3831-A305 study and ALKS 3831 in 
ALK3831-A306 study), or PBO/ALKS 3831 (placebo in ALK3831-A305 study and ALKS 3831 
in ALK3831-A306 study). 
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 statistical tests and confidence intervals (CIs), unless stated otherwise, will be 2-sided and 
will be set at an alpha level of 0.05. 
All source data will be presented as subject data listings. 
3.2. 
Definitions of Analysis Populations 
3.2.1. 
Safety Population 
The Safety Population will include all subjects who enrolled and received at least 1 dose of study 
drug during the treatment period. The Safety Population will be used for the safety analyses. 
3.2.2. 
Efficacy Population 
The Full Analysis Set (FAS) will include all subjects in the Safety Population who have at least 
one postbaseline PANSS assessment. 
3.3. 
Disposition 
The number and percentage of subjects completing or prematurely discontinuing the study 
including reasons for discontinuation will be summarized by treatment sequence and overall for 
the following: 
• Subjects who enrolled in the study  
• Subjects in the Safety Population  
• Subjects in the FAS Population  


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• Subjects who completed the treatment period 
• Subjects who discontinued treatment along with reasons for discontinuation 
3.4. 
Protocol Deviation 
Subjects with major protocol deviations in the following categories will be summarized by 
treatment sequence and oveall. A supportive listing will be provided as well. 
• Did not meet the inclusion/exclusion criteria 
• Received prohibited medications 
• Lack of adherence with study medication, as defined by subjects taking less than 70% 
of protocol specified amount of study medication 
• Dosing error 
3.5. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as gender, age, race, ethnicity, weight, and 
BMI will be summarized by treatment sequence and overall for the Safety and FAS population.  
3.6. 
Prior and Concomitant Medication 
Prior medications are defined as medications taken prior to the first dose of study drug in 
ALK3831-A306 study. Concomitant medications are defined as medications taken on or after the 
first dose of study drug in ALK3831-A306 study. All medications will be coded using the World 
Health Organization WHO-DD Enhanced + Herbal (version: March 2016) or higher. 
Concomitant medications are defined as medications taken during the treatment period and will 
be summarized by the preferred drug name for the Safety population. All reported medications 
(including those initiated after the last dose of study medication) will be included in 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. 
3.7. 
Treatment Adherence Rate and Duration of Study Drug 
Administration 
3.7.1. 
Treatment Adherence Rate 
Treatment adherence to the daily dosing schedule during treatment period will be summarized by 
treatment sequence for Safety Population. Treatment adherence will be calculated as follows: 
100 × Total tablets dispensed −total tablets returned −total tablets lost
Total tablets scheduled to be taken
 


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3.7.2. 
Duration of Study Drug Administration 
Duration of study drug administration (ALKS 3831) is defined as the number of days from the 
date of the first dose of study drug to the date of the last dose of study drug, inclusive (ie, last 
dose date – first dose date + 1 day). Duration of study drug administration will be summarized 
for the Safety Population by treatment sequence and overall. 
The overall mean and modal dose of olanzapine will be summarized by treatment sequence and 
overall. Number and percentage of subjects will be summarized by their final dose level by 
treatment sequence and overall. 
3.8. 
Efficacy Analyses 
3.8.1. 
 General Considerations 
All statistical analysis will be performed at the 5% significance level. All confidence intervals 
(CI) will be 2-sided 95% confidence intervals. Efficacy analysis will be carried out using the 
FAS population. PANSS total and subscale scores, CGI-S, PANSS response analyses and body 
weight will be based on both observed data and the LOCF (last observation carried forward) 
imputation, that is, the last observed non-missing postbaseline value will be carried forward for 
missing postbaseline assessments.  
3.8.2. 
Efficacy Analysis 
The following endpoints will be used to evaluate durability of treatment effect and summarized 
by treatment sequence and overall for FAS population:  
• Change from baseline in PANSS total score, and subscale scores (positive, negative, 
and general psychopathology subscales) by visit 
• Change from baseline in PANSS Excited Component (EC) score (comprised of 5 
items, P4. excitement, G4. tension,  P7. hostility, G8. uncooperativeness, and G14. 
poor impulse control) by visit 
• Change from baseline in PANSS Marder factor scores by visit 
• Change from baseline in CGI-S by visit 
• Proportion of Subjects with PANSS response ( ≥ 30% improvement from baseline in 
PANSS total score)  
• Time to first relapse  
• Time to first remission 
• Time to discontinuation  
In general, continuous and categorical endpoints will be summarized using descriptive statistics 
by treatment sequence and overall. Change from baseline within the treatment sequence and 
overall may also be tested using an one-sample t-test.  


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The PANSS Marder factor model2 consisted of the following 5 factors:  
• Negative symptoms  
− N1. blunted affect  
− N2. emotional withdrawal 
− N3. poor rapport 
− N4. passive social withdrawal 
− N6. lack of spontaneity 
− G7. motor retardation 
− G16. active social avoidance  
• Positive symptoms  
− P1. delusions 
− P3. hallucinatory behavior 
− P5. grandiosity 
− P6. suspiciousness 
− N7. stereotyped thinking 
− G1. somatic concern 
− G9. unusual thought content 
− G12. lack of judgment and insight  
• Disorganized thought  
− P2. conceptual disorganization 
− N5. difficulty in abstract thinking 
− G5. mannerisms and posturing 
− G10. disorientation  
− G11. poor attention 
− G13. disturbance of volition 
− G15. preoccupation 
• Uncontrolled hostility/excitement  
− P4. excitement 
− P7. hostility 


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− G8. uncooperativeness 
− G14. poor impulse control  
• Anxiety/depression  
− G2. anxiety 
− G3. guilt 
− G4. tension 
− G6. depression 
Stabilization is defined as meeting all of the following stablization criteria: 
• PANSS total score ≤ 80 
• PANSS score ≤ 4 on each of the following items: 
− P2: conceptual disorganization 
− P3: hallucinatory behavior 
− P6: suspiciousness 
− G9: unusual thought content 
After a subject achieves stabilization, relapse and remission are defined as following:  
• Relapse: ≥ 30% increase in PANSS total score or re-hospitalization for psychotic 
symptoms.   
• Remission: PANSS score ≤3 (mild or less) on each of the following items in two 
consecutive efficacy assessments  
− P1: delusions 
− G9: unusual thought content  
− P3: hallucinatory behavior  
− P2: conceptual disorganization 
− G5: mannerisms/posturing 
− N1: blunted affect 
− N4: social withdrawal 
− N6: lack of spontaneity  
Time to first relapse  will be estimated using the Kaplan-Meier method by treatment sequence 
and overall. It is defined as the time from the date of stabilization to the date of first relapse. 
Subjects who completed the treatment without relapse will be censored at the date of last dose. 
Time to first remission will be analyzed similarly.  


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Time to treatment discontinuation will be analyzed similarly using the Kaplan-Meier method by 
treatment sequence and overall. Both all cause dicontinuation 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 to the date of last dose of study drug. 
Other subjects will be censored at the last dose of the study drug.  
3.8.3. 
 Other Assessments 
• Change from baseline in IWQOL-Lite scales (total score, physical function, self-
esteem, sexual life, public distress, and work) by visit 
• Change from baseline in EQ-5D-5L index value and VAS score by visit 
• Cigarette use 
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)3: 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 
The EQ-5D-5L is a validated quality of life questionnaire developed by the EuroQol Group in 
order to provide a simple, generic utility measure for characterizing current health states of 
patients. EQ-5D-5L is designed for self-completion by subjects. It consists of 2 parts – the EQ-
5D-5L descriptive system and the visual analogue scale (VAS). 
The EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels. 
The 5 dimensional 5-level systems are converted into an index value. Values for theoretically 
possible health states are calculated using a regression model and weighted according to the 
social preferences of the U.S. population (Van Hout et al, 2012)4. The VAS records the 
respondent’s self-rated health on a vertical visual analogue scale. The VAS has 100 (Best health 
you can imagine) at the top, and 0 (Worst health you can imagine) at the bottom. This 
information can be used as a quantitative measure of health outcomes as judged by the individual 
respondents. EQ-5D-5L self-reported VAS data generates information on the self-perceived 
overall health-related quality of life. Change from baseline in EQ-5D-5L index value and VAS 
score will be analyzed. 
Number of cigarettes used will be summarized at each visit by treatment sequence and overall. 


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3.8.3.1. 
Examination of Subgroups 
Subgroup analysis by region (US vs non-US) will be performed for selected endpoints, including 
but not limited to, change from baseline in PANSS total and subscale scores, and PANSS 
response.  
3.8.4. 
Multiple Comparison / Multiplicity 
Not applicable. 
3.9. 
Safety Analysis 
All safety endpints will be summarized by treatment sequence and overall for the Safety 
Population. 
3.9.1. 
Adverse Events 
Incidence of treatment emergent AEs 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 19.0 or higher. The verbatim term will be included in 
the AE listings. 
An AE (coded by preferred term) will be considered as treatment emergent AE (TEAE) if the 
event is newly occurring or worsening on or after the date of first dose of study drug in this 
study.  
The number and percentage of subjects reporting TEAEs during the treatment period will be 
presented by treatment sequence and overall for the following categories:  
• System organ class and preferred term  
• Preferred term, and including the following subset: 
− TEAEs experienced by ≥5% of subjects (in any group) System organ class, 
preferred term, and severity  
− System organ class, preferred term for serious TEAEs  
− System organ class, preferred term, and relationship  
− System organ class, preferred term for study drug related TEAEs  
− System organ class, preferred term , and severity 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, preferred term and treatment sequence and 
overall.  


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The number and percentage of subjects who have serious adverse events (SAE) and AEs leading 
to premature discontinuation from the treatment will be summarized by system organ class, 
preferred term, and treatment sequence and overall.  
3.9.1.1. 
Other significant AEs 
In addition, incidence of a selected subset of relevant AEs in this class of drugs (eg, 
Extrapyramidal symptoms (EPS) TEAEs, AEs associated with abuse potential, drug withdrawal, 
and suicide related events, etc.) will be summarized by preferred term and treatment sequence 
and overall. The selection of AEs per subset will be based on the preferred terms and customized 
or Standardized MedDRA queries (SMQs).  
3.9.2. 
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 treatment 
sequence, overall, and by visit. 
Clinical laboratory test values, scheduled or unscheduled, will be considered potentially 
clinically significant (PCS) if they meet PCS criteria listed in Table 1. The number and 
percentage of subjects who have postbaseline PCS clinical laboratory values will be summarized 
by treatment sequence and overall. The percentages will be calculated based on the number of 
subjects with non-PCS baseline value and have at least 1 postbaseline assessment. All PCS 
values including baseline PCS values will be included in supportive listings. 
Shift tables for selected metabolic parameters (glucose, total cholesterol, LDL, HDL, 
tryglyceride, and HbA1c) and liver function tests will be presented. The criteria are summarized 
in Table 2, Table 3 and Table 4.  


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Table 1: 
Criteria of Potentially Clinically Significant (PCS) Abnormality for Selected 
Analytes 
Parameters 
Criteria 
Chemistry 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase (U/L) 
≥3 × ULN 
Alanine Aminotransferase (U/L) 
≥3 × ULN 
Aspartate Aminotransferase (U/L) 
≥3 × ULN 
Bilirubin, Total 
≥2.0 mg/dL 
Blood Urea Nitrogen 
>30 mg/dL 
Cholesterol, Random 
>300 mg/dL 
Cholesterol, Fasting 
≥240 mg/dL 
Cholesterol, HDL Fasting 
≤30 mg/dL 
Cholesterol, LDL Fasting 
≥160 mg/dL 
Creatine Kinase (U/L) 
≥3 × ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<50 mg/dL or  
≥200 mg/dL 
Glucose, Fasting 
<50 mg/dL or  
≥126 mg/dL 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
Lactate Dehydrogenase (U/L) 
>3 × ULN 
Prolactin (Female) 
>30 ng/mL 
Prolactin (Male) 
>20 ng/mL 
Sodium 
<130 mmol/L or 
>150 mmol/L 
Triglycerides, Fasting (Female) 
≥120 mg/dL 
Triglycerides, Fasting (Male) 
≥160 mg/dL 


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


Alkermes, Inc.                                                                                                                                     
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Normal (<150) to high (≥200) 
Normal (<150) to very high (≥500) 
Borderline (≥150 and <200) to high (≥200) 
Borderline (≥150 and <200) to very high (≥500) 
Normal/borderline (<200) to high (≥200) 
Normal/borderline (<200) to very high (≥500) 
Normal (<150) to borderline/high/very high (≥150) 
Increase ≥50 mg/dL 
 
Table 3: 
Shift Category from Baseline to Any Postbaseline in Glucose and HbA1c 
Serum glucose (fasting) mg/dL 
Normal (<100) to High (≥126) 
Impaired (≥100 and <126) to High (≥126) 
Normal/Impaired (<126) to High (≥126) 
Increase ≥10 mg/dL 
HbA1c % 
Shift from baseline (<5.7%) to postbaseline ≥5.7% 
Shift from baseline (<5.7%) to postbaseline ≥5.7% and <6.5% 
Shift from baseline (<5.7%) to postbaseline ≥6.5% 
 
Table 4: 
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) 


Alkermes, Inc.                                                                                                                                     
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Shift from Normal to >1 x ULN   
Shift from Normal to ≥2 x ULN   
3.9.3. 
Vital Signs, Body Weight, and ECG 
3.9.3.1. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values at each scheduled time 
point will be presented by treatment sequence 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 5. The number and percentage of subjects with PCS 
postbaseline values will be tabulated by treatment sequence. The percentages will be calculated 
based on the number of subjects with non-PCS baseline values and at least 1 postbaseline 
assessment. The numerator will be the  number of subjects with non-PCS baseline values and at 
least 1 postbaseline PCS value. A supportive listing of subjects with PCS postbaseline values 
will be provided. 
All vital signs will be presented in the subject data listing. 
Orthostatic hypotension (20/10 mmHg) is defined as a fall in systolic blood pressure of at least 
20 mmHg and a fall in the diastolic blood pressure of at least 10 mmHg upon standing from 
supine. Orthostatic hypotension (30 mmHg) is defined as a fall in systolic blood pressure of at 
least 30 mmHg upon standing from supine. 
Orthostatic tachycardia is defined as a heart rate increase of 30 beats per minute (bpm) or more 
upon standing from supine, or over 120 bpm upon standing. 
The number and percentage of subjects with orthostatic hypotension or orthostatic tachycardia 
occurring at any postbaseline visit will be summarized for by treatment sequence. 
Table 5: 
Criteria for Potentially Clinically Significant (PCS) Blood Pressure or Pulse 
Rate 
Parameter 
Criteria 
Supine Systolic Blood Pressure 
≤90 and decrease ≥20 mm Hg 
≥180 and increase ≥20 mm Hg 
Supine Diastolic Blood Pressure 
≤50 and decrease ≥15 mm Hg 
≥105 and increase ≥15 mm Hg 
Supine Heart Rate 
≤50 and decrease ≥15 bpm 
≥120 and increase ≥15 bpm 
3.9.3.2. 
Weight and Body Mass Index 
Weight (kg), BMI (kg/m2) and waist circumferences (cm) (baseline and change from baseline) 
will be summarized using both observed data and LOCF imputation for missing data. Absolute 


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and percent change from baseline in body weight will be summarized by treatment sequence and 
overall.  
Number and percentage of subjects with ≥7% or  ≥10% weight gain from baseline based on the 
observed data and LOCF will be summarized by treatment sequence and overall and 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 by treatment sequence and overall. 
Criteria for PCS are presented below. 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 6: 
Criteria for Potentially Clinically Significant (PCS) Changes from Baseline 
in Body Weight 
Parameter 
Criteria 
Body Weight 
Decrease from Baseline ≥7% 
Increase from Baseline ≥7% 
 
3.9.3.3. 
Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc interval) at baseline and change from baseline values at each scheduled 
assessment timepoint and at the end of the treatment period will be presented by treatment 
sequence for the treatment period. QTc interval will be calculated using both Bazett 
(QTcB = QT/(RR)½) and Fridericia (QTcF = QT/(RR)⅓) corrections; if RR is not available, it 
will be replaced with 60/HR in the correction formula. 
Electrocardiogram parameter values are considered PCS if they meet or exceed the higher-limit 
PCS criteria listed in Table 7 . The number and percentage of subjects with PCS postbaseline 
ECG values will be tabulated by treatment sequence. The percentages will be calculated based 
on the number of subjects with non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator is the number of subjects with non-PCS baseline values and at least 1 
postbaseline PCS value. A supportive listing of subjects with PCS values will be provided. 
Table 7: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF 
Parameter 
Criteria 
QTcB and QTcF 
>450 to ≤480 msec 
>480 to ≤500 msec 
>500 msec 
Change from baseline >30 to ≤60 msec 


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Parameter 
Criteria 
Change from baseline >60 msec 
3.9.4. 
Abnormal Movement Scales 
Extra pyramidal symptoms (EPS) will be evaluated as AEs and also as assessed by abnormal 
movement scales. Abnormal movement scales will include the following: Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale 
(SAS). 
For all abnormal movement scales, total scores and subscale scores will be summarized by 
treatment sequence at each visit for the absolute value and for changes from baseline. 
Number and percentage of subjects meeting the criteria for treatment emergent Parkinsonism 
(SAS total score>3), for treatment emergent akathisia (BARS global clinical assessment of 
akathisia score ≥2), for treatment emergent dyskinesia (AIMS score ≥3 on any of the first 
7 items, or a score ≥2 on two or more of any of the first 7 items) at any postbaseline visit will be 
summarized by treatment sequence. 
A listing will be provided for every abnormal movement scale. Listing for treatment emergent 
EPS will be provided. 
3.9.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used to measure the presence and intensity of suicidal ideation 
and behavior. 
Suicidal behavior and suicidal ideation will be summarized for the Safety Population. The 
number of subjects with suicidal ideation and suicidal behavior will be summarized by treatment 
sequence when applicable. 
Supportive tabular display of subjects with all values will be provided. 
Table 8: 
C-SSRS Categories for Analysis  
Category 
C-SSRS Item response is “YES” 
Suicidal behavior 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 


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Suicidal ideation 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without 
intent to act 
Active suicidal ideation with some intent to act, without specific 
plan 
Active suicidal ideation with specific plan and intent 
Non-suicidal Self-Injurious Behavior Non-suicidal Self-Injurious Behavior 
3.10. 
Pharmacokinetic/ Pharmacodynamic Data Analysis 
Not applicable. 
4. 
INTERIM ANALYSES 
No interim analysis is planned for this study. 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
There are no major deviations from the protocol specified analysis. 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits at scheduled timepoints as specified in the protocol 
(Table 1 Schedule of Visits and Assessments). 
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. 
Visit Day is calculated as date of visit – date of the first dose of study drug + 1 day. 


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Last postbaseline values are defined as the last valid postbaseline values collected for each 
subject during the treatment period.  
6.2. 
Handling of Partial Dates of Concomitant Medication 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. In 
the case of 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, laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only 
observed data will be used for analyses, and missing data will not be imputed. 
7. 
GENERAL STATISTICAL METHODOLOGY 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of subjects in each category for categorical variables) will 
be provided by treatment sequence. 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, unless otherwise 
specified: 
Table 9: 
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. 


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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. 
10. 
REFERENCES 
1. Alkermes ALK3831-A306 Study Protocol Amendment 2.0 Date: 25 Apr 2017 
2. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American trials. J 
Clin Psychiatry. 1997; 58(12): 538-546. 
3. Tessier A et al. Understanding the Determinants of Weight-Related Quality of Life 
among Bariatric Surgery Candidates. Journal of Obesity 2012; 2012: 713426  
4. Van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-
5L to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug;15(5):708-15