Conditions: Schizophrenia
Keywords: Schizophrenia Olanzapine Samidorphan Alkermes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 347
Healthy volunteers: no

Brief summary:
This is a Phase 2, randomized, placebo-controlled multicenter study, which will be conducted in 2 parts. The study duration for each subject will be approximately 33 weeks and will include 25 study visits.

Detailed description:

Arms:
arm 1: Olanzapine + low dose samidorphan tablets taken once daily arm 2: Olanzapine + medium dose samidorphan tablets taken once daily arm 3: Olanzapine + high dose samidorphan tablets taken once daily arm 4: Olanzapine + placebo tablets taken once daily

Interventions: intervention 1: Samidorphan (Low Dose) intervention 2: Samidorphan (Medium Dose) intervention 3: Samidorphan (High Dose) intervention 4: Placebo intervention 5: Olanzapine
Intervention descriptions: intervention 1: Tablets taken once daily intervention 2: Tablets taken once daily intervention 3: Tablets taken once daily intervention 4: Tablets taken once daily intervention 5: Tablets taken once daily

Protocol document:
Prot_000.pdf: 
A Phase 2, Randomized, Multicenter, Safety, Tolerability, 
and Dose-Ranging Study of Samidorphan, a Component of 
ALKS 3831, in Adults with Schizophrenia Treated with 
Olanzapine 
 
 
Unique Protocol ID: 
ALK3831-302 
NCT Number: 
NCT01903837 
Date of Protocol:  
13 June 2014 
 


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1. 
TITLE PAGE 
ALK3831-302 
 
A Phase 2, Randomized, Multicenter, Safety, Tolerability, 
and Dose-Ranging Study of Samidorphan, a Component of 
ALKS 3831, in Adults with Schizophrenia Treated with 
Olanzapine 
 
Document Status 
Final 
Final Version Date: 
Amendment #3-CZ: 13 June 2014 
Amendment #2: 26 February 2014 
Amendment #1: 05 June 2013 
Original Protocol: 17 April 2013 
Study Sponsor 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
Telephone: 
 
Alkermes Medical Monitor: 
 
Telephone: 
 
 
Medical Monitor 
 
Telephone: 
 
24-Hour Telephone: 
 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 
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CONTACT INFORMATION 
Role in Study 
Name 
Address and Telephone 
Alkermes Clinical Program 
Manager 
 
Alkermes, Inc.  
852 Winter Street 
Waltham, MA 02451 
Telephone: 
 
Alkermes Medical Monitor  
 
Alkermes, Inc.  
852 Winter Street 
Waltham, MA 02451 
Telephone: 
 
Alkermes Drug Safety Manager 
 
Alkermes, Inc.  
852 Winter Street 
Waltham, MA 02451 
Telephone: 
 
 
Medical Monitor and 24-hour 
Emergency Contact 
 
 
 
 
Del Mar, CA 92014-5881 
Office telephone: 
 
Mobile & 24-hour: 
 
eFax: 
 
PPD
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2. 
SYNOPSIS 
Name of Sponsor/ Company: Alkermes, Inc. 
Name of Investigational Product: ALKS 3831 
Name of Active Ingredients: samidorphan and olanzapine 
Title of Study: A Phase 2, Randomized, Multicenter, Safety, Tolerability, and Dose-Ranging Study of 
Samidorphan, a Component of ALKS 3831, in Adults with Schizophrenia Treated with Olanzapine 
No. of Study Centers: This is a multi-center study 
Studied Period: 
Estimated date first patient consented: June 2013 
Estimated date last patient completed: June 2015 
Phase of development: 2 
Objectives: 
The objectives of this study are to evaluate 3 doses of samidorphan co-administered with olanzapine 
(ALKS 3831) in subjects with schizophrenia to (1) evaluate ALKS 3831 as a treatment for 
schizophrenia, (2) assess the safety and tolerability of ALKS 3831, and (3) characterize the impact of the 
samidorphan component of ALKS 3831 on weight and other metabolic factors. 
Methodology: 
This is a Phase 2, randomized, placebo-controlled multicenter study, which will be conducted in 2 parts: 
Part A and Part B. Part A will begin with screening and will include a 1-week olanzapine lead-in period 
followed by a 12-week double-blind, placebo-controlled treatment period where subjects will receive 
samidorphan or placebo (in addition to the olanzapine prescribed on Study Day 1). Part B will include an 
additional 12-week treatment period where all subjects will receive active olanzapine + samidorphan (ie, 
ALKS 3831). At the end of Part B, samidorphan dosing will stop, but olanzapine dosing will continue 
uninterrupted through the 4-week follow-up period, which includes 2 safety visits. 
This study will use an independent Data Safety Monitoring Board (DSMB) to monitor for tolerability of 
study drug. After at least 1 week of safety data has been collected for 40 randomized subjects, the 
DSMB will review the accumulated safety data for all subjects. After at least 1 week of safety data has 
been collected for 150 randomized subjects, the DSMB will review the accumulated safety data for all 
subjects. Complete details of the membership and functioning of this board will be available in the 
DSMB Charter. 
During clinic visits, assessments of psychotic symptoms using measures such as the Positive and 
Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) will occur. Body 
weight will be measured using consistent methods at every visit. Alcohol and drug use will be monitored 
throughout the study. Concentrations of samidorphan, RDC-9986 (primary metabolite of samidorphan), 
and olanzapine will be determined in plasma samples collected at Visits 2-23. 
Part A (Screening, Olanzapine Lead-in, and Double-blind Treatment Period) 
Screening assessments will occur in the 30-day period before subjects report to the clinic for verification 
of eligibility and initiation of olanzapine treatment (Study Day 1). On Study Day 1 (Visit 2), all eligible 
subjects will be initiated on olanzapine. Olanzapine dose will be selected and titrated by the principal 
investigator (PI) based upon individual subject needs and consistent with current clinical practice. 
Subjects will return one week later (ie, Study Day 8, Visit 3) for a 2-night inpatient stay and the start of 
the 12-week double-blind placebo-controlled treatment period. At this visit, subjects will be randomized 
in a 1:1:1:1 ratio to receive samidorphan (5, 10, or 20 mg) or placebo. Olanzapine dosing will continue 
uninterrupted. Thus, the Part A treatment groups will be as follows: 


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• 
Olanzapine + Samidorphan (5 mg) 
• 
Olanzapine + Samidorphan (20 mg) 
• 
Olanzapine + Samidorphan (10 mg) 
• 
Olanzapine + Placebo 
All study drug will be taken once daily by mouth. Olanzapine and samidorphan/placebo tablets should 
be taken together (ie, at the same time). Randomization will be stratified by the amount of weight 
change during the olanzapine lead-in period (ie, from Day 1 to Day 8), with subjects grouped into the 
following 3 strata: 
• Weight change ≤0 kg 
• Weight increase >0 to <1 kg 
• Weight increase ≥1 kg 
Subjects will be discharged from the inpatient unit on Study Day 10 (Visit 5) and will return on Study 
Day 15 (Visit 6). 
Subjects are not required to be taking any antipsychotic medication at the time of screening or Visit 2. 
However, those who are will be tapered off of their prior antipsychotic medication within two weeks 
after initiation (ie, by Study Day 15, Visit 6). This cross-taper from prior antipsychotic treatment to 
olanzapine will be conducted under the care and discretion of the PI and consistent with current clinical 
practice. 
After Study Day 15 subjects will return to the clinic weekly through the first month of double-blind 
treatment (ie, Study Day 36) and then every 2 weeks thereafter for the remainder of Part A. Any subject 
who prematurely discontinues during Part A will be asked to return to the clinic for an early termination 
(ET) visit and will be asked to return for follow-up visits 2 and 4 weeks later. 
Part A Visit Schedule 
 
Screening 
Olanzapine 
Lead-In 
Double-Blind Placebo-Controlled Treatment Period 
Transition* 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Day 
-30 to -1 
1 
8 
9 
10 
15 
22 
29 
36 
50 
64 
78 
92 
Week 
 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
* Transition (Visit 13) is the end of Part A and the beginning of Part B (Part B begins with dosing at Visit 13). 
Shaded cells represent inpatient stays. 
Assessments prior to study drug administration at Visit 13 (the transition visit) will serve as end of 
Part A assessments; dosing and post-dose assessments will be considered Part B assessments. 
Part B (Active ALKS 3831 Treatment and Safety Follow-up Periods) 
After completion of Part A (ie, at Visit 13), subjects will transition into Part B and will continue onto a 
12-week active treatment period during which all subjects will receive ALKS 3831 (ie, olanzapine plus 
samidorphan). Subjects who had been receiving ALKS 3831 during the double-blind period will 
continue on the same dose for the 12-week active treatment period. Subjects who had been receiving 
olanzapine + placebo in the double-blind period will continue on the same dose of olanzapine and will 
be transitioned from placebo to samidorphan (at the highest dose). 
At Visit 13 (Study Day 92), subjects will be admitted for a 2-night inpatient stay (Visits 13-15, Study 
Days 92-94) to allow for monitoring following initiation of samidorphan dose in subjects originally 
assigned to the olanzapine + placebo group. The inpatient stay is required for all subjects. After 
discharge (Study Day 94), subjects will return 5 days later for Visit 16 (Study Day 99). After Visit 16, 
subjects will be seen weekly for the next 3 weeks (Visits 17-19) and then at 2-week intervals for the 
remainder of the study (Visits 20-25). 
The subject will take the final samidorphan dose the night before Visit 23 (Study Day 176). No 
samidorphan dose will be administered onsite during Visit 23. Olanzapine dosing will continue 
uninterrupted through a 4-week follow-up period: A safety follow-up visit will occur 2 weeks after and 


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4 weeks after Visit 23. Any subject who prematurely discontinues from the study during Part A or Part B 
will be asked to return to the clinic for an ET visit and follow-up visits 2 and 4 weeks after the ET visit. 
Part B Visit Schedule 
 
Transition* 
Active ALKS 3831 Treatment Period 
Follow-
Up 
Visit 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23/ET 
24 
25 
Day 
92 
93 
94 
99 
106 
113 
120 
134 
148 
162 
176 
19
0 
204 
Week 
13 
14 
15 
16 
17 
19 
21 
23 
25 
27 
29 
* Transition (Visit 13) is the end of Part A and the beginning of Part B (Part B begins with dosing at Visit 13) 
Shaded cells represent inpatient stays. 
Number of subjects (planned): Approximately 280 subjects will be randomized. 
Diagnosis and main criteria for inclusion: 
Adults (18-50 years of age) with stable schizophrenia who may benefit from olanzapine treatment, who 
have a body mass index (BMI) of 17-30 kg/m2, who have maintained a stable body weight for at least 
3 months prior to screening (change ≤5%) and from screening to Visit 2 (change ≤1 kg), and who have 
not been exposed to olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for more than 
1 week within the past year or at any time in the 3 months prior to screening will be considered for 
participation. Complete eligibility criteria are listed in Section 7.1 and Section 7.2. 
Investigational product dosage and mode of administration: 
ALKS 3831 refers to the combination of olanzapine and samidorphan. In this study, olanzapine and 
samidorphan will be co-administered. Commercially available olanzapine for oral administration will be 
supplied or arranged for dispensing by the investigative site. 
Samidorphan will be provided by the sponsor. Each tablet contains samidorphan (2.5, 5 or 10 mg). 
Subjects will take 2 tablets per day by mouth (ie, doses of samidorphan will be 5, 10, or 20 mg). 
Samidorphan is a Schedule II controlled substance according to the United States Drug Enforcement 
Agency and will require proper handling. 
Reference product dosage and mode of administration: 
Placebo consists of tablets identical in size and appearance to the samidorphan tablets, but without active 
samidorphan. Subjects will take 2 tablets per day by mouth. 
Duration of study: The study duration for each subject will be approximately 33 weeks and will include 
25 study visits. This includes up to one month for screening, a 1-week lead-in period of olanzapine 
dosing, two 12-week treatment periods (a 12-week double-blind placebo-controlled period and a 
12-week period where all subjects get active ALKS 3831), and safety follow-up visits which occur 2 and 
4 weeks after Visit 23. 
Criteria for evaluation: 
Safety Assessments 
Safety will be evaluated based on the following measures: 
• 
Incidence of Adverse events (AEs) 
• 
Clinical laboratory test (chemistry, hematology, and urinalysis) results 
• 
Vital signs including blood pressure 


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• 
Electrocardiograms (ECGs) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Laboratory parameters including HDL, LDL, total cholesterol, triglycerides, fasting glucose 
and insulin, ratio of fasting glucose to fasting insulin, hemoglobin A1c (HbA1c), C-reactive 
protein, leptin, bicarbonate, and carbohydrate deficient transferrin (CDT) 
Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
preferred terms and system organ classes. Concomitant medications will be categorized using the World 
Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system. 
Pharmacokinetic Assessments 
For all subjects, plasma samples will be collected according to the schedule in Table 1 and Table 2 for 
quantifying olanzapine, samidorphan, and RDC-9986 (primary metabolite of samidorphan) 
concentrations. Pharmacokinetic (PK) data may be used to assess compliance with study drug 
administration and/or in a subsequent population PK evaluation conducted outside of this study. 
Efficacy Assessments 
Efficacy will be evaluated based on following measures: 
• 
Positive and Negative Syndrome Scale (PANSS) 
• 
Body weight 
• 
Waist circumference 
• 
Clinical Global Impressions-Severity (CGI-S) 
• 
Impact of Weight on Quality of Life – Lite Questionnaire (IWQOL-Lite) 
• 
Personal and Social Performance Scale (PSP) 
• 
Timeline Follow-Back (TLFB) assessment of alcohol drinking 
• 
Food Craving Inventory (FCI) 
Other Assessments: 
Pharmacogenetic assessments to explore the relationship between olanzapine-induced weight gain and 
genotype and identify people susceptible to weight gain 
Endpoints: 
Primary Endpoint: Absolute change in PANSS total score from randomization to the end of Part A 
Secondary Endpoints: 
• 
Percent change in body weight 
• 
Number and percentage of subjects with adverse events from randomization to the end of 
Part A 
• 
Absolute change in body weight 
• 
Proportion of subjects exhibiting significant weight gain (definition of weight gain will 
include body weight gain greater than 7%) 
• 
Absolute change in CGI-S 
 


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Additional Endpoints: 
• 
Change in waist circumference 
• 
Change in blood lipid concentrations including LDL, HDL, total cholesterol and 
triglycerides 
• 
Change in assessments related to glucose regulation including fasting glucose and insulin, 
fasting glucose to fasting insulin ratio, HbA1c, C-reactive protein, leptin and bicarbonate 
• 
Change in vital signs including blood pressure 
• 
Change in IWQOL-Lite scales (physical function, self-esteem, sexual life, public distress 
and work) and total score 
• 
Change in PSP 
• 
Change in FCI 
• 
Change in alcohol and drug use 
Statistical methods: 
Once all subjects have completed Part A of the study, an unblinded analysis of the 12-week placebo-
controlled data will be performed. This analysis may be conducted prior to the completion of Part B of 
the study. 
Safety 
All subjects who receive at least 1 dose of study drug (olanzapine, samidorphan, or placebo) will be 
included in the safety analysis. The secondary endpoint, number and percentage of subjects with adverse 
events from randomization to the end of Part A, will be analyzed descriptively by treatment group. 
Adverse events will be summarized overall and by MedDRA® preferred terms and system organ class 
as well as by severity and by relationship to study drug. Additional analysis of safety assessments will 
include summary statistics including mean, median, interquartile range, minimum, and maximum for 
continuous variables and number and percent for categorical variables. These statistics will be provided 
for the following: AEs, ECG parameters, laboratory test results, vital signs, and C-SSRS results during 
the entire study. 
Efficacy 
The efficacy analysis will be conducted on 2 full analysis set (FAS) populations: 
• 
The FAS 1 population will include all subjects who are randomized, receive at least one 
dose of study drug, and have at least one post-baseline PANSS assessment. 
• 
The FAS 2 population will include all FAS 1 subjects who gained weight during the initial 
week of olanzapine treatment prior to randomization and have at least one post-baseline 
weight assessment. 
The primary endpoint is the absolute change in PANSS total score from randomization to the end of Part 
A (ie, the end of the 12-week, placebo-controlled double-blind treatment period) and will be evaluated 
by treatment group (ALKS 3831 vs. the placebo group [olanzapine alone]) using a 2-sided mixed-model 
for repeated measures (MMRM) to test for equivalence at an alpha level of 0.05. The primary analysis 
will be conducted in the FAS 1 population. More details about this analysis will be provided in the 
statistical analysis plan (SAP). 
The secondary endpoint, percent change in weight from randomization to the end of Part A, will be 
evaluated by treatment group using an MMRM approach similar to that of the primary endpoint. 
However, this will be a superiority analysis. Each treatment group will be compared to the placebo 


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group with a 2-sided hypothesis test to test for superiority at an alpha level of 0.05. The secondary 
efficacy analysis will also be conducted in the FAS 1 population. More details about this analysis will be 
provided in the SAP. 
Analysis of other secondary endpoints and additional endpoints will include inferential analyses and 
descriptive analyses by visit (mean, standard deviation, median, minimum, and maximum for continuous 
variables and number and percent for categorical variables), as appropriate. 
Analyses for the primary and secondary endpoints will be repeated in the FAS 2 population as sensitivity 
analyses when applicable. Additional details regarding these analyses will be provided in the SAP. 
Sample size considerations 
Sample size calculations are based on the primary endpoint of absolute change in PANSS total score. 
These calculations assume an equivalence margin of 10 points, a standard deviation of 20 points, and a 
true difference of 0 points. With these assumptions, 280 randomized subjects provide 95% power to 
detect equivalence on the primary endpoint (absolute PANSS total score change from randomization to 
the end of Part A) with a 2-sided test at an alpha level of 0.05. These 280 subjects represent 70 subjects 
for each treatment arm (ALKS 3831 5 mg, ALKS 3831 10 mg, ALKS 3831 20 mg, and placebo) in a 
1:1:1:1 ratio. For the primary analysis, subjects in the 3 ALKS 3831 treatment groups will be pooled for 
comparison with placebo. If this analysis shows equivalence, follow-up analyses on individual dose 
levels will be performed. Assuming a 20% discontinuation rate prior to randomization, an estimated 350 
subjects will be enrolled in this study. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
4. 
LIST OF ABBREVIATIONS.....................................................................................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Background .................................................................................................................15 
5.2. 
Study Drugs ................................................................................................................16 
5.2.1. 
Samidorphan ...............................................................................................................16 
5.2.2. 
Olanzapine ..................................................................................................................16 
5.3. 
Study Rationale ...........................................................................................................16 
5.4. 
Dose Rationale ............................................................................................................17 
6. 
OBJECTIVES .............................................................................................................18 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................19 
7.1. 
Subject Inclusion Criteria ...........................................................................................19 
7.2. 
Subject Exclusion Criteria ..........................................................................................20 
7.3. 
Subject Withdrawal ....................................................................................................22 
7.4. 
Replacement of Subjects .............................................................................................23 
8. 
STUDY DESIGN .......................................................................................................23 
8.1. 
Overall Study Design and Plan ...................................................................................23 
8.1.1. 
Part A (Screening, Olanzapine Lead-In, and Double-Blind Placebo-
Controlled Treatment Period) .....................................................................................24 
8.1.2. 
Part B (Active ALKS 3831 Treatment and Safety Follow-up Periods) .....................25 
8.2. 
Schedule of Visits and Assessments ...........................................................................25 
8.3. 
Study Procedures Descriptions ...................................................................................33 
8.3.1. 
Informed Consent .......................................................................................................33 
8.3.2. 
Demographics, Medical and Psychiatric History .......................................................33 
8.3.3. 
Drug Testing ...............................................................................................................33 
8.3.4. 
Timeline Follow-Back ................................................................................................33 
8.3.5. 
Concomitant Medication Review ...............................................................................33 
8.3.6. 
Vital Signs ..................................................................................................................33 


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8.3.7. 
Physical Examination, Height ....................................................................................34 
8.3.8. 
Body Weight and Waist Circumference .....................................................................34 
8.3.9. 
12-Lead Electrocardiogram ........................................................................................34 
8.3.10. 
Adverse Event Monitoring .........................................................................................35 
8.3.11. 
Laboratory Assessments .............................................................................................35 
8.3.11.1. 
Specialty Laboratory Assessments .............................................................................36 
8.3.11.2. 
Pregnancy Screening ..................................................................................................37 
8.3.12. 
Pharmacokinetic Assessments ....................................................................................37 
8.3.13. 
Clinical Global Impressions-Severity .........................................................................37 
8.3.14. 
Columbia Suicide Severity Rating Scale ....................................................................37 
8.3.15. 
Positive and Negative Syndrome Scale ......................................................................37 
8.3.16. 
Personal and Social Performance Scale ......................................................................37 
8.3.17. 
Food Craving Inventory ..............................................................................................37 
8.3.18. 
Impact of Weight on Quality of Life - Lite ................................................................37 
8.3.19. 
Audio Recording .........................................................................................................38 
8.3.20. 
Olanzapine Administration .........................................................................................38 
8.3.21. 
Randomization ............................................................................................................38 
8.3.22. 
Drug Dispensation and Reconciliation .......................................................................38 
8.3.23. 
Emergency Treatment Card ........................................................................................39 
8.3.24. 
Clinical Validation Inventory for Study Admission ...................................................39 
8.4. 
Study Requirements and Restrictions .........................................................................39 
8.4.1. 
Prohibited Medications ...............................................................................................39 
8.4.2. 
Contraception ..............................................................................................................40 
8.4.3. 
Other Restrictions .......................................................................................................40 
8.4.4. 
Pain Management .......................................................................................................41 
9. 
TREATMENT OF SUBJECTS ..................................................................................42 
9.1. 
Study Drug Dose and Administration .........................................................................42 
9.2. 
Treatment Compliance ................................................................................................42 
9.3. 
Randomization and Blinding ......................................................................................43 
9.4. 
Breaking Study Blind .................................................................................................43 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................44 
10.1. 
Study Drug ..................................................................................................................44 
10.2. 
Packaging and Labeling ..............................................................................................44 


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10.3. 
Storage ........................................................................................................................44 
10.4. 
Accountability .............................................................................................................44 
10.5. 
Handling and Disposal ................................................................................................44 
11. 
ASSESSMENT OF EFFICACY ................................................................................46 
11.1. 
Primary Endpoint ........................................................................................................46 
11.2. 
Secondary Endpoints ..................................................................................................46 
11.3. 
Additional Endpoints ..................................................................................................46 
12. 
PHARMACOKINETIC/ PHARMACODYNAMIC ASSESSMENTS .....................47 
13. 
ASSESSMENT OF SAFETY .....................................................................................48 
13.1. 
Safety Endpoints .........................................................................................................48 
13.2. 
Definition of Adverse Event .......................................................................................48 
13.3. 
Definition of Serious Adverse Event ..........................................................................48 
13.4. 
Relationship to Study Drug ........................................................................................49 
13.4.1. 
Adverse Events of Special Interest .............................................................................50 
13.5. 
Monitoring and Recording of Adverse Events ...........................................................51 
13.6. 
Reporting of Serious Adverse Events .........................................................................51 
14. 
STATISTICS ..............................................................................................................52 
14.1. 
Sample Size Considerations .......................................................................................52 
14.2. 
General Statistical Methodology ................................................................................52 
14.2.1. 
Efficacy Population ....................................................................................................52 
14.2.2. 
Safety Population ........................................................................................................52 
14.3. 
Demographics and Baseline Data ...............................................................................52 
14.4. 
Efficacy Analyses .......................................................................................................53 
14.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................53 
14.6. 
Safety and Tolerability Analyses ................................................................................53 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................55 
15.1. 
Study Monitoring ........................................................................................................55 
15.2. 
Audits and Inspections ................................................................................................55 
15.3. 
Institutional Review Board/ Independent Ethics Committee .....................................55 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16.1. 
Case Report Forms .....................................................................................................56 
16.2. 
Confidentiality of Data ...............................................................................................56 
17. 
ETHICAL CONSIDERATIONS................................................................................57 


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17.1. 
Ethics Review .............................................................................................................57 
17.2. 
Ethical Conduct of the Study ......................................................................................57 
17.3. 
Written Informed Consent ..........................................................................................57 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................59 
18.1. 
Data Capture ...............................................................................................................59 
18.2. 
Inspection of Records .................................................................................................59 
18.3. 
Retention of Records ..................................................................................................59 
18.4. 
Use of Information and Publication Policy ................................................................60 
19. 
REFERENCES ...........................................................................................................61 
APPENDIX A. SAMPLE CLINICAL GLOBAL IMPRESSIONS-SEVERITY (CGI-S) 
SCALE ........................................................................................................................62 
APPENDIX B. SAMPLE COLUMBIA SUICIDE SEVERITY RATING SCALE (C-
SSRS) ..........................................................................................................................65 
APPENDIX C. SAMPLE POSITIVE AND NEGATIVE SYNDROME SCALE 
(PANSS) .....................................................................................................................72 
APPENDIX D. SAMPLE PERSONAL AND SOCIAL PERFORMANCE (PSP) 
SCALE ........................................................................................................................89 
APPENDIX E. SAMPLE FOOD CRAVING INVENTORY (FCI)...........................................92 
APPENDIX F. SAMPLE IMPACT OF WEIGHT ON QUALITY OF LIFE - LITE 
(IWQOL-LITE) QUESTIONNAIRE .........................................................................94 
APPENDIX G. PARTIAL LIST OF PROHIBITED CYTOCHROME P450 (CYP) 
3A4 INDUCERS AND MODERATE-TO-STRONG INHIBITORS ........................97 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments (Part A)
 
 ..............................................................................27
Table 2: 
Schedule of Assessments (Part B)
 
 ..............................................................................30
Table 3: 
Clinical Laboratory Assessments
 
 ...............................................................................36
Table 4: 
Causality Guidelines
 
 ...................................................................................................50
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic
 
 .............................................................................................26


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4. 
LIST OF ABBREVIATIONS 
Abbreviation or term 
Explanation 
AE 
adverse event 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen 
ECG 
electrocardiogram 
C-SSRS 
Columbia Suicide Severity Rating Scale 
C-VISA™ 
Clinical Validation Inventory for Study Admission 
CATIE 
Clinical Antipsychotic Trials of Intervention Effectiveness 
CDT 
carbohydrate deficient transferrin 
CGI-S 
Clinical Global Impressions-Severity 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CRO 
Contract Research Organization 
CTA 
Clinical Trial Agreement 
CDT 
carbohydrate deficient transferrin 
CYP 
cytochrome P450 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data Safety Monitoring Board 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ECT 
Electroconvulsive Therapy 
ECG 
Electrocardiogram 
ET 
early termination 
FAS 
full analysis set 
FCI 
Food Craving Inventory 


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Abbreviation or term 
Explanation 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HbA1c 
hemoglobin A1c 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IWQOL-Lite 
Impact of Weight on Quality of Life-Lite 
IWRS 
Interactive Web Response System 
LDH 
lactic dehydrogenase 
MedDRA© 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model for repeated measures 
OTC 
over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PI 
principal investigator 
PK 
Pharmacokinetic(s) 
PSP 
Personal and Social Performance Scale 
QTcF 
QT Interval-Frederica Formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operating procedure 
TLFB 
Timeline Follow Back 
US 
United States 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background 
Olanzapine is regarded as one of the most effective antipsychotics with well-recognized efficacy 
and other advantages such as decreased incidence of extrapyramidal symptoms. However, it also 
has safety and tolerability limitations which have been demonstrated to affect compliance and 
retention of patients on olanzapine therapy [Lieberman, 2005]. In particular, results of the 
CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study identify olanzapine as 
an effective atypical antipsychotic agent associated with the highest weight gain (4.2 kg over up 
to 18 months of treatment and an overall >7% body weight in 30% of subjects) and a 
comparatively higher discontinuation rate due to increases in body weight and metabolic effects 
than other antipsychotic agents [Lieberman, 2005]. Further, it is estimated that between 40-60% 
of people with schizophrenia abuse alcohol and/or illicit drugs [Lubman, 2010], and these “dual 
diagnosis” patients have worse outcomes on a variety of measures [Batki, 2009;Dixon 1999]. 
ALKS 3831 is a combination drug under investigation for treatment of schizophrenia. The 
principle active component in ALKS 3831 is olanzapine. The other active component is 
samidorphan, a new chemical entity that clinical studies have shown to limit the weight gain 
caused by olanzapine alone. This effect was first seen in a proof-of- concept study conducted in 
healthy adults (Study ALK33-301). This effect appears to be specific to antipsychotic weight 
gain because samidorphan did not cause meaningful changes in weight when administered as a 
single agent in adults with binge eating disorder (Study ALK33-101). 
As stated previously, despite being regarded as one of the most effective antipsychotics for the 
treatment of schizophrenia, safety and tolerability limitations have affected compliance and 
retention of patients on olanzapine therapy. As a result, many patients are switched from 
olanzapine to other antipsychotics to address tolerability issues even if the alternative 
antipsychotic is regarded as less effective. The presence of samidorphan in ALKS 3831 is to 
enhance the benefit and decrease the risk of the principal ingredient, olanzapine. 
In addition to enhancing the safety of olanzapine, samidorphan may help with substance abuse in 
schizophrenia. Comorbid substance abuse is regarded as a considerable obstacle in the treatment 
and management of many patients with schizophrenia. Samidorphan (also referred to as ALKS 
33 or RDC-0313) is structurally derived from naltrexone and like naltrexone, acts as an 
antagonist at μ-opioid receptors with mixed agonist/antagonist activity at both κ and δ receptors. 
In laboratory animals and in humans, samidorphan is a potent µ-antagonist. Clinical data have 
shown that samidorphan blocked both the subjective and physiological effects of the opioid 
agonist remifentanil (Study ALK33-004). In adults with alcohol dependence, samidorphan was 
associated with a reduction in drinking behavior (Study ALK33-005). 
Thus, the combination of samidorphan and olanzapine (ie, ALKS 3831) as a fixed-dose 
combination may result in an enhanced therapeutic agent for the treatment of patients with 
schizophrenia. ALKS 3831 could thereby address the need for antipsychotics with improved 
benefit/risk profiles for schizophrenia patients for whom olanzapine is the optimal antipsychotic 
choice as well as dual diagnosis patients and expand the population of patients for whom 
olanzapine is the antipsychotic of choice. 


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5.2. 
Study Drugs 
In this study, samidorphan and olanzapine will be co-administered oral tablets. The following 
sections provide an overview of samidorphan and olanzapine. Detailed information about the 
study drugs can be found in the ALKS 3831 Investigator’s Brochure (IB) and Zyprexa® 
(olanzapine) United States (US) Package Insert [2011] respectively. 
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 as a single agent 
for the treatment of reward disorders, in combination with buprenorphine for the treatment of 
major depressive disorder and for the treatment of cocaine dependence, and in combination with 
olanzapine for the treatment of schizophrenia. Based on its chemical structure, samidorphan is a 
Schedule II controlled substance according to the US Drug Enforcement Agency and will require 
proper handling (see Section 10). 
Ten clinical studies of samidorphan have been conducted to date, 8 of which included subjects 
that received samidorphan alone (not in combination with another product). Overall, 
approximately 600 subjects have been exposed to samidorphan. 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 and was originally approved for the 
treatment of schizophrenia, but has since been approved for other indications including the 
treatment of schizophrenia in adolescents and bipolar disorder. The safety and tolerability profile 
of olanzapine is well documented, and adverse event labeling is supported by an extensive safety 
database that includes over 8,500 adult patients [2011]. Commonly reported AEs consistent 
across all or most dosage forms in short-term, placebo controlled trials include somnolence, 
constipation, dry mouth, accidental injury, weight gain, postural hypotension, dizziness, asthenia, 
fever and abnormal gait. 
5.3. 
Study Rationale 
Schizophrenia is a lifelong illness and changes in medication are often made to better manage 
evolving symptoms and to control side effects and/or tolerability issues. Similar to what was 
done in the landmark CATIE study [Lieberman, 2005], this study is seeking to enroll patients 
that are psychiatrically stable, where stability is largely defined by the absence of significant 
fluctuations or an acute exacerbation of symptoms. In these patients, stability may still reflect a 
sub-optimal condition that could be improved by transitioning to a different medication. Other 
patients may be well-controlled on their current antipsychotic, but may be experiencing 
unpleasant or intolerable side effects such as hyperprolactinemia or extrapyramidal symptoms. 
These patients may also benefit from switching to a different medication. 


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In this Phase 2 study, such patients will be transitioned to olanzapine which is widely regarded as 
one of the most efficacious antipsychotics currently available. Patients with stable symptoms 
who are not currently taking an antipsychotic, but who may benefit from treatment with 
olanzapine, are also eligible to participate in this study. In addition to olanzapine, subjects will 
also receive samidorphan. Samidorphan may offer a range of potential benefits when 
administered with olanzapine for patients with schizophrenia including attenuated weight gain 
and a reduction in concomitant substance abuse. Both of these benefits have the potential to 
increase patient retention on therapy and improve long term outcomes. 
One Phase 1 study, ALK33-301, has been conducted in healthy adults (N = 106) to determine the 
safety, tolerability, and efficacy of samidorphan taken with olanzapine to mitigate olanzapine-
induced weight gain. The co-administration of samidorphan (5 mg) and olanzapine when 
administered once daily for 3 weeks to healthy volunteers was generally well tolerated and 
resulted in significantly less weight gain compared with subjects administered olanzapine alone. 
Aside from a positive effect on weight gain, samidorphan did not appear to impact the adverse 
event profile of olanzapine in this Phase 1 study. The co-administration of samidorphan and 
olanzapine did not impact the pharmacokinetics (PK) of either individual drug. 
Alkermes refers to the combination of olanzapine and samidorphan as ALKS 3831. The current 
Phase 2 study in adults with schizophrenia will assess the efficacy of ALKS 3831 on psychiatric 
symptoms, the safety and tolerability of ALKS 3831, and whether subjects receiving ALKS 3831 
gain less weight than subjects receiving placebo. 
Future studies will explore other anticipated benefits conferred by ALKS 3831 opioid 
modulation. 
5.4. 
Dose Rationale 
Commercially available olanzapine will be administered at the dose selected by the principal 
investigator (PI) based on the individual subject’s clinical condition. 
Clinical studies investigating the safety, tolerability, PK, and exploratory efficacy with 
samidorphan have found this compound to be safe and generally well tolerated following single 
oral doses of 1-55.7 mg and up to 12-weeks of once daily oral or sublingual (1-10 mg) 
administration (see ALKS 3831 IB). The samidorphan dose levels (oral administration) in the 
current trial (5, 10, and 20 mg) were selected based on PK, pharmacologic, and safety 
considerations. It is expected that these doses will be sufficient to establish a therapeutic dose 
range and inform dose selection for future studies.  
Based on the divergent metabolic pathways of samidorphan and olanzapine, and supported by 
the results of a prior clinical trial and an in vitro investigation, no PK drug-drug interactions are 
anticipated in the patient population. 


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6. 
OBJECTIVES 
The objectives of this study are to evaluate 3 doses of samidorphan co-administered with 
olanzapine (ALKS 3831) in subjects with schizophrenia to (1) evaluate ALKS 3831 as a 
treatment for schizophrenia (2) assess the safety and tolerability of ALKS 3831; and (3) 
characterize the impact of the samidorphan component of ALKS 3831 on weight and other 
metabolic factors. 


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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 main 
informed consent form (ICF) before initiation of any study specific procedures (see 
Section 17.3) 
2. Subject is age 18 to 50 years, inclusive, at screening 
3. Subject has a body mass index (BMI) of 17.0-30.0 kg/m2, inclusive, at screening 
4. Subject has a diagnosis of schizophrenia (based on Diagnostic and Statistical Manual of 
Mental Disorders [DSM] criteria) that is clinically stable as evidenced by both of the 
following: 
• No hospitalizations for acute exacerbations of schizophrenia within 2 months before 
screening 
• Clinical Global Impressions-Severity (CGI-S) score of ≤3 (mild) at screening and 
Visit 2 
5. Subject has a total Positive and Negative Syndrome Scale (PANSS) score ≤80 at 
screening and Visit 2 
6. Subject has stable positive symptoms as shown by a score ≤4 on PANSS for items related 
to delusion, hallucination, conceptual disorganization, and unusual thought content, at 
screening and Visit 2. 
7. Subject currently resides in a stable residence or living arrangement, has been in this 
residence/living arrangement for at least 8 weeks prior to screening, and the 
residence/living arrangement is not anticipated to change during the study. 
8. Subject agrees to maintain current level of fitness or exercise regimen for the duration of 
the study 
9. Subject reports a stable body weight for at least 3 months prior to screening 
(change ≤5%) and from screening to Visit 2 (change ≤1 kg) 
10. Subject agrees to use an acceptable method of contraception for the duration of the study 
(as described in Section 8.4.2). 
11. Subject must have an informant or caregiver who meets the following criteria: 
a. Informant or caregiver will be in contact with the subject several times per week. 
b. If necessary, the informant or caregiver will accompany the subject to visits. 
c. Informant or caregiver will help ensure maximum subject adherence to study 
procedures. 


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12. Subject is fluent in the language (oral and written) in which assessments will be made, 
and can be reliably rated. 
7.2. 
Subject Exclusion Criteria 
Subjects with any of the following conditions will be excluded from participation in this study. 
1. Subject does not meet duration of illness eligibility requirements for one of the following 
reasons: 
• Subject initiated first antipsychotic treatment within the past 12 months. 
• Subject has had symptoms lasting <2 years. 
2. Subject presents with comorbid neuropsychiatric disorders including the following: 
• Axis I (according to DSM criteria) diagnosis of schizoaffective disorder or bipolar 
disorder, or current major depressive disorder that is untreated and/or unstable. 
Current major depressive disorder that is treated and stable is not a criterion for 
exclusion. 
• Clinically significant cognitive difficulties including dementia, delirium, or amnestic 
syndromes, or any other cognitive disorder present within the past 2 years that could 
interfere with participation in the study 
• Drug induced or toxic psychosis 
• Any other psychiatric condition that could interfere with participation in the study 
3. Subject has a diagnosis (based on DSM-5 criteria) of moderate or severe alcohol or drug 
use disorder currently or at any time during the 3 months prior to screening. Nicotine and 
caffeine use are allowed. 
4. Subject poses a current suicide risk as confirmed by the baseline Columbia-Suicide 
Severity Rating Scale (C-SSRS) by a response of “Yes” to question #4 or 5 with ideation 
or suicidal behavior occurring in the past year 
5. Subject reports positive human immunodeficiency virus (HIV) status at screening 
6. Subject has diabetes or meets any of the following criteria: 
• Hemoglobin A1c (HbA1c) ≥6.5% at Visit 1 
• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) at Visit 2 
• A random plasma glucose ≥200 mg/dL (11.1 mmol/L) at Visit 1 
7. Subject has a clinically significant or unstable medical illness, condition, or disorder that 
would be anticipated to potentially compromise subject safety or adversely affect the 
evaluation of efficacy, including (but not necessarily limited to) the following: 
• Clinically significant hypotension or hypertension not controlled by medical therapy 
• Unstable thyroid dysfunction in the past 6 months (eg, hypothyroidism, 
hyperthyroidism, or thyroiditis that was untreated, or discovered and treatment was 


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initiated within the 6 months prior to screening) or a TSH value outside of the normal 
range (high or low) at screening 
• Personal or family history of neuroleptic malignant syndrome 
• Dyslipidemia, defined for this study as total cholesterol >280 mg/dL or triglycerides 
>500 mg/dL, at screening 
• Inflammatory bowel disease or any other gastrointestinal (GI) disorder associated 
with weight loss, anorexia nervosa, bulimia nervosa, or binge eating disorder 
• Neurologic conditions including the following: 
− History of seizure disorder or a condition associated with seizures 
− History of brain tumor, subdural hematoma or other clinically significant 
neurological condition within the 12 months prior to screening 
− Head trauma with loss of consciousness within the 12 months prior to screening 
− Active acute or chronic central nervous system (CNS) infection 
− Stroke within the 6 months prior to screening 
8. Subject has a cardiac condition that might confound the results of the study or pose 
additional risk when administering the investigational agents to the subject or preclude 
successful completion of the study. Such conditions include the following: 
• Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction 
defect; a history of myocardial infarction or unstable angina; or clinically significant 
ECG abnormality at Visit 1 or Visit 2. 
• QT interval >450 msec for men and >470 msec for women, as corrected by the 
Fridericia formula (QTcF), observed at Visit 1 or Visit 2. 
9. Subject has a laboratory abnormality that would compromise the well-being of the 
subject, or has any of the following specific laboratory results at Visit 1 or Visit 2: 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value ≥3 times 
the upper limit of the laboratory normal reference range 
• Absolute neutrophil count (ANC) ≤1.5 × 103 per μL at Visit 1 and <1.0 ×103 per μL 
at Visit 2 
• Platelet count ≤75 × 103 μL 
• Serum creatinine >2.5 mg/dL 
• Positive pregnancy test result 
10. Subject is pregnant or breastfeeding or is planning to become pregnant within 60 days of 
the last study drug administration 
11. Subject has had any GI surgical procedures within one year prior to screening 
12. Subject has had a surgical procedure for weight loss or is planning to have liposuction 
during the study 


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13. Subject has had significant changes in diet or exercise regimen within the 6 weeks prior 
to screening or plans to join a weight management program during the study. 
14. Subject has started a smoking cessation program within the 6 months prior to screening 
or anticipates quitting smoking during the study 
15. Subject requires or has had electroconvulsive therapy (ECT) treatment in the 2 month 
period prior to randomization 
16. Subject has a positive urine drug screen for benzodiazepines, opioids, amphetamine/ 
methamphetamine, or cocaine at screening (Exception: A positive screen for 
benzodiazepine may not be exclusionary if the PI or designated investigator confirms that 
such medication was medically indicated and consults the 
 Medical 
Monitor before enrolling a subject with such a finding) 
17. Subject has taken opioid medications within the 14 days prior to screening and/or 
anticipates a need to take opioid medication during the study period 
18. Subject has a history of hypersensitivity to or intolerance of olanzapine 
19. Subject has used olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for 
more than one week during the past year or at any time during the past 3 months 
20. Subject is currently on a statin medication (an HMG-CoA reductase inhibitor) that was 
initiated or has had the dose changed within the 3 months prior to screening 
21. Subject has current or pending legal charges with the potential for incarceration that 
could interfere with the study scheduling 
22. Subject is currently participating in or has recently participated in another clinical trial in 
which the subject received an experimental or investigational drug or agent within the 3 
months prior to screening 
23. Subject is employed by Alkermes or its affiliates (including permanent, temporary 
contract worker, or designee responsible for the conduct of the study) or is an immediate 
family member* of an Alkermes or affiliate employee 
24. Subject is investigator-site personnel or an immediate family member* of investigator-
site personnel 
* Immediate family is defined as a spouse, parent, child, or sibling whether biological or 
legally adopted. 
7.3. 
Subject Withdrawal 
A subject may be discontinued from the study at any time if the subject, PI (or designee), or 
sponsor determines that it is not in the best interest of the subject to continue participation. If a 
subject has an ANC<1.0 ×103 per μL at anytime from Visit 2 to Visit 25, the PI (or designee) 
should discontinue the subject from participation immediately. 
If a subject withdraws from the study for any reason, any ongoing AEs and/or a low ANC will be 
followed until resolution, until deemed stable by the PI, or until the subject is deemed by the PI 
to be lost to follow-up. If, in the opinion of the PI, it is necessary to monitor a subject beyond the 
PPD


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safety follow-up visit, the follow-up period may be extended as necessary. In such instances, the 
sponsor and the PI will agree to an acceptable follow-up schedule. 
In the event that a subject chooses to withdraw from the study, the PI (or designee) should make 
a reasonable effort to ascertain the reason(s) for withdrawal while fully respecting the subject’s 
rights. The subject should complete an ET visit when possible and subjects should be encouraged 
to return for follow-up visits 2 and 4 weeks after the ET visit. If the subject fails or refuses to 
return to the study center, an attempt must be made to contact the subject by telephone in order 
to assess as many safety and efficacy parameters as possible. All data collected over the 
telephone must be documented and kept in the subject’s record. 
The PI must maintain a record of all subjects who fail to complete the study. A full explanation 
of the reason for study discontinuation will be made on the appropriate electronic case report 
form (eCRF). If a subject is lost to follow-up, a reasonable attempt to contact the subject must be 
made and documented. 
7.4. 
Replacement of Subjects 
Subjects who withdraw from the study after randomization will not be replaced. 
8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
It is not unusual for prescribing physicians to consider a change in a patient’s antipsychotic 
medication (see Section 5.3). Reasons for considering a change often include insufficient control 
of symptoms and/or tolerability issues. In some cases, patients who are apparently adequately 
controlled may wish to change therapies in hopes of even better control or fewer side effects. 
This study will include subjects who have a diagnosis of schizophrenia who have not been 
exposed to olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for more than 
one week within the past year or at any time in the 3 months prior to screening.  
This is a Phase 2, randomized, placebo-controlled multicenter study, which will be conducted in 
two parts: Part A and Part B. Part A will begin with screening and will include a 1-week 
olanzapine lead-in period followed by a 12-week double-blind, placebo-controlled treatment 
period where subjects will receive samidorphan or placebo (in addition to the olanzapine 
prescribed on Study Day 1). Part B will include an additional 12-week treatment period where all 
subjects will receive active olanzapine + samidorphan (ie, ALKS 3831). At the end of Part B, 
samidorphan dosing will stop, but olanzapine dosing will continue uninterrupted through the 4-
week follow-up period, which includes 2 safety visits. 
This study will use an Independent Data Safety Monitoring board (DSMB) to monitor for 
tolerability of study drug. After at least one week of safety data has been collected for 40 
randomized subjects, the DSMB will review the accumulated safety data for all subjects. After at 
least one week of safety data has been collected for 150 randomized subjects, the DSMB will 
review the accumulated safety data for all subjects. Complete details of the membership and 
functioning of this board will be available in the DSMB Charter. 


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This is Alkermes’ first study of the co-administration of olanzapine and samidorphan in a 
population of adults with schizophrenia. In addition, this study includes higher doses of 
samidorphan than the 5-mg dose that was used in a prior study (ALK33-301). Samidorphan has 
been associated with somnolence, and olanzapine has been associated with orthostatic 
hypotension. In ALK33-301, there was no apparent additive effect of the co-administration on 
either of these adverse effects. However, because the current study involves higher doses of 
samidorphan than studied previously, it was desired to take a conservative approach by 
monitoring subjects in an inpatient setting for 2 nights following randomization (Visit 3) and 
transition (Visit 13). 
During clinic visits, assessments of psychotic symptoms using measures such as the PANSS and 
CGI-S will occur. Body weight will be measured using consistent methods at every visit. 
Alcohol and drug use will be monitored throughout the study. Concentrations of samidorphan, 
RDC-9986 (primary metabolite of samidorphan), and olanzapine will be determined in plasma 
samples collected at Visits 2-23. 
8.1.1. 
Part A (Screening, Olanzapine Lead-In, and Double-Blind Placebo-Controlled 
Treatment Period) 
Screening assessments will occur in the 30-day period before subjects report to the clinic for 
verification of eligibility and initiation of olanzapine treatment (Study Day 1). On Study Day 1 
(Visit 2), all eligible subjects will be initiated on olanzapine. Olanzapine dose will be selected 
and titrated by the PI based upon individual subject needs and consistent with current clinical 
practice. Subjects will return one week later (ie, Study Day 8, Visit 3) for a 2-night inpatient stay 
and the start of the 12-week double-blind placebo-controlled treatment period. At this visit, 
subjects will be randomized in a 1:1:1:1 ratio to receive samidorphan (5 mg, 10 mg, or 20 mg) or 
placebo. Olanzapine dosing will continue uninterrupted. Thus, the Part A treatment groups will 
be as follows: 
• Olanzapine + Samidorphan (5 mg) 
• Olanzapine + Samidorphan (20 mg) 
• Olanzapine + Samidorphan (10 mg) 
• Olanzapine + Placebo 
All study drug will be taken once daily, by mouth, at the same time. Subjects will be encouraged 
to take study drug in the evening or at bedtime. Study drug administration may be adjusted to 
accommodate study procedures. Randomization will be stratified by the amount of weight 
change during the olanzapine lead-in period (ie, from Day 1 to Day 8), with subjects grouped 
into the following 3 strata: 
• Weight change ≤0 kg 
• Weight increase >0 to <1 kg • Weight increase ≥1 kg 
This stratification will be used for analyses of secondary endpoints as specified in the statistical 
analysis plan (SAP). 
Subjects will be discharged from the clinic on Study Day 10 (Visit 5), and will return on Study 
Day 15 (Visit 6). 
Subjects are not required to be taking any antipsychotic medication at the time of screening or 
Visit 2. However, those who are will be tapered off of their prior antipsychotic medication within 
2 weeks after initiation (ie, by Study Day 15, Visit 6). This cross-taper from prior antipsychotic 


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treatment to olanzapine will be conducted under the care and discretion of the PI and consistent 
with current clinical practice. 
After Study Day 15 subjects will return to the clinic weekly through the first month of double-
blind treatment (ie, Study Day 36) and then every 2 weeks thereafter for the remainder of Part A. 
Any subject who prematurely discontinues during Part A will be asked to return to the clinic 
immediately for an ET visit and after 2 and 4 weeks for follow-up visits. 
Assessments prior to study-drug administration at Visit 13 (the transition visit) will serve as end 
of Part A assessments; dosing and post-dose assessments will be considered Part B assessments. 
8.1.2. 
Part B (Active ALKS 3831 Treatment and Safety Follow-up Periods) 
After completion of Part A (ie, at Visit 13), subjects will transition into Part B and will continue 
onto a 12-week active treatment period during which all subjects will receive ALKS 3831 (ie, 
olanzapine + samidorphan). Subjects who had been receiving ALKS 3831 during the double-
blind period will continue on the same dose for the 12-week active treatment period. Subjects 
who had been receiving olanzapine + placebo in the double-blind period will continue on the 
same dose of olanzapine and will be transitioned from placebo to samidorphan (at the highest 
dose). 
At Visit 13 (Study Day 92), subjects will be admitted for a 2-night inpatient stay to allow for 
monitoring following initiation of samidorphan dose in subjects originally assigned to the 
olanzapine + placebo group. Because treatment assignments in the double-blind period must 
remain blind until all subjects have completed Part A or been discontinued from the study, the 
inpatient stay is required for all subjects. After discharge (Study Day 94), subjects will return 
5 days later for Visit 16 (Study Day 99). After Visit 16, subjects will be seen weekly for the next 
3 weeks (Visits 17-19) and then at 2-week intervals for the remainder of the study (Visits 20-25). 
The subject will take the final samidorphan dose the night before Visit 23 (Study Day 176). No 
samidorphan dose will be administered onsite during Visit 23. Olanzapine dosing will continue 
uninterrupted. Two safety follow-up visits will occur 2 and 4 weeks after Visit 23. Any subject 
who prematurely discontinues from the study during Part B will be asked to return to the clinic 
for an ET visit and follow-up visits 2 and 4 weeks after the ET visit. 
8.2. 
Schedule of Visits and Assessments 
The schedule of visits and assessments for Part A is shown in Table 1. The schedule of visits and 
assessments for Part B is shown in Table 2. 
Because fasting glucose and insulin levels will be measured at some visits, subjects will be 
instructed not to eat or drink for 8 hours before these visits: Visit 2, Visit 3, Visit 13, and Visit 
23/ET (see Table 1 and Table 2). Random glucose and insulin levels will be measured at visits 
where glucose and insulin measurements are indicated, but fasting is not required. 
For a missed visit, the site should attempt to contact the subject to reschedule. 
Premature discontinuation procedures are provided in Section 7.3. 


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13 June 2014 
ALK3831-302 
Page 26 
Figure 1: 
Study Design Schematic 
 
 
 
 
 
 
 
 
PART A 
 
 
 
 
PART B 
Study 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23/ 
ET 
24 
25 
Study 
Day 
-30 
to -1 
1 
8 
9 
10 
15 
22 
29 
36 
50 
64 
78 
92 
93 
94 
99 
106 
113 
120 
134 
148 
162 
176 
190 
20 
Study 
Week 
 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
14 
15 
16 
17 
19 
21 
23 
25 
27 
29 
 
 
 
 
Randomization 
(Day 8 only) 
Follow-Up 
Screening 
Transition Visit 
(Day 92) 
Active ALKS 3831 Treatment Period 
Double-blind Treatment 
Olanzapine Only 


Protocol Amendment #3-CZ 
CONFIDENTIAL  
Alkermes, Inc 
13 June 2014 
ALK3831-302 
Page 27 
Table 1: 
Schedule of Assessments (Part A) 
 
Screening 
Olanza-
pine 
Double-Blind Placebo-Controlled Treatment Period 
Transition1 
 
Outpatient Visits 
Inpatient Stay 
Outpatient Visits 
Inpatient 
Stay2 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Study Day 
-30 to -1 
1 
8 
(±1) 
9 
(±1) 
10 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±2) 
36 
(±2) 
50 
(±2) 
64 
(±2) 
78 
(±2) 
92 
(±2) 
Study Week 
 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical/Psychiatric 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight, and Waist 
Circumference3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test4 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Drug Screens5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timeline Follow-Back (TLFB)6 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Vital Signs7 
X 
X 
X8 
X8 
X8 
X8 
X 
X 
X 
X 
X 
X 
X8 
Blood and urine samples for clinical 
labs9 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
Hemoglobin A1c, C-reactive protein, 
leptin 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Carbohydrate Deficient Transferrin 
(CDT) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Electrocardiogram (ECG)10 
X 
X11 
X 
 
X 
X 
 
 
 
 
 
 
X 
Physical Examination12 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Columbia Suicide Severity Rating 
Scale (C-SSRS)13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Amendment #3-CZ 
CONFIDENTIAL  
Alkermes, Inc 
13 June 2014 
ALK3831-302 
Page 28 
 
Screening 
Olanza-
pine 
Double-Blind Placebo-Controlled Treatment Period 
Transition1 
 
Outpatient Visits 
Inpatient Stay 
Outpatient Visits 
Inpatient 
Stay2 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Study Day 
-30 to -1 
1 
8 
(±1) 
9 
(±1) 
10 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±2) 
36 
(±2) 
50 
(±2) 
64 
(±2) 
78 
(±2) 
92 
(±2) 
Study Week 
 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Positive and Negative Syndrome Scale 
(PANSS) 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Clinical Global Impressions-Severity 
(CGI-S) 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Eligibility Criteria Review 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense Emergency Treatment Card 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pharmacogenetic blood sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood samples for PK 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Personal and Social Performance Scale 
(PSP) 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
Food Craving Inventory (FCI) 
 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
Impact of Weight on Quality of Life – 
Lite Questionnaire (IWQOL-Lite) 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Interactive Web Response System 
(IWRS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Olanzapine Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Double-Blind Samidorphan/ Placebo 
Dosing14 
 
 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
 
Adverse Event (AE) Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Amendment #3-CZ 
CONFIDENTIAL  
Alkermes, Inc 
13 June 2014 
ALK3831-302 
Page 29 
 
Screening 
Olanza-
pine 
Double-Blind Placebo-Controlled Treatment Period 
Transition1 
 
Outpatient Visits 
Inpatient Stay 
Outpatient Visits 
Inpatient 
Stay2 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Study Day 
-30 to -1 
1 
8 
(±1) 
9 
(±1) 
10 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±2) 
36 
(±2) 
50 
(±2) 
64 
(±2) 
78 
(±2) 
92 
(±2) 
Study Week 
 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Validation Inventory for 
Study Admission (C-VISA™) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1 Transition Visit = the end of Part A and the beginning of Part B. Assessments at this visit are included in both schedules for convenience. 
2 All measures should be taken pre-dose at Visit 13 except where indicated 
3 Height will be measured at screening only; weight and waist circumference will measured at all indicated visits 
4 Serum pregnancy test at screening; urine pregnancy test at other time points 
5 Centralized drug screen testing at screening, local drug screen testing via dipstick at other time points. The urine drug screen includes benzodiazepines, opioids, 
amphetamine/methamphetamine, and cocaine. 
6 Alcohol use only 
7 Orthostatic blood pressure and heart rate measurements will be taken anytime pre-dose and approximately 1 hour post-dose at Visits 3 - 6 and Visit 13 only. At 
all other dosing visits, routine vital sign assessments will be conducted anytime pre-dose. At all other visits (when no dosing occurs) assessments will be 
conducted anytime. 
8 Collect pre-dose and post-dose data 
9 An overnight fast is required for labs at Visit 2, Visit 3, and Visit 13. Thyroid stimulating hormone should be assessed at screening only. 
10 ECG will be measured anytime pre-dose and approximately 3 hours post-dose except for Visit 1 and Visit 2 where only 1 ECG will be done. For Visit 2, the 
ECG should be completed before dosing. For Visit 6, dosing may be done earlier than normal to accommodate post-dose procedure. 
11 Collect data pre-dose 
12 Full physical examination at screening; brief physical examination at all other scheduled time points 
13 At screening, the "Baseline" version will be administered, and at all other visits the "Since Last Visit" version will be administered. 
14 During inpatient visits, study drug will be administered by the study staff. Otherwise, study drug will be dispensed for self-administration by the subject  


Protocol Amendment #3-CZ 
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13 June 2014 
ALK3831-302 
Page 30 
Table 2: Schedule of Assessments (Part B) 
 
Transition1 
Active ALKS 3831 Treatment Period 
Follow-Up 
 
Inpatient Stay 
Outpatient Visits 
Study Visit 
132 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23/ET 
24 
25 
Study Day: 
92 
(±2) 
93 
(±2) 
94 
(±2) 
99 
(±1) 
106 
(±2) 
113 
(±2) 
120 
(±2) 
134 
(±2) 
148 
(±2) 
162 
(±2) 
176 
(±2) 
190 
(±2) 
204 
(±2) 
Study Week 
13 
14 
15 
16 
17 
19 
21 
23 
25 
27 
29 
Weight and Waist Circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screens4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timeline Follow-Back (TLFB)5 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Vital Signs6 
X7 
X7 
X7 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood and urine samples for clinical 
labs8 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Hemoglobin A1c, C-reactive protein, 
leptin 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Carbohydrate Deficient Transferrin 
(CDT) 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Blood samples for PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examination 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Electrocardiogram (ECG)9 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Positive and Negative Syndrome 
Scale (PANSS) 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Personal and Social Performance 
Scale (PSP) 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 


Protocol Amendment #3-CZ 
CONFIDENTIAL  
Alkermes, Inc 
13 June 2014 
ALK3831-302 
Page 31 
 
Transition1 
Active ALKS 3831 Treatment Period 
Follow-Up 
 
Inpatient Stay 
Outpatient Visits 
Study Visit 
132 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23/ET 
24 
25 
Study Day: 
92 
(±2) 
93 
(±2) 
94 
(±2) 
99 
(±1) 
106 
(±2) 
113 
(±2) 
120 
(±2) 
134 
(±2) 
148 
(±2) 
162 
(±2) 
176 
(±2) 
190 
(±2) 
204 
(±2) 
Study Week 
13 
14 
15 
16 
17 
19 
21 
23 
25 
27 
29 
Columbia Suicide Severity Rating 
Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impressions-Severity 
(CGI S) 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Food Craving Inventory (FCI) 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
X 
Impact of Weight on Quality of Life 
– Lite Questionnaire (IWQOL-Lite) 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Interactive Web Response System 
(IWRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Olanzapine Dosing10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Samidorphan Dosing11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect Emergency Treatment Card 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Adverse Event (AE) Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Transition Visit (end of Part A and beginning of Part B). Assessments at this visit are included in both schedules for convenience. 
2 All data should be collected pre-dose at Visit 13 except where indicated 
3 Urine pregnancy test 
4 Local drug screen testing via dipstick. The urine drug screen includes benzodiazepines, opioids, amphetamine/methamphetamine, and cocaine. Additional drug 
tests may be conducted at the discretion of the investigator. 
5 Alcohol use only 
6 Orthostatic blood pressure and heart rate measurements will be taken pre-dose and approximately 1 hour post-dose at Visits 13 – 16. At all other dosing visits, 
routine vital sign assessments will be conducted anytime pre-dose. At all other visits (when no dosing occurs) assessments will be conducted anytime. 
7 Collect pre-dose and post-dose data. 


Protocol Amendment #3-CZ 
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Alkermes, Inc 
13 June 2014 
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Page 32 
8 An overnight fast is required for labs on Visit 13 and Visit 23/ET 
9 ECG will be measured anytime pre-dose and approximately 3 hours post-dose except for Visit 23/ET and Visit 24 where no dosing occurs. For Visit 16, dosing 
may be done earlier than normal to accommodate post-dose procedure. 
10 The subject will take olanzapine uninterrupted through Visit 25 
11 The subject will take the final samidorphan dose the night before Visit 23 


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Alkermes, Inc 
13 June 2014 
ALK3831-302 
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8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject (and caregiver 
as required) by the PI or designee as described in the site-specific ICF approved by the 
overseeing Institutional Review Board (IRB)/Independent Ethics Committee (IEC) (see 
Section 17.3). 
8.3.2. 
Demographics, Medical and Psychiatric History 
Demographic data and medical/psychiatric history will be reviewed and documented according 
to the schedule shown in Table 1. 
8.3.3. 
Drug Testing 
A urine drug test for prohibited substances, including benzodiazepines, opioids, amphetamine/ 
methamphetamine, and cocaine, will be performed at the time points specified in Table 1 and 
Table 2. 
8.3.4. 
Timeline Follow-Back 
Alcohol use will be recorded using the Timeline Follow-Back (TLFB) method [Sobell and 
Sobell 1992] at the time points specified in Table 1 and Table 2. At each visit where TLFB is to 
be performed, alcohol use data will be collected for the prior 30-day period. 
8.3.5. 
Concomitant Medication Review 
Concomitant medications will be reviewed at every visit. The medications include prescription 
and nonprescription medications, vitamins, and supplements. 
Study staff 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. 
8.3.6. 
Vital Signs 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
assessed at every visit. Blood pressure and heart rate will be measured after the subject has been 
resting in a seated or supine position for at least 5 minutes. 
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. 


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13 June 2014 
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Orthostatic blood pressure and heart rate will be measured according to the schedule shown in 
Table 1 and Table 2. 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 
For Part A, orthostatic blood pressure and heart rate measurements will be taken anytime pre-
dose and approximately 1 hour post-dose at Visits 3 - 6 and Visit 13 only. At all other dosing 
visits, routine vital sign assessments will be conducted anytime pre-dose. At all other visits 
(when no dosing occurs) assessments will be conducted anytime. 
For Part B, orthostatic blood pressure and heart rate measurements will be taken pre-dose and 
approximately 1 hour post-dose at Visits 13 - 16. At all other dosing visits, routine vital sign 
assessments will be conducted anytime pre-dose. At all other visits (when no dosing occurs) 
assessments will be conducted anytime. 
8.3.7. 
Physical Examination, Height 
A physical examination will be performed according to the schedule shown in Table 1 and 
Table 2. 
Height will be measured at Visit 1 only. 
8.3.8. 
Body Weight and Waist Circumference 
Body weight will be measured 3 times at every visit. The median weight will be calculated by an 
Interactive Web Response System (IWRS) system at Visit 2 and Visit 3 to calculate the change 
in weight during the first week of olanzapine exposure. At Visit 2, as part of the eligibility 
assessment, the PI or designee must ensure that the subject’s body weight has not changed by 
greater than 1 kg. Body weight will also be measured prior to discharge from the inpatient stay. 
Subjects should be asked to void immediately prior to the body weight measurement. Subjects 
should be weighed on the same scale for each measurement under the same conditions. Subjects 
should remove all personal items, such as watches and jewelry, prior to body weight 
measurement. Subjects should be weighed in hospital gowns with a consistent amount of 
undergarments for each measurement. Subjects will be weighed 3 times. The median weight will 
be calculated by an IWRS system as described above at Visit 2 and Visit 3 and entered into an 
electronic data capture (EDC) system at all other visits. 
Waist circumference will be measured according to the schedule shown in Table 1 and Table 2. 
8.3.9. 
12-Lead Electrocardiogram 
A 12-lead ECG will be conducted according to the schedule shown in Table 1 and Table 2. For 
Part A, ECG will be measured anytime pre-dose and approximately 3 hours post-dose except for 
Visit 1 and Visit 2 where only 1 ECG will be done. For Visit 2, the ECG should be completed 


Protocol Amendment #3-CZ 
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13 June 2014 
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before dosing. For Visit 6, dosing may be done earlier than normal to accommodate post-dose 
procedures. 
For Part B, ECG will be measured anytime pre-dose and approximately 3 hours post-dose except 
for Visit 23/ET and Visit 24 where no dosing occurs. For Visit 16, dosing may be done earlier 
than normal to accommodate post-dose procedure. 
8.3.10. 
Adverse Event Monitoring 
AEs will be monitored continuously from the time a subject signs the informed consent 
document until the completion of the final study visit. AEs and serious adverse events (SAEs) 
are defined in Sections 13.2 and 13.3, respectively. Section 13.5 provides guidance on the 
monitoring and reporting requirements for AEs. Section 13.6 provides guidance on the reporting 
requirements for SAEs. 
8.3.11. 
Laboratory Assessments 
Blood and urine samples for laboratory assessments will be collected according to the schedule 
shown in Table 1 and Table 2. Overnight fasting (no eating or drinking for 8 hours before the 
visit) will be required for labs at Visit 2, Visit 3, Visit 13, and Visit 23/ET. Otherwise, samples 
will be collected in accordance with the site’s usual procedures and analyzed by a central 
laboratory. Follow-up samples may be obtained for repeat testing as clinically indicated. 
Specific hematology, biochemistry, and urinalysis assessments are listed in Table 3. Overnight 
fasting is required for some visits because fasting glucose and insulin levels (value and absolute 
change from baseline) will be measured. Otherwise, random glucose and insulin levels will be 
taken. 


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13 June 2014 
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Table 3: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cell count 
• 
Total and differential 
(absolute) white blood cell 
count 
• 
Platelets 
• 
Sodium 
• 
Potassium 
• 
Bicarbonate 
• 
Glucose1 
• 
Creatinine 
• 
Total protein 
• 
Blood urea nitrogen (BUN) 
• 
Albumin 
• 
Albumin/globulin ratio 
• 
Total bilirubin 
• 
Alanine transferase (ALT) 
• 
Aspartate transferase (AST) 
• 
Lactic dehydrogenase (LDH) 
• 
Gamma-glutamyl transferase 
(GGT) 
• 
Alkaline phosphatase 
(ALK-P) 
• 
Creatine phosphokinase 
(CPK) 
• 
Insulin1 
• 
Triglyceride 
• 
Total, HDL and LDL 
cholesterol 
• 
Prolactin 
• 
Thyroid stimulating hormone 
(TSH)2 
• 
Color 
• 
pH 
• 
Specific gravity 
• 
Ketones 
• 
Protein 
• 
Glucose1 
• 
Bilirubin 
• 
Nitrite 
• 
Urobilinogen 
• 
Occult blood 
• 
Cotinine 
• 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
1 Requires fasting where indicated on Table 1 and Table 2 (see also Section 8.3.11) 
2 Assessed at screening only 
8.3.11.1. Specialty Laboratory Assessments 
In addition to the clinical laboratory assessments listed in Table 3, HbA1c, C-reactive protein, 
leptin, and carbohydrate deficient transferrin (CDT) will be assessed at select visits, as indicated 
in Table 1 and Table 2. 
A blood sample for pharmacogenetic analyses exploring the relationship between olanzapine-
induced weight gain and genotype will be collected according to the schedule in Table 1. This 
sample will be stored by a third party for up to 10 years after study completion (instructions will 
be given for shipping to storage facility). Note: This sample should only be taken if subjects have 


Protocol Amendment #3-CZ 
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agreed to it by signing a separate DNA consent form (see Section 17.3). Subjects may be 
enrolled in the study without consenting to this procedure, in which case it should not be done. 
8.3.11.2. Pregnancy Screening 
A pregnancy test will be performed on all women according to the schedule in Table 1 and 
Table 2. At screening, a serum pregnancy test will be performed. A urine pregnancy test will be 
performed at all other scheduled time points. A positive result at any time will necessitate the 
subject’s withdrawal from the study. 
8.3.12. 
Pharmacokinetic Assessments 
Samidorphan, RDC-9986 (primary metabolite of samidorphan), and olanzapine concentrations 
will be determined from plasma samples collected according to the schedule in Table 1 and 
Table 2. The time of last study drug administration and the associated PK blood draw must both 
be recorded in each subject’s appropriate source documents. PK samples will be stored at -20°C 
± 10°C. 
Pharmacokinetic data may be used to assess compliance with study drug administration and/or 
included in a subsequent population PK analysis conducted outside of this study. 
8.3.13. 
Clinical Global Impressions-Severity 
The PI or designee will complete the CGI-S (Appendix A) scale at the time points shown in 
Table 1 and Table 2. 
8.3.14. 
Columbia Suicide Severity Rating Scale 
The PI or designee will complete the C-SSRS (Appendix B) according to the schedule in Table 1 
and Table 2. At Screening, the “Baseline” version will be administered, and at all other visits, the 
“Since Last Visit” version will be administered. 
8.3.15. 
Positive and Negative Syndrome Scale 
The PI or designee will complete the PANSS (Appendix C) according to the schedule in Table 1 
and Table 2. 
8.3.16. 
Personal and Social Performance Scale 
The PI or designee will complete the 5-point PSP scale (Appendix D) according to the schedule 
in Table 1 and Table 2. 
8.3.17. 
Food Craving Inventory 
The subject will complete the Food Craving Inventory (Appendix E) according to the schedule in 
Table 1 and Table 2. 
8.3.18. 
Impact of Weight on Quality of Life - Lite 
The subject will complete the Impact of Weight on Quality of Life - Lite (Appendix F) 
questionnaire according to the schedule in Table 1 and Table 2. 


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8.3.19. 
Audio Recording 
The screening interview and administration of assessments may be recorded using an audio 
digital pen. A third party may review these recordings for quality assurance and confirmation of 
subject eligibility. 
8.3.20. 
Olanzapine Administration 
Subjects will receive olanzapine for once daily administration according to the schedule in 
Table 1 and Table 2. The dose will be at the discretion of the PI. 
Initiation on olanzapine, including transition from another antipsychotic (as applicable), is a 
highly individualized process. Formalizing the potential clinical scenarios may pose undue 
burden and/or risk to subjects. Clinical judgment is essential, and for this reason, the details of 
this process are left to the discretion of the treating physician, who will follow current clinical 
practice. 
8.3.21. 
Randomization 
After confirming eligibility on Visit 3, and after a 1-week olanzapine lead-in period, subjects will 
be randomized as outlined in Section 9.3. 
8.3.22. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. The study drug use and 
storage information will be explained to/reviewed with the subject. 
Study drugs include samidorphan and matching placebo tablets, and olanzapine tablets, all for 
oral administration. Samidorphan is a Schedule II substance, and should be stored, dispensed, 
and otherwise handled in accordance with the associated regulations. 
Olanzapine will be prescribed by the PI and dispensed for oral administration by study staff. 
During the inpatient stays, study drug will be dispensed once daily, and the time of 
administration will be at the discretion of study staff. Time of administration at any visit 
(inpatient or outpatient) may be adjusted as needed to accommodate post-dose measurements. 
Before being discharged from each inpatient stay, and at each post-randomization outpatient visit 
until Visit 23/ET, all subjects will receive blister cards containing samidorphan or placebo for 
self administration. Subjects will be instructed to take 2 tablets per day from the blister card in 
addition to their olanzapine tablet(s) once daily in the evening or at bedtime until Visit 23. The 
subject will take the final samidorphan dose the night before Visit 23. No samidorphan dose will 
be administered onsite during Visit 23. Olanzapine dosing will continue uninterrupted. Two 
safety follow-up visits will occur 2 and 4 weeks after Visit 23. Any subject who prematurely 
discontinues from the study during Part B will be asked to return to the clinic for an ET visit and 
follow-up visits 2 and 4 weeks after the ET visit. 
Subjects will be instructed to keep all unused tablets in their blister card and not to mix tablets 
between blister cards and bottles. 
Subjects will be instructed to return the original containers and any remaining study drug at each 
subsequent visit. Study drug accountability will be documented as the number of tablets 


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dispensed, dosed, lost/missing, or remaining. If applicable, the site will discuss noncompliance 
with the subject. 
8.3.23. 
Emergency Treatment Card 
An emergency treatment card will be distributed to each subject prior to discharge at Visit 5. The 
card will indicate that the subject may be receiving an opioid antagonist and/or olanzapine and 
will include the PI’s contact information, a suggested pain management plan, and information 
regarding opiate blockade. Subjects will be instructed to keep the emergency treatment card with 
them at all times. Study personnel will confirm that the subjects have the card in their possession 
at each study visit. The treatment cards will be collected at Visit 23/ET. 
8.3.24. 
Clinical Validation Inventory for Study Admission 
The PI or designee will complete the Diagnostic Validation Workbook as part of the Clinical 
Validation Inventory for Study Admission (C-VISA™) at Visit 1. This workbook is a structured 
method for assessing and documenting study eligibility based on the criteria given in Section 7. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Prohibited Medications 
Use or expected use of any of the following medications (including generic equivalents or 
alternative brand names) within 60 days prior to screening or during the study period is 
prohibited. 
• All prescription or over-the-counter (OTC) agents taken for the purpose of weight 
reduction, including (but not limited to) the following anti-obesity agents: 
− Prescription drugs such as orlistat (Xenical), sibutramine (Meridia), Belviq 
(lorcaserin); and phentermine (Adipex-P, Ionamin, Pro-Fast SA, Pro-Fast SR, 
Fastin, Oby-Trim, Zantryl, Teramine, Phentride, Phentercot, Obephen, Oby-cap), 
Qsymia (phentermine and topiramate) 
− Over-the-counter anti-obesity agents (eg, herbal supplements or other alternative 
remedies such as Cortislim, Dexatrim, Acutrim, Orlistat) 
• Systemic steroids administered by oral, intravenous, or intramuscular route 
• Antipsychotic agents including clozapine, mesoridazine, chlorpromazine, or 
thioridazine 
• Zyprexa oral disintegrating tablets, Zyprexa Relprevv™ intramuscular injection (long-
acting), or Zyprexa IntraMuscular injection (short-acting) 
• Topiramate (Topamax®); Calcitonin (eg, Miacalcin®), Exenatide (Byetta®); 
Sulfonylureas (eg, Diamicron®, Amaryl®, Glucotrol®, Micronase®); Meglitinides (eg, 
Starlix®, Prandin®); Metformin or any hypoglycemic agent 
Use of opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) within 14 days before 
screening is prohibited. Use of opioid antagonists, including naltrexone (any formulations) and 


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naloxone within 60 days before screening through the follow-up visit is prohibited. Note: during 
the study period, opioid agonists should be avoided (refer to Section 8.4.4). 
Use of hypnotic agents for insomnia (eg, benzodiazepines, zolpidem, trazodone) is permissible. 
Short half-life benzodiazepines are preferable for the treatment of insomnia over long half-life 
benzodiazepines due to the potential for lingering effects on daytime functioning and study 
assessments. 
Treatment of agitation and/or anxiety with benzodiazepines is permissible, but the dose should 
be kept as stable as possible throughout the study so as not to interfere with daytime functioning 
and study assessments. Special care should be taken with dosing of benzodiazepines on study 
visit days so as not to influence efficacy ratings (eg, PANSS); doses of benzodiazepines should 
be withheld if scheduled to be taken within several hours of a PANSS rating. 
Use of moderate to strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 (prescription 
medications, OTC medications, or dietary supplements) within 30 days before randomization 
through follow-up is prohibited. A partial list of CYP3A4 modulators is provided in Appendix G. 
Medications that are contraindicated with olanzapine use or exhibit drug-interaction potential 
with olanzapine will be defined and prohibited at the discretion of the PI. 
See Section 8.3.5 for details regarding the concomitant medication review. 
8.4.2. 
Contraception 
All subjects must agree to use an acceptable method of contraception for the duration of the 
study. Subjects who are abstinent must agree to use an acceptable contraceptive method should 
they become sexually active. The following are considered acceptable methods: 
• Condom (barrier method) plus 
− Intrauterine device (IUD) 
or 
− Hormonal contraceptive (such as birth control pills or patches, a vaginal ring, or a 
contraceptive implant) 
Sexually active male subjects must agree use a condom in addition to his partner's normal use of 
contraception. 
Exemptions: Subjects who are surgically sterile are exempt from the requirement to use 
contraception. Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
are considered surgically sterile. In addition, women who are postmenopausal are also exempt 
from the requirement to use contraception. 
8.4.3. 
Other Restrictions 
Subjects will be instructed to maintain their normal caffeine intake as well as normal 
activity/exercise throughout the study. Subjects are prohibited from participating in a weight 
management program for the duration of the study. 


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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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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
Study drugs include samidorphan and matching placebo tablets, and olanzapine tablets, all for 
oral administration. Samidorphan is a Schedule II substance, and should be stored, dispensed, 
and otherwise handled in accordance with the associated regulations. 
Olanzapine will be prescribed by the PI and will be dispensed for oral administration by study 
staff. 
During the inpatient stays, study drug will be dispensed once daily, and the time of 
administration will be at the discretion of the clinic staff. Time of administration at any visit 
(inpatient or outpatient) may be adjusted as needed to accommodate post-dose measurements. 
Before being discharged from each inpatient stay, and at each outpatient post-randomization 
study visit until Visit 23/ET, all subjects will receive blister cards containing samidorphan or 
placebo for self administration. Subjects will be instructed to take 2 tablets per day from the 
blister card and their olanzapine tablet(s) once daily in the evening or at bedtime until Visit 23. 
The subject will take the final samidorphan dose the night before Visit 23. No samidorphan dose 
will be administered onsite during Visit 23/ET. Olanzapine dosing will continue uninterrupted. 
Two safety follow-up visits will occur 2 and 4 weeks after Visit 23. Any subject who 
prematurely discontinues from the study during Part B will be asked to return to the clinic for an 
ET visit and follow-up visits 2 and 4 weeks after the ET visit. 
Subjects should take all study drug tablets (olanzapine and samidorphan/placebo) orally and at 
the same time. Subjects should be advised that somnolence may occur with dosing and thus they 
should avoid driving or operating heavy machinery until they have determined how the study 
drug affects them. 
Subjects will be instructed to keep all unused tablets in their blister card and not to mix tablets 
between blister cards and bottles. Subjects will also be instructed to return unused tablets to the 
site when they return for their next visit. If dosing occurs at this visit, the dose should be taken 
from subjects’ next blister card. The dose should not be taken from the blister card the subjects 
are returning. 
If a dose is missed or forgotten, subjects will be instructed to resume the regular dosing schedule 
the following evening. Subjects will be instructed not to take a double dose to try to “make up” 
for a missed dose. 
9.2. 
Treatment Compliance 
As described in Section 8.3.22, study personnel will assess treatment compliance at every visit 
from first dose of study drug at Visit 2 through Visit 23/ET accounting for the dispensed tablets 
(samidorphan, olanzapine, and placebo accounting for dosed, lost/missing, or remaining tablets). 
Additional measures of compliance may be used; these will be described in the Operational Plan 
as necessary. Study drug accountability will be performed using an EDC system. Subjects who 
have demonstrated compliance during the first week of olanzapine study will be randomized to 
double-blind treatment (samidorphan or placebo). 


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Noncompliance will be discussed with the subject as needed. 
9.3. 
Randomization and Blinding 
Part A of this study will be conducted in a double-blind fashion. On Day 8 (Visit 3), subjects will 
be randomized to receive one of the following regimens in a 1:1:1:1 ratio: 
• Olanzapine + Samidorphan (5 mg) 
• Olanzapine + Samidorphan (10 mg) 
• Olanzapine + Samidorphan (20 mg)  
• Olanzapine + Placebo 
Randomization will be performed centrally through an IWRS system and will be stratified by the 
amount of weight change during the olanzapine lead-in period (ie, from Day 1 to Day 8), with 
subjects grouped into the following 3 strata: 
• Weight change ≤0 kg 
• Weight increase >0 to <1 kg 
• Weight increase ≥1 kg 
Alkermes staff, clinical staff, and subjects will remain blinded to treatment assignment until Part 
A of the study is complete. All 
 staff will remain blinded except when their 
study function requires unblinding (eg, drug supply management, IWRS operation, DSMB 
operation, etc). These unblinded staff will follow procedures designed to ensure that study 
integrity is maintained. 
9.4. 
Breaking Study Blind 
The PI is responsible for all trial-related medical decisions. Emergency unblinding may be done 
without contacting a medical monitor. Any premature unblinding should be promptly 
documented and explained to the medical monitor within 24 hours following disclosure of study 
drug assignment. Breaking the blind for a single subject will not affect the blind for the 
remaining subjects. 
Once Part A of the study is complete (ie, the final subject has completed the final Part A 
assessment), the Part A data will be locked, unblinded, and the Part A data analyses will be 
conducted. This may occur prior to the completion of Part B of the study; however individual 
treatment assignments will remain blinded to the sites. 
PPD


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Commercially available olanzapine will be supplied or arranged for dispensing by the 
investigative site. 
Samidorphan will be provided by the sponsor. Each tablet contains 2.5, 5, or 10 mg. Subjects 
will take 2 tablets per day (ie, doses of samidorphan will be 5, 10, or 20 mg) by mouth. 
Samidorphan is a Schedule II substance and will require proper handling, storage, and 
accountability in accordance with local, regulations, and operating procedures. 
Placebo consists of tablets, identical in size and appearance to the samidorphan tablets. Subjects 
will take 2 tablets per day by mouth. 
10.2. 
Packaging and Labeling 
Samidorphan and placebo will be packaged in blister packs. Blister packs will be provided in 
weekly or biweekly configurations. The weekly blister pack will contain 18 tablets, which 
provides one week of dosing with sufficient overage to allow for 2 additional once daily doses. 
The biweekly packs will contain 32 tablets, providing 2 weeks of dosing with sufficient overage 
to allow for 2 additional once daily doses. 
Blister pack labels will meet all applicable local and regulatory requirements. 
10.3. 
Storage 
Under the US Controlled Substances Act, samidorphan is considered a Schedule II substance 
because it is derived from opium alkaloids. Therefore, samidorphan and/or blinded study drug 
must be stored in accordance with restrictions related to Schedule II substances. The site will 
take adequate precautions, including storage of the investigational drug in a securely locked, 
substantially constructed cabinet, or other securely locked, substantially constructed enclosure, 
access to which is limited, to prevent theft or diversion of the substance. 
10.4. 
Accountability 
The clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Refer to Section 9 for additional study drug reconciliation procedures. 
10.5. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed in accordance with regulations for controlled substances. Study drug destruction 
will occur only at the end of the trial and upon notification/approval by the sponsor. Packages 
may be destroyed on site according to Good Clinical Practice (GCP), site procedures and in 
accordance with all regulations for controlled substances. Alternatively, the sponsor may arrange 


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for destruction with a third party vendor operating in accordance with GCP. Redispensation or 
disposal of drug product during the course of the trial is prohibited. 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Primary Endpoint 
The primary endpoint is the absolute change in PANSS total score from randomization to the end 
of Part A. 
11.2. 
Secondary Endpoints 
• Percent change in body weight 
• Absolute change in body weight 
• Proportion of subjects exhibiting significant weight gain (definition of weight gain 
will include body weight gain greater than 7%) 
• Absolute change in CGI-S 
11.3. 
Additional Endpoints 
• Change in waist circumference 
• Change in IWQOL-Lite scales (physical function, self-esteem, sexual life, public 
distress and work) and total score 
• Change in PSP 
• Change in FCI 
• Change in alcohol and drug use 


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12. 
PHARMACOKINETIC/ PHARMACODYNAMIC ASSESSMENTS 
For all subjects, samidorphan, RDC-9986 (primary metabolite of samidorphan) and olanzapine 
concentrations will be determined from plasma samples collected according to the schedule in 
Table 1 and Table 2. PK data may be used to assess compliance with study drug administration 
and/or included in a subsequent population PK analysis conducted outside of this study. 


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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed from randomization to the end of Part A. Part B data will be used to 
examine longer-term safety. The number and percentage of subjects with AEs from 
randomization to the end of Part A is included as a secondary endpoint. In addition to this 
secondary endpoint, safety will be evaluated based on AEs, vital signs, clinical laboratory 
assessments (hematology, blood clinical biochemistry, and urinalysis), 12-lead ECG findings, 
and data from C-SSRS surveys. 
13.1. 
Safety Endpoints 
• Number and percentage of subjects with adverse events from randomization to the 
end of Part A 
• Change in blood lipid concentrations including LDL, HDL, total cholesterol and 
triglycerides 
• Change in assessments related to glucose regulation including fasting glucose and 
insulin, fasting glucose to fasting insulin ratio, HbA1c, c-reactive protein, leptin and 
bicarbonate 
• Change in vital signs including blood pressure 
13.2. 
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 main 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 PI (or designated investigator). Clinically significant values will be considered 
AEs and recorded as such on the eCRFs. 
13.3. 
Definition of Serious Adverse Event 
A serious adverse event (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 reaction that, had it occurred in a more severe form, 
might have caused death. 


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• Requires inpatient hospitalization or prolongation of existing hospitalization. Hospital 
admission for elective surgery scheduled prior to study entry is not considered an 
SAE. 
• Results in disability/incapacity (eg, a substantial disruption of a person’s ability to 
conduct normal life functions) 
• Is a congenital anomaly/ birth defect 
Important medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered 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. 
At Visits 3 and 13, subjects are admitted for a 2-night inpatient stay at the study site, per the 
protocol. If prolongation of this protocol-required stay is necessary for the management of the 
subject’s schizophrenia without a worsening of the subject’s baseline clinical status or the 
development of new signs or symptoms, and is confirmed as such by the medical monitor, the 
event should be categorized as an AE, not an SAE. 
Admission to an inpatient unit or hospital for a non-medical reason (ie, social-stay admission) 
during the trial is considered an AE, not an SAE. 
13.4. 
Relationship to Study Drug 
The assessment of study drug relationship to each AE will be reported on the appropriate source 
document (and SAE form, in the event of an SAE) by the PI (or designated investigator) 
according to his/her best clinical judgment. The criteria listed in Table 4 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. However, relationship and action taken will be separated out in the EDC to 
assess for olanzapine and samidorphan/placebo separately. The PI (or designated investigator) 
can attribute relationship to olanzapine, samidorphan/placebo or both. 


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Table 4: 
Causality Guidelines 
Relationship1 
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. 
1 Relationship will be assessed twice: once for olanzapine and once for samidorphan/placebo 
13.4.1. 
Adverse Events of Special Interest 
PIs or their designees will be required to record additional details for AEs of special interest 
related to abuse liability. These AEs fall into general categories including (but not limited to) 


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substance-related disorders, euphoria, sedation, stimulation, hallucinations, motor impairment, 
and cognitive impairment. More details on these AEs will be provided outside of this protocol. 
13.5. 
Monitoring and Recording of Adverse Events 
AE data collection will begin after a subject signs the main ICF and will continue until 
completion of the safety follow-up visit. Any AE or SAE having an onset after the safety 
follow-up visit will not be collected or reported unless the PI (or designated investigator) feels 
that the event may be related to the study drug. 
Subjects will be instructed by the PI (or designee) to report the occurrence of any AE. All 
volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The PI (or designated investigator) will assess all AEs regarding any causal relationship to the 
study drug (see Section 13.4), 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 PI, or until the subject is 
deemed by the PI to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the IB 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 PI (or designated investigator). If a subject withdraws from the study 
for any reason
13.6. 
Reporting of Serious Adverse Events 
, any ongoing AEs will be followed until resolution, until deemed stable by the PI, 
or until the subject is deemed by the PI to be lost to follow-up. 
All SAEs must be reported to 
 within 24 hours of discovery, by faxing the 
report to the following: 
Attention: 
 Medical Monitor 
US Fax Number: 
 
EU Fax Number: 
 
The written report should be submitted on the SAE form provided for this purpose. The report 
must include the PI’s (or designated 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. This assessment will be done 
twice: once for olanzapine and once for samidorphan/placebo. The report submitted will include 
both assessments. 
PPD
PPD
PPD
PPD


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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
Sample size calculations are based on the primary endpoint of absolute change in PANSS total 
score. These calculations assume an equivalence margin of 10 points, a standard deviation of 
20 points, and a true difference of 0 points. With these assumptions, 280 randomized subjects 
provide 95% power to demonstrate equivalence on the primary endpoint (absolute PANSS total 
score change from randomization to the end of Part A) with a 2-sided test at an alpha level of 
0.05. These 280 subjects represent 70 subjects for each treatment arm (ALKS 3831 5 mg, 
ALKS 3831 10 mg, ALKS 3831 20 mg, and placebo) in a 1:1:1:1 ratio. For the primary analysis, 
subjects in the 3 ALKS 3831 treatment groups will be pooled for comparison with placebo. If 
this analysis shows equivalence, follow-up analyses on individual dose levels will be performed. 
Assuming a 20% discontinuation rate prior to randomization, an estimated 350 subjects will be 
enrolled in this study. 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
statistical analysis plan to be finalized before database lock and unblinding. In general, summary 
statistics, including n, mean with (SD), median, minimum, and maximum for continuous 
variables and number (%) of subjects in each category for categorical variables will be provided 
by treatment group for all variables. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
All statistical tests and CIs, unless stated otherwise, will be 2-sided and will be set at α = 0.05. 
14.2.1. 
Efficacy Population 
The efficacy analysis will be conducted on 2 analysis populations: 
• The FAS 1 population will include all subjects who are randomized, receive at least 
one dose of study drug, and have at least one post-baseline PANSS assessment. 
• The FAS 2 population will include all FAS 1 subjects who gained weight during the 
initial week of olanzapine treatment prior to randomization and have at least one 
post-baseline weight assessment. 
14.2.2. 
Safety Population 
The safety population, defined as all randomized subjects who receive at least 1 dose of study 
drug (olanzapine, samidorphan, or placebo), will be used in the safety analyses. 
14.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, ethnicity, weight, BMI will 
be summarized with descriptive statistics to assess the comparability of the study groups. 


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If there are heterogeneities between treatment groups in any of the subject characteristics that are 
of clinical importance or could affect the treatment outcome, the impact of the imbalances will 
be investigated and, if necessary, appropriate adjustments will be considered in the efficacy and 
safety analyses. 
Medical history will be summarized for the safety population using the number of observations 
and percentage of subjects by body system. 
14.4. 
Efficacy Analyses 
The primary endpoint is the absolute change in PANSS total score from randomization to the end 
of Part A (ie, the end of the 12-week, placebo-controlled double-blind treatment period) and will 
be evaluated by treatment group (ALKS 3831 vs. the placebo group [olanzapine alone]) using a 
2-sided mixed-model for repeated measures (MMRM) to test for equivalence at an alpha level of 
0.05. The primary analysis will be conducted in the FAS 1 population. More details about this 
analysis will be provided in the SAP. 
The secondary endpoint, percent change in weight from randomization to the end of Part A, will 
be evaluated by treatment group using an MMRM approach similar to that of the primary 
endpoint. However, this will be a superiority analysis. Each treatment group will be compared to 
the placebo group with a 2-sided hypothesis test to test for superiority at an alpha level of 0.05. 
The secondary efficacy analysis will also be conducted in the FAS 1 population. More details 
about this analysis will be provided in the SAP. 
Analysis of other secondary endpoints and additional endpoints will include inferential analyses 
and descriptive analyses by visit (mean, SD, median, minimum, and maximum for continuous 
variables and number and percent for categorical variables), as appropriate. 
Analyses for the primary and secondary endpoints will be repeated in the FAS 2 population as 
sensitivity analyses when applicable. Additional details regarding these analyses will be provided 
in the SAP. 
14.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
For all subjects, plasma samples will be collected on Visits 2-23 to quantify the concentrations of 
olanzapine, samidorphan, and RDC-9986 (primary metabolite of samidorphan). Pharmacokinetic 
data may be used to assess compliance and/or included in subsequent population PK evaluation 
conducted outside of this study. 
14.6. 
Safety and Tolerability Analyses 
Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA©) preferred terms and system organ classes. Descriptive summary statistics will be 
provided for AEs, laboratory tests, and vital signs and will include mean, SD, median, minimum 
and maximum for continuous variables and number and percent for categorical variables. 
The incidence of AEs, including clinically significant abnormal laboratory tests or ECG values, 
will be summarized for each treatment group and overall, by severity and by relationship to study 
drug. The summary tables will include the number and percent of subjects with AEs overall, by 


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system organ class, and by preferred terms within each system organ class. AEs resulting in 
treatment discontinuation or modification will be identified. 
Laboratory tests will be summarized by visit for the absolute value itself and for change from 
baseline. Tables showing the shift from baseline will also be presented. 
ECG findings will be summarized by visit. Concomitant medications will be categorized and 
presented using the World Health Organization (WHO) drug Anatomical Therapeutic Chemical 
(ATC) classification system. 


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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. A paper copy of the 
laboratory reports will be generated and will remain with the source documents at the site. 
15.2. 
Audits and Inspections 
By signing the protocol, the PI agrees that, within local regulatory restrictions and institutional 
and ethical considerations, authorized representatives of Alkermes, a regulatory authority, and/or 
an IRB/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, workbooks, subjects’ medical records) to determine whether these activities 
were conducted, and data recorded, analyzed, and accurately reported according to the protocol, 
GCP guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements. 
The PI (or designee) should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
15.3. 
Institutional Review Board/ Independent Ethics Committee 
The PI 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 forms and 
recruitment materials (and as required, caregiver consent forms), must be maintained by the PI 
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 
compliance, Alkermes may 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 eCRFs will be completed by the clinic staff prior to review by the 
Alkermes monitor or designated representative. All eCRFs will be reviewed by the PI, as noted 
by his or her electronic signature, after review by the Alkermes monitor or designated 
representative. 
The Alkermes monitor or designated representative will review source records on-site and 
compare them to the data collected on the eCRF. 
16.2. 
Confidentiality of Data 
By signing this protocol, the PI 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 Trial 
Agreement (CTA) 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 ICFs 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 
PI. The protocol must be re-approved by the IRB/IEC upon receipt of amendments and annually, 
as local regulatory requirements require. 
The PI 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. 
In accordance with applicable local regulatory requirements, the PI may be obligated to provide 
periodic safety updates on the conduct of the study at his or her site and notification of study 
closure to the IRB/IEC. Such periodic safety updates and notifications are the responsibility of 
the PI and not of the sponsor. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the sponsor in a timely fashion. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. GCP is an international ethical and scientific quality 
standard used for designing, conducting, recording, and reporting studies involving the 
participation of human subjects. Alkermes is committed to complying with this standard to 
provide assurance that the rights, safety, and well-being of study subjects will be protected, 
consistent with the principles having their origin in the Declaration of Helsinki. 
17.3. 
Written Informed Consent 
The PI (or authorized designee) at each center will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, potential and possible risks and 
benefits of the study. Each prospective subject will receive an IRB-approved ICF that 
summarizes all pertinent study information (the main ICF) and a separate IRB-approved ICF that 
summarizes only the pharmacogenetic testing (the DNA ICF) and will be given ample time to 
read the forms 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 must sign the 
main ICF before any study-specific procedures are conducted. The subject does not need to sign 
the DNA ICF to participate in the main study, but the pharmacogenetic testing outlined in 
Section 8.3.11.1 should not be conducted unless the subject signs the DNA ICF. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB, the CRO (Contract Research Organization) if applicable, 


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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 
ICFs, which must be reviewed and signed by all applicable study participants. 
The time that informed consent is obtained must be documented. The PI must maintain original, 
signed ICFs in the subject’s source documents. Original, signed ICFs also 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 CTA for further details. Principal investigators are 
responsible for handling data in a manner consistent with local and international regulations on 
personal data (including health information) collection and protection (eg, in the Czech 
Republic: Act No. 101/2000 Coll. on personal data protection). 
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 PI or designee. Data entries will be verified for accuracy and 
correctness by independent monitors. The electronic data capture system maintains a full audit 
trail. 
When available, 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 PI (or designated investigator). Any out of range laboratory values 
that meet the definition of an adverse event (see Section 13) will be documented accordingly. 
AEs will be coded using MedDRA. Concomitant medications will be categorized using the 
WHO-ATC classification system. 
18.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The PI 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 essential clinical study documents (eg, worksheets, drug accountability 
forms, and other administrative documentation) shall be governed by the terms and conditions of 
the site’s CTA. If the CTA does not state specific document retention terms, then the site shall 
keep essential clinical study documentation for the longer of 
• Ten years after discontinuation of the study, or 
• Two years following the date a marketing application is approved for the study drug 
for the indication for which it is being investigated pursuant to the study, or 
• If no application is to be filed or if the application is not approved for such indication, 
until 2 years after the date the study is terminated. 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. A third-party blood-sample storage facility will retain blood samples for genotyping for 
up to ten years after discontinuation of the study. 


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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 PIs and the sponsor. Please refer to 
the CTA for details on the procedures for publishing and presenting data. 


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19. 
REFERENCES 
Batki SL, Meszaros ZS, Strutynski K, Dimmock JA, Leontieva L, Ploutz-Snyder R, Canfield K, 
Drayer RA (2009) Medical comorbidity in patients with schizophrenia and alcohol 
dependence. Schizophr Res 107:139-146 
Dixon L (1999) Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on 
outcomes. Schizophr Res 35 Suppl:S93-100 
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, 
Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of 
antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209-1223 
Lubman DI, King JA, Castle DJ (2010) Treating comorbid substance use disorders in 
schizophrenia. Int Rev Psychiatry 22:191-201 
Sobell LC, Sobell MB (1992) Timeline Follow-Back: A technique for assessing self-reported 
alcohol consumption. In: Litten RZ, Allen JP eds. Measuring Alcohol Consumption: 
Psychosocial and Biological Methods. The Humana Press, Totowa, NJ, pp. 41-72 
Zyprexa [Package Insert]. Indianapolis, IN: Eli Lilly,& Co.; 2011. 
 


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APPENDIX A. SAMPLE CLINICAL GLOBAL IMPRESSIONS-
SEVERITY (CGI-S) SCALE 


Rating Clinician-rated
Administration time Varies with familiarity with
patient
Main purpose To provide a global rating of illness
severity, improvement and response to treatment
Population Adults
Commentary
Amongst the most widely used of extant brief assessment
tools in psychiatry, the CGI is a 3-item observer-rated
scale that measures illness severity (CGIS), global
improvement or change (CGIC) and therapeutic response.
The illness severity and improvement sections of the
instrument are used more frequently than the therapeutic
response section in both clinical and research settings. The
Early Clinical Drug Evaluation Program (ECDEU) ver-
sion of the CGI (reproduced here) is the most widely used
format, and asks that the clinician rate the patient relative
to their past experience with other patients with the same
diagnosis, with or without collateral information. Several
alternative versions of the CGI have been developed, how-
ever, such as the FDA Clinicians’ Interview-Based
Impression of Change (CIBIC), which uses only informa-
tion collected during the interview, not collateral. The
CGI has proved to be a robust measure of efficacy in
many clinical drug trials, and is easy and quick to admin-
ister, provided that the clinician knows the patient well. 
Scoring
The CGI is rated on a 7-point scale, with the severity of
illness scale using a range of responses from 1 (normal)
through to 7 (amongst the most severely ill patients).
CGI-C scores range from 1 (very much improved)
through to 7 (very much worse). Treatment response
ratings should take account of both therapeutic efficacy
and treatment-related adverse events and range from 0
(marked improvement and no side-effects) and 4
(unchanged or worse and side-effects outweigh the thera-
peutic effects). Each component of the CGI is rated sepa-
rately; the instrument does not yield a global score.
Versions
CGI for bipolar disorder (CGI-BD), FDA Clinicians’
Interview-Based Impression of Change (CIBIC),
Clinicians’ Interview-Based Impression of Change-Plus
(CIBIC+), NYU CIBIC+, Parke-Davis Pharmaceuticals
Clinical Interview-Based Impression (CIBI); the CGI has
been translated into most languages.
Additional references 
Leon AC, Shear MK, Klerman GL, Portera L,
Rosenbaum JF, Goldenberg I. A comparison of
symptom determinants of patient and clinician global
ratings in patients with panic disorder and depression. J
Clin Psychopharmacol 1993; 13(5):327–31. 
Spearing MK, Post RM, Leverich GS, Brandt D, Nolen
W. Modification of the Clinical Global Impressions
(CGI) Scale for use in bipolar illness (BP): the CGI-BP.
Psychiatry Res 1997; 73(3):159–71. 
Zaider TI, Heimberg RG, Fresco DM, Schneier FR,
Liebowitz MR. Evaluation of the clinical global
impression scale among individuals with social anxiety
disorder. Psychol Med 2003; 33(4):611–22. 
Address for correspondence
Not applicable – the CGI is in the public domain.
125
Clinical Global Impression (CGI)
Reference: Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976.
Rockville, MD, U.S. Department of Health, Education, and Welfare
Page 63


126
1. Severity of illness
Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?
0 = Not assessed
4 = Moderately ill
1 = Normal, not at all ill
5 = Markedly ill
2 = Borderline mentally ill
6 = Severely ill
3 = Mildly ill
7 = Among the most extremely ill patients
2. Global improvement: Rate total improvement whether or not, in your judgement, it is due entirely to drug treatment.
Compared to his condition at admission to the project, how much has he changed?
0 = Not assessed
4 = No change
1 = Very much improved
5 = Minimally worse
2 = Much improved
6 = Much worse
3 = Minimally improved
7 = Very much worse
3. Efficacy index: Rate this item on the basis of drug effect only.
Select the terms which best describe the degrees of therapeutic effect and side effects and record the number in the box where the two
items intersect.
EXAMPLE: Therapeutic effect is rated as ‘Moderate’ and side effects are judged ‘Do not significantly interfere with patient’s functioning’.
Therapeutic effect
Side effects
None
Do not significantly 
Significantly interferes
Outweighs
interfere with
with patient’s 
therapeutic
patient’s functioning
functioning
effect
Marked
Vast improvement. Complete or nearly complete
01
02
03
04
remission of all symptoms
Moderate
Decided improvement. Partial remission of
05
06
07
08
symptoms
Minimal
Slight improvement which doesn’t alter status
09
10
11
12
of care of patient
Unchanged or worse
13
14
15
16
Not assessed = 00
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. Rockville, MD, U.S. Department of Health,
Education, and Welfare
Clinical Global Impression (CGI)
Page 64


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APPENDIX B. SAMPLE COLUMBIA SUICIDE SEVERITY RATING 
SCALE (C-SSRS) 


 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
Version 1/14/09 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidality depends on clinical judgment. 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
  
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes,” 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Lifetime:  
Time He/She 
Felt Most 
Suicidal 
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 
 □    □ 
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.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
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 
 □    □ 
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 
 □    □ 
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 
 □    □ 
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 ). Ask about time he/she was feeling the most suicidal.  
                                             
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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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
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 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
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 
□   □ 
 
 
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 
□   □ 
 
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 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal         
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g. surface scratches). 
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Page 68


 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidality depends on clinical judgment. 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 For reprints of the C-SSRS contact 
, New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
  
Page 69
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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 
 □    □ 
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 
 □    □ 
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 
 □    □ 
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 
 □    □ 
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 
 □    □ 
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 
Page 70


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 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
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 
□   □ 
 
 
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 
□   □ 
 
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 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Completed Suicide: 
   Yes    No 
□   □ 
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 
 
 
 
______ 
 
Page 71


Protocol Amendment #3-CZ 
CONFIDENTIAL 
Alkermes, Inc 
05 June 2014 
ALK3831-302 
Page 72 
APPENDIX C. SAMPLE POSITIVE AND NEGATIVE SYNDROME 
SCALE (PANSS) 


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Protocol Amendment #3-CZ 
CONFIDENTIAL 
Alkermes, Inc 
05 June 2014 
ALK3831-302 
Page 89 
APPENDIX D. SAMPLE PERSONAL AND SOCIAL PERFORMANCE 
(PSP) SCALE 


 
 
Personal and Social Performance (PSP) Scale and points scale. 
 
 
(1) Make note of the patient’s level of dysfunction during the past month for the 4 main areas below. the functioning 
criteria below must be used to determine the level of dysfunction. Note that there are some common criteria for areas 
a-c and other criteria specifically for area d. 
 
 
Absent 
Mild 
Manifest 
Marked 
Severe 
Very severe 
a) 
Self-care 
 
 
 
 
 
 
 
 
 
 
 
 
b) 
Personal and social relationships 
 
 
 
 
 
 
c) 
Socially useful activities, including work and study 
 
 
 
 
 
 
d) 
Disturbing and aggressive behaviour 
 
 
 
 
 
 
 
 
Level of severity: areas a-c 
(i) Absent 
(ii) Mild: only recognised by someone who is very close to the person 
(iii) Manifest: difficulties that are clearly visible to anybody, although they do not substantially interfere 
with the person’s ability to perform a role in this area, taking into account his/her socio-cultural context, 
age, sex and level of education. 
(iv) Marked: difficulties considerably hinder the person from performing his/her role in this area. the person is 
still capable of performing some tasks, although insufficiently and occasionally, without professional or social 
help. If the person is helped by someone, s/he may qualify for the previous level of functioning. 
(v) Severe: difficulties that make the person unable to perform any role in this area if not helped by a 
professional, or the person has a destructive role, however, there are no survival risks 
(vi) Very severe: deterioration and extreme difficulties which may put the person’s survival at risk 
 
Levels of severity: area d 
(i) Absent 
(ii) Mild: being rude, unsociable or slight complaints 
(iii) Manifest: speaking too loudly or speaking to others in a too familiar manner, or eating in a socially 
unacceptable way 
(iv) Marked: insulting other people in public, breaking or throwing objects, frequently behaving in a 
socially unacceptable way, but not dangerous way (e.g. undressing or urinating in public) 
(v) Severe: frequent verbal threats or physical attacks without intention or possible serious injuries 
(vi) Very severe: frequent aggressive acts, aimed to cause serious injuries 
 
(2) Choose a 10-point range. The 10-point range is based on the level of dysfunction for the 4 main areas: (a) socially 
useful activities, including work and study; (b) personal and social relationships;(c) self-care; and (d) disturbing and 
aggressive behavior. 
 
100-91        Excellent functioning in all 4 areas. The person is held in high consideration for his/her good 
qualities, adequately copes with life’s problems, and is involved in a wide range of interests and 
activities 
90-81          Good functioning in all 4 areas, only has common problems or difficulties 
80-71          Mild difficulties for 1 or more a-c areas 
70-61          Manifest but not marked difficulties in 1 or more a-c areas or mild difficulties in d 
60-51          Marked difficulties for 1 or more a-c areas or manifest difficulties in d 
50-41          Marked difficulties in 2 or more areas, or severe difficulties in 1 or more a-c areas, with or 
without marked difficulties in d 
40-31          Severe difficulties in 1 area and marked difficulties in at least 1 of the a-c areas, or marked difficulties in d 
30-21          Severe difficulties in 2 a-c areas, or severe difficulties in d, with or without deterioration in a-c areas 
20-11          Severe difficulties in all a-d areas or very severe difficulties in d with or without 
deterioration in general a-c areas. If the person reacts to provocative stimuli, the suggested rating is 20-
16; if not, 15-11. 
10-1            Lack of independence for basic functioning, with extreme behaviour, but with no risk to survival (6-10) 
or with risk to survival, e.g. death risk due to malnutrition, dehydration, infections, inability to recognise 
manifest dangerous situations (1-5) 
 
 
 
Page 90


 
 (3) Adjustment within the 10-point range 
• The level of dysfunction in other areas should be taken into consideration, adding points within the 10-point range 
(e.g. from 31 to 40). Consider: 
 
  taking care of physical and psychological health 
  Accommodation, place of residence, looking after living space 
  Contributing to housekeeping activities, participating in family life or at day centre/halls of residence 
  Personal and sexual relationships 
  Looking after children 
  Social network, friends and co-workers 
  Adjusting to social norms 
  General interests 
  Using transport, telephone 
  Strategies for coping with crisis situations 
• Risk and suicidal behaviour are not taken into account on this scale 
 
(4) Write the final score (0-100):________ 
 
Page 91


Protocol Amendment #3-CZ 
CONFIDENTIAL 
Alkermes, Inc 
05 June 2014 
ALK3831-302 
Page 92 
APPENDIX E. SAMPLE FOOD CRAVING INVENTORY (FCI) 


Food Craving Inventory-II 
 
For each of the foods listed below (Items 1 – 28), please mark the appropriate bubble using the 
following scale.    
A craving is defined as an intense desire to consume a particular food (or food type) that is difficult to 
resist. 
Over the past month, how often have you experienced a craving for the food?  
 
 
Never 
Rarely  
(once or 
twice) 
(
 
Sometimes 
 
Often 
Always/ 
Almost every 
day 
 
 
 
 
 
 
 
1. 
Cake 
 
 
 
 
 
2. 
Pizza 
 
 
 
 
 
3. 
Fried Chicken 
 
 
 
 
 
4. 
Gravy 
 
 
 
 
 
5. 
Sandwich Bread 
 
 
 
 
 
6. 
Sausage 
 
 
 
 
 
7. 
French fries 
 
 
 
 
 
8. 
Cinnamon Rolls 
 
 
 
 
 
9. 
Rice 
 
 
 
 
 
10. Hot dog 
 
 
 
 
 
11. Hamburger 
 
 
 
 
 
12. Biscuits 
 
 
 
 
 
13. Ice cream 
 
 
 
 
 
14. Pasta 
 
 
 
 
 
15. Fried fish 
 
 
 
 
 
16. Cookies 
 
 
 
 
 
17. Chocolate 
 
 
 
 
 
18. Pancakes or waffles 
 
 
 
 
 
19. Corn bread 
 
 
 
 
 
20. Chips 
 
 
 
 
 
21. Rolls 
 
 
 
 
 
22. Cereal 
 
 
 
 
 
23. Donuts 
 
 
 
 
 
24. Candy 
 
 
 
 
 
25. Brownies 
 
 
 
 
 
26. Bacon 
 
 
 
 
 
27. Steak 
 
 
 
 
 
28. Baked potato 
 
 
 
 
 
 
Page 93


Protocol Amendment #3-CZ 
CONFIDENTIAL 
Alkermes, Inc 
05 June 2014 
ALK3831-302 
Page 94 
APPENDIX F. SAMPLE IMPACT OF WEIGHT ON QUALITY OF LIFE-
LITE (IWQOL-LITE) QUESTIONNAIRE 


Impact of Weight on Quality of Life Questionnaire-Lite Version (IWQOL-Lite)
Please answer the following statements by circling the number that best applies
to you in the past week. Be as open as possible. There are no right or wrong
answers.
Physical Function
ALWAYS
USUALLY
SOMETIMES
RARELY
NEVER
TRUE
TRUE
TRUE
TRUE
TRUE
1.
Because of my weight I have trouble
5
4
3
2
1
picking up objects.
2.
Because of my weight I have trouble tying
5
4
3
2
my shoes.
3.
Because of my weight I have difficulty
5
4
3
2
getting up from chairs.
4.
Because of my weight I have trouble using
5
4
3
2
stairs.
5.
Because of my weight I have difficulty
5
4
3
2
putting on or taking off my clothing.
6.
Because of my weight I have trouble with
5
4
3
2
mobility.
7.
Because of my weight I have trouble
5
4
3
2
crossing my legs.
8.
brea
9.
10.
11.
Self-esteem
RARELY
NEVER
TRUE
TRUE
1.
2
1
2.
Because of my
2
not what it coul
3.
Because of my
2
myself.
4.
Because of my we
2
5.
Because of my weight I am afraid of being
5
4
3
2
rejected.
6.
Because of my weight I avoid looking in
5
4
3
2
mirrors or seeing myself in photographs.
7.
Because of my weight I am embarrassed to
5
4
3
2
be seen in public places.
IWQOL-Lite (English-US)
Copyright. 2000. Duke University. All Rights Reserved.
Direct all correspondence to
Obesity and Quality ofLife Consulting,
1004 Norwood Avenue, Durham, NC 27707 USA; email:
fax:
Page 95
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Sexual Life
ALWAYS
USUALLY
SOMETIMES
RARELY
NEVER
TRUE
TRUE
TRUE
TRUE
TRUE
1.
Because of my weight I do not enjoy sexual
5
4
3
2
1
activity.
2.
Because of my weight I have little or no
5
4
3
2
1
sexual desire.
3.
Because of my weight I have difficulty with
5
4
3
2
1
sexualpertormance.
4.
Because of my weight I avoid sexual
5
4
3
2
1
encounters whenever possible.
2.
3.
4.
2
5.
2
RARELY
NEVER
TRUE
TRUE
1.
4
2
2.
5
4
3
2
3.
5
4
3
2
4.
5
4
3
2
IWQOL-Lite (English-US)
Copyright. 2000. Duke University. All Rights Reserved.
Page 96


Protocol Amendment #3-CZ 
CONFIDENTIAL 
Alkermes, Inc 
05 June 2014 
ALK3831-302 
Page 97 
APPENDIX G. PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INDUCERS AND MODERATE-TO-STRONG 
INHIBITORS 
Moderate to Strong CYP3A4 inhibitors: 
Partial List of Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers (This is not an 
exhaustive list.) 
Amprenavir 
Aprepitant 
Atazanavir 
Boceprevir 
Ciprofloxacin 
Clarithromycin 
Conivaptan 
Crizotinib 
Darunavir/ ritonavir 
Diltiazem 
Erythromycin 
Fosamprenavir 
Fluconazole 
Imatinib 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir/ ritonavir 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprenavir 
Telithromycin 
Troleandomycin 


Protocol Amendment #3-CZ 
CONFIDENTIAL 
Alkermes, Inc 
05 June 2014 
ALK3831-302 
Page 98 
Verapamil 
Voriconazole 
Partial List of Moderate to Strong CYP3A4 inducers: 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
Nevirapine 
Phenobarbital 
Phenytoin 
Rifampin 
Rifabutin 
St. John’s Wort 

SAP_001.pdf: 
A Phase 2, Randomized, Multicenter, Safety, Tolerability, 
and Dose-Ranging Study of Samidorphan, a Component of 
ALKS 3831, in Adults with Schizophrenia Treated with 
Olanzapine 
 
 
Unique Protocol ID: 
ALK3831-302 
NCT Number: 
NCT01903837 
Date of Statistical Analysis 
Plan:  
02 Dec 2014 
 


Alkermes, Inc. 
 
Statistical Analysis Plan 
 
Protocol Number: ALK3831-302 
 
A Phase 2, Randomized, Multicenter, Safety, Tolerability, and Dose-
Ranging Study of Samidorphan, a Component of ALKS 3831, in Adults 
with Schizophrenia Treated with Olanzapine 
 
 
 
Final Version: 1.0 
Date: December 2nd, 2014 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this plan 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. 
CONFIDENTIAL 
ALK3831-302: Statistical Analysis Plan 
Final Version: 1.0 
Page 2 of 29 
SIGNATURE PAGE 
Author:        
Date              
Date    
Alkermes, Inc.     
Approved by:        
Date                   
Date    
Alkermes, Inc.     
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Alkermes, Inc. 
CONFIDENTIAL 
ALK3831-302: Statistical Analysis Plan 
 
Final Version: 1.0 
Page 3 of 29 
TABLE OF CONTENTS 
ABBREVIATIONS 
5 
1 
INTRODUCTION 
7 
1.1 
STUDY OBJECTIVES 
7 
1.2 
SUMMARY OF THE STUDY DESIGN 
7 
2 
SAMPLE SIZE CONSIDERATIONS 
8 
3 
DATA ANALYSIS 
8 
3.1 
GENERAL STATISTICAL METHODOLOGY 
8 
3.1.1 Baseline Definition 
8 
3.2 
DEFINITIONS OF ANALYSIS SETS (POPULATIONS) 
9 
3.2.1 Enrolled Population 
9 
3.2.2 Efficacy Populations 
9 
3.2.3 Safety Population 
9 
3.3 
DISPOSITION 
9 
3.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
10 
3.5 
TREATMENT COMPLIANCE RATE AND EXTENT OF EXPOSURE 
10 
3.6 
EFFICACY ANALYSIS 
11 
3.6.1 Change in PANSS total  Score 
11 
3.6.1.1 Sensitivity Analysis 
12 
3.6.2 Percent Change in Body Weight 
12 
3.6.2.1 Sensitivity Analysis 
13 
3.6.3 Absolute Change in Body Weight 
13 
3.6.4 Proportion of Subjects Exhibiting Significant Weight Gain 
13 
3.6.5 Examination of Subgroups 
14 
3.6.6 Change in Clinical Global Impression - Severity 
14 
3.6.7 Efficacy Analysis for the Additional Endpoints 
14 
3.7 
SAFETY ANALYSIS 
15 
3.7.1 General Considerations 
15 
3.7.2 Adverse Events 
16 
3.7.2.1 Treatment-Emergent Adverse Event 
16 
3.7.2.2 Deaths, Serious and Other Significant AEs 
17 
3.7.3 Clinical Laboratory Parameters 
17 
3.7.4 Vital Signs 
20 
3.7.5 Electrocardiograms 
21 
3.7.6 Prior and Concomitant Medications 
22 
3.7.7 Columbia Suicide Severity Rating Scale 
23 
3.8 
PHARMACOKINETIC/PHARMACODYNAMIC DATA ANALYSIS 
23 
3.9 
INTERIM ANALYSES AND DATA SAFETY MONITORING BOARD 
23 
3.10 
DEVIATIONS FROM THE PROTOCOL AND SPECIFIED ANALYSES 
24 


Alkermes, Inc. 
CONFIDENTIAL 
ALK3831-302: Statistical Analysis Plan 
 
Final Version: 1.0 
Page 4 of 29 
3.11 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF DATA 
24 
3.11.1 Analysis Visit 
24 
3.11.1.1 Scheduled analysis visit 
24 
3.11.1.2 Unscheduled visit 
24 
3.11.1.3 Early termination (ET) visit 
24 
3.11.1.4 Follow-up Visits 
26 
3.11.2 Last Post-baseline Values 
26 
3.11.3 Any Post-baseline Values 
26 
3.11.4 Missing Safety Data 
26 
3.11.5 Handling of Partial Dates of Concomitant Medication 
26 
4 
MOCK TABLES, LISTINGS AND GRAPHS 
26 
5 
REFERENCES 
26 
6 
APPENDIX A STANDARDIZED MEDICAL QUERY 
PREFERRED TERMS FOR EXTRAPYRAMIDAL SYMPTOM (EPS)-
RELATED SMQS 
27 
 
 
 


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ABBREVIATIONS 
AE  
Adverse Event  
ANCOVA 
Analysis of Covariance 
BMI  
Body Mass Index  
CDT 
Carbohydrate Deficient Transferrin 
CGI-S 
Clinical Global Impression–Severity 
CI 
Confidence Interval 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
C-VISA 
Clinical Validation Inventory for Study Admission 
DSMB 
Data Safety Monitoring Board 
ET 
Early Termination 
ECG  
Electrocardiogram 
FAS 
Full Analysis Set 
FCI 
Food Craving Inventory 
eCRF  
Electronic Case Report Form 
FAS 
Full Analysis Set 
HbA1c 
Hemoglobin A1c 
HDL 
High Density Lipoprotein 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IWQOL-Lite 
Impact of Weight on Quality of Life-Lite 
IWRS 
Interactive Web Response Systems 
LDL 
Low Density Lipoprotein 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
PANSS 
Positive and Negative Syndrome Scale 
PBO   
Placebo 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PSP 
Personal and Social Performance 
PT 
Preferred Term 
QOL 
Quality of Life 
QTcB 
QTcB – Bazett’s correction formula 
QTcF 
QTcF – Friderica’s correction formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TLF 
Table, Listing, and Figure 
TLFB  
Timeline Follow-Back 
TEAE 
Treatment-Emergent Adverse Event 


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WHO-ATC 
World Health Organization Anatomical Therapeutic Chemical 
 
 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for analyses and 
data presentation for reporting efficacy and safety results for study ALK3831-302. This 
document has been prepared based on Alkermes ALK3831-302 Study Protocol Amendment 2 
(dated 16 February 2014) [1]. 
1.1 STUDY OBJECTIVES 
The objectives of this study are to evaluate 3 doses of samidorphan co-administered with 
olanzapine (ALKS 3831) in subjects with schizophrenia to (1) evaluate ALKS 3831 as a 
treatment for schizophrenia, (2) assess the safety and tolerability of ALKS 3831, and (3) 
characterize the impact of samidorphan component of ALKS 3831 on weight and other 
metabolic factors. 
1.2 SUMMARY OF THE STUDY DESIGN 
This is a Phase 2, randomized, placebo-controlled multicenter study that is divided into 2 parts: 
Part A and Part B. 
Part A will begin with screening followed by a 1-week olanzapine lead-in period where 
subjects will receive olanzapine daily and a 12-week double-blind, placebo-controlled 
treatment period where subjects will receive samidorphan or placebo (in addition to the 
olanzapine prescribed on Study Day 1) daily. Olanzapine dosing will be selected and titrated 
by the investigator based upon individual subject needs and consistent with current clinical 
practice. Subjects will be randomized in a 1:1:1:1 ratio to receive either samidorphan (5, 10, or 
20 mg) or placebo. 
Part B will include an additional 12-week treatment period where all subjects will receive 
active olanzapine + samidorphan (ie, ALKS 3831). Subjects randomized to samidorphan 
during Part A will continue receiving the same dose of samidorphan during Part B. Subjects 
randomized to placebo during Part A will receive the highest dose of samidorphan during Part 
B. Dose level during Part B will be double-blind. For all subjects, samidorphan dosing will 
stop at the end of Part B, but olanzapine dosing will continue uninterrupted through a 4-week 
follow-up period, which includes 2 safety visits. 
This study will use an independent Data Safety Monitoring Board (DSMB) to monitor subject 
safety data. After at least one week of safety data has been collected for 40 randomized 
subjects, the DSMB will review the accumulated safety data for all subjects. After at least one 
week of safety data has been collected for 150 randomized subjects, the DSMB will review the 
accumulated safety data for all subjects. Additional reviews of the data may occur at the 
discretion of the DSMB. Complete details of the data review procedures of the DSMB are 
available in the DSMB charter. 


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This is the first study of ALKS 3831 in a population of adults with schizophrenia. Subjects will 
be monitored in an inpatient setting for 2 nights following randomization (Visit 3) and during 
the transition from Part A to Part B (Visit 13). These are the two periods where samidorphan 
treatment may be initiated. Subjects will be monitored in an inpatient setting whether or not 
samidorphan treatment is being initiated in order to maintain double-blind dosing and a 
consistent subject experience consistent across treatment groups. 
2 
SAMPLE SIZE CONSIDERATIONS 
Sample size calculations are based on the primary endpoint of absolute change in PANSS total 
score. These calculations assume an equivalence margin of 10 points, a standard deviation of 
20 points, and a true difference of 0 points. With these assumptions, 280 randomized subjects 
provide 95% power to demonstrate equivalence on the primary endpoint (absolute PANSS total 
score change from randomization to the end of Part A) with a 2-sided test at an alpha level of 
0.05. These 280 subjects represent 70 subjects for each treatment arm (ALKS 3831 5 mg, 
ALKS 3831 10 mg, ALKS 3831 20 mg, and placebo) in a 1:1:1:1 ratio. For the primary 
analysis, subjects in the 3 ALKS 3831 treatment groups will be pooled for comparison with 
placebo. If this analysis shows equivalence, follow-up analyses on individual dose levels will 
be performed. Assuming a 20% discontinuation rate prior to randomization, an estimated 350 
subjects will be enrolled in this study. 
 
3 
DATA ANALYSIS 
3.1 GENERAL STATISTICAL METHODOLOGY 
In general, descriptive 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 group for all variables. 
 
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.  
Body weight will be measured 3 times at every visit. The median weight will be used in 
summary tables or figures. 
3.1.1 Baseline Definition 
Baseline for Part A is defined as the last non-missing observation on or before the first dose of 
study drug following randomization at Visit 3 (Day 8).  
Baseline for Part B is defined as the last non-missing observation on or before the date of the 
first dose of study drug at Visit 13 (Day 92).   


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3.2 DEFINITIONS OF ANALYSIS SETS (POPULATIONS) 
3.2.1 Enrolled Population  
Enrolled population is defined as all subjects who enrolled in the study and received at least 
one dose of olanzapine before randomization.  
3.2.2 Efficacy Populations 
The efficacy analysis will be conducted on 2 analysis populations: 
 FAS 1 Population is defined as all randomized subjects who received at least one dose 
of study drug and have at least one post-baseline assessment of PANSS total score.  
 FAS 2 Population is defined as all FAS 1 subjects who gained weight during the first 
week of olanzapine treatment prior to randomization and have at least one post-baseline 
weight assessment.  
FAS 1 population will be the primary efficacy population for analyses on all efficacy variables. 
3.2.3 Safety Population 
 Safety Population is defined as all randomized subjects who received at least 1 dose of 
study drug.  
 Safety Population for Part B is defined as all randomized subjects who enrolled in Part 
B and received at least 1 dose of study drug in Part B. 
 
3.3 DISPOSITION 
The subject disposition will be summarized for the enrolled population by treatment group and 
overall and will include the following  
 Subjects who were randomized 
 Subjects in Safety Population  
 Subjects in the FAS 1 Population  
 Subjects in the FAS 2 Population  
 Subjects who completed the olanzapine lead-in period and continued into Part A  
 Subjects who discontinued the study during the olanzapine lead-in period along with 
reasons for discontinuation 
 Subjects who completed the Part A placebo-controlled period and continued into Part B 
 Subjects who discontinued the study during Part A placebo-controlled period along with 
reasons for discontinuation 


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 Subjects in Safety Population for Part B 
 Subjects who completed Part B ALKS 3831 treatment period 
 Subjects who discontinued the study during Part B ALKS 3831 treatment period along 
with reasons for discontinuation 
 Subjects entering the safety follow-up period will include  
o Subjects who completed the safety follow-up after discontinuation in the 
olanzapine lead-in period 
o Subjects who discontinued the safety follow-up after discontinuation in the 
olanzapine lead-in period  
o Subjects who completed the safety follow-up after discontinuation in Part A 
placebo-controlled period 
o Subjects who discontinued during the safety follow-up period after 
discontinuation in Part A placebo-controlled period 
o Subjects who completed the safety follow-up after Part B ALKS 3831 treatment 
period 
o Subjects who discontinued during the safety follow-up period after Part B 
ALKS 3831 period 
3.4  DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics such as gender, age, race, ethnicity, weight, BMI, 
PANSS, and CGI-S will be summarized by treatment group and overall for FAS 1 Population, 
FAS 2 Population, and Safety Population.  
If there are heterogeneities between treatment groups in any of the subject characteristics that 
are of clinical importance or could affect the treatment outcome, the impact of the imbalances 
will be investigated and, if necessary, appropriate adjustments will be considered in the 
efficacy and safety analyses. 
Medical and psychiatric history will be summarized by treatment group and overall using the 
number and percentage of subjects by category for the Safety Population.  
 
3.5 TREATMENT ADHERENCE RATE AND EXTENT OF EXPOSURE 
Treatment adherence refers to a subject's adherence to the daily dosing schedule as assessed by 
the number of tablets of samidorphan or placebo dispensed, returned and lost. Treatment 


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adherence of samidorphan or placebo will be calculated as a percentage for the treatment 
periods as follows: 
 
𝐴𝑑ℎ𝑒𝑟𝑒𝑛𝑐𝑒=  100 × (𝑇𝑜𝑡𝑎𝑙 𝑇𝑎𝑏𝑙𝑒𝑡𝑠 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑇𝑎𝑏𝑙𝑒𝑡𝑠 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑇𝑎𝑏𝑙𝑒𝑠 𝐿𝑜𝑠𝑡)
𝑇𝑜𝑡𝑎𝑙 𝑇𝑎𝑏𝑙𝑒𝑡𝑠 𝑆𝑐ℎ𝑒𝑑𝑢𝑙𝑒𝑑 𝑡𝑜 𝑏𝑒 𝑇𝑎𝑘𝑒𝑛
 
 
Treatment adherence of samidorphan/placebo will be summarized for Part A using the Safety 
Population and for Part B using the Safety population for Part B.  
Exposure 
to 
study 
drug 
will 
be 
summarized 
separately 
for 
olanzapine 
and 
samidorphan/placebo. It will be summarized for Part A using Safety Population and for Part B 
using the Safety Population for Part B. The exposure is defined as follows.  
𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑑𝑎𝑦𝑠) =  𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔+ 1 
In addition, the time-weighted average olanzapine dose level will be summarized for Part A 
placebo-controlled period and Part B ALKS 3831 treatment period using the FAS 1 population. 
Average olanzapine dose level in a treatment period is defined as follows. 
 
𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑙𝑎𝑛𝑧𝑎𝑝𝑖𝑛𝑒 𝑑𝑜𝑠𝑒 𝑙𝑒𝑣𝑒𝑙= 𝑆𝑢𝑚(𝑜𝑙𝑎𝑛𝑧𝑎𝑝𝑖𝑛𝑒 𝑑𝑜𝑠𝑒 𝑙𝑒𝑣𝑒𝑙∗𝑑𝑎𝑦𝑠 𝑜𝑛 𝑠𝑢𝑐ℎ 𝑑𝑜𝑠𝑒 𝑙𝑒𝑣𝑒𝑙)
 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒
 
 
3.6 EFFICACY ANALYSIS 
3.6.1 Change in PANSS total  Score 
The primary endpoint is the change in PANSS total score from randomization to Day 92 and 
will be evaluated by treatment group (ALKS 3831 pooled vs. the placebo group [olanzapine 
alone]) using a 2-sided mixed-model for repeated measures (MMRM) to test for equivalence at 
an alpha level of 0.05. The primary analysis will be conducted in the FAS 1 population.  
 
The null hypothesis is that the PANSS total score change from randomization to Day 92 of 
ALKS 3831 treatment group will be different to that of the placebo group [olanzapine alone]. 
The bound of the 2-sided 95% CIs of the difference between the changes of ALKS 3831 – 
Placebo [olanzapine alone] will be outside the equivalence interval of -10 and 10. 
 
If this analysis shows equivalence, similar analyses on individual dose levels will be 
performed.  
 
Change in PANSS total score from baseline to Day 92 will be analyzed using MMRM model. 
The MMRM model will include variables for weight change strata in the olanzapine lead-in 
period, treatment group, visit, and treatment group-by-visit interaction term as categorical fixed 
effect, baseline value will be included as a covariate. An AR(1) covariance structure will be 


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applied for the MMRM. The Kenward-Roger approximation [2] will be used to adjust the 
denominator degree of freedom. The analysis will be performed on all observed post-
randomization scores without imputation of missing data. 
A sample of SAS implementation code for analyzing change from randomization to Day 92 
using an MMRM is given below. 
proc mixed data=datain; 
class strata usubjid trt visit; 
model change = strata trt visit trt*visit base  
/ DDFM=KENWARDROGER; 
      repeated visit/ type=AR(1) subject=usubjid; 
lsmeans trt*visit / diff cl; 
run; 
 
The least squares (LS) mean, standard error (SE), and LS mean difference between pooled 
ALKS 3831 treatment group and placebo [olanzapine alone], as well as between each 
ALKS 3831 treatment group and the placebo [olanzapine alone] at Day 92, along with the 95% 
CI, will be summarized.  
3.6.1.1 Sensitivity Analysis  
ANCOVA (analysis of covariance) model will be conducted with the olanzapine lead-in period 
weight change strata and treatment group as factor and the baseline weight as the covariate for 
FAS 1. The ANCOVA model will be based on the LOCF (last observation carried forward) 
imputation, that is, if a subject misses a post-baseline scheduled visit, a record for the 
scheduled visit will be imputed using the value from the most recent post-baseline visit. 
 
For both FAS 1 and FAS 2 populations, summary of change from baseline in PANSS total 
score and subscales at each visit will also be presented using descriptive statistics. Change 
from Part B baseline will also be summarized at each visit in Part B.   
3.6.2 Percent Change in Body Weight 
The secondary endpoint, percent change in weight from randomization to Day 92, will be 
evaluated by treatment group using an MMRM approach similar to that of the primary 
endpoint. Pooled and individual ALKS 3831 treatment group will be compared to the placebo 
[olanzapine alone] group with a 2-sided hypothesis test to test for superiority at an alpha level 
of 0.05. The secondary efficacy analysis will be conducted in both FAS 1 and FAS 2 
population. The MMRM model includes variables for the weight change strata in olanzapine 
lead-in period, treatment group, visit, and treatment group-by-visit interaction term as 
categorical fixed effect; baseline weight value will be included as a covariate. 
 


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3.6.2.1 Sensitivity Analysis 
To assess the robustness of the MMRM results on the percent weight change, ANCOVA and 
LOCF analysis will be conducted with the olanzapine lead-in period weight change strata and 
treatment group as factor and the baseline weight as the covariate  (similar as Section 3.6.1.1).  
In addition, the MMRM model will include treatment group, visit, and treatment group-by-visit 
interaction term as categorical fixed effect; baseline BMI value and continuous weight change 
value in the olanzapine lead-in period will be included as covariates.  
Percent weight change will also be analyzed by a linear mixed effects model with treatment as 
fixed effect, visit and treatment by visit interaction as random effect, and with adjustment for 
the olanzapine lead-in period weight change strata as factor and baseline weight as covariates.  
In this model, visit will be treated as a continuous variable and will be the number of days from 
Day 8. Denominator degrees of freedom will be estimated using the Kenward–Roger 
approximation.  Change from baseline at Day 92 will be obtained from the model. 
 For both FAS 1 and FAS 2 populations, summary of weight change from baseline at each visit 
will also be presented using descriptive statistics for both Part A and Part B. Change from Part 
B baseline will also be summarized at each visit in Part B.  
Waterfall plots will be produced for the percent change from baseline to Day 92 by the 
treatment group.   
3.6.3 Absolute Change in Body Weight 
 The statistical analysis for absolute change in weight will be similar to the analysis for percent 
change in body weight (Section 3.6.2). 
3.6.4 Proportion of Subjects Exhibiting Significant Weight Gain 
A subject will be considered as exhibiting significant weight gain if he or she has a body 
weight change of ≥5%, ≥7% or ≥10% from baseline. 
The proportion of subjects with significant weight gain will be estimated at each visit by the 
treatment group. Pooled and individual ALKS 3831 treatment group will be compared with 
placebo [olanzapine alone] group, and the difference with 95% CI will be reported for each 
comparison. It will be based on the observed values.  A Cochran-Mantel-Haenszel (CMH) 
option will be used to make adjustment for the olanzapine lead-in period weight change strata. 
A sample of SAS implementation code is provided below (assuming ≥7% weight gain is coded 
1 and <7% weight gain is coded 2 for the responder variable). 
 
proc freq data=datain; 
 
tables strata*trt01p*responder/CMH; 
 
where trt01p in ('ALKS3831' 'Placebo')  
 
and avisit='Week 12'; 
run;  


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The proportion of subjects with significant weight gain based on observed cases without 
imputation will also be summarized at each visit by treatment group for Part A and Part B. 
3.6.5 Examination of Subgroups 
For percent change in body weight and proportion of subjects exhibiting significant weight 
gain, the following subgroup analysis will be performed with similar analysis methods as 
described in Sections 3.6.2 and 3.6.4 when appropriate:  
 Weight gain category during the olanzapine lead-in period (change ≤0 kg, increase >0 
to <1 kg,  increase ≥ 1 kg) 
 BMI (<25, ≥25)  
 BMI (<27, ≥27) 
 Gender (male, female) 
 Age (≥18-<=39,≥ 40-<=50) 
 Region (US, non-US) 
3.6.6 Change in Clinical Global Impression - Severity 
The CGI-S is a 7-point scale ranging from 1=normal to 7=extremely ill. . 
The change from baseline to Day 92 in CGI-S will be carried out using the MMRM model 
including the weight change strata in olanzapine lead-in period, treatment group, visit, and a 
treatment group-by-visit interaction term as categorical fixed effects; baseline CGI-S value will 
be included as a covariate. 
A summary of CGI-S at each visit will be presented using descriptive statistics for Part A and 
Part B.  
3.6.7 Efficacy Analysis for the Additional Endpoints 
Unless otherwise specified, exploratory efficacy endpoints will be summarized in descriptive 
statistics by visit and treatment groups. They include change in waist circumference, change in 
IWQOL-Lite scales (total score, physical function, self-esteem, sexual life, public distress, and 
work), change in PSP, change in FCI (total score, high fat, sweets, carbohydrates/starches, fast-
food fats), and change in alcohol and drug use.  
For change in waist circumference, MMRM will also be conducted, including the weight 
change strata in olanzapine lead-in period, treatment group, visit, and treatment group-by-visit 
interaction term as categorical fixed effects; baseline value will be included as a covariate. 
 
For IWQOL-Lite scale is a 31-item self-report measure of obesity-specific quality of life. The 


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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 [4]. The transformed scores range from 0 to 100, with 100 
representing the best and 0 the most impaired quality of life. 
 
𝑇𝑟𝑎𝑛𝑠𝑓𝑜𝑟𝑚𝑒𝑑 𝑆𝑐𝑜𝑟𝑒= 𝑚𝑎𝑥𝑖𝑚𝑢𝑚 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑠𝑐𝑜𝑟𝑒−𝑎𝑐𝑡𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒
𝑡𝑒𝑠𝑡 𝑠𝑐𝑜𝑟𝑒 𝑟𝑎𝑛𝑔𝑒
𝑋100 
 
 
For FCI, total scores and subscores for high fat, sweets, carbohydrates/starches and fast-food 
fats will be calculated as following:   
FCI Total score = average response for items 1 to 28. Possible range is 1-5.  
High fat subscore=average response for items 3, 4, 6, 10, 15, 19, 26 and 27. Possible range is 
1-5.  
Sweets subscore=average response for items 1, 8, 13, 16, 17, 23, 24 and 25. Possible range is 
1-5.  
Carbohydrates/starches subscore=average response for items 5, 9, 12, 14, 18, 21, 22 and 28. 
Possible range is 1-5. 
 
Fast-food fats subscore=average response for items 2, 7, 11 and 20. Possible range is 1-5. 
For alcohol use as assessed by TLFB, percent of drinking days for the prior 30 days will be 
summarized at each visit.  
Number and percentage of subjects with any drug use at each scheduled time point will be 
summarized by treatment group. It will also be summarized for individual drugs.  
3.7 SAFETY ANALYSIS 
3.7.1 General Considerations 
Safety analyses will be primarily based on Safety Populations and include AEs, clinical 
laboratory assessments (hematology, blood clinical biochemistry, and urinalysis), vital signs, 
ECG parameters, and data from C-SSRS surveys in Part A and Part B treatment periods. 
Safety analyses will be performed on observed data, and no missing values will be imputed. 


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3.7.2 Adverse Events 
Reported AE terms will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA®) version 15.0. The 
verbatim term will be included in the AE listings. 
3.7.2.1 Treatment-Emergent Adverse Event 
An AE will be considered as treatment-emergent AE (TEAE) if the event is newly occurring or 
after the first dose of study drug. AEs will be identified as emerging in the following periods: 
 TEAEs during the olanzapine lead-in period 
 TEAEs for the Part A placebo-controlled period 
 TEAEs for the Part B ALKS 3831 treatment period 
 TEAEs for the Part A placebo-controlled period and Part B ALKS 3831 treatment 
period combined 
 TEAEs during the follow-up period:  
o after discontinuation in the olanzapine lead-in period  
o after discontinuation in Part A placebo-controlled period 
o after discontinuation or completion of Part B ALKS 3831 treatment period 
 
All AEs will be listed by subject, but only TEAEs will be included in the summary tables. 
Summary tables will be produced for the specified periods above.  
An overall summary of TEAEs such as all TEAEs, treatment-related TEAEs, TEAEs leading 
to study discontinuation, serious TEAEs, serious and treatment-related TEAEs, and TEAEs 
resulting in death will be summarized for each treatment group. 
In addition, the following summary tables will be produced: 
 TEAEs experienced by ≥2% of subjects in any treatment group for Part A placebo-
controlled period, Part B ALKS 3831 treatment period, and combined period 
 Treatment-related TEAEs experienced by ≥2% of subjects in any treatment group for 
Part A placebo-controlled period, Part B ALKS 3831 treatment period, and combined 
period 


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 The number and percentage of subjects with TEAEs by treatment group, SOC, PT, and 
severity for Part A placebo-controlled period, Part B ALKS 3831 treatment period, and 
combined period 
A subject with the same AE more than once will be counted once in the number and percentage 
of subjects calculation for that AE. Similarly, if a subject has more than one AE in an SOC, the 
subject will be counted only once in the total number of subjects with an AE for that SOC. If a 
subject has the same AE on multiple occasions, the highest severity (severe>moderate>mild) or 
drug relationship (definitely related>probably related>possibly related>probably not 
related>definitely not related) recorded for the event will be presented. 
An AE that occurs after a subject provides informed consent but before the first dose of study 
drug will be considered as a pre-treatment AE. 
3.7.2.2 Deaths, Serious and Other Significant AEs 
The number and percentage of subjects with at least one treatment emergent SAE will be 
summarized by System Organ Class, and Preferred Term for each treatment group for Part A 
placebo-controlled period, Part B ALKS 3831 treatment period, and combined period. Subjects 
with AEs leading to study discontinuation will be summarized similarly. Subjects who died 
during the study will be listed. 
3.7.2.2.1 Other significant AEs 
The following categories for adverse events were selected based on effects that have been 
observed with olanzapine. The PTs to be included in each category were based on Standardized 
MedDRA queries (SMQs) or custom searches if the SMQs did not exist or were inadequate. 
These significant AEs will be summarized by the AE category, PT and treatment group.  
 Extrapyramidal symptoms (list of PTs provided in Appendix) 
 Nausea or vomiting (include these 2 PTs) 
 Sedation (including sedation, somnolence, lethargy or hypersomnia) 
3.7.3 Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional units. Only laboratory results at the 
scheduled visits will be included in the summary tables. All lab data will be included in the 
listings. 
Results will be summarized for hematology and chemistry by visit and the treatment group for 
Part A and Part B.  
Additionally, for select parameters, number and percentage of subjects with values considered 
potentially clinically significant (PCS) occuring at any time post-baseline will be summarized 


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by treatment group. Criteria for PCS are presented in Table 1 and Table 2. Criteria for shift in 
lipids, glucose and HbA1c are presented in Table 3 and Table 4.  
Table 1: 
Potentially Clinically Significant Results Criteria for Chemistry 
Parameters 
Criteria 
Albumin 
<2.5 g/dL 
Alkaline phosphatase (U/L) 
≥3 x ULN 
Alanine Aminotransferase (U/L) 
≥3 x ULN 
Aspartate Aminotransferase (U/L) 
≥3 x ULN 
Alanine Aminotransferase (U/L) 
≥3 x 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 x ULN 
Creatinine 
≥2.0 mg/dL 
Glucose, Random 
<50 mg/dL or 
≥200 mg/dL 
Potassium 
<3 mmol/L or 
>5.5 mmol/L 
Lactate Dehydrogenase (U/L) 
>3 x ULN 
Phosphate 
<2 mg/dl or 
>5 mg/dl 
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 2: 
Potentially Clinically Significant Results Criteria for Hematology 
Parameters 
Criteria 
 
Eosinophils 
>1.0 x 103/uL 
Hematocrit (Female) 
<=32% 
Hematocrit (Male) 
<=37% 
Neutrophils, Absolute 
<1.5 x 103/uL 
Platelets 
<75.0 x 103 cells/uL or 
≥ 700.0 x 103 cells/uL 
Leukocytes 
≤ 2.8 x 103/uL or 
≥ 16.0 x103/uL 
 
Table 3: 
Shifts Category in Lipid Parameters from Baseline to Any Post-Baseline. 
Total cholesterol (fasting) mg/dL 
Normal (<200) to High (≥240) 
Borderline (≥200 and < 240) to High (≥240) 
Normal/Borderline (<240) to High (≥240) 
Normal (<200) to borderline/High (≥200) 
Increase ≥40 mg/dL 
LDL Cholesterol (fasting) mg/dL 
Normal (<100) to high (≥160) 
Borderline (≥100 and < 160) to high (≥160) 
Normal/borderline (<160) to high (>-160) 
Normal (< 100) to borderline/high (≥100) 
Increase ≥30 mg/dL 
HDL Cholesterol (fasting) mg/dL 
Normal (≥40) to low (<40) 
Decrease ≥20 mg/dL 
Triglycerides (fasting) mg/dL 
Normal (<150) to high (≥200) 


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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 4: 
Shift Category in Glucose and HbA1c from baseline to any post-baseline 
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 (fasting) % 
Shift from baseline (<6.1%) to: 
   Post-baseline ≥6.1% 
   Post-baseline ≥8% 
   Post-baseline ≥10% 
   Post-baseline ≥12% 
3.7.4 Vital Signs 
Descriptive statistics for vital signs and changes from baseline values at each scheduled time 
point will be presented by treatment group. Additionally, number and percentage of subjects 
with values considered PCS occurring at any time post-baseline will be summarized by 
treatment group. Criteria for PCS are presented in Table 5.   


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Table 5:  Criteria Potentially Clinically Significant (PCS) Blood Pressure or Pulse Rate  
 
Parameter 
PCS Criterion 
Systolic blood pressure, supine  
Low:≤ 90mm Hg and decrease ≥20 mm Hg 
 
High: ≥180 mm Hg and increase ≥20 mm Hg 
Diastolic blood pressure, supine 
Low: ≤ 50mm Hg and decrease ≥15 mm Hg 
 
High: ≥105 mm Hg and increase ≥15 mm Hg 
Pulse, supine 
Low: ≤ 50 bpm and decrease ≥15 bpm 
 
High: ≥120 bpm and increase ≥15 bpm 
All vital signs will be presented in the subject data listing. 
Orthostatic hypotension (20/10) is defined as a fall in systolic blood pressure of at least 20 
mmHg and a fall in the diastolic blood pressure of at least 10 mmHg upon standing from 
supine. Orthostatic hypotension (30) is defined as a fall in systolic blood pressure of at least 30 
mmHg upon standing from supine.  
Orthostatic tachycardia is defined as a heart rate increase of 30 beats per minute (bpm) or more 
upon standing from supine, or over 120 bpm upon standing.  
The number and percentage of subjects with orthostatic hypotension or orthostatic tachycardia 
occurring at any post-baseline timepoint will also be summarized by treatment group.  
3.7.5 Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS interval, 
QT interval, QTcB [QT interval corrected using Bazett’s method], QTcF [QT interval corrected 
using Fridericia's method]) and changes from baseline values at each scheduled time point will 
be presented by treatment group. Any other ECG parameters that are collected will be 
presented in the listings only. 
In addition, the number and percentages of subjects with any post-baseline results meeting 
supra-threshold QTc criteria, as defined in Table 6, based on ICH (International Conference on 
Harmonization) Guidance E14[3] will be presented by treatment for QTcB and QTcF. A listing 
will present all values for a subject and parameter for cases where at least one value for that 
parameter was potentially significant. 
 
 


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Table 6: 
Abnormal results for Electrocardiogram 
Parameter 
Abnormal ECG Results Criteria 
QTcB, QTcF 
 
>500 milliseconds 
o >60 millisecond change from baseline 
o >30 - <=60 millisecond change from baseline 
 
>480 and ≤500 milliseconds 
o >60 millisecond change from baseline 
o >30 - <=60 millisecond change from baseline 
 
>450 and ≤ 480 milliseconds 
o >60 millisecond change from baseline 
o >30 - <=60 millisecond change from baseline 
 
>60 millisecond change from baseline 
 
>30 - <=60 millisecond change from baseline 
 
3.7.6 Prior and Concomitant Medications 
Prior medications are defined as medications taken prior to the first dose of the randomized 
study medication. Concomitant medications are defined as medications taken during the 
treatment period. Concomitant medications for Part A placebo-controlled period are defined as 
medications taken between the first dose of the randomized medication to the end of Part A 
treatment period (inclusive). Concomitant medications for Part B ALKS 3831 treatment period 
are defined as medications taken between the first dose of the samidorphan to the end of Part B 
treatment period (inclusive).  
All medications as documented by the investigator will be coded using the World Health 
Organization Anatomical Therapeutic Chemical (WHO-ATC) drug dictionary, version March 
2012. 
Prior and concomitant medications will be summarized by the Preferred Term and by treatment 
group. Medication taken only during the follow-up period will be presented in the subject data 
listing only. For the summary tables, if a subject has taken a prior or concomitant medication 
more than once, the subject will be counted only once for the medication. Partial date 
imputation for medications is described in Section 3.11.5. All reported medications will be 
presented in the subject data listing. 


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3.7.7 Columbia Suicide Severity Rating Scale 
Response to individual items of C-SSRS as well as the presence (yes or no) of any completed 
suicide, suicide attempt, preparatory actions towards imminent suicidal behavior, suicidal 
ideation, and non-suicidal self-injurious behavior at any post-baseline visit will be summarized 
using number and percentage of subjects for each category.   
Table 7. C-SSRS category mapping.  
Category 
Definition 
(“Yes” answer to any one of the following) 
Completed suicide  
Completed Suicide 
Suicide attempt 
Actual attempt 
Preparatory actions towards imminent suicidal 
behavior 
 
Interrupted attempt 
 
Aborted attempt 
 
Preparatory acts or behavior 
Suicide 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 
3.8 PHARMACOKINETIC/PHARMACODYNAMIC DATA ANALYSIS 
Subject listings for the concentrations, PK sampling time, and the prior drug dosing time of 
samidorphan, RDC-9986 (primary metabolite of samidorphan), and olanzapine will be 
provided.   
3.9 INTERIM ANALYSES AND DATA SAFETY MONITORING BOARD 


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An independent Data Safety Monitoring Board (DSMB) will monitor for tolerability of study 
drug. Complete details of can be found in DSMB SAP.  
3.10 
DEVIATIONS FROM THE PROTOCOL AND SPECIFIED ANALYSES 
There are no deviations from the protocol specified analyses. 
3.11 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF DATA 
3.11.1 Analysis Visit 
Unless otherwise specified, this provides general rules across datasets in ADaMs. 
3.11.1.1 Scheduled analysis visit  
Scheduled analysis visits are visits upon scheduled time points 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 would be one valid value of assessment kept for each scheduled 
analysis visit in summary/analysis statistics. 
The scheduled repeat measurements at the same visit will be handled as described in SAP 
Section 3.1. 
3.11.1.2 Unscheduled visit 
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 will be included as collected in eCRF in listings. 
3.11.1.3 Early termination (ET) visit 
An early termination (ET) visit can be mapped to a scheduled visit and be used for analysis and 
summaries only if there is no valid value already at the mapped visit.   
A mapped ET visit will be treated as a scheduled visit to be included in table summaries. 
Otherwise, it will be treated as an unscheduled visit. 
Two rules will be used to map an ET visit. 
First, a 7-day (inclusive) window (≤last dose date + 7) will be used to determine if the 
assessment at the ET visit is considered to be an on-treatment result.  If an ET visit is within 7 
days after the last dose of samidorphan/placebo, it will be considered as a valid on-treatment 


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visit.  
Second, visit windows (inpatient stay is excluded) will be applied to determine to which visit 
an ET valid on-treatment assessment can be mapped to.  Visit windows are defined in Table 8 
below.  
If a subject didn’t complete the Part A, his/her ET assessment will not be mapped to Part B 
visits, i.e. Visit 14 to 23. 
Table 8:  Visit Window Definition 
Analysis Visit to be Mapped to 
Target Study Day 
Visit Window 
Visit 6 
15 
[9, 18]  
Visit 7 
22 
[19, 25] 
Visit 8 
29 
[26, 32] 
Visit 9 
36 
[33, 43]  
Visit 10 
50 
[44, 57] 
Visit 11 
64 
[58, 71] 
Visit 12 
78 
[72, 85]  
Visit 13 
92 
[86, 98] 
Visit 16 
99 
[99, 102] 
Visit 17 
106 
[103, 109]  
Visit 18 
113 
[110, 116] 
Visit 19 
120 
[117, 127] 
Visit 20 
134 
[128, 141]  
Visit 21 
148 
[142, 155] 
Visit 22 
162 
[156, 169] 
Visit 23 
176 
[170, 183] 
 


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3.11.1.4 Follow-up Visits 
Follow-up visits for ET subjects will be reported after the lead-in period, Part A placebo-
controlled period and Part B ALKS 3831 treatment period respectively. 
   
For Part B, the follow-up visit after ET and that after completion of treatment in Part B will be 
reported without distinction. 
3.11.2 Last Post-baseline Values 
Last post-baseline values are defined as the last valid post-baseline values collected for each 
subject during the treatment period or a specified reporting period. Values collected at 
unscheduled visits can be used to derive the last post-baseline values. 
3.11.3 Any Post-baseline Values 
Any post-baseline values are defined as any valid values collected from scheduled or 
unscheduled visits, if applicable.   
3.11.4 Missing Safety Data 
Missing data from safety assessment or evaluation will not be imputed. However, they will be 
reviewed for possible data issues. 
3.11.5 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. 
4 MOCK TABLES, LISTINGS AND GRAPHS 
Mock-up tables, listings, and graphs will be provided in a separate document. 
5 REFERENCES 
1. Alkermes ALK3831-302 Study Protocol Amendment 2 (dated 26 February 2014) 
2. Kenward MG and Roger JH (1977) Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997; 53: 983–997 
3. ICH Guidance "E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs” 
4.  Tessier A et al. (2012) Understanding the Determinants of Weight-Related Quality of Life 
among Bariatric Surgery Candidates. Journal of Obesity 2012; 2012: 713426 


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6 APPENDIX A STANDARDIZED MEDICAL QUERY PREFERRED TERMS 
FOR EXTRAPYRAMIDAL SYMPTOM (EPS)-RELATED SMQS 
Akathisia 
 
 
SMQ Level:  2 
SMQ Code:  20000096 
 
Preferred Terms: 
 Akathisia 
 With and without; 
o Restlessness  
o Psychomotor hyperactivity 
o Hyperkinisia 
 
Dyskinisia 
 
SMQ Level:  2 
SMQ Code:  20000097 
 
Preferred Terms: 
 Athetosis 
 Ballismus 
 Buccoglossal syndrome 
 Chorea 
 Choreoathetosis 
 Dopamine dysregulation syndrome 
 Dyskinesia 
 Dyskinesia oesophageal 
 Grimacing 
 Pharyngeal dyskinesia 
 Protrusion tongue 
 Rabbit syndrome 
 Respiratory dyskinesia 
 Tardive dyskinesia 
 Muscle twitching 
 Tic 
 
Dystonia 
 
 
SMQ Level: 2  
SMQ Code:  20000098 
 
Preferred Terms: 
 Dystonia 
 Dystonic tremor 
 Emprosthotonus 
 Meige's syndrome 


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 Oculogyric crisis 
 Opisthotonus 
 Oromandibular dystonia 
 Pleurothotonus 
 Spasmodic dysphonia 
 Torticollis 
 Trismus 
 Writer's cramp 
 Abasia 
 Blepharospasm 
 Facial spasm 
 Laryngospasm 
 Muscle contractions involuntary 
 Muscle spasms 
 Muscle spasticity 
 Muscle tightness 
 Oesophageal spasm 
 Oropharyngeal spasm 
 Posture abnormal 
 Posturing 
 Risus sardonicus 
 Tongue spasm 
 Uvular spasm 
 
Parkinson-like events 
 
 
SMQ Level: 2  
SMQ Code:  20000099 
 
Preferred Terms: 
 Akinesia 
 Bradykinesia 
 Cogwheel rigidity 
 Freezing phenomenon 
 Hypertonia 
 Masked facies 
 Muscle rigidity 
 On and off phenomenon 
 Parkinson's disease 
 Parkinsonian crisis 
 Parkinsonian gait 
 Parkinsonian rest tremor 
 Parkinsonism 


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 Parkinsonism hyperpyrexia syndrome 
 Resting tremor 
 Action tremor 
 Bradyphrenia 
 Drooling 
 Dysphonia 
 Extrapyramidal disorder 
 Gait disturbance 
 Hypokinesia 
 Micrographia 
 Mobility decreased 
 Motor dysfunction 
 Movement disorder 
 Muscle tone disorder 
 Musculoskeletal stiffness 
 Postural reflex impairment 
 Postural tremor 
 Tremor 
 Walking disability