Clinical trial NCT03188185
Conditions: Major Depressive Disorder
Keywords: Alkermes Major Depressive Disorder Treatment Refractory MDD ALKS 5461
Sponsor: Alkermes, Inc.
Start date: 2017-06-12; Completion date: 2020-03-05
Enrollment: 278 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, and tolerability of adjunctive ALKS 5461 in adults who have treatment refractory MDD.

Detailed description:

Arms: arm 1: Sublingual tablets arm 2: Sublingual tablets
Interventions: intervention 1: ALKS 5461 intervention 2: ALKS 5461 Placebo
Intervention descriptions: intervention 1: Samidorphan + buprenorphine, administered sublingually intervention 2: Placebo tablet, administered sublingually

Protocol documents:
Prot_000.pdf: 
A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 
5461 in Treatment Refractory Major Depressive Disorder 
 
 
Unique Protocol ID: 
ALK5461-217 
NCT Number: 
NCT03188185 
Date of Protocol:  
25 Jan 2018 
 


1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK5461-217 
 
 
Study title: 
A Phase 3b Efficacy and Safety Study of Adjunctive 
ALKS 5461 in Treatment Refractory Major Depressive 
Disorder 
Document version and date: 
v 3.0: (incorporates Amendment 2 [25 Jan 2018] and 
Administrative Change Memo 1 [10 Jul 2017]) 
v 2.0 (incorporates Amendment 1): 18 Apr 2017 
Original Protocol: 11 Jan 2017 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


 
 
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CONTACT INFORMATION 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone 
Alkermes Medical Monitors 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Telephone: 
 
Mobile Phone: 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Telephone: 
 
Mobile Phone: 
 
CRO Medical Monitor and 
(24-Hour Emergency Contact) 
 
 
Raleigh, NC 27604 USA 
Telephone: 
 
SAE and Pregnancy Reporting 
Safety 
and Pharmacovigilance 
FAX Number: 
 
E-mail: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of Investigational Product: ALKS 5461 
Name of Active Ingredient: Buprenorphine (BUP) and samidorphan (SAM) 
Title of Study: A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 5461 in Treatment Refractory 
Major Depressive Disorder 
Investigators: Multicenter, multinational study to be conducted at approximately 35 sites 
Study Period: 
Estimated date of first subject’s consent: Q2 2017 
Estimated date of last subject’s last visit: Q3 2021 
Phase of Development: 3b 
Objectives: 
• 
To evaluate the efficacy of adjunctive ALKS 5461 for treatment refractory major depressive 
disorder (MDD) in adults 
• 
To evaluate the safety and tolerability of adjunctive ALKS 5461 in adults who have treatment 
refractory MDD 
Methodology: This is a Phase 3b multicenter study of adjunctive ALKS 5461 2/2 that will utilize a 
randomized, double-blind, 2-stage, placebo-controlled, sequential parallel comparison design (SPCD). 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of adjunctive ALKS 5461 2/2 
(2 mg buprenorphine [BUP]/2 mg samidorphan [SAM]) sublingually (SL) once a day in male and female 
subjects with treatment refractory MDD (defined as having at least 2 inadequate responses to 
antidepressant therapies [ADTs] in the current major depressive episode [MDE]). ALKS 5461 2/2 or 
placebo will be administered to subjects for 5 weeks in Stage 1 and for 6 weeks in Stage 2 (see study 
design schematic below). 
Potential subjects will be evaluated during a Screening Period lasting up to 4 weeks. Screening will 
include an assessment of each subject’s history of inadequate response to ADT. Based on this assessment 
at Screening, qualifying subjects will either participate in an 8-week Prospective Lead-in (PLI) Period 
(prospective inadequate responders [PIRs]) or will be eligible to bypass the PLI Period and proceed 
directly to Stage 1 (historic inadequate responders [HIRs]). 
In Stage 1, a greater proportion of subjects will receive placebo than ALKS 5461 to ensure an adequate 
number of placebo nonresponders will be rerandomized in Stage 2. In Stage 1, all eligible subjects will be 
randomized 2:5 to receive either ALKS 5461 2/2 or placebo, respectively, for 5 weeks. Subjects receiving 
placebo in Stage 1 will be categorized as either placebo responders or nonresponders at the end of 
Stage 1. 
In Stage 2, subjects receiving ALKS 5461 2/2 in Stage 1 and subjects responding to placebo in 
Stage 1 will continue on placebo for 6 weeks (see study flow diagram). Placebo nonresponders will be 
rerandomized 1:1 to receive either ALKS 5461 2/2 or placebo for 6 weeks. 
From the beginning of Stage 1 to the end of Stage 2, all participating subjects will take study drug 
(ALKS 5461 2/2 or placebo) and continue to take an approved ADT. On Day 1 (Visit 2) and for the 
remainder of visits during the Treatment Period, subjects will self-administer study drug in the presence 
of study staff. Subjects will self-administer study drug at home on days where there are not study visits. 
During Stages 1 and 2, subjects will return to the clinic every week for assessments. Subjects will return 
to the clinic for a Safety Follow-up Visit (Visit 14) one week after Visit 13. The total study duration for a 
given subject will be up to approximately 24 weeks, which includes a Screening Period of up to 4 weeks, 


 
 
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a PLI Period of up to 8 weeks (if required as determined during Screening), two treatment periods of 5-
and 6-weeks duration (Stages 1 and 2 respectively), and a 1-week Follow-up Period. A schematic of the 
study design and a diagram depicting subject flow through the study are provided below. 
 
Study Design Schematic 
 
Study Flow Diagram 
 
Number of Subjects Planned: Approximately 450 subjects will be randomized in Stage 1. 
Main Criteria for Subject Inclusion: Male and female subjects between 18 and 70 years of age, 
inclusive, who meet Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) 
criteria for primary diagnosis of MDD, in which the current major depressive episode (MDE) has lasted at 
least 8 weeks (if entering the PLI Period) or 12 weeks (if bypassing the PLI Period) and up to 5 years, and 
have had an inadequate responses to adequate courses of treatment with selective serotonin reuptake 
inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) during the current MDE may be 
eligible for participation in this study. Subjects must also agree to use an acceptable method of 
contraception for the duration of the study and at least 30 days after the last dose of study drug unless 
surgically sterile or postmenopausal, and be willing and able to follow study procedures as outlined in the 
protocol. 
Investigational Product, Dosage, Duration, and Mode of Administration: ALKS 5461 consists of 
BUP and SAM in a 1:1 ratio. ALKS 5461 2/2 (2 mg BUP: 2 mg SAM) will be administered as a 
once-daily SL tablet for up to 11 weeks. 


 
 
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Reference Therapy, Dosage, Duration, and Mode of Administration: Placebo matched to ALKS 5461 
will be administered as a once-daily SL tablet for up to 11 weeks. 
Duration of Study: The total study duration will be up to approximately 24 weeks, which includes a 
Screening Period of up to 4 weeks, a PLI Period of up to 8 weeks (if required as determined during 
Screening), two treatment periods of 5- and 6-week duration (Stages 1 and 2 respectively) and a 1-week 
Safety Follow-up Period. 
Criteria for Evaluation: 
Primary Efficacy Endpoint: 
1. Average change from baseline to Week 3 to the end of treatment period in Montgomery-Åsberg 
Depression Rating Scale-6 (MADRS-6) scores 
2. Average change from baseline to Week 3 to the end of treatment period in Montgomery-Åsberg 
Depression Rating Scale-10 (MADRS-10) scores 
3. Change from baseline to the end of treatment period in MADRS-10 scores 
Secondary Efficacy Endpoints: 
• 
MADRS response, defined as a ≥50% reduction in MADRS-10 score from baseline to the end of 
treatment period 
• 
MADRS remission, defined as MADRS-10 score ≤10 
Exploratory Endpoints: 
• 
Change over time in Clinical Global Impression-Severity (CGI-S) scores 
• 
Absolute Clinical Global Impression-Improvement (CGI-I) scores over time 
• 
Change over time in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form 
(Q-LES-Q-SF) scores 
• 
Change over time in Brief Pain Inventory-Short Form (BPI-SF) scores 
• 
Change over time in Snaith-Hamilton Pleasure Scale (SHAPS) scores 
• 
Change over time in Connor-Davidson Resilience Scale (CD-RISC-25) scores 
Statistical Methods: Summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables, and number and percentage of subjects in each category for categorical 
variables) will be provided for evaluated variables. All individual subject level data will be presented as 
data listings. 
Study Populations: The Safety Population will consist of all enrolled subjects receiving at least one dose 
of study drug (placebo or ALKS 5461). The Full Analysis Set (FAS) population will consist of all 
subjects in the Safety Population who have at least one post-Baseline MADRS assessment. The 
Pharmacokinetic (PK) Population will consist of all subjects who have at least one measurable plasma 
concentration of any analyte during the Treatment Period. 
Efficacy Analyses: The primary endpoint analysis will be carried out using mixed-model repeated 
measures (MMRM) in the context of a Sequential Parallel Comparison Design (SPCD) for each endpoint 
analyzed within each Stage of the trial separately. The models will include variables for Treatment Group, 
Visit, Treatment group-by-visit interaction term, and site as categorical fixed effects. Baseline value and 
baseline by visit interaction will be included as covariates in the model. The comparisons of ALKS 5461 
2/2 vs placebo will be made, and the least-squares mean difference along with the corresponding 95% 
confidence interval and P-value will be reported. Adjustments for multiplicity of the primary endpoints 
will be made using a hierarchical testing approach with the order of testing being the rank order in which 
the primary endpoints are listed. 
Secondary efficacy endpoints (ie, proportion of subjects achieving treatment response and proportion of 


 
 
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subjects achieving remission at the end of the treatment period) will be evaluated using a chi-squared test. 
Further details will be described in the Statistical Analysis Plan (SAP). 
Pharmacokinetic Analyses: The PK data may be used in a subsequent population PK evaluation 
conducted outside of this study. By-subject listings of plasma concentrations will be provided. 
Safety Analyses: All safety assessments including those collected during the Follow-up Period and 
adverse events (AEs) collected in the PLI will be summarized using descriptive statistics. Reported AE 
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent AEs (TEAEs) will be defined as AEs that occur or worsen after the first dose of study drug. The 
incidence of TEAEs will be summarized by system organ classes and preferred terms and by severity and 
relationship to study drug. Subjects with SAEs, and AEs leading to discontinuation from the study will be 
summarized. Results of clinical laboratory tests, vital signs, and ECG parameters will also be summarized 
for the absolute value and for change from baseline. The number and percentage of subjects with 
potentially clinically significant (PCS) values will also be summarized. The number and percentage of 
subjects with C-SSRS assessments at post-Baseline will be summarized. Concomitant medications will be 
categorized using the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) 
classification system. Listings will be provided for all concomitant medications. 
Sample Size Considerations: Approximately 450 subjects are planned to be randomized in Stage 1 to 
have approximately 200 subjects rerandomized to treatment in Stage 2. This will provide at least 80% 
power to show superiority for ALKS 5461 2/2 compared to placebo at the one-sided alpha level 0.025, for 
each of the primary endpoints, assuming an effect size of at least 0.20 in Stage 1, 0.44 in Stage 2, and 
0.32 overall (weighted average of Stage 1 and Stage 2); and a SD of 6.25 and 8.5 for MADRS-6 and 
MADRS-10 scores, respectively. Details on the clinical study simulations conducted to evaluate power 
and type 1 error control will be provided in the SAP.  
Interim Analysis: A single interim analysis is planned when approximately 265 subjects have completed 
Stage 1 and approximately 120 subjects have completed Stage 2. A group sequential design with a single 
interim analysis for potential early efficacy conclusion stop is employed. The primary analysis will be 
based on the SPCD method of combination of treatment mean differences between treatments in Stages 1 
and 2. The interim analysis will be conducted by an external independent statistical center and reviewed 
by external data monitoring committee (DMC). Alkermes will remain blinded throughout the interim 
analysis. The one-sided P-value required for efficacy conclusion at both interim and final analyses is 
<0.0147 (constant significance levels (Pocock 1977) in order to control overall type 1 error at 0.025 in a 
one-sided test. Further details will be described in the SAP for interim analysis and charter guiding the 
independent DMC. 
 


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3.
TABLE OF CONTENTS
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................7 
4. 
LIST OF ABBREVIATIONS.....................................................................................12 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Study Dose Selection ..................................................................................................16 
5.2. 
Study Rationale and Selection of Study Design .........................................................16 
6. 
OBJECTIVES .............................................................................................................17 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................18 
7.1. 
Subject Inclusion Criteria ...........................................................................................18 
7.1.1. 
At Screening (Visit 1) .................................................................................................18 
7.1.1.1. 
All Subjects .................................................................................................................18 
7.1.1.2. 
Subjects Entering the Prospective Lead-in Period ......................................................18 
7.1.1.3. 
Subjects Bypassing the Prospective Lead-in Period (Historical Inadequate 
Responders) ................................................................................................................19 
7.1.2. 
Visit 2..........................................................................................................................20 
7.1.2.1. 
All Subjects .................................................................................................................20 
7.1.2.2. 
Subjects Participating in the Prospective Lead-in Period (Prospective 
Inadequate Responders) ..............................................................................................20 
7.2. 
Subject Exclusion Criteria ..........................................................................................20 
7.3. 
Subject Withdrawal ....................................................................................................23 
7.4. 
Replacement of Subjects .............................................................................................24 
8. 
STUDY DESIGN .......................................................................................................25 
8.1. 
Overall Study Design and Plan ...................................................................................25 
8.1.1. 
Screening Period (Visit 1) ..........................................................................................26 
8.1.2. 
Prospective Lead-in Period (Visits 1a-1f) ..................................................................27 
8.1.3. 
Stage 1 (Visits 2-7) .....................................................................................................28 
8.1.4. 
Stage 2 (Visits 8-13) ...................................................................................................28 
8.1.5. 
Safety Follow-up Period (Visit 14) .............................................................................28 
8.2. 
Schedule of Visits and Assessments ...........................................................................28 


 
 
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8.3. 
Study Procedures Descriptions ...................................................................................34 
8.3.1. 
Informed Consent .......................................................................................................34 
8.3.2. 
Eligibility Review .......................................................................................................34 
8.3.3. 
Demographics and Medical History ...........................................................................34 
8.3.4. 
Concomitant Medication Review ...............................................................................34 
8.3.5. 
Substance Use .............................................................................................................35 
8.3.6. 
Vital Signs and Weight ...............................................................................................35 
8.3.7. 
Physical Examination and Height ...............................................................................35 
8.3.8. 
12-Lead Electrocardiogram ........................................................................................35 
8.3.9. 
Structured Interviews and Questionnaires ..................................................................36 
8.3.9.1. 
Assessments for Study Eligibility ...............................................................................36 
8.3.9.2. 
Safety Assessments .....................................................................................................37 
8.3.9.3. 
Efficacy Assessments .................................................................................................37 
8.3.9.4. 
Exploratory Assessments ............................................................................................37 
8.3.10. 
Laboratory Assessments .............................................................................................38 
8.3.10.1. 
Serology Testing .........................................................................................................38 
8.3.10.2. 
Breath Alcohol Test ....................................................................................................38 
8.3.10.3. 
Urine Drug Screen ......................................................................................................38 
8.3.10.4. 
Pregnancy Testing ......................................................................................................39 
8.3.10.5. 
Hematology, Biochemistry, and Urinalysis ................................................................39 
8.3.11. 
Pharmacokinetic Sampling for Study Drug and Antidepressant Therapy 
Concentrations ............................................................................................................41 
8.3.12. 
Drug Dispensation and Reconciliation .......................................................................41 
8.3.12.1. 
Review of Text Message Adherence Reminder Use ..................................................41 
8.3.13. 
Adverse Event Monitoring .........................................................................................41 
8.4. 
Study Requirements and Restrictions .........................................................................41 
8.4.1. 
Contraception and Pregnancy .....................................................................................41 
8.4.2. 
Concomitant Medications ...........................................................................................42 
8.4.2.1. 
Medications Requiring Washout ................................................................................43 
8.4.2.2. 
Permitted Medications ................................................................................................43 
8.4.2.3. 
Prohibited Medications ...............................................................................................45 
9. 
TREATMENT OF SUBJECTS ..................................................................................47 
9.1. 
Study Drug Dose and Administration .........................................................................47 


 
 
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9.1.1. 
Description of ALKS 5461 and Placebo ....................................................................47 
9.1.2. 
Study Drug Dose and Dosing Regimen ......................................................................47 
9.2. 
Treatment Adherence of Study Drug and ADT ..........................................................47 
9.3. 
Method of Assigning Subjects to Treatment ..............................................................48 
9.4. 
Blinding and Unblinding ............................................................................................48 
9.4.1. 
Blinding ......................................................................................................................48 
9.4.2. 
Unblinding ..................................................................................................................48 
9.5. 
Study Drug and Antidepressant Therapy Dose Adjustment and Stopping 
Rules ...........................................................................................................................49 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................50 
10.1. 
Study Drug ..................................................................................................................50 
10.2. 
Packaging and Labeling ..............................................................................................50 
10.3. 
Storage ........................................................................................................................50 
10.4. 
Accountability .............................................................................................................50 
10.5. 
Handling and Disposal ................................................................................................51 
11. 
ASSESSMENT OF EFFICACY ................................................................................52 
11.1. 
Primary Efficacy Endpoint .........................................................................................52 
11.2. 
Secondary Efficacy Endpoints ....................................................................................52 
11.3. 
Exploratory Endpoints ................................................................................................52 
12. 
ASSESSMENT OF PHARMACOKINETICS ...........................................................53 
13. 
ASSESSMENT OF SAFETY .....................................................................................54 
13.1. 
Definition of Adverse Event .......................................................................................54 
13.2. 
Definition of a Serious Adverse Event .......................................................................54 
13.3. 
Relationship to Study Drug ........................................................................................55 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................57 
13.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................57 
14. 
STATISTICS ..............................................................................................................58 
14.1. 
Sample Size Considerations .......................................................................................58 
14.2. 
General Statistical Methodology ................................................................................58 
14.2.1. 
Study Populations .......................................................................................................58 
14.2.1.1. 
Safety Population ........................................................................................................58 
14.2.1.2. 
Full Analysis Set .........................................................................................................58 
14.2.1.3. 
Pharmacokinetic Population .......................................................................................58 


 
 
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14.3. 
Demographics and Baseline Characteristic Data ........................................................58 
14.4. 
Efficacy Analyses .......................................................................................................59 
14.5. 
Pharmacokinetic Analyses ..........................................................................................59 
14.6. 
Patient Questionnaire ..................................................................................................59 
14.7. 
Safety and Tolerability Analyses ................................................................................59 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................62 
15.1. 
Study Monitoring ........................................................................................................62 
15.2. 
Audits and Inspections ................................................................................................62 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................62 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 
16.1. 
Case Report Forms .....................................................................................................63 
16.2. 
Confidentiality of Data ...............................................................................................63 
17. 
ETHICAL CONSIDERATIONS................................................................................64 
17.1. 
Ethics Review .............................................................................................................64 
17.2. 
Ethical Conduct of the Study ......................................................................................64 
17.3. 
Written Informed Consent ..........................................................................................64 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................66 
18.1. 
Data Capture ...............................................................................................................66 
18.2. 
Inspection of Records .................................................................................................66 
18.3. 
Retention of Records ..................................................................................................66 
18.4. 
Use of Information and Publication Policy ................................................................67 
19. 
REFERENCES ...........................................................................................................68 
20. 
APPENDIX A: MASSACHUSETTS GENERAL HOSPITAL 
ANTIDEPRESSANT TREATMENT RESPONSE QUESTIONNAIRE 
(ATRQ)–SAMPLE .....................................................................................................70 
21. 
APPENDIX B: DAILY DOSING TABLE FOR ANTIDEPRESSANT 
THERAPY TAKEN DURING THE STUDY ............................................................77 
22. 
APPENDIX C: PATIENT QUESTIONNAIRE .........................................................78 
23. 
APPENDIX D: MAXIMUM DOSES OF ANTIPSYCHOTICS APPROVED 
FOR MDD ..................................................................................................................79 
24. 
APPENDIX E: PARTIAL LIST OF PROHIBITED CYTOCHROME P450 
(CYP) 3A4 INHIBITORS AND INDUCERS ............................................................80 
 


 
 
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LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ..........................................................12 
Table 3: 
Schedule of Assessments ............................................................................................29 
Table 4: 
Schedule of Assessments: Prospective Lead-in Period ..............................................33 
Table 5: 
Clinical Laboratory Assessments ...............................................................................40 
Table 6: 
Medications Requiring Washout Prior to Visit 2 .......................................................43 
Table 7: 
Adverse Event Causality Guidelines ..........................................................................56 
Table 8: 
Daily Dosing Allowed for Antidepressant Therapy Taken During the Study ............77 
Table 9: 
Maximum antipsychotic approved doses for MDD ....................................................79 
Table 10: Partial List of Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers .......................80 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................25 
Figure 2: 
Study Flow Diagram ...................................................................................................26 
 


 
 
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4. 
LIST OF ABBREVIATIONS 
Table 2: 
List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Full Form or Definition 
ADT 
Antidepressant therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (classification system) 
ATRQ 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
BPI-SF 
Brief Pain Inventory-Short Form 
BUP 
Buprenorphine 
CD-RISC-25 
Connor-Davidson Resilience Scale 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
COWS 
Clinical Opiate Withdrawal Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSA 
Clinical Study Agreement 
CST 
Clinical Surveillance Team 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual for Mental Disorders-Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
17-item Hamilton Rating Scale for Depression 
HIR 
Historic inadequate responders 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 


 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form or Definition 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IxRS 
Interactive Voice or Web Response System 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MADRS-6  
 
The sum of 6 MADRS items: reported sadness (item 1); apparent sadness 
(item 2); inner tension (item 3); lassitude (item 7); inability to feel 
(item 8); and pessimistic thoughts (item 9) 
MADRS-10  
 
The sum of 10 MADRS items: reported sadness (item 1), apparent 
sadness (item 2), inner tension (item 3), reduced sleep (item 4), reduced 
appetite (item 5), concentration difficulties (item 6), lassitude (item 7), 
inability to feel (item 8), pessimistic thoughts (item 9), and suicidal 
thoughts (item 10) 
MAOIs 
Monoamine oxidase inhibitors 
MDD 
Major depressive disorder 
MDE 
Major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI v7.0.2 
Mini International Neuropsychiatric Interview 7.0.2 
MMRM 
Mixed model repeated measures 
OTC 
Over-the-counter 
PIR 
Prospective inadequate responders 
PK 
Pharmacokinetics 
PLI 
Prospective lead-in 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form 
QTcB 
QT interval corrected using the Bazett formula 
QTcF 
QT interval corrected using the Fridericia formula 
SAE 
Serious adverse event 
SAM 
Samidorphan 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SIGH-D 
Structured Interview Guide for the HAM-D 
SIGMA 
Structured Interview Guide for the MADRS 


 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form or Definition 
SL 
Sublingual 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SPCD 
Sequential parallel comparison design 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 


 
 
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5. 
INTRODUCTION 
Major depressive disorder (MDD) is a serious, and in some cases life-threatening, condition. 
Current therapy is limited and insufficient. Selective serotonin reuptake inhibitors (SSRI) or 
serotonin-norepinephrine reuptake inhibitors (SNRI) are recommended as first-line therapy; 
however, the large majority of patients do not experience an adequate response (Rush et al, 
2006). For patients with MDD who have an inadequate response to approved first-line 
antidepressant therapy (ADT) the only currently approved agents for adjunctive treatment are 
atypical antipsychotics. However, this class of medicines is associated with serious toxicity, 
including tardive dyskinesia, which may be irreversible, as well as neuroleptic malignant 
syndrome and agranulocytosis, both of which are potentially fatal. Further, metabolic adverse 
effects of some antipsychotics contribute to significant long term co-morbidity, eg, increased 
adiposity, insulin-resistance, cardiovascular disease etc (Newcomer and Haupt 2006). These 
conditions and other side effects of the atypical antipsychotics commonly lead to discontinuation 
of treatment (Spielmans et al, 2013). 
The development of an adjunctive treatment that avoids the toxicity associated with atypical 
antipsychotics is an important step toward addressing the suboptimal treatment of MDD and the 
related public health consequences. The Sponsor is developing ALKS 5461, a fixed-dose, 
combination tablet consisting of buprenorphine (BUP) and samidorphan (SAM) in a 
1:1 (weight/weight) ratio for once-daily, sublingual (SL) administration as an adjunctive therapy 
to antidepressants for the treatment of MDD. 
ALKS 5461 consists of a combination of BUP, a µ-opioid receptor partial agonist that also 
blocks κ-opioid activation and SAM, a potent, µ-opioid receptor antagonist. ALKS 5461 offers a 
unique mechanism of action for the treatment of MDD: modulation of the opioid system. 
ALKS 5461 is intended to support opioid tone in brain regions with impaired endogenous 
activity and dampen opioid tone in upregulated region. From 1982 to the present, there have 
been several published studies of BUP in depressed patients (Bodkin et al, 1995; Emrich et al, 
1982; Karp et al, 2014; Nyhuis et al, 2008). These studies demonstrated striking antidepressant 
effects with BUP treatment, particularly in patients with MDD who have had multiple prior 
inadequate responses to therapy. Despite this evidence of efficacy with BUP, the risk of 
diversion, abuse and dependence have precluded routine clinical use of BUP, and opioids in 
general, in the treatment of depression. ALKS 5461 was specifically designed to confer 
therapeutic benefits in the treatment of depression through the opioid system, while addressing 
the risk of abuse or addiction and dependence potential normally associated with opioids. SAM 
(a μ-opioid receptor antagonist) is a new molecular entity optimized for high potency and high 
SL bioavailability, which facilitates coformulation with BUP (a μ-opioid receptor partial agonist) 
for SL administration. 
Efficacy has been observed with ALKS 5461 in subjects with MDD in a Phase 2 study 
(Study ALK5461-202), and several Phase 3 studies have recently completed. Although the 
primary endpoint was not met for one Phase 3 study (Study ALK5461-205), supportive evidence 
of the efficacy of ALKS 5461 in the treatment of MDD was observed. In a differently designed 
Phase 3 study (Study ALK5461-206) ALKS 5461 2/2 showed improvement vs Baseline; 
however, the net treatment effect was obscured by a large placebo effect. The third Phase 3 study 


 
 
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(Study ALK5461-207) of ALKS 5461 in MDD met the pre-specified primary endpoints of 
significantly reducing depression scores compared to placebo, as measured by MADRS-6 and 
MADRS-10. The Phase 3 long-term safety study (Study ALK5461-208) for ALKS 5461 is 
ongoing. In the completed studies with ALKS 5461, ALKS 5461 was generally well-tolerated. 
Altogether these findings support continued investigation of ALKS 5461 and indicate that it has 
the potential to address an unmet medical need for treatment of the serious condition of MDD. 
Results from nonclinical and clinical investigations available to date on the pharmacokinetics 
(PK), safety, and efficacy of ALKS 5461, as well as of SAM and BUP as individual and 
coadministered therapeutic agents, are summarized in the ALKS 5461 Investigator’s Brochure. 
5.1. 
Study Dose Selection 
In the completed studies with ALKS 5461, ALKS 5461 was generally well-tolerated. In 
Phase 2 and Phase 3 studies, data on the short-term and long-term safety and tolerability of 
ALKS 5461 have been and are being collected. The selected dose of ALKS 5461 2/2 in the 
current study is supported by clinical safety, tolerability and efficacy data from prior studies of 
ALKS 5461. 
5.2. 
Study Rationale and Selection of Study Design 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of adjunctive 
ALKS 5461 2/2 (2 mg BUP/ 2 mg SAM) SL once a day in male and female subjects with 
treatment refractory MDD (defined as having at least 2 inadequate responses to antidepressant 
therapies [ADTs] in the current major depressive episode [MDE]). This study will utilize a 
sequential parallel comparison design (SPCD) that is intended to address high placebo response 
common to clinical trials in MDD. The study will employ two treatment stages, with the majority 
of subjects in the first treatment stage randomized to placebo. Subjects randomized to placebo in 
Stage 1 who do not exhibit a response (ie, placebo nonresponders) will be rerandomized in Stage 
2. All other subjects will receive placebo. The efficacy analysis will be performed on the full 
analysis set (FAS) and include (a) subjects in Stage 1 and (b) subjects in Stage 2 who were 
placebo nonresponders in Stage 1. Efficacy will be evaluated as the weighted average of the 
efficacy estimates from individual stages. The duration of Stage 1 and Stage 2 will be 5 and 6 
weeks, respectively.   


 
 
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6. 
OBJECTIVES 
The objectives of this study are: 
• To evaluate the efficacy of adjunctive ALKS 5461 for treatment refractory MDD in 
adults 
• To evaluate the safety and tolerability of adjunctive ALKS 5461 in adults who have 
treatment refractory MDD 


 
 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Note that an inadequate response to ADT is defined as <50% reduction in symptom severity to a 
course of treatment at an adequate dose at least 8 weeks in duration, inclusive of up to 3 weeks of 
titration into the adequate dose range, as assessed by the Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (ATRQ). Even if this antidepressant is taken 
concomitantly with a second antidepressant, for the purposes of this study, only one ADT 
inadequate response will be considered. 
An adequate dose of an ADT is defined as a dose that is greater than or equal to the minimum 
dose on the ATRQ (see Section 20). Note that ADTs taken during the study may not exceed the 
maximum daily dose listed in Section 21. 
7.1. 
Subject Inclusion Criteria 
7.1.1. 
At Screening (Visit 1) 
7.1.1.1. 
All Subjects 
Each subject must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
1. Be willing and able to provide government issued identification. If government issued 
identification does not contain a photograph, a second form of photographic identification 
will be required 
2. Is between 18 and 70 years of age, inclusive 
3. Be willing and able to provide informed consent 
4. Be willing and able to provide informed consent for assessment of participation in 
multiple clinical studies via a clinical study subject registry 
5. Have a body mass index (BMI) of 18.0 to ≤40.0 kg/m2 
6. Is willing to abide by the contraception requirements for the duration of the study (please 
refer to Section 8.4.1 for additional details regarding contraception) 
7. Have a Diagnostic and Statistical Manual for Mental Disorders-Fifth Edition (DSM-5) 
primary diagnosis of MDD as assessed and confirmed by the Mini International 
Neuropsychiatric Interview 7.0.2 ([MINI v7.0.2] administered by qualified site staff); 
primary diagnosis is defined as the primary source of current distress and functional 
impairment, in the opinion of the Investigator 
8. Be willing and able to follow the study procedures and visits as outlined in the protocol 
(including agreeing not to enroll in any other clinical studies) 
7.1.1.2. 
Subjects Entering the Prospective Lead-in Period 
In addition to the general inclusion criteria listed in Section 7.1.1.1, in order to qualify for 
participation in this study, each subject entering the PLI Period must meet all of the following 
criteria: 


 
 
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9. Have a current MDE with duration of at least 8 weeks and up to 5 years at Screening 
10. One of the following: 
a. Not be currently taking any ADT  
b. SSRI or SNRI being taken for the current MDE is not at an adequate dose and/or 
duration is ≤4 weeks  
c. Is experiencing an inadequate response to their current ADT and switching ADT is in 
in the best interest of the subject per investigator judgment and ADT will be 
discontinued 2 weeks prior to Visit 1a 
11. Have 1 to 3 prior inadequate responses to ADT in the current MDE at Screening/Visit 1. 
Prior inadequate response within the current MDE must be to an ADT medication listed 
on the ATRQ (see Section 8.3.9.1.1) 
12. Have a 17-item Hamilton Rating Scale for Depression (HAM-D) total score ≥22 at 
Screening/Visit 1 and at PLI Visit 1a 
7.1.1.3. 
Subjects Bypassing the Prospective Lead-in Period (Historical Inadequate 
Responders) 
In addition to the general inclusion criteria listed in Section 7.1.1.1, in order to qualify for 
participation in this study, each subject bypassing the PLI Period must meet all of the following 
criteria: 
13. Have a current MDE duration of at least 12 weeks and up to 5 years at Screening 
14. Currently treated with an SSRI or SNRI (ie, paroxetine, fluoxetine, sertraline, citalopram, 
escitalopram, vilazodone, vortioxetine, venlafaxine, duloxetine, desvenlafaxine, or 
levomilnacipran) for at least 8 weeks at Visit 2. The 8 weeks of ADT is inclusive of up to 
3 weeks for titration into the adequate dose range, with the same, adequate dose over the 
last 4 weeks that is expected to remain stable throughout the study and which does not 
exceed the labeled maximum daily dose. The 8 weeks of ADT may include up to 28 days 
of the Screening Period 
15. Have an inadequate response to current ADT treatment1 
16. Have 2 to 4 inadequate responses to ADT (inclusive of current inadequate response) in 
the current MDE by Visit 22. Prior inadequate response within the current MDE must be 
to an ADT medication listed on the ATRQ (see Section 8.3.9.1.1) 
17. Have a HAM-D total score ≥18 at Screening 
 
1 HIR subjects can enter the study as a PIR if the subject is experiencing an inadequate response to their 
current ADT and switching ADT is in the best interest of the subject per investigator judgment. ADT will 
then be discontinued 2 weeks prior to Visit 1a of the PLI. 
 
2At Screening, HIR subjects who are on an adequate dose of ADT, but whose ADT duration 
is >4 and <8 weeks, may complete the remaining duration requirement (<4 weeks) in the Screening 
Period (ie, before Visit 2). 


 
 
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Note for inclusion criteria 11, 14, and 16: If a subject experienced an adequate response to an 
ADT for at least 4 weeks and subsequently relapsed (tachyphylaxis), but remained on the same 
ADT at the same or lower dose, this would not represent an inadequate response to the ADT. 
7.1.2. 
Visit 2 
7.1.2.1. 
All Subjects 
In addition to the general inclusion criteria listed in Section 7.1.1.1, in order to qualify for 
participation in this study, each subject must meet all of the following criteria: 
18. Have 2 to 4 inadequate responses to ADT within the current MDE 
19. Have confirmation of ADT medication history  
20. Have detectable concentrations of approved ADT during Screening or PLI Period as 
assessed by PK sampling 
21. Have a site-administered HAM-D total score ≥18 at Visit 2 
22. Have a Clinical Global Impression-Severity (CGI-S) score of ≥4 at Visit 2 
23. Have met criteria for HIR/PIR as determined by an interactive voice or web response 
system (IxRS) at Visit 2 
7.1.2.2. 
Subjects Participating in the Prospective Lead-in Period (Prospective 
Inadequate Responders) 
In addition to the general inclusion criteria listed in Section 7.1.1.1 and Section 7.1.2.1, in order 
to qualify for participation in this study, each subject participating in the PLI Period must meet 
all of the following criteria: 
24. Have been treated during the PLI Period with escitalopram, sertraline, duloxetine, 
venlafaxine, or fluoxetine for at least 8 weeks, inclusive of up to 3 weeks of titration into 
the adequate dose range, with the same adequate dose over the last 4 weeks that does not 
exceed the labeled maximum daily dose. Note that if the subject cannot tolerate the 
selected ADT upon treatment initiation, it is acceptable to switch to another one of the 
5 available ADTs within the first week of treatment, as deemed appropriate by the 
Investigator. The second ADT must then be taken for at least 7 weeks and in the adequate 
dose range for at least 5 weeks, with the same dose over the last 4 weeks that does not 
exceed the maximum daily dose 
25. Have met additional masked criteria for PIR as determined by an IxRS at Visit 1f 
7.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions to be qualified to participate in this 
study. 
1. Has any finding that in the view of the Investigator or Medical Monitor would 
compromise the safety of the subject or affect their ability to adhere to the protocol visit 
schedule or fulfill visit requirements 


 
 
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2. Has any other significant medical condition (eg, neurological, psychiatric, or metabolic) 
or clinical symptom that could unduly risk the subject or affect the interpretation of study 
data (eg, unstable hypothyroidism or active cancer or treatment for cancer within the last 
5 years [with the exception of non-melanomatous skin cancers], poorly controlled 
diabetes [HbA1c > 9.0], or gastric bypass) 
3. Has any current primary DSM-5 diagnosis other than MDD, where primary diagnosis is 
defined as the primary source of current distress and functional impairment, in the 
opinion of the Investigator 
4. Have any of the following psychiatric conditions per DSM-5 criteria, as assessed by the 
MINI v7.0.2. Conditions not assessable by the MINI v7.0.2 should be assessed by clinical 
judgment: 
a. Lifetime history of a diagnosis of delirium, dementia, schizophrenia, or other 
psychotic disorder (including psychotic depression), or bipolar I or II disorder 
b. History within the past 12 months of a DSM-5 diagnosis of eating disorder, 
obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, or acute 
stress disorder 
c. Clinically significant current DSM-5 diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal, or histrionic personality disorder 
d. Current diagnosis or clinical evidence of any cognitive disorder at Screening 
5. Has experienced hallucinations, delusions, or any psychotic symptoms in the current 
MDE 
6. Has been hospitalized for MDD within 3 months before Screening 
7. Has initiated any psychosocial intervention (eg, psychotherapy, support group, or social 
counseling) within 6 weeks of Screening or have an anticipated need for initiating any 
psychosocial intervention during the study in the judgment of the Investigator and/or 
Medical Monitor. A stable course of any psychosocial intervention initiated >6 weeks 
prior to Screening is permitted to continue throughout the study 
8. Has used: 
a. Antipsychotics other than quetiapine or quetiapine XR, oral aripiprazole, 
olanzapine/fluoxetine, or brexpiprazole with 1 year of screening or within the current 
MDE, whichever is longer3 
b. Any long-acting antipsychotic (lifetime) 
c. Ketamine (lifetime) 
d. A course of pharmacotherapy (including prescription or over the counter medications) 
or natural supplements for insomnia, if initiated within 30 days of screening 
 
 
3 Number of subjects treated with antipsychotics within the current MDE prior to enrollment will be monitored 
throughout the study. The Sponsor reserves the right to restrict subjects entering the study with the goal of achieving 
fewer than 30% of subjects with previous exposure to antipsychotics within the current MDE. This threshold of 30% 
is approximate and it is recognized that that the final proportion might be lower or higher. 


 
 
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9. Started on a prohibited medication between Screening and Visit 2 other than those being 
washed out as indicated in the prohibited medications requiring washout (see 
Section 8.4.2.1) 
10. Has used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid 
antagonists (eg, naloxone, naltrexone) within 14 days prior to Screening, has an 
anticipated need for opioid use at any point during the study (eg, planned surgery), or has 
used an extended-release formulation of an opioid antagonist within 2 months prior to 
Screening 
11. Subject is unwilling to discontinue the use of prohibited medications or the Investigator 
recommends against discontinuation of prohibited medications 
12. Has received electroconvulsive therapy treatment within the last 2 years or within the 
current MDE or failed a course of electroconvulsive treatment at any time 
13. Poses a current suicide risk, as evidenced by any of the following: 
a. In the opinion of the Investigator, the subject may be at risk for suicide 
b. The subject responds “Yes” to Question 4 (“Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan”) or Question 5 (“Active Suicidal Ideation with 
Specific Plan and Intent”) on the Baseline/Screening Columbia-Suicide Severity 
Rating Scale (C-SSRS), within the past 12 months 
c. The subject has attempted suicide within the past 2 years 
14. Has a QT interval >450 msec for males and >470 msec for females, assessed in a relaxed 
state, as corrected by the Fridericia formula (QTcF) observed at Visit 1 or 2 
15. Has an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
measurement of >2 × the upper limit of normal (ULN) at Visit 1 
16. Has current evidence of or history of any of the following: 
a. Compromised respiratory function (eg, chronic obstructive pulmonary disease, 
respiratory depression, signs or symptoms of hypoxia at Screening) 
b. Thyroid pathology (unless stabilized and euthyroid for >3 months at the time of 
Screening) 
c. Seizure disorder (excluding febrile seizures) 
d. Hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection 
e. Myasthenia gravis 
f. Any contraindicated medical condition as per the approved labeling for BUP 
17. Has current evidence of or a history (in the past 12 months) of alcohol or substance use 
disorder (excluding tobacco) per DSM-5 criteria as assessed by the MINI v7.0.2 
18. Has a positive breath alcohol test at Screening or Visit 2 
19. Has a positive test for drugs of abuse at Screening or Visit 2 (excluding drugs that are 
permitted as per protocol; see Section 8.4.2.2) 
20. Is pregnant, planning to become pregnant, or is breastfeeding during the study 
21. Has a history of either of the following: 
a. Severe gastrointestinal intolerance, allergy, or hypersensitivity to opioid agonists (eg, 
BUP, oxycodone) or opioid antagonists (eg, naltrexone, naloxone) 


 
 
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b. Nausea and/or vomiting when taking an opioid agonist or opioid antagonist that 
interfered with the ability to continue on the drug 
22. Has had a significant blood loss (>500 mL) or blood donation (including platelets or 
plasma) within 60 days of Screening or between Screening and Randomization or 
anticipated blood donation at any time during the study 
23. Has participated or is currently participating in any of the following: 
a. An interventional clinical study for any indication (except for MDD) within the last 
2 years 
b. An interventional clinical study for MDD within the past 6 months 
24. Has participated or is currently participating in the double-blind portion or open-label 
extension phase of a prior clinical study of ALKS 5461 
25. Is an employee of the Investigator or study center, or immediate family4 of such 
employees or the Investigator 
26. Is an employee or immediate family4 of an employee (permanent, temporary contract 
worker, or designee responsible for the conduct of the study) of Alkermes or designated 
clinical research organization 
7.3. 
Subject Withdrawal 
Subjects who do not qualify at Visit 2, including subjects who complete the PLI Period but who 
are not randomized into Stage 1, will be considered screen failures. Subjects who are screen 
failures may be eligible for rescreening only if rescreening is approved by the Medical Monitor. 
Subjects who withdraw after entering treatment (Stage 1 or 2) will not be replaced. Subjects are 
considered to have completed the study if they completed visits spanning the duration of the 
Treatment Period and the Safety Follow-up Visit. 
A subject may be withdrawn from the study at any time if the subject, Investigator, or Sponsor or 
designee determines that it is not in the best interest of the subject to continue. 
Examples of reasons for withdrawal may include, but are not limited to, the following: 
• Adverse Event (AE) 
• Lack of efficacy 
• Physician’s decision 
• Pregnancy 
• Protocol deviation (including noncompliance with study drug or study procedures) 
• Withdrawal by subject 
• Lost to follow-up 
• Study terminated by Sponsor 
• Other 
 
4 Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. 


 
 
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Subjects may not enter another clinical study while participating in this study. If entry in another 
clinical study is confirmed by subject report or through confirmation using a clinical study 
subject registry, the subject will be withdrawn from the study. 
If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the Investigator, or until the subject is deemed by the 
Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is necessary to 
monitor a subject beyond the Safety Follow-up Visit, the Follow-up Period may be extended as 
necessary. In such instances, the Sponsor and the Investigator will agree to an acceptable 
follow-up schedule. 
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Subjects are to be asked to return to the clinic for an Early Termination (ET) Visit. The 
ET visit should be scheduled as close as possible to the subject’s last dose and will mimic the 
assessments scheduled to be conducted at Visit 13. Additionally, an attempt will be made to 
schedule a Follow-up Visit 1 week after the subject’s last dose equivalent to Visit 14. If the 
subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. 
The Investigator must maintain a record of all subjects who fail to complete the study. A full 
explanation of the reason for study discontinuation will be made on the appropriate electronic 
case report form (eCRF). The reason for discontinuation will be documented. If a subject is lost 
to follow-up, reasonable attempts to contact the subject must be made and documented. 
7.4. 
Replacement of Subjects 
Subjects who withdraw after entering treatment (Stages 1 or 2) will not be replaced. 


 
 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of adjunctive 
ALKS 5461 2/2 (2 mg BUP/2 mg SAM) SL once a day in male and female subjects with 
treatment refractory MDD. This is a Phase 3b multicenter study of adjunctive ALKS 5461 2/2 
that will utilize a SPCD, which is intended to address high placebo response common to clinical 
trials in MDD. The study will employ two treatment stages, with the majority of subjects in the 
first treatment stage randomized to placebo (ie, Stage 1 randomization ratio 2:5 for ALKS 5461 
2/2:placebo, respectively). Subjects randomized to placebo in Stage 1 who do not exhibit a 
response (ie, placebo nonresponders) will be rerandomized in Stage 2 to ALKS 5461 2/2 or 
placebo in a 1:1 ratio. All other subjects will receive placebo. The efficacy analysis will be 
performed on the FAS population and include (a) subjects in Stage 1 and (b) subjects in Stage 2 
who were placebo nonresponders in Stage 1. Efficacy will be evaluated as the weighted average 
of the efficacy estimates from individual stages. The duration of Stage 1 and Stage 2 will be 
5 and 6 weeks, respectively. 
ALKS 5461 2/2 (plus current, approved ADT) or placebo (plus current, approved ADT) will be 
administered to subjects for 5 weeks in Stage 1 and for 6 weeks in Stage 2 (see Figure 1). For the 
purpose of ensuring the integrity of the study and minimizing expectancy effects, certain study 
design details (eg, criteria used to define Stage 1 nonresponders) are not fully described in this 
protocol; such details are further described within a separate restricted-access unmasked protocol 
addendum. 
During Stages 1 and 2, subjects will return to the clinic every week for assessments. Subjects 
will return to the clinic for a Safety Follow-up Visit (Visit 14), 1 week after Visit 13. The total 
study duration for a given subject will be up to approximately 24 weeks, which includes a 
Screening Period of up to 4 weeks, an 8-week PLI Period (if required as determined during 
Screening), two treatment periods of 5- and 6-weeks duration (Stages 1 and 2 respectively) and a 
1-week Follow-up Period. 
A schematic of the study design is provided below in Figure 1. A diagram depicting subject flow 
through the study is provided in Figure 2. 
Figure 1: Study Design Schematic 
 


 
 
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Figure 2: 
Study Flow Diagram 
 
Details regarding assessments in Stages 1 and 2 and the Follow-up Period are provided in 
Section 8.1.3, Section 8.1.4, and Section 8.1.5, respectively. Details regarding visit-specific 
study procedures are provided in Section 8.3. 
8.1.1. 
Screening Period (Visit 1) 
Potential subjects will be evaluated during a Screening Period lasting up to 4 weeks. Screening 
will include an assessment of each subject’s history of inadequate response to ADT. Based on 
this assessment at Screening, qualifying subjects will either participate in an 8-week PLI Period 
(prospective inadequate responders [PIRs]) or will be eligible to bypass the PLI Period and 
proceed directly to Stage 1 (historic inadequate responders [HIRs]). Throughout the PLI Period, 
subjects will return to the clinic for brief assessments. 
All HIR subjects who are on an adequate dose of ADT at the Screening Visit, but whose ADT 
duration is more than 4 weeks and less than 8 weeks, may complete the remaining dosing 
duration requirement in the Screening Period. 
Subjects will be eligible to bypass the PLI Period if at Screening they meet all of the following 
criteria: 
• Have a current MDE duration of at least 12 weeks and up to 5 years at Screening 
• Currently treated with an SSRI or SNRI for at least 8 weeks at Visit 2. The 8 weeks 
of ADT is inclusive of up to 3 weeks for titration into the adequate dose range, with 
the same, adequate dose over the last 4 weeks that is expected to remain stable 
throughout the study and which does not exceed the labeled maximum daily dose 
• Have an inadequate response to current ADT treatment 
• Have 2 or 3 inadequate responses to ADT (inclusive of current inadequate response) 
in the current MDE. Prior inadequate response within the current MDE must be to an 
ADT medication listed on the ATRQ 
• Have a HAM-D total score ≥18 at Screening 


 
 
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• Have met criteria for HIR as determined by an interactive voice or web response 
system (IxRS) at Visit 2 
The prior inadequate response during the current MDE (if any) must have been to an ADT listed 
on the ATRQ and may be at any dose that exceeds the minimum dose listed on the ATRQ. 
8.1.2. 
Prospective Lead-in Period (Visits 1a-1f) 
Subjects will participate in the 8-week prospective lead-in if, at Screening/Visit 1, they meet all 
of the following criteria: 
• Have a current MDE with duration of at least 8 weeks and up to 5 years at 
Screening/Visit 1; 
• Are not currently taking an ADT OR whose SSRI or SNRI taken for the current MDE 
is not at an adequate dose (see Section 21) or if the duration is ≤ 4 weeks OR subject 
is experiencing an inadequate response to their current ADT and switching ADT is in 
the best interest of the subject per investigator judgment and ADT will be 
discontinued 2 weeks prior to Visit 1a; 
• Have had 1 to 3 prior inadequate responses to an ADT (as listed in Section 21) in the 
current MDE at Screening/Visit 1 (prior inadequate response within the current MDE 
must be to an ADT listed in Section 21); and 
• Have a HAM-D total score of ≥22 at Screening/Visit 1 and at PLI Visit 1a 
Note: If a subject experienced an adequate response to an ADT for at least 4 weeks and 
subsequently relapsed (tachyphylaxis), but remained on the same ADT at the same or lower 
dose, this would not represent an inadequate response to the ADT. 
Subjects who participate in the PLI Period will receive open-label administration of one of the 
following approved ADTs after meeting entry criteria at Visit 1a (HAM-D total 
score ≥22): escitalopram, sertraline, duloxetine, venlafaxine, or fluoxetine for at least 8 weeks, 
inclusive of up to 3 weeks of titration into the adequate dose range, with the same adequate dose 
over the last 4 weeks that does not exceed the labeled maximum daily dose. Note that if the 
subject cannot tolerate the selected ADT upon treatment initiation, it is acceptable to switch to 
another one of the 5 available ADTs within the first week of treatment, as deemed appropriate by 
the Investigator. The second ADT must then be taken for at least 7 weeks and in the adequate 
dose range for at least 5 weeks, with the same dose over the last 4 weeks that does not exceed the 
maximum daily dose. 
Throughout the PLI Period, subjects will return to the clinic for brief assessments (Visits 1a-1f) 
that will occur weekly for the first 4 weeks and biweekly for the remainder of the PLI Period. At 
Visit 1f, subjects will be assessed for eligibility in an automated interactive response system 
(IxRS) using masked criteria. Based on this assessment, subjects will be classified as either one 
of the following: 
• Eligible to continue in the study: These subjects will be scheduled for Visit 2. If at 
Visit 2, all entry criteria are met, subjects will be designated as PIR subjects, and may 
enter the double-blind Treatment Period 


 
 
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• Screen failures: Screen failures may be eligible for rescreening with Medical Monitor 
approval 
8.1.3. 
Stage 1 (Visits 2-7) 
Regardless of method of entry, all subjects will have been taking an SSRI or SNRI for at least 
8 weeks at the beginning of Stage 1 (Visit 2) and at an adequate dose for at least 5 weeks, and at 
the same dose for at least 4 weeks. At Visit 2, PIR and HIR subjects who meet all entry criteria 
will be eligible to enter the 5-week Treatment Period and will be randomized 2:5 to receive 
either ALKS 5461 2/2 or placebo for 5 weeks. 
From Visits 2 to 7, all participating subjects will take study drug (ALKS 5461 2/2 or placebo) 
and continue to take an approved ADT. 
On Day 1 (Visit 2) and for the reminder of visits during the Treatment Period, subjects will 
self-administer study drug in the presence of study staff. Subjects will self-administer study drug 
when at home on days when there are not study visits. 
8.1.4. 
Stage 2 (Visits 8-13) 
In Stage 2, subjects receiving ALKS 5461 2/2 in Stage 1 and subjects responding to placebo in 
Stage 1 will continue on placebo for 6 weeks (see Figure 2). Placebo nonresponders will be 
rerandomized 1:1 to receive either ALKS 5461 2/2 or placebo for 6 weeks. All participating 
subjects will continue to take an approved ADT. 
Staff will dispense study drug (ALKS 5461 or placebo) during on-site visits for subjects to 
self-administer study drug at home on days where there are not study visits. At those scheduled 
on-site study visit days, subjects will self-administer one dose of study drug in the presence of 
study staff. Subjects will return to the clinic every week for assessments. 
8.1.5. 
Safety Follow-up Period (Visit 14) 
Subjects who complete Stage 2 (Visit 13) or who prematurely discontinue during either 
Stage 1 or 2 should return to the clinic 1 week later for a Safety Follow-up Visit (Visit 14). 
8.2. 
Schedule of Visits and Assessments 
The schedule of assessments for all study subjects is shown in Table 3. The schedule of 
assessments during the PLI Period is shown in Table 4. 
Premature discontinuation procedures are provided in Section 7.3. All ET Visit procedures are 
listed in Table 3. 


 
 
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Table 3: 
Schedule of Assessments 
Day 
SCNa 
PLI 
(see 
Table 4) 
Stage 1 
Stage 2 
Safety 
Follow
-up 
1 
8 
(±2) 
15 
(±2) 
22 
(±2) 
29 
(±2) 
36 
(±2) 
43 
(±2) 
50 
(±2) 
57 
(±2) 
64 
(±2) 
71 
(±2) 
ET/78b 
(±2) 
85 
(±3) 
Visit 
1 
1a-1f 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualification/ Diagnostic Assessments 
Eligibility Reviewc 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Psychiatric 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-site ATRQ 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MINI v7.0.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
17-item HAM-D 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
Serology Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol Testd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment by 
IxRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Qualification/ Safety Assessments 
Urine Drug Screend,f 
X 
 
Xe 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
Pregnancy Testing (all 
women)g 
X 
Xe 
 
 
 
 
X 
X 
 
 
 
 
 
 


 
 
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Table 3: 
Schedule of Assessments (Continued) 
Day 
SCNa 
PLI 
(see 
Table 4) 
Stage 1 
Stage 2 
Safety 
Follow
-up 
1 
8 
(±2) 
15 
(±2) 
22 
(±2) 
29 
(±2) 
36 
(±2) 
43 
(±2) 
50 
(±2) 
57 
(±2) 
64 
(±2) 
71 
(±2) 
ET/78b 
(±2) 
85 
(±3) 
Visit 
1 
1a-1f 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Symptom-driven Physical 
Examination 
 
 
Xe 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
Weight/Vital Signsh 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRSi 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Xe 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
Blood and Urine Safety 
Samples 
X 
Xe 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
COWSj 
 
Xe 
 
 
 
 
 
Xe 
 
 
 
 
X 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Reviewk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Substance Usel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
MADRSm 
X 
 
Xe 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
 
CGI-S 
X 
Xe 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
 
Q-LES-Q-SF 
 
Xe 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
 


 
 
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Table 3: 
Schedule of Assessments (Continued) 
Day 
SCNa 
PLI 
(see 
Table 4) 
Stage 1 
Stage 2 
Safety 
Follow
-up 
1 
8 
(±2) 
15 
(±2) 
22 
(±2) 
29 
(±2) 
36 
(±2) 
43 
(±2) 
50 
(±2) 
57 
(±2) 
64 
(±2) 
71 
(±2) 
ET/78b 
(±2) 
85 
(±3) 
Visit 
1 
1a-1f 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Additional Study Procedures 
HAM-A 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
BPI-SF 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
SHAPS 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
CD-RISC-25 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Patient Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Sample for ADT 
Concentrationn 
Xo 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
Plasma Samples for Study 
Drug Concentrationn 
 
 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
Witness Study Drug Dosep 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense Study Drugq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Drug Adherence 
Reviewr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADT Adherence Reviewr 
 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of Text Message 
Adherence Reminder Uset 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ADT=antidepressant therapy; ATRQ=Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; BPI-SF=Brief Pain 
Inventory-Short Form; CD-RISC-25=Connor-Davidson Resilience Scale; CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global 
Impression-Severity; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=Early 
Termination; HAM-A=Hamilton Rating Scale for Anxiety; HAM-D=17-item Hamilton Rating Scale for Depression; HIR=historic inadequate responder; 
IxRS=Interactive voice or web response system; MADRS=Montgomery-Åsberg Depression Rating Scale; MINI v7.0.2=Mini International Neuropsychiatric 


 
 
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Interview 7.0.2; PIR=prospective inadequate responder; PLI=Prospective Lead-in; Q-LES-Q-SF=Quality of Life Enjoyment and Satisfaction 
Questionnaire-Short Form; SCN=Screening; SHAPS=Snaith-Hamilton Pleasure Scale 
a For HIR subjects, Screening Period will occur within 28 days prior to Visit 2. For PIR subjects, Screening Period will occur within 28 days prior to Visit 1a. 
For PIR subjects, an 8-week PLI Period including Visits 1a through 1f will occur between Screening and Visit 2. See Table 4 for Schedule of Assessments 
during the PLI Period. 
b If a subject terminates early, then an Early Termination (ET) Visit will be arranged, at which time all Visit 13 assessments will be performed. Additionally, an 
attempt will be made to schedule a Follow-up Visit 1 week after the subject’s last dose equivalent to Visit 14. 
c Sites will complete the CST Pre-Baseline Packet at Screening (Visit 1) and submit the data to the CST so that review may be completed as soon as possible 
after Screening (Visit 1) and before the next study visit. 
d Breath alcohol test and urine drug screen may be repeated at any point during the study based on Investigator’s judgment. 
e Assessment must be completed predose. 
f Centralized drug screen testing at Screening, local drug screen testing (via dipstick) at other timepoints. 
g Serum pregnancy at Screening, urine pregnancy for all other timepoints. 
h Vital sign measurements at all visits include oral temperature, blood pressure, heart rate, and respiratory rate. Blood pressure, heart rate, and respiratory rate 
will be measured after the subject is in a supine position for at least 5 minutes. 
i At Screening the “Baseline/Screening” version of the C-SSRS will be administered and at all other visits the “Since Last Visit” version will be administered. 
j The COWS will be administered by a medical professional. 
k All medications (prescription and nonprescription, including vitamins, and herbal supplements) taken 2 months prior to Screening, including psychiatric 
medication taken 5 years prior to Screening, and all ADTs will be recorded at Screening. Any changes will be recorded at subsequent visits. 
l Subject will be queried at Screening on substances (including illicit drugs, alcohol, and tobacco) used within 30 days, with updates made at each subsequent 
visit. 
m The MADRS should be administered prior to the HAM-D, CGI-I, CGI-S, HAM-A, C-SSRS, Q-LES-Q-SF, BPI-SF, SHAPS, and CD-RISC-25 on visits when 
multiple assessments are scheduled. 
n The PK samples will evaluate concentrations of BUP, SAM, and ADT at specified visits. One pre-dose PK should be drawn at each indicated visit. When PK 
and safety blood samples are scheduled to be collected on the same day, efforts will be made to collect during the same draw. 
o Applies only to HIR subjects. 
p Study drug will be self-administered at all on-site visits in the presence of study site personnel. 
q Study drug will be dispensed for self-administration at Visits 2 through12. Subjects will be advised to take the study drug at bedtime on days where there are 
not study visits, starting on Day 2. Time of dosage administration may be subsequently adjusted by the Investigator based on tolerability. 
r Adherence for study drug and ADT based on subject query and pill count. 
s For PIR subjects only. 
t Text adherence reminders on subjects’ personal mobile devices will occur daily throughout the Treatment Period. 


 
 
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Table 4: 
Schedule of Assessments: Prospective Lead-in Period 
Week (± 2 days) 
SCNa 
1 
2 
3 
4 
6 
8 
PLI Visit 
1a 
1b 
1c 
1d 
1e 
1f 
17-item HAM-D 
Procedures for 
Visit 1 are 
displayed in 
Table 3. 
Xb 
 
X 
 
X 
X 
Initiate/Prescribe ADT 
Xc 
 
 
 
 
 
ADT Dose Adjustment, as needed 
X 
X 
X 
X 
 
 
Plasma Sample for ADT 
Concentration 
 
 
 
X 
 
 
ADT Adherence Reviewd 
 
X 
X 
X 
X 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
Concomitant Medication Reviewe 
X 
X 
X 
X 
X 
X 
Substance Use 
X 
X 
X 
X 
X 
X 
C-SSRSf 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Testing 
X 
 
 
 
 
 
Eligibility Assessment by IxRS 
 
 
 
 
 
Xg 
Abbreviations: ADT=antidepressant therapy; C-SSRS=Columbia-Suicide Severity Rating Scale; HAM-D=17-item Hamilton Rating Scale for Depression; 
IxRS=Interactive voice or web response system; PLI=Prospective Lead-in; SCN=Screening 
a Screening to occur within 28 days of Visit 1a. 
b At Visit 1a, HAM-D to be completed prior to any other procedures. A subject with a HAM-D <22 will be considered ineligible per inclusion criterion 12, will 
be considered a screen failure, and will not participate in any further procedures. 
c After confirming a HAM-D score of ≥ 22 at Visit 1a, ADT will be initiated at the discretion of the Investigator and as locally available. 
d Adherence based on subject query and pill count. 
e Any changes to concomitant medications since prior visit should be recorded, including changes to ADT, prescription and nonprescription medications, 
vitamins, and herbal supplements. 
f “Since Last Visit” version will be administered at all timepoints. 
g Eligibility for continuation to be assessed by IxRS. Based on this assessment, subjects will be deemed either eligible to continue into Visit 2 or ineligible to 
continue into the double-blind Treatment Period of this study. Subjects deemed eligible will continue into the double-blind Treatment Period. 


 
 
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8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The schedule of assessments for all study 
subjects is shown in Table 3. The schedule of assessments during the PLI Period is shown in 
Table 4. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the Principal 
Investigator or designated study personnel as outlined in Section 17.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential subject. 
8.3.2. 
Eligibility Review 
An eligibility review will be conducted by the Investigator at the visits specified in Table 3 using 
the subject inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. 
For those subjects that participate in the PLI Period, eligibility will be confirmed based on 
HAM-D scores at Visit 1 and PLI Visit 1a. A subject who does not meet the HAM-D criteria at 
entry to Visit 1a (HAM-D total score ≥22) will be considered a screen failure and will not 
participate in further procedures. 
For subjects participating in the PLI Period, an additional eligibility review will be conducted by 
an IxRS at Visit 1f and Visit 2 using masked criteria. Based on this assessment, subjects will be 
classified as one of the following: 
• Eligible to continue in the study: These subjects will be scheduled for Visit 2. If at 
Visit 2, all entry criteria are met, subjects will be designated as PIR subjects, and will 
be randomized into the double-blind Treatment Period (Stage 1) 
• Screen failures: Screen failures may be eligible for rescreening with Medical Monitor 
approval 
For all subjects at Visit 2, the Investigator will conduct an eligibility review using the subject 
inclusion criteria in Section 7.1.2.1, exclusion criteria in Section 7.2, and filling out the ATRQ. 
Subjects meeting eligibility criteria at Visit 2 will be randomized into Stage 1. 
8.3.3. 
Demographics and Medical History 
Subject’s demographic data and medical history will be reviewed and documented at the 
timepoints specified in Table 3. The psychiatric history should include start date of first episode 
of MDD, duration of current MDE, number of lifetime MDEs, number of prior lifetime ADT 
failures, and number of ADT failures within the current MDE. 
8.3.4. 
Concomitant Medication Review 
At Screening, all subjects will be asked about psychiatric medications they have taken within the 
last 5 years (including all ADTs as specified in Table 3), and any other medications they have 
taken in the last 2 months, including prescription and nonprescription medications, vitamins, and 


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supplements. At each subsequent visit, review of concomitant medications will be repeated as 
specified in Table 3 and Table 4. 
The Investigator will record the following data on all medications used by the subject, as 
applicable: name, dose, regimen, route of administration, start and stop dates, and the indication 
for use. 
8.3.5. 
Substance Use 
Substances (including illicit drugs, alcohol, and tobacco) consumed/used within 30 days will be 
reviewed and recorded at the timepoints specified in Table 3 and Table 4, including name, 
amount, frequency, and start and stop dates. Changes at each subsequent visit as specified in 
Table 3 and Table 4 will be recorded for all participating subjects. 
8.3.6. 
Vital Signs and Weight 
Vital signs (ie, oral temperature, blood pressure, heart rate, and respiratory rate) will be assessed 
at the timepoints specified in Table 3. Blood pressure, heart rate, and respiratory rate will be 
measured after the subject has been resting in a supine position for at least 5 minutes. 
Effort will be made to measure all blood pressure and pulse rate from the same arm, preferably 
the subject’s dominant arm, throughout the study. 
The blood pressure cuff will be calibrated per study site standard procedures. Automated 
measurement is preferred, but if performed manually, pulse rate will be measured in the brachial 
artery for at least 30 seconds. 
All subjects will be weighed at the timepoints shown in Table 3. 
Subjects should be weighed on the same scale for each measurement under the same conditions, 
with a consistent amount of clothing for each measurement. Subjects should remove shoes and 
all personal items prior to body weight measurement. 
8.3.7. 
Physical Examination and Height 
A complete physical examination will be performed at the Screening Visit only as specified in 
Table 3. A symptom-driven physical examination will be performed at the timepoints specified 
in Table 3. Height will be measured at the Screening Visit only as specified in Table 3. 
8.3.8. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be conducted at the timepoints specified in Table 3. All 
scheduled ECGs must be performed after the subject has rested quietly for at least 5 minutes in 
the supine position. 
Electrocardiograms will be conducted using calibrated equipment and assessed by a qualified 
clinician. The following ECG parameters will be collected: heart rate, RR, PR, QRS, and QT. 
QTcB (QT interval corrected using the Bazett formula) and QTcF (QT interval corrected using 
the Fridericia formula) will be automatically calculated by the ECG machine. 


 
 
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8.3.9. 
Structured Interviews and Questionnaires 
Brief descriptions of each of the structured interviews and questionnaires to be administered are 
provided below. 
Table 3 and Table 4 show the timepoints at which each measure should be administered. 
Clinician-administered scales, structured interviews, and questionnaires will be administered by 
trained and qualified study personnel. 
The Montgomery-Åsberg Depression Rating Scale (MADRS) will be administered prior to the 
other structured interview scales (ie, HAM-D, CGI-S, Clinical Global Impression-Improvement 
[CGI-I], Hamilton Rating Scale for Anxiety [HAM-A], C-SSRS, Quality of Life Enjoyment and 
Satisfaction Questionnaire-Short Form [Q-LES-Q-SF], Brief Pain Inventory-Short Form 
[BPI-SF], Snaith-Hamilton Pleasure Scale [SHAPS], and Connor-Davidson Resilience Scale 
[CD-RISC-25]) on visits when multiple assessments are scheduled. 
8.3.9.1. 
Assessments for Study Eligibility 
8.3.9.1.1. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
The ATRQ is a questionnaire used to document history of ADT and to determine treatment 
resistance in MDD (Chandler et al, 2010). The ATRQ will be administered at the timepoints 
indicated in Table 3. The ATRQ executed at the site will be administered by a trained-rater. A 
sample of the ATRQ can be found in Section 20. 
8.3.9.1.2. Mini International Neuropsychiatric Interview 
Known as the MINI v7.0.2, this is a short, clinician-administered diagnostic interview, with an 
administration time of approximately 15 minutes. The MINI v7.0.2 has been validated against 
the much longer Structured Clinical Interview for DSM diagnoses. The MINI v7.0.2 will be 
administered at the Screening Visit as specified in Table 3. 
8.3.9.1.3. Seventeen-item Hamilton Rating Scale for Depression 
The HAM-D is a clinician-administered 17-item depression scale designed to be sensitive to 
treatment effects (Hamilton 1960). The Structured Interview Guide for the HAM-D (SIGH-D) 
will be used for administration during visits, at the timepoints specified in Table 3 and Table 4. 
8.3.9.1.4. Clinical Surveillance Team Eligibility Review 
The Clinical Surveillance Team (CST) is a division of 
 CNS Clinical Development. 
The CST eligibility review is an independent evaluation of the eligibility of the subject. Sites will 
complete the CST Pre-Baseline Packet at Screening and submit the data to the CST so that 
review may be completed as soon as possible after Screening and before the next study visit as 
indicated in Table 3. The Investigator may use the results of this tool at his or her discretion. 
PPD


 
 
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8.3.9.2. 
Safety Assessments 
8.3.9.2.1. Columbia-Suicide Severity Rating Scale 
The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior 
(Posner et al, 2011). The “Baseline/Screening” version of the instrument will be administered at 
the Screening visit only and the “Since-Last-Visit” version will be administered at all other 
timepoints as specified in Table 3 and Table 4. 
8.3.9.2.2. Clinical Opiate Withdrawal Scale 
The COWS is an 11-item questionnaire designed to measure a patient’s level of opiate 
withdrawal (Wesson and Ling 2003). The COWS should be administered by a medical 
professional at the timepoints specified in Table 3. 
8.3.9.3. 
Efficacy Assessments 
8.3.9.3.1. Montgomery-Åsberg Depression Rating Scale 
The MADRS is a clinician-administered, 10-item depression scale designed to be sensitive to the 
effects of antidepressant treatment (Montgomery and Asberg 1979). The Structured Interview 
Guide for the MADRS (SIGMA) will be used for administration during visits, at the timepoints 
specified in Table 3.  
8.3.9.3.2. Clinical Global Impression–Severity 
The CGI-S is a clinician-administered scale that measures severity of mental illness (Guy 2000). 
The CGI-S asks that the clinician rates the subject relative to their past experience with patients 
with MDD. The CGI-S will be administered during visits, at the timepoints specified in Table 3. 
8.3.9.3.3. Clinical Global Impression–Improvement 
The CGI-I is a clinician-administered scale that measures intensity of mental illness (Guy 2000). 
The CGI-I asks that the clinician rates the subject relative to their past experience with patients 
with MDD. The CGI-I will be administered during visits, at the timepoints specified in Table 3. 
8.3.9.4. 
Exploratory Assessments 
8.3.9.4.1. Hamilton Rating Scale for Anxiety 
The HAM-A is a clinician-administered 14-item scale developed to measure the severity of 
anxiety symptoms (Hamilton 1959). The Structured Interview Guide for the HAM-A (SIGH-A) 
will be used for administration of the scale at the timepoint specified in Table 3. 
8.3.9.4.2. Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form 
The Q-LES-Q-SF is a self-report measure designed to measure the degree of enjoyment and 
satisfaction experienced by subjects in various areas of daily functioning (Endicott et al, 1993). 
Summary scores have been found to be reliable and valid measures of these dimensions in a 
group of depressed outpatients. The Q-LES-Q will be administered during visits, at the 
timepoints specified in Table 3. 


 
 
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8.3.9.4.3. Brief Pain Inventory-Short Form 
The BPI-SF is a self-report measure that takes approximately 5 minutes to administer and is 
designed to assess the severity of pain as well as its impact on functioning. The BPI-SF will be 
administered at the timepoints specified in Table 3. 
8.3.9.4.4. Snaith-Hamilton Pleasure Scale 
Anhedonia is defined as the loss of capacity to experience pleasure from routine life activities. It 
is a core deficit identified in major depression (DSM-5) (Hasler et al, 2004). The SHAPS is a 
patient-rated questionnaire that evaluates anhedonia and contains 14 items (Snaith et al, 1995). 
These items assess the individual’s ability to enjoy and draw pleasure from routine life activities. 
The questionnaire covers enjoyment within the domains of social interaction, interests/pastimes, 
sensory experience, and food/drink. The scale has been validated and has shown excellent 
psychometric properties in clinical samples (Nakonezny et al, 2010; Snaith et al, 1995). The 
SHAPS will be administered at the timepoints specified in Table 3. 
8.3.9.4.5. Connor-Davidson Resilience Scale 
Resilience can be defined as a measure of stress coping ability (Luthar et al, 2000). The 
CD-RISC-25 is a brief, self-rated measure of resilience that has sound psychometric properties 
(Connor and Davidson 2003). The CD-RISC-25 will be utilized to quantify the change in 
resilience with treatment in the study. It will be administered at the timepoints specified in 
Table 3. 
8.3.9.4.6. Patient Questionnaire 
A questionnaire will be administered at the Screening visit as specified in Table 3 in order to 
determine items of importance to patients with depression interested in research participation 
(see Section 22). The questionnaire will request that subjects rate the importance of symptoms of 
depression that appear on the MADRS. 
8.3.10. 
Laboratory Assessments 
8.3.10.1. Serology Testing 
Tests for HIV, hepatitis B surface antigen, and hepatitis C antibody will be performed at 
Screening and must be negative to qualify for study participation, as indicated in Table 3. 
8.3.10.2. Breath Alcohol Test 
A breath alcohol test will be conducted at the timepoints indicated in Table 3. A negative breath 
alcohol test will be required for a subject to enter into the study. However, the test may be 
repeated at any time during the study based on Investigator judgment. 
8.3.10.3. Urine Drug Screen 
All subjects will undergo a urine drug screening for drugs of abuse at Visit 1. Laboratory 
analysis of the urine drug screen at Visit 1 will be centralized. At all other timepoints specified in 
Table 3, subjects will have a urine drug screen via dipstick; results will be analyzed by the local 
laboratory. Samples will be collected in accordance with the site’s usual procedures. 


 
 
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Urine drug screening will be performed for amphetamines, barbiturates, benzodiazepines, 
cocaine (metabolite), tetrahydrocannabinol, opioids, and phencyclidine. The opioid panel to be 
administered at Visit 1 (analyzed centrally) will include BUP, codeine, hydrocodone, 
hydromorphone, methadone, morphine, oxycodone, and oxymorphone. 
Drug screens administered after Visit 1 (analyzed locally) will include all aforementioned 
opioids except for BUP because appearance of BUP in these samples could lead to unblinding of 
treatment assignment. 
A negative urine drug screen at Visit 1 and Visit 2 will be required for a subject to continue in 
the study. However, an exception may be made for a benzodiazepine, when such medication is 
medically indicated for insomnia. The Visit 1 and/or Visit 2 urine drug screen may be repeated 
based on Investigator judgment. 
The urine drug screen may also be performed at any time during the study, should the 
Investigator feel it is warranted. Action taken in response to a positive urine drug screen after 
Visit 2 should be based on a medical evaluation in consultation with the Medical Monitor. 
8.3.10.4. Pregnancy Testing 
A serum pregnancy test will be administered to all participating female subjects at Screening as 
specified in Table 3. At the Screening visit, results must be negative for the subject to be eligible 
for the study. 
At all other timepoints specified in Table 3, all female subjects will have urine pregnancy testing; 
results must be negative for a subject to continue in the study. 
A positive pregnancy test result at any time will necessitate the subject’s immediate withdrawal 
from the study and reporting to Alkermes within 24 hours as detailed in Section 13.5. Additional 
follow-up will be required as detailed in Section 8.4.1. 
8.3.10.5. Hematology, Biochemistry, and Urinalysis 
Blood and urine samples for laboratory assessments will be collected at the timepoints specified 
in Table 3. Specific hematology, biochemistry, and urinalysis assessments are listed in Table 5. 
Samples will be collected in accordance with the site’s usual procedures and analyzed by a 
central laboratory. 


 
 
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Table 5: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Glycosylated Hemoglobin 
(HbA1C)a 
Platelets 
Red blood cell count 
Total and differential [(absolute)] 
white blood cell count 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine phosphokinase 
Creatinine 
C-Reactive Protein 
Gamma-glutamyl transferase 
Glucoseb 
High-density lipoprotein 
Lactic dehydrogenase 
Low-density lipoprotein 
Magnesium 
Phosphorus 
Potassium 
Prolactina 
Sodium 
Thyroid-stimulating hormonec 
Total bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocytes 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Abbreviation: ET=Early Termination Visit 
a Only at Visit 1, Visit 2, Visit 7, and Visit 13/ET 
b Nonfasting 
c Only at Visit 1 
Reference ranges for evaluated laboratory tests will be supplied by the assigned laboratory 
before the study starts. Procedures for sampling and processing laboratory assessments will be 
described in a separate laboratory manual. 
In the event of a difficult blood draw or where there is a limited quantity of blood available for 
testing, blood collection for biochemistry should be prioritized over hematology. 
If unexplained abnormal laboratory test values are observed, follow-up samples may be obtained 
for repeat testing as clinically indicated. 


 
 
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Results of clinical laboratory testing will appear on electronically produced laboratory reports 
submitted directly to the site from the central laboratory, if applicable. 
8.3.11. 
Pharmacokinetic Sampling for Study Drug and Antidepressant Therapy 
Concentrations 
Plasma samples for PK will be collected at the timepoints indicated in Table 3 and Table 4. 
The date and time of last dose of study drug as well as ADT, and the date and time of the PK 
blood draw will be recorded. Blood samples for these analyses will be stored at -20°C±10°C. 
Samples will be assayed by a central laboratory for determination of BUP and SAM 
concentrations, as well as relevant metabolites. Concentrations of background ADTs that 
subjects report taking during the study will also be quantified. 
8.3.12. 
Drug Dispensation and Reconciliation 
On Day 1 (Visit 2), subjects will self-administer the first dose of study drug in the presence of 
study staff. For the remainder of Stages 1 and 2, staff will dispense study drug during visits 
(see Table 3) to observe self-administration of first dose and for subjects to self-administer study 
drug when at home. The study drug use and storage information will be explained to/reviewed 
with subjects. Subjects will be advised to take the study drug at bedtime (see Section 9.1.2). 
See Section 9.2, and Section 10.4 for additional information regarding treatment adherence and 
accountability. 
8.3.12.1. Review of Text Message Adherence Reminder Use 
Remote adherence reminders will be sent to subjects via text messages to their personal mobile 
devices. Text message adherence reminders will occur daily during the Treatment Period 
(see Table 3). Reviews of the use of these reminders will occur at each on-site visit during the 
Treatment Period (see Table 3). 
8.3.13. 
Adverse Event Monitoring 
The monitoring of AEs will begin once informed consent is obtained and will be performed at 
each visit (see Section 13). All AEs will be monitored continuously until the completion of the 
final study visit (see Table 3 and Table 4). 
Section 13.1 and 13.2, respectively define AEs and serious adverse events (SAEs). 
Section 13.4 provides guidance on the monitoring and recording requirements for AEs. 
Section 13.5 provides guidance on the reporting requirements for SAEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study and 30 days after the final dose of study drug unless they are surgically 
sterile or postmenopausal (see below). The following are considered acceptable methods of 
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1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with
spermicide)
2. Intrauterine device
3. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive
patch, contraceptive implant); oral contraceptives are required to be initiated at least
30 days prior to Screening
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
are considered surgically sterile. Surgical sterility in a partner is not considered an approved 
acceptable method of contraception for subjects. 
Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to Screening in women who are 45 years of age or older. 
If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The ET and Safety Follow-up Visits will be scheduled and the 
pregnancy will be reported to Alkermes. Pregnancies will be followed until completion or 
termination. Pregnancies in female partners of male subjects should also be reported and will be 
followed in the same manner. 
A Pregnancy Report Form must be submitted to Alkermes (fax number in Section 13.5) within 
24 hours of awareness of the pregnancy, irrespective of whether an AE has occurred. The 
pregnancy will be followed until delivery or termination. If the outcome of the pregnancy meets 
the criteria for classification as a SAE, it should be reported following the SAE procedure (see 
Section 13.5). 
8.4.2. 
Concomitant Medications 
All medications taken by a given subject 2 months prior to Visit 1 through follow-up and all 
ADTs taken in the current MDE will be recorded as detailed in Section 8.3.4. The concomitant 
medication review on each visit will include all prescription medications including ADT, 
over-the-counter medications, and vitamins and dietary supplements. 
Subjects are permitted to continue taking concomitant medications during the study provided that 
these medications are clinically appropriate and are not prohibited by the exclusion criteria or 
study restrictions (see Section 8.4.2.1 for details on medications requiring washout and 
Section 8.4.2.3 for details on prohibited medications). The Investigator may discontinue or adjust 
the dose of any of these concomitant medications to ensure subject safety. At the Investigator’s 
discretion, new concomitant medications may be administered during the course of the study for 
the treatment of an AE or a change in disease state. If a prohibited medication is needed, the 
Investigator should notify the Medical Monitor as soon as possible to discuss the continued 
participation of the subject in the study. 


 
 
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Dose adjustment of approved ADT during the PLI Period is permitted for optimal therapeutic 
effect within the recommended approved dose range (see Section 8.4.2.2.1). Dosing of ADT 
must remain within the recommended dose range and may not exceed the maximum labeled 
dose, per US Food and Drug Administration (FDA) approved labeling. At Visit 2, no changes in 
ADT (medication or dose level) can be made for the duration of the treatment periods (ie, during 
Stages 1 and 2, and the Safety Follow-up; see Section 8.4.2.2.1). 
8.4.2.1. 
Medications Requiring Washout 
In order to be enrolled at Visit 2 and at the Investigator’s discretion, subjects must wash out from 
prohibited medications. Durations for some specific medications are listed in Table 6. For other 
prohibited medications, the minimum duration of washout should be at least 2 weeks, and should 
be discussed with the Medical Monitor. Washouts must be completed (ie, the subject must be off 
the prohibited medication) by Visit 1a (for PIR) or Visit 2 (for HIR). Subjects for whom washout 
is determined not to be clinically appropriate must be excluded from study participation. 
Table 6: 
Medications Requiring Washout Prior to Visit 2 
Medication Name 
Washout Duration 
Lithium 
4 weeks 
Monoamine oxidase inhibitors (MAOIs) 
4 weeks 
Bupropion 
4 weeks 
Anti-epileptic and antipsychotica drugs 
2 weeks 
Others (psychostimulants, T3) 
At least 2 weeksb 
a Previous use of aripiprazole, quetiapine, brexpiprazole, or fluoxetine/olanzapine permitted up to a maximally 
approved dose for MDD, outlined in Section 23 (see Exclusion Criterion 8.a). 
b Should be discussed with Medical Monitor. 
8.4.2.2. 
Permitted Medications 
At the Investigator’s discretion, new concomitant medications may be administered during the 
course of the study for the treatment of an AE or a change in disease state. Details regarding 
ADTs and pain management therapies that are permitted in the study are provided below. 
8.4.2.2.1. Antidepressant Therapy 
In this protocol, ADT refers to the following medications, defined for each of the following 
3 circumstances: 
• Historical ADT, completed in current MDE prior to Screening may include any 
antidepressant medication listed on the ATRQ 
• For HIR subjects, current ADT at Screening is limited to citalopram, escitalopram, 
fluoxetine, paroxetine, sertraline, vilazodone, vortioxetine, desvenlafaxine, 
duloxetine, levomilnacipran, or venlafaxine 
• For PIR subjects, ADT during the PLI Period is limited to escitalopram, fluoxetine, 
sertraline, duloxetine, or venlafaxine. For PIR subjects, they should not be assigned to 
an ADT or a different formulation of the same ADT that they have failed during the 


 
 
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current MDE. Further, if a PIR subject had a prior failure to citalopram, he/she should 
not be assigned to receive escitalopram 
At Visit 2, all subjects must have been on an SSRI or SNRI regimen for ≥8 weeks, inclusive of 
up to 3 weeks for titration into the adequate dose range, with the same, adequate dose over the 
last 4 weeks, and must agree to continue with and make no changes to this regimen (medication 
or dose level) for the duration of the study. 
For PIR subjects, if the subject cannot tolerate the chosen ADT upon treatment initiation at 
Visit 1a, it is acceptable to switch to another one of the 5 ADTs within the first week of 
treatment (by Visit 1b), as judged appropriate by the Investigator. The second ADT must then be 
taken for at least 7 weeks prior to Visit 2 and in the adequate dose range for at least 5 weeks, 
with the same adequate dose over the last 4 weeks. 
An adequate dose is defined as a dose that is greater than or equal to the minimum dose on the 
ATRQ (see Section 21). For ADT taken during the course of the study (ie, not historical ADT), 
doses may not exceed the maximum labeled dose. 
The approved ADT regimen may not be changed or modified after the first 4 weeks of the PLI 
Period and throughout the remainder of the study for PIR subjects and must be unchanged from 
4 weeks prior to Visit 2 throughout the remainder of the study for HIR subjects. 
It is noted that ADT usage patterns will be monitored throughout the study to ensure 
approximately representative ADT utilization. The Sponsor reserves the right to restrict specific 
ADT usage. Additionally, no more than 4 of every 6 subjects at a site should be assigned to any 
one ADT without permission from the Medical Monitor. 
Subjects in the United States must use the ADT pharmacy card provided during the study and 
may not seek reimbursement from their private insurance and/or local, state or federally funded 
healthcare programs for ADT utilized in the study. 
8.4.2.2.2. Pain Management 
Because the ALKS 5461 co-formulation contains SAM, a μ-opioid receptor antagonist, subjects 
may experience reduced or ineffective analgesia when taking an opioid analgesic agent 
concurrently with ALKS 5461, including several days after last dosing of ALKS 5461. 
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, study drug should not be 
administered. If opioid analgesics are required after study drug has been administered, it may 


 
 
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take several days for opiate sensitivity to be restored, since SAM is an opioid antagonist and 
could interfere with opioid-mediated pain management. 
8.4.2.3. 
Prohibited Medications 
If a prohibited medication is needed, the Investigator should notify the Medical Monitor as soon 
as possible to discuss the continued participation of the subject in the study. 
Prohibited medications include: antipsychotics, additional antidepressants other than the assigned 
background antidepressant, mood stabilizers, varenicline, anxiolytics, and CYP3A4 inhibitors 
and inducers (see Section 24 for a list of prohibited inducers and moderate-to-strong inhibitors of 
CYP3A4). All prohibited medications will be discontinued during Screening with a washout 
period of 2 to 4 weeks, unless specified otherwise. This is not an exhaustive list of prohibited 
medications. The Investigator should consult with the Medical Monitor regarding other 
potentially prohibited medications. 
Prohibited medication or treatment categories include, but are not restricted to, the following: 
• Agents that might have antidepressant or related pharmacodynamics effects. This 
includes but is not restricted to: 
− MAOIs (eg, phenelzine, tranylcypromine, selegiline) 
− Lithium 
− Tricyclic antidepressants (eg, amitriptyline, nortriptyline, desipramine) 
− Psychostimulants (eg, methylphenidate, dextroamphetamine/amphetamine) 
− Bupropion  
− Additional agents (prescription or over-the-counter [OTC]) for purpose of treating 
MDD or augmenting the effects of the ADT 
• Anti-epileptic medications (eg, topiramate, gabapentin, lamotrigine, or 
oxcarbazepine) at any dose or duration for any indication 
• Opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) or opioid 
antagonists (eg, naloxone or naltrexone) 
• The initiation or dose adjustment of hormone replacement therapy (including 
testosterone) or a hormonal contraceptive. Such therapy is permissible if a stable dose 
of hormone replacement therapy or hormonal contraceptive is taken for at least 
30 days before Visit 1a (PIR) or Visit 2 (HIR) and the same stable dose is expected to 
be taken throughout the study (please refer to Section 8.4.1 for additional details 
regarding contraception) 
• Use of systemic corticosteroids within 30 days before Visit 1a (PIR) or Visit 2 (HIR) 
and throughout the study 
• Antipsychotics 
• The receipt of new onset psychotherapy within 6 weeks of Screening or new onset 
psychotherapy at any time during the study (including any significant change in 


 
 
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psychotherapy) is prohibited; a stable psychotherapy regimen that has been initiated 
>6 weeks prior to Screening is permitted. For subjects who are receiving a stable 
psychotherapy regimen upon entry into the study, efforts should be made to maintain 
a psychotherapy regimen and schedule consistent with that existing at the beginning 
of the study 
• Use of moderate-to-strong inhibitors or inducers of CYP3A4 (prescription 
medications, over-the-counter medications, or dietary supplements) within 30 days 
before Screening through follow-up is prohibited (refer to Section 24 for a list of 
CYP3A4 inhibitors and inducers) 
Initiation of a course of pharmacotherapy (including prescription or over-the-counter 
medications) or natural supplements for insomnia (eg, benzodiazepines, zolpidem, trazodone, 
antihistamines, melatonin) is not permitted if started within 30 days of screening or if started at 
any time during the study. Prescriptions, over-the-counter medications, and natural supplements 
are permitted to be used for insomnia if they have been used stably for at least 30 days before 
screening not more than 3×/week, and are expected to be used stably ≤3 times per week 
throughout the study. Note that although antihistamines are restricted per these criteria when 
used for insomnia, they are permitted as needed throughout the study for indications other than 
insomnia (eg, environmental allergies). 
Permitted dose levels for hypnotics when used for insomnia are limited to ≤2 mg/day of 
lorazepam (or equivalent benzodiazepine dose), ≤100 mg/day of trazodone, ≤10 mg/day of 
zolpidem or zaleplon, and ≤12.5 mg/day of zolpidem extended-release. 
Hypnotic agents for psychiatric indications other than insomnia are prohibited from 30 days prior 
to screening through the follow-up visit. 
Pharmacotherapy (including prescription or over the counter medications) or natural supplements 
for anxiety are prohibited from 30 days prior to screening through the follow-up visit. 


 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
9.1.1. 
Description of ALKS 5461 and Placebo 
ALKS 5461 consists of BUP, a US Schedule III narcotic, and SAM, a US Schedule II controlled 
substance. Thus, ALKS 5461 should be treated as a Schedule II controlled substance within the 
US. Outside the US, ALKS 5461 should be handled according to local regulations. See 
Section 10 for information on storage and handling of controlled substances. 
The ALKS 5461 drug product will be formulated as tablets for SL administration and will 
contain a ratio of 1:1 BUP: SAM as free base equivalents by weight. 
Placebo will be prepared using a similar formulation composition without BUP and SAM to 
create blinded study drug. 
9.1.2. 
Study Drug Dose and Dosing Regimen 
Subjects will take one SL tablet per day of study drug (ie, ALKS 5461 2/2 or placebo) for 
5 weeks in Stage 1 and 6 weeks in Stage 2. 
At Visit 2 (Day 1) and at scheduled on-site study visit days, subjects will take study drug in the 
presence of study site personnel who will visually confirm that the tablet has dissolved 
completely. The tablet must not be swallowed. Eating and drinking should be avoided for 
15 minutes after dosing. From Day 2 on, subjects will self-administer study drug; it is 
recommended that subjects take study drug at bedtime. Timing of self-administration may be 
subsequently adjusted by the Investigator based on tolerability. 
If, in the opinion of the Investigator, the ADT should be taken at approximately the same time of 
day as the study drug, then the ADT should be taken first followed by study drug. 
9.2. 
Treatment Adherence of Study Drug and ADT 
As indicated in Table 3, subjects will receive at each specified dispensing visit a supply of study 
drug (ALKS 5461 or placebo) that will last until the following visit. Study drug and ADT 
adherence reviews will include pill counts at each visit as specified in Table 3. Subjects will be 
instructed to bring each dispensed blister pack with them to each subsequent visit to return any 
remaining study drug, and drug adherence will be reviewed. Remote adherence reminders will be 
sent to subjects daily during the Treatment Period via text message to their personal mobile 
devices. Subjects will be instructed to bring in containers of their approved ADT for verification 
of dosing adherence. Study drug adherence will be determined at each on-site visit by counting 
tablets returned and comparing counts with the calculated expected number. ADT adherence will 
also be reviewed with subjects at each on-site visit via pill count. Physical check of medication 
including prescription fill date is required and must be documented in source. The concentrations 
of BUP and SAM, and background ADTs will be quantified as described in Section 8.3.11. 


 
 
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Samples will be assayed by a central laboratory for determination of BUP and SAM 
concentrations, as well as relevant metabolites. Concentrations of background ADTs that 
subjects report taking during the study will also be quantified. 
9.3. 
Method of Assigning Subjects to Treatment 
Based on an assessment of history of inadequate response to ADT, eligible subjects will be 
assigned at Screening to begin either an 8-week PLI Period (PIR subjects) or to bypass the PLI 
Period and proceed to Stage 1 (HIR subjects). 
At the beginning of Stage 1, all eligible subjects will be randomized to receive either 
ALKS 5461 or placebo for 5 weeks. Once a randomization number has been assigned, that 
number must not be used again if, for example, a subject is withdrawn from the study. 
At the beginning of Stage 2, subjects receiving ALKS 5461 2/2 in Stage 1 and subjects who 
responded to placebo in Stage 1 (placebo responders) will continue on placebo for 6 weeks 
(see Figure 2). Placebo nonresponders will be rerandomized to receive either ALKS 5461 2/2 or 
placebo for 6 weeks. 
For both stages, codes will be prepared by an independent biostatistician who is not otherwise 
involved in this study. Study drug randomization will remain blinded to the subjects, 
Investigator, and Sponsor during the course of the study. 
9.4. 
Blinding and Unblinding 
9.4.1. 
Blinding 
The PLI Period will include open-label assignment to escitalopram, sertraline, duloxetine, 
venlafaxine, or fluoxetine, chosen at the Investigator’s discretion. 
All attempts will be made to conceal the treatment assignment of blinded study drug from the 
subjects, investigators, study personnel, and Sponsor personnel throughout the study. 
9.4.2. 
Unblinding 
Unblinding will occur after the database lock. 
If the Investigator deems it necessary to break the study blind in the interest of a subject’s 
medical safety, he or she must make every effort to contact the 
 Medical Monitor 
before the blind is broken. If the site is unable to contact the 
 Medical Monitor, 
every effort must be made to contact the Sponsor’s Medical Monitor. If the site is unable to 
contact the Medical Monitor prior to breaking the blind, the Medical Monitor must be contacted 
within 24 hours following disclosure of study drug assignment. 
The Investigator is responsible for all study-related medical decisions. When the Investigator 
deems it necessary, emergency unblinding may be done without contacting a Medical Monitor. 
Any premature unblinding should be promptly documented and explained to the Medical 
Monitor. 
If the blinded code is broken by any party, the reason must be fully documented. Breaking the 
blind for a single subject will not affect the blind for the remaining subjects. 
PPD
PPD


 
 
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9.5. 
Study Drug and Antidepressant Therapy Dose Adjustment and 
Stopping Rules 
Elective dose reduction is not permitted during the study. If a subject develops tolerability issues, 
the Investigator should discuss management options with the Medical Monitor. If the subject is 
unable to tolerate the study drug dose level despite attempted management options, or refuses to 
continue taking study drug, study drug should be discontinued. 
Dose adjustment of approved ADT during the PLI Period is permitted for optimal therapeutic 
effect within the recommended approved dose range for the first 4 weeks (see Section 8.4.2.2.1). 
Dosing of ADT must remain within the recommended dose range and may not exceed the 
maximum labeled dose, per US Food and Drug Administration (FDA) approved labeling. At 
Visit 2, no changes in ADT (medication or dose level) can be made for the duration of the 
treatment periods ([ie, during Stages 1 and 2] see Section 8.4.2.2.1). 
The study may be stopped at any time or study sites may be closed at the Sponsor’s discretion. 


 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The investigational product for this study is ALKS 5461, a fixed-dose combination of BUP, a 
μ-opioid receptor partial agonist, and SAM, a μ-opioid receptor antagonist. 
The ALKS 5461 drug product is formulated as tablets for SL administration and will contain a 
ratio of 1:1 BUP:SAM (2 mg BUP/ 2 mg SAM) as free base equivalents by weight. 
Placebo will be prepared using a similar formulation composition without SAM and BUP. 
Buprenorphine is a Schedule III narcotic in the US, and SAM is a Schedule II controlled 
substance in the US. Therefore, within the US, ALKS 5461 must be handled in accordance with 
restrictions related to Schedule II controlled substances. Outside the US, ALKS 5461 should be 
handled according to local regulations. 
All study drug is white to off-white in color nondebossed triangle-shaped tablet. The SL tablet 
formulation contains excipients commonly used in products approved by the FDA, and accepted 
for use as food additives in Europe, including lactose monohydrate, microcrystalline cellulose, 
crospovidone, sucralose, citric acid, sodium citrate, and magnesium stearate. 
10.2. 
Packaging and Labeling 
Study drug will be packaged in child-resistant blister packs. All packaging will be labeled in a 
manner that meets applicable local and regulatory requirements. 
Subjects will receive child-resistant blister packs containing 9 tablets at each dispensing visit as 
specified in Table 3 to supply a sufficient number of tablets to last until the next scheduled visit. 
Subjects should follow the dosing instructions as printed on the packaging. 
10.3. 
Storage 
ALKS 5461 must be stored in accordance with local controlled substance requirements, and in 
the US, restrictions related to Schedule II controlled substances. 
The Investigator 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 
into illegal channels of distribution. 
Complete details on storage condition requirements can be found in the Investigator’s Brochure. 
10.4. 
Accountability 
The Investigator will be responsible for the oversight of recording the receipt and administration 
of study drug, and for insuring the supervision of the storage and allocation of these supplies. 
The Investigator is required to maintain current drug dispensing and accountability logs 
throughout the study. The Investigator may delegate accountability duties to an appropriate and 
qualified pharmacist or staff member who is under the supervision of the Investigator. 


 
 
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The Investigator or designee must allow the Clinical Research Associate or equivalent to 
perform drug reconciliation during each study monitoring visit. All unused supplies will be 
checked against the study drug movement records before investigational drug is returned or 
destroyed. 
Subject-level study drug accountability will be documented in the subjects’ source documents 
and eCRFs. If drug cannot be accounted for, actions will be taken that are appropriate for a drug 
containing controlled substances. These actions may include but are not limited to re-training 
subject on adherence or discontinuation of subject from the study. 
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. Any broken or chipped tablets should be stored at 
the sites until drug accountability is completed. 
Refer to Section 9 for additional study drug reconciliation procedures. 
10.5. 
Handling and Disposal 
All unused study drug must be handled and disposed of in accordance with Good Clinical 
Practice (GCP), Good Manufacturing Practice and Schedule II controlled substance 
requirements, as applicable. At the end of the study the Sponsor will provide additional 
instruction as to the disposition of unused study drug. Until instructions have been provided, 
each study site must store unused materials on site in the manner described in Section 10.3. All 
study medication must be accounted for in a drug accountability record. 


 
 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoints are: 
1. Average change from baseline to Week 3 to the end of treatment period in 
MADRS-6 scores 
2. Average change from baseline to Week 3 to the end of treatment period in 
MADRS-10 scores 
3. Change from baseline to the end of treatment period in MADRS-10 scores 
The MADRS-10 is the sum of all 10 items and ranges from 0 to 60. The MADRS-6 represents 
the core symptoms of depression and is defined as the sum of the following 6 items: item 1 
reported sadness; item 2 apparent sadness; item 3 inner tension; item 7 lassitude; item 8 inability 
to feel; and item 9 pessimistic thoughts. MADRS-6 scores range from 0 to 36. 
11.2. 
Secondary Efficacy Endpoints 
In addition, secondary endpoints are: 
• MADRS response, defined as a ≥50% reduction in MADRS-10 score from Baseline 
to the end of treatment period 
• MADRS remission, defined as MADRS-10 score ≤10 
11.3. 
Exploratory Endpoints 
Exploratory endpoints are: 
• Change over time in CGI-S scores 
• Absolute CGI-I scores over time 
• Change over time in Q-LES-Q-SF scores 
• Change over time in BPI-SF scores 
• Change over time in SHAPS scores 
• Change over time in CD-RISC-25 scores 


 
 
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12. 
ASSESSMENT OF PHARMACOKINETICS 
Concentrations of BUP, SAM, their relevant metabolites, and reported background ADTs will be 
quantified in plasma samples collected for PK evaluation. Plasma samples will be collected at 
timepoints shown in Table 3 and Table 4. By-subject listings and summary tables of plasma 
concentrations will be provided. 
Pharmacokinetic data may be used in a subsequent population PK evaluation conducted outside 
of this study. 


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


 
 
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• Important medical events that may not result in death, be immediately life 
threatening, or require hospitalization may be considered to be SAEs when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require intervention to prevent one of the other outcomes listed above. 
Admission to a hospital or an inpatient unit for a nonmedical reason (ie, social stay admission) 
during the study, in the absence of untoward medical occurrence, will not be considered an SAE, 
but will be captured as an AE. 
Hospitalization due to worsening of behavioral health-related issues should be reported as an 
SAE. 
13.3. 
Relationship to Study Drug 
The assessment of study drug relationship to each AE will be reported on the appropriate source 
document (and SAE form, in the event of an SAE) by the Investigator (or designated 
Subinvestigator) according to his/her best clinical judgment. The criteria listed in Table 7 should 
be used to guide this assessment. Please note that not all criteria must be present to be indicative 
of a particular drug relationship. All study drugs are considered “test drugs” for the purposes of 
the definitions listed in the table. 


 
 
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Table 7: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for assessment 
Definitely related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Rechallenge (if feasible) is positive. 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class. 
Probably related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Possibly related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE could have been due to another equally likely cause. 
Dechallenge (if performed) is positive. 
Probably not 
related 
There is evidence of exposure to the test drug. 
AND 
There is another more likely cause of the AE. 
Dechallenge (if performed) is negative or ambiguous. 
Rechallenge (if performed) is negative or ambiguous. 
Definitely not 
related 
The subject did not receive the test drug. 
OR 
Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable. 
OR 
There is another obvious cause of the AE. 
Abbreviation: AE=adverse event 


 
 
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13.4. 
Monitoring and Recording of Adverse Events 
All AE data collection will begin after a subject signs the ICF and will continue until completion 
of the Safety Follow-up Visit. Any AE or SAE having an onset after the Safety Follow-up Visit 
will not be collected or reported unless the Investigator feels that the event may be related to the 
study drug. 
Subjects will be instructed by the Investigator or designee to report the occurrence of any AE. 
All volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The Investigator will assess all AEs regarding any causal relationship to the study drug 
(see Section 13.3), the intensity (severity) of the event, action taken, and subject outcome. 
The following criteria should be used to guide the assessment of intensity (severity): 
• Mild: Causes awareness of sign or symptom, but is easily tolerated; does not interfere 
with usual activities 
• Moderate: Causes discomfort enough to interfere with usual activities 
• Severe: Is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE, and any therapeutic measures that are taken, 
shall be at the discretion of the Investigator. If a subject withdraws from the study for any reason, 
any ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or 
until the subject is deemed by the Investigator to be lost to follow-up. 
13.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported to 
 within 24 hours of 
discovery, by faxing the report to the following: 
Attention: 
 Safety and Pharmacovigilance 
FAX Number: 
 
In case of fax issues, e-mail: 
 
The written report for SAEs should be submitted on the SAE form provided for this purpose. The 
SAE report must include the Investigator’s opinion as to whether the event is study drug-related. 
If this relationship is determined to be possibly, probably, or definitely related to study drug, 
evidence to support this assessment must also be provided. 
The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 
PPD
PPD
PPD
PPD


 
 
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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
Approximately 450 subjects are planned to be randomized in Stage 1 to have approximately 
200 subjects rerandomized to treatments in Stage 2. This will provide at least 80% power to 
show superiority for ALKS 5461 2/2 compared to placebo at the one-sided alpha level 0.025, for 
each of the three primary endpoints, assuming an effect size of at least 0.20 in Stage 1, 0.44 in 
Stage 2, and 0.32 overall (average of Stage 1 and Stage 2); and a SD of 6.25 and 8.5 for 
MADRS-6 and MADRS-10 scores, respectively. Details on the clinical study simulations 
conducted to evaluate power and type 1 error control will be provided in the Statistical Analysis 
Plan.  
14.2. 
General Statistical Methodology 
The statistical analysis methods are briefly described below. A comprehensive description of the 
statistical analysis will be included in the Statistical Analysis Plan (SAP) to be finalized before 
database lock and unblinding. 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum values for 
continuous variables, and number and percentage of subjects in each category for categorical 
variables) will be provided for evaluated variables. All individual subject level data will be 
presented as data listings. 
Unless stated otherwise, statistical tests will be one-sided with alpha=0.025 and confidence 
intervals will be two-sided and will be set at an alpha of 0.05. 
14.2.1. 
Study Populations 
14.2.1.1. Safety Population 
The Safety Population will consist of all enrolled subjects who received at least one dose of 
study drug (placebo or ALKS 5461). 
14.2.1.2. Full Analysis Set 
The Full Analysis Set (FAS) Population will consist of all subjects in the Safety Population who 
have at least one post-Baseline MADRS assessment. 
14.2.1.3. Pharmacokinetic Population 
The PK Population is defined as all subjects who have at least one measurable plasma 
concentration of any analyte during the Treatment Period. 
14.3. 
Demographics and Baseline Characteristic Data 
Demographics and baseline characteristics such as gender, age, race, weight, BMI, vital signs, 
and clinical laboratory data will be summarized with descriptive statistics to assess the 
comparability of the study groups. If there are heterogeneities between study groups in any of the 
subject characteristics that are of clinical importance or could affect the treatment outcome, the 


 
 
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impact of the imbalances will be investigated and, if necessary, appropriate adjustments made in 
the efficacy and safety analyses. 
Psychiatric history including duration of current MDE, number of lifetime MDEs, number of 
prior lifetime ADT failures and number of ADT failures within the current MDE will be 
summarized by Treatment Group and overall for the safety populations using the number of 
observations and percentage of subjects reporting each category. 
14.4. 
Efficacy Analyses 
The primary efficacy endpoints will be: 
1. Average change from baseline to Week 3 to the end of treatment period in 
MADRS-6 scores 
2. Average change from baseline to Week 3 to the end of treatment period in 
MADRS-10 scores 
3. Change from baseline to the end of treatment period in MADRS-10 scores 
The primary endpoint analysis will be carried out on the full analysis set using mixed model 
repeated measures (MMRM) in the context of a Sequential Parallel Comparison Design (SPCD) 
for each endpoint analyzed separately, in Stage 1 and in Stage 2. The models will include 
variables for treatment group, visit, treatment group-by-visit interaction term, and site as 
categorical fixed effects. Baseline value and baseline value-by-visit interaction will be included 
as covariates in the model. The comparisons of ALKS 5461 2/2 vs placebo will be made, and the 
least-squares mean difference along with the corresponding 95% confidence interval and P-value 
will be reported. Adjustments for multiplicity of the primary endpoints will be made using a 
hierarchical testing approach with the order of testing being the rank order in which the primary 
endpoints are listed. The study will be considered positive in the final analysis if the efficacy 
endpoint MADRS-6 from baseline to Week 3 through the end of the treatment period is 
statistically significant. 
Secondary efficacy endpoints (ie, proportion of subjects achieving treatment response and 
proportion of subjects achieving remission at the end of the treatment period) will be evaluated 
using a chi-squared test. 
Further details will be described in the SAP. 
14.5. 
Pharmacokinetic Analyses 
No formal PK analysis will be performed for this study. Descriptive summaries of concentration 
data will be provided and by-subject listings of plasma concentrations will be provided. 
14.6. 
Patient Questionnaire 
By-subject listings of data from the patient questionnaire will be provided. 
14.7. 
Safety and Tolerability Analyses 
All safety assessments including those collected during the Follow-up Period and AEs collected 
in the PLI will be summarized using descriptive statistics. Reported AE terms will be coded 


 
 
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using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs 
(TEAEs) will be defined as AEs that occur or worsen after the first dose of study drug. The 
incidence of TEAEs will be summarized by system organ classes and preferred terms and by 
severity and relationship to study drug. Subjects with SAEs and AEs leading to discontinuation 
from the study will be summarized. Results of clinical laboratory tests, vital signs, and ECG 
parameters will also be summarized for the absolute value and for change from Baseline. The 
number and percentage of subjects with potentially clinically significant (PCS) values will also 
be summarized. The number and percentage of subjects with C-SSRS assessments at 
post-Baseline will be summarized. Concomitant medications will be categorized using the World 
Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system. 
Listings will be provided for all concomitant medications. 
14.8. 
Interim Analysis 
A single interim analysis is planned when approximately 265 subjects have completed Stage 1 
and approximately 120 subjects have completed Stage 2. A group sequential design with a single 
interim analysis for potential early efficacy conclusion stop is employed. The primary analysis 
will be based on the SPCD method of combination of treatment mean differences between 
treatments in Stages 1 and 2. The interim analysis will be conducted by an external independent 
statistical center and reviewed by external data monitoring committee (DMC). Alkermes will 
remain blinded throughout the interim analysis. The one-sided P-value required for efficacy 
conclusion at both the interim and final analyses is <0.0147 (constant significance levels (Pocock 
1977)) in order to control overall type 1 error at 0.025 in a one-sided test. 
The external and independent DMC will consist of three voting members (including one 
chairperson) and one nonvoting member, chosen by Alkermes based on their qualifications, 
expertise, and experience. The activities of the DMC will be coordinated by the chairperson of 
the DMC. The DMC will be supported by an independent statistical team, consisting of an 
independent statistician (a nonvoting member of the DMC) and an independent programming 
team, who are part of an independent statistical center. Dissemination of interim study results 
and deliberations of the DMC prior to “end of study” will be carefully controlled by the DMC 
and others with knowledge of the data in order to ensure study integrity and to avoid any 
introduction of bias.  
The primary charge of the DMC will be to evaluate efficacy outcomes according to details 
included in the prespecified SAP for interim analysis. In the event the study is not stopped early 
for efficacy, Alkermes intends to continue enrollment to yield approximately 450 randomized 
subjects in Stage 1 and approximately 200 randomized subjects in Stage 2. The study will not be 
stopped early for futility. 
The DMC will not make decisions about the study, but will rather make recommendations. 
Within 2 business days following the DMC meeting to discuss the interim analysis results, the 
DMC Chairperson will send DMC recommendations to the Alkermes Steering Committee. 
Should the DMC recommend stopping the study, the DMC will also recommend to Alkermes 
that all subject enrollment activity should stop until the decision to terminate or to continue the 
study is finalized by Alkermes. 


 
 
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Further details will be described in the SAP for interim analysis and in the charter guiding the 
activities associated with the interim analysis and of the DMC. 


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


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


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


 
 
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Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB, and then signed by all applicable study 
participants. 
The time that informed consent is obtained must be documented. The Investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 


 
 
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18. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the Investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture systems maintain full audit trails. 
The assessments described in Section 8.3.9 will be captured via an electronic data capture 
method, with the exception of the MINI v7.0.2 which will be captured on paper. A paper copy of 
all laboratory reports will remain with the source documents at the study site. All electronic 
source data collected outside of the eCRF, such as assessments captured by electronic data 
capture, central laboratory, central ECG or central MRI data, will be transferred directly to EDC 
or directly to Alkermes for incorporation into the final datasets. All out-of-range laboratory 
values will be deemed as clinically significant or not clinically significant by the Investigator. 
Clinically significant values will be considered AEs and will be recorded as such on the eCRFs. 
All AEs will be coded using MedDRA. Concomitant medications will be categorized using the 
WHO-ATC classification system. 
18.2. 
Inspection of Records 
Alkermes or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts, and source documents and other records relative to study conduct. 
18.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the Sponsor to inform the Investigator/institution as to when 
these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 


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


 
 
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19. 
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Nakonezny PA, Carmody TJ, Morris DW, Kurian BT, Trivedi MH. Psychometric evaluation of 
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Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to 
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Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 
1977;64(2):191-199. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704. 
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 
2006;163(11):1905-1917. 
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the 
assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 
1995;167(1):99-103. 
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive atypical 
antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of 
life, and safety outcomes. PLoS Med. 2013;10(3). doi: 10.1371/journal.pmed.1001403. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 
2003;35(2):253-259. 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 70 of 80 
20. 
APPENDIX A: MASSACHUSETTS GENERAL HOSPITAL 
ANTIDEPRESSANT TREATMENT RESPONSE 
QUESTIONNAIRE (ATRQ)–SAMPLE 
Adapted for ALK5461-217 Visit 1: 
Please use an interview format to record the responses to this questionnaire. Begin by saying, 
“I’d like to summarize your use of antidepressant medication during this current episode of 
depression which began on [date episode began]. Do you agree that [date episode began] is 
when the current period of depression started?” Please circle the subject’s answer, and record 
the date of onset of the most recent depressive episode below. 
 
YES  NO 
 
Date: _____________ 
 
1.  “Have you received any treatment for depression with medications since the beginning of 
THIS CURRENT episode or period of depression, from [date episode began] until today?” 
Please circle the subject’s answer. 
YES  NO 
 
2. If YES, review the list on pages 2 and 3 and put a check next to any medication(s) that the 
subject has taken for at least 8 weeks during THIS episode or period of depression. “Let’s review 
each medication you have taken, and let me know which ones you have taken for at least 8 weeks 
during this episode of depression.” 
 
3. Of those medication(s) that the subject has taken for at least 8 weeks (checked from the list 
on pages 2 and 3), put a second check next to those that the subject has taken at a dosage equal 
to or greater than the minimum dosage listed for that medication for at least 5 weeks. “Now, 
let’s go through each, and let me know which of these you have taken at a dosage equal to or 
greater than the dose I mention, for at least 5 weeks.” 
 
4. For all medication(s) that have at least 1 check mark on the list on pages 2 and 3, please put a 
third check next to those that the subject has taken with another drug [e.g., buspirone (Buspar), 
lithium, psychostimulants such as methylphenidate (Ritalin), atypical antipsychotics such as 
olanzapine (Zyprexa)] added to augment or boost the antidepressant effect. “Were any of the 
medications you mentioned taken with another drug to augment or boost the antidepressant 
effect of another antidepressant? If so, which ones?” 
 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 71 of 80 
5. Of the medications checked on pages 2 and 3, please write below the name of the one that the 
subject reports helped them the most with their depression: “Of the medications that you have 
taken during this episode of depression, which one do you feel helped you the most with your 
depression? 
__________________________________________________________________________ 
 
6. “If a rating of 100 is “completely improved” and 0 is “not improved at all”, how close to 100 
did you get on this medication?” Read the four options below, and put a check next to the 
answer provided. 
a) less than 25% improved 
b) between 25% and 49% improved 
c) between 50% and 75% improved 
d) more than 75% improved 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 72 of 80 
List of Antidepressant Medications. 
 
Drug Class 
Brand Name 
Generic Name 
At least 
8 weeks 
Minimum 
Dose 
At least 5 weeks 
at ≥ minimum 
dose 
Agent added to 
augment or boost 
effect? 
 
Tricyclic Antidepressants 
 
Adapin 
doxepin 
_____ 
150mg/d 
_____ 
_____ 
Anafranil 
clomipramine 
_____ 
150mg/d 
_____ 
_____ 
Asendin 
amoxapine 
_____ 
150mg/d 
_____ 
_____ 
Endep/Elavil 
amitriptyline 
_____ 
150mg/d 
_____ 
_____ 
Ludiomil 
maprotiline 
_____ 
150mg/d 
_____ 
_____ 
Norpramin 
desipramine 
_____ 
150mg/d 
_____ 
_____ 
Pamelor 
nortriptyline 
_____ 
75mg/d 
_____ 
_____ 
Sinequan 
doxepin 
_____ 
150mg/d 
_____ 
_____ 
Surmontil 
trimipramine 
_____ 
150mg/d 
_____ 
_____ 
Tofranil 
imipramine 
_____ 
150mg/d 
_____ 
_____ 
Vivacti 
protriptyline 
_____ 
30mg/d 
_____ 
_____ 
Azafen 
pipofezine* 
_____ 
150mg/d 
_____ 
_____ 
Agedal/Elronon 
noxiptiline* 
_____ 
100mg/d 
_____ 
_____ 
 
 
Monoamine Oxidase Inhibitors (MAOIs) 
 
Marplan 
isocarboxazid 
_____ 
30mg/d 
_____ 
_____ 
Nardil 
phenelzine 
_____ 
45mg/d 
_____ 
_____ 
Parnat 
tranylcypromine 
_____ 
30mg/d 
_____ 
_____ 
Emsam 
selegiline patch 
_____ 
6mg/24 hrs 
_____ 
_____ 
Aurorix 
moclobemide* 
_____ 
300mg/d 
_____ 
_____ 
Pirazidol 
pirlindole* 
_____ 
200mg/d 
_____ 
_____ 
 
 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
Luvox 
fluvoxamine* 
_____ 
50mg/d 
_____ 
_____ 
Paxil 
paroxetine 
_____ 
20/25/mg/d 
_____ 
_____ 
Prozac 
fluoxetine 
_____ 
20mg/d 
_____ 
_____ 
Zoloft 
sertraline 
_____ 
50mg/d 
_____ 
_____ 
Celexa 
citalopram 
_____ 
20mg/d 
_____ 
_____ 
Lexapro 
escitalopram 
_____ 
10mg/d 
_____ 
_____ 
Viibryd 
vilazodone 
_____ 
40mg/d 
_____ 
_____ 
Brintellix 
vortioxetine 
_____ 
10mg/d 
_____ 
_____ 
 
* Note: This medication is not FDA approved for major depressive disorder in the United States. Subjects should not 
be enrolled while taking this medication, although they may have a previous failure of an adequate trial of this 
medication within this major depressive episode. 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 73 of 80 
Drug Class 
Brand Name 
Generic Name 
At least 
8 weeks 
Minimum 
Dose 
At least 5 
weeks at ≥ 
minimum dose 
Agent added to 
augment or boost 
effect? 
 
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) 
 
Effexor 
venlafaxine 
_____ 
150mg/d 
_____ 
_____ 
Cymbalta 
duloxetine 
_____ 
60mg/d 
_____ 
_____ 
Pristiq 
desvenlafaxine 
_____ 
50mg/d 
_____ 
_____ 
Savella 
milnacipran* 
_____ 
100mg/d 
_____ 
_____ 
Fetzima 
levomilnacipran 
_____ 
40mg/d 
_____ 
_____ 
 
 
Other Antidepressants 
 
Desyrel 
trazodone 
_____ 
300mg/d 
_____ 
_____ 
Serzone 
nefazodone 
_____ 
300mg/d 
_____ 
_____ 
Wellbutrin 
bupropion 
_____ 
300mg/d 
_____ 
_____ 
Remeron 
mirtazapine 
_____ 
15mg/d 
_____ 
_____ 
Valdoxan 
agomelatine* 
_____ 
25mg/d 
_____ 
_____ 
Stablon 
tianeptine* 
_____ 
37.5mg/d 
_____ 
_____ 
Edronax 
reboxetine* 
_____ 
4mg/d 
_____ 
_____ 
Bolvidon/Depnon, 
Norval/Tolvon 
mianserin* 
_____ 
30mg/d 
_____ 
_____ 
Insidon 
opipramol* 
_____ 
150mg/d 
_____ 
_____ 
 
*Note: This medication is not FDA approved for major depressive disorder in the United States. Subjects should not 
be enrolled while taking this medication, although they may have a previous failure of an adequate trial of this 
medication within this major depressive episode. 
 
Did you receive electro-convulsive treatment (ECT) during this current episode (please circle one): 
 
YES 
NO 
 
Did you ever receive vagal nerve stimulation (VNS) or deep brain stimulation (DBS) (please circle one): 
 
YES 
NO 
 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 74 of 80 
Adapted for ALK5461-217 Visit 2: 
Please use an interview format to record the responses to this questionnaire. Begin by saying, 
“I’d like to summarize your use of antidepressant medication between Visit 1 on [date patient 
completed Visit 1] and today.” 
 
1.  “Are you currently taking any antidepressant medication(s)?” Please circle the subject’s 
answer. 
YES  NO 
 
2. If YES, review the list on pages 2 and 3 and put a check next to any medication(s) that the 
subject has been taking for at least 8 weeks, (or at least 7 weeks if the subject switched to a 
second ADT during the PLI). “Let’s review each medication you have taken since the last visit 
(including ones you may have started before the last visit) or are currently taking, and let me 
know which one you have taken for at least 8 weeks.” Adjust language appropriately as noted 
above if the subjected switched to a new ADT during the PLI and the 7-week duration is 
relevant). 
 
3. Of those medication(s) that the subject has taken for at least 8 weeks (or 7 weeks as 
described in item 2) and checked from the list on pages 2 and 3, put a second check next to 
those that the subject has been taking at a dosage equal to or greater than the minimum dosage 
listed for that medication for at least 5 weeks. “Now, let’s go through each, and let me know 
which of these you have taken at a dosage equal to or greater than the dose I mention, for at 
least 5 weeks.” 
 
4. For the new medication(s) that have at least 1 check mark on the list on pages 2 and 3, 
please put a third check next to those that the subject has taken with another drug [e.g., 
buspirone (Buspar), lithium, psychostimulants such as methylphenidate (Ritalin), atypical 
antipsychotics such as olanzapine (Zyprexa)] added to augment or boost the antidepressant 
effect. “Where any of the medications you mentioned taken with another drug to augment or 
boost the antidepressant effect of another antidepressant? If so, which ones?” 
 
5. Record the degree to which the subject thinks they have improved with the current antidepressant 
treatment. “Now I’d like to talk about how much you think your depression has improved with your 
current antidepressant. If a rating of 100 is “completely improved” and 0 is “not improved at 
all”, how close to 100 did you get on this medication?” Read the four options below, and put a 
check next to the answer provided. 
a) less than 25% improved 
b) between 25% and 49% improved 
c) between 50% and 75% improved 
d) more than 75% improved 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 75 of 80 
List of Antidepressant Medications. 
Drug Class 
Brand Name 
Generic Name 
At least 
8 weeks** 
Minimum 
Dose 
At least 5 weeks 
at ≥ minimum 
dose 
Agent added to 
augment or boost 
effect? 
 
Tricyclic Antidepressants 
 
Adapin 
doxepin 
_____ 
150mg/d 
_____ 
_____ 
Anafranil 
clomipramine 
_____ 
150mg/d 
_____ 
_____ 
Asendin 
amoxapine 
_____ 
150mg/d 
_____ 
_____ 
Endep/Elavil 
amitriptyline 
_____ 
150mg/d 
_____ 
_____ 
Ludiomil 
maprotiline 
_____ 
150mg/d 
_____ 
_____ 
Norpramin 
desipramine 
_____ 
150mg/d 
_____ 
_____ 
Pamelor 
nortriptyline 
_____ 
75mg/d 
_____ 
_____ 
Sinequan 
doxepin 
_____ 
150mg/d 
_____ 
_____ 
Surmontil 
trimipramine 
_____ 
150mg/d 
_____ 
_____ 
Tofranil 
imipramine 
_____ 
150mg/d 
_____ 
_____ 
Vivacti 
protriptyline 
_____ 
30mg/d 
_____ 
_____ 
Azafen 
pipofezine* 
_____ 
150mg/d 
_____ 
_____ 
Agedal/Elronon 
noxiptiline* 
_____ 
100mg/d 
_____ 
_____ 
 
 
Monoamine Oxidase Inhibitors (MAOIs) 
 
Marplan 
isocarboxazid 
_____ 
30mg/d 
_____ 
_____ 
Nardil 
phenelzine 
_____ 
45mg/d 
_____ 
_____ 
Parnat 
tranylcypromine 
_____ 
30mg/d 
_____ 
_____ 
Emsam 
selegiline patch 
_____ 
6mg/24 hrs 
_____ 
_____ 
Aurorix 
moclobemide* 
_____ 
300mg/d 
_____ 
_____ 
Pirazidol 
pirlindole* 
_____ 
200mg/d 
_____ 
_____ 
 
 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
Luvox 
fluvoxamine* 
_____ 
50mg/d 
_____ 
_____ 
Paxil 
paroxetine 
_____ 
20/25/mg/d 
_____ 
_____ 
Prozac 
fluoxetine 
_____ 
20mg/d 
_____ 
_____ 
Zoloft 
sertraline 
_____ 
50mg/d 
_____ 
_____ 
Celexa 
citalopram 
_____ 
20mg/d 
_____ 
_____ 
Lexapro 
escitalopram 
_____ 
10mg/d 
_____ 
_____ 
Viibryd 
vilazodone 
_____ 
40mg/d 
_____ 
_____ 
Brintellix 
vortioxetine 
_____ 
10mg/d 
_____ 
_____ 
 
* Note: This medication is not FDA approved for major depressive disorder in the United States. Subjects should not 
be enrolled while taking this medication, although they may have a previous failure of an adequate trial of this 
medication within this major depressive episode. 
 
** Or at least 7 weeks if the subject switched to a second ADT during the PLI Period. 
 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 76 of 80 
Drug Class 
Brand Name 
Generic Name 
At least 
8 weeks** 
Minimum 
Dose 
At least 5 
weeks at ≥ 
minimum dose 
Agent added to 
augment or boost 
effect? 
 
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) 
 
Effexor 
venlafaxine 
_____ 
150mg/d 
_____ 
_____ 
Cymbalta 
duloxetine 
_____ 
60mg/d 
_____ 
_____ 
Pristiq 
desvenlafaxine 
_____ 
50mg/d 
_____ 
_____ 
Savella 
milnacipran* 
_____ 
100mg/d 
_____ 
_____ 
Fetzima 
levomilnacipran 
_____ 
40mg/d 
_____ 
_____ 
 
 
Other Antidepressants 
 
Desyrel 
trazodone 
_____ 
300mg/d 
_____ 
_____ 
Serzone 
nefazodone 
_____ 
300mg/d 
_____ 
_____ 
Wellbutrin 
bupropion 
_____ 
300mg/d 
_____ 
_____ 
Remeron 
mirtazapine 
_____ 
15mg/d 
_____ 
_____ 
Valdoxan 
agomelatine* 
_____ 
25mg/d 
_____ 
_____ 
Stablon 
tianeptine* 
_____ 
37.5mg/d 
_____ 
_____ 
Edronax 
reboxetine* 
_____ 
4mg/d 
_____ 
_____ 
Bolvidon/Depnon, 
Norval/Tolvon 
mianserin* 
_____ 
30mg/d 
_____ 
_____ 
Insidon 
opipramol* 
_____ 
150mg/d 
_____ 
_____ 
 
*Note: This medication is not FDA approved for major depressive disorder in the United States. Subjects should not 
be enrolled while taking this medication, although they may have a previous failure of an adequate trial of this 
medication within this major depressive episode. 
 
** Or at least 7 weeks if the subject switched to a second ADT during the PLI Period. 
 
Did you receive electro-convulsive treatment (ECT) during this current episode (please circle one): 
 
YES 
NO 
 
Did you ever receive vagal nerve stimulation (VNS) or deep brain stimulation (DBS) (please circle one): 
 
YES 
NO 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 77 of 80 
21. 
APPENDIX B: DAILY DOSING TABLE FOR ANTIDEPRESSANT 
THERAPY TAKEN DURING THE STUDY 
Table 8: 
Daily Dosing Allowed for Antidepressant Therapy Taken During the Study 
Brand Name 
Generic Name 
Minimum 
Adequate Daily 
Dose (mg) 
Maximum Daily 
Dose (mg) 
Permitted for 
PIR Subjects? 
SSRIs 
Paxil 
paroxetine 
20/25 
50 
No 
Paxil CR 
paroxetine 
20/25 
62.5 
No 
Prozac 
fluoxetine 
20 
80 
Yes 
Zoloft 
sertraline 
50 
200 
Yes 
Celexa 
citalopram 
20 
40 
No 
Lexapro 
escitalopram 
10 
20 
Yes 
Viibryd 
vilazodone 
40 
40 
No 
Brintellix 
vortioxetine 
10 
20 
No 
SNRIs 
Effexor 
venlafaxine 
150 
375 
Yes 
Effexor XR 
venlafaxine 
150 
225 
Yes 
Cymbalta 
duloxetine 
60 
120 
Yes 
Pristiq 
desvenlafaxine 
50 
400 
No 
Fetzima 
levomilnacipran 
40 
120 
No 
Abbreviations: CR=controlled-release; PIR=prospective inadequate responder; SNRIs=serotonin-norepinephrine 
reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; XR=extended-release 


 
 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0) 
 
 
CONFIDENTIAL 
Page 78 of 80 
22. 
APPENDIX C: PATIENT QUESTIONNAIRE 
Question 1: Below is a list of symptoms associated with depression. We are interested in knowing how important each one is to you. 
Please rate each item on how important it is to you from 0 (Not important) to 4 (Extremely important / Essential). Please rate each 
item independently of the others. 
Item # 
Description 
Importance to you (0 to 4) 
0 - Not 
important 
1 - Somewhat 
important 
2 - Important 
3 - Very 
important 
4 -Extremely 
important / 
Essential 
1 
Feeling sad or unhappy 
 
 
 
 
 
2 
Looking sad or depressed to 
other people 
 
 
 
 
 
3 
Feeling anxious or nervous or 
agitated 
 
 
 
 
 
4 
Ability to fall and stay asleep 
 
 
 
 
 
5 
Interest in food (lack of interest 
or increased appetite) 
 
 
 
 
 
6 
Ability to concentrate or collect 
thoughts 
 
 
 
 
 
7 
Ability to get things started, how 
quickly you are able to get 
everyday things done 
 
 
 
 
 
8 
Interest in things you typically 
enjoy, ability to experience joy, 
zest for life 
 
 
 
 
 
9 
Feelings of guilt, putting 
yourself down 
 
 
 
 
 
10 
Feeling that life isn't worth 
living, better off dead 
 
 
 
 
 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0) 
 
CONFIDENTIAL 
Page 79 of 80 
23. 
APPENDIX D: MAXIMUM DOSES OF ANTIPSYCHOTICS 
APPROVED FOR MDD 
Table 9 lists the antipsychotics for which prior use is allowed in this study. It gives the maximum 
approved doses for MDD of these antipsychotics. 
Table 9: 
Maximum antipsychotic approved doses for MDD 
Antipsychotic 
Maximum approved dose 
Aripiprazole 
30 mg/day 
Quetiapine 
300 mg/day 
Brexpiprazole 
3 mg/day 
Olanzapine/fluoxetine 
12 mg/50 mg/day 


 
 
Alkermes, Inc. 
Protocol ALK5461-217 v 3.0 (Amendment 2.0)  
CONFIDENTIAL 
Page 80 of 80 
24. 
APPENDIX E: PARTIAL LIST OF PROHIBITED 
CYTOCHROME P450 (CYP) 3A4 INHIBITORS AND INDUCERS 
The following is a list of CYP3A4 inhibitors and inducers that subjects are to avoid within 
30 days before Screening through follow-up. This list is not comprehensive. 
Table 10: 
Partial List of Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers 
Moderate-to-Strong Inhibitors 
Moderate-to-Strong Inducers 
Aprepitant 
Imatinib 
Bosentan 
Boceprevir 
Ketoconazole 
Carbamazepine 
Ciprofloxacin 
Lopinavir/Ritonavir  
Efavirenz 
Clarithromycin  
Nefazodone  
Enzalutamide 
Conivaptan  
Nelfinavir  
Etravirine 
Crizotinib 
Posaconazole  
Modafinil 
Danoprevir/Ritonavir 
Ritonavir  
Phenobarbital 
Diltiazem  
Saquinavir/Ritonavir  
Phenytoin 
Erythromycin  
Telaprevir 
Rifampin 
Fluconazole 
Troleandomycin  
Rifabutin 
Indinavir/Ritonavir  
Verapamil  
St. John’s Wort 
Itraconazole  
Voriconazole  
– 
Source: (Food and Drug Administration 2016) 
 

SAP_001.pdf: 
A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 
5461 in Treatment Refractory Major Depressive Disorder 
 
 
Unique Protocol ID: 
ALK5461-217 
NCT Number: 
NCT03188185 
Date of Statistical Analysis 
Plan:  
02 Oct 2019 
 


TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
ALK5461-217 
Study Title: 
A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 5461 in 
Treatment Refractory Major Depressive Disorder 
Document Status: 
Final, Version 2.0 
Document Date: 
02 Oct 2019 
Based on: 
ALK5461-217 Study Protocol Versions: 
v4.0 (incorporates Amendment 3 [02 Oct 2019] and Administrative 
Change Memo 2 [10 Apr 2019]) 
v3.0 (incorporates Amendment 2 [25 Jan 2018] and Administrative 
Change Memo 1 [10 Jul 2017]) 
v2.0 (incorporates Amendment 1): 18 Apr 2017 
Original Protocol v1.0: 11 Jan 2017 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 


Alkermes, Inc. 
 
ALK5461-217 
CONFIDENTIAL 
 
Statistical Analysis Plan 
 
 
Page 2 of 67 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.2. 
Summary of the Study Design ......................................................................................7 
1.3. 
Screening and Prospective Lead-in Period ...................................................................8 
1.4. 
Double-Blind Treatment Period ...................................................................................8 
1.5. 
Safety Follow-up Period ...............................................................................................9 
1.6. 
Criteria for Evaluation ..................................................................................................9 
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION .......................10 
3. 
DATA ANALYSIS ....................................................................................................10 
3.1. 
Study Population .........................................................................................................10 
3.1.1. 
Definition of Analysis Populations (Analysis Sets) ...................................................10 
3.1.1.1. 
Safety Populations ......................................................................................................10 
3.1.1.2. 
Full Analysis Set Populations .....................................................................................12 
3.1.1.3. 
Pharmacokinetic Population .......................................................................................14 
3.1.2. 
Disposition ..................................................................................................................14 
3.1.3. 
Protocol Deviations ....................................................................................................15 
3.2. 
Demographic and Baseline Characteristics ................................................................16 
3.3. 
Prior and Concomitant Medications ...........................................................................17 
3.4. 
Treatment Adherence Rate and Extent of Exposure ...................................................17 
3.5. 
Efficacy Analyses .......................................................................................................18 
3.5.1. 
Primary Efficacy Endpoints ........................................................................................18 
3.5.2. 
General Consideration ................................................................................................18 
3.5.2.1. 
Pooling of Centers ......................................................................................................19 
3.5.2.2. 
Examination of Subgroups .........................................................................................20 
3.5.3. 
Efficacy Analysis for Primary Efficacy Endpoint ......................................................21 
3.5.3.1. 
Primary Efficacy Analysis ..........................................................................................21 
3.5.3.2. 
Effect Size ...................................................................................................................22 
3.5.3.3. 
Sensitivity Analysis ....................................................................................................22 
3.5.3.4. 
Supportive Analysis for Primary Endpoints ...............................................................24 


Alkermes, Inc. 
 
ALK5461-217 
CONFIDENTIAL 
 
Statistical Analysis Plan 
 
 
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3.5.4. 
Efficacy Analysis for the Secondary Efficacy Endpoints ...........................................24 
3.5.4.1. 
Average of the Differences in Change from Vaseline at Each Week from 
Week 3 to the End of Treatment Period in MADRS-10 .............................................25 
3.5.4.2. 
Proportion of MADRS Treatment Responders at the End of Treatment 
Period ..........................................................................................................................25 
3.5.4.3. 
Proportion of Subjects Achieving Remission at the End of Treatment Period ..........26 
3.5.5. 
Efficacy Analysis for the Exploratory Efficacy Endpoints ........................................26 
3.6. 
Safety Analysis ...........................................................................................................27 
3.6.1. 
General Consideration ................................................................................................27 
3.6.2. 
Adverse Events ...........................................................................................................29 
3.6.3. 
Deaths, Serious and Other Significant Adverse Events ..............................................30 
3.6.4. 
Adverse Events of Special Interest .............................................................................30 
3.6.5. 
Clinical Laboratory Parameters ..................................................................................31 
3.6.6. 
Vital Signs and Electrocardiogram .............................................................................33 
3.6.6.1. 
Vital Signs ..................................................................................................................33 
3.6.6.2. 
Electrocardiograms .....................................................................................................34 
3.6.7. 
Clinical Opiate Withdrawal Scale (COWS) Scores ....................................................35 
3.6.8. 
Columbia-Suicide Severity Rating Scale ....................................................................36 
3.7. 
Pharmacokinetic/ Pharmacodynamic Data Analysis ..................................................38 
4. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE ....................38 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................38 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........38 
6.1. 
Analysis Visit Windows .............................................................................................38 
6.2. 
Efficacy Data Handling ..............................................................................................39 
6.3. 
Safety Data Handling ..................................................................................................39 
6.4. 
Handling of Partial Dates of Concomitant Medication ..............................................39 
6.5. 
Pharmacokinetic Data Handling .................................................................................39 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................40 
7.1. 
Statistical Conventions ...............................................................................................40 
7.2. 
Reporting Precision ....................................................................................................40 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................40 
9. 
MOCK TABLES, LISTINGS AND FIGURES .........................................................40 


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10. 
REFERENCES ...........................................................................................................41 
Appendix 1: Independence of Estimated Treatment Effects in 2 Stages for SPCD with Binary 
Endpoints ...............................................................................................................42 
Appendix 2: AESI – Abuse Potential .........................................................................................44 
Appendix 3: AESI – Dependence ...............................................................................................46 
Appendix 4: AESI – Withdrawal ................................................................................................47 
Appendix 5: AESI – Suicidal Ideation and Behavior .................................................................49 
Appendix 6: AESI – Hypomania/ Mania ....................................................................................50 
Appendix 7: AESI – CNS Depression and Sedation ..................................................................51 
Appendix 8: AESI – Respiratory Depression .............................................................................52 
Appendix 9: AESI – Orthostatic Hypotension ...........................................................................53 
Appendix 10: AESI – Hypersensitivity ........................................................................................55 
Appendix 11: AESI – Hepatic Effects ..........................................................................................65 
 
LIST OF TABLES 
Table 1: 
The United States Census Bureau Regions ................................................................20 
Table 2: 
Summary Approach for Safety Endpoints ..................................................................28 
Table 3: 
Criteria of Potentially Clinically Significant Abnormality for Selected 
Analytes ......................................................................................................................32 
Table 4: 
Criteria for Potentially Clinically Significant Abnormal Vital Sign Values ..............34 
Table 5: 
Criteria for Potentially Clinically Significant Abnormal ECG Values ......................35 
Table 6: 
Columbia-Suicide Severity Rating Scale Categories for Analysis .............................36 
Table 7: 
Treatment-Emergent Suicide-Related Events for Analysis ........................................37 
Table 8: 
Degree of Precision .....................................................................................................40 
Table 9: 
Subject Accounting by Response Status in 2 Stages of SPCD ...................................42 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................7 
Figure 2: 
Study Flow Diagram .....................................................................................................9 
Figure 3: 
Primary Safety Populations ........................................................................................12 
Figure 4: 
Efficacy Populations ...................................................................................................13 
 


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LIST OF ABBREVIATIONS 
The following abbreviations are used in the statistical analysis plan (SAP). 
Abbreviation 
Definition 
ADT 
Antidepressant Therapy 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical (classification system) 
BLOQ 
Below Lower Limit of Quantification 
BMI 
Body Mass Index 
BUP 
Buprenorphine 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CNS 
Central Nervous System 
COWS 
Clinical Opiate Withdrawal Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CI 
Confidence Interval 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FAS 
Full Analysis Set 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
17 Item Hamilton Rating Scale for Depression 
HIR 
Historical Inadequate Response 
HR 
Heart Rate 
IxRS 
Interactive Voice or Web Response System 
LOCF 
Last Observation Carried Forward 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
Major Depressive Disorder 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
MMRM 
Mixed Model for Repeated Measures 
nBUP 
nor-buprenorphine 
PDEAE 
Post-discontinuation Emergent Adverse Event 
NR 
Non-responder 
PIR 
Prospective Inadequate Response 
PK 
Pharmacokinetic 
PLI 
Prospective Lead-in 
PMM 
Pattern Mixture Model 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form 
QTcB 
QTcB – Bazett’s correction formula 
QTcF 
QTcF – Fridericia’s correction formula 
SAE 
Serious Adverse Event 
SAM 
Samidorphan 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SIGH-D 
Structured Interview Guide for the HAM-D 
SIGMA 
Structured Interview Guide for the MADRS 
SL 
Sublingual 
SNRI 
Serotonin-Norepinephrine Reuptake Inhibitor 
SPCD 
Sequential Parallel Comparison Design 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TEAE 
Treatment Emergent Adverse Events 
ULN 
Upper limit of normal 
WHO-ATC 
World Health Organization Anatomical Therapeutic Chemical 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data presentation to be 
used for analyzing and reporting efficacy and safety data for study ALK5461-217. This 
document has been prepared based on Alkermes ALK5461-217 Study Protocol Amendment 3.0 
(dated 02 Oct 2019) and the associated Unmasked Addendum Amendment 2.0 (dated 
25 Jan 2018). 
1.1. 
Study Objectives 
The objectives of this study are: 
• To evaluate the efficacy of adjunctive ALKS 5461 for treatment refractory major 
depressive disorder (MDD) in adults 
• To evaluate the safety and tolerability of adjunctive ALKS 5461 in adults who have 
treatment refractory MDD 
1.2. 
Summary of the Study Design 
This is a Phase 3b multicenter study of adjunctive ALKS 5461 2/2 (2 mg buprenorphine 
[BUP]/2 mg samidorphan [SAM], hereafter referred to as ALKS 5461 2/2) that will utilize a 
randomized, double-blind, two-stage, placebo-controlled, sequential parallel comparison design 
(SPCD). The purpose of this study is to evaluate the efficacy, safety, and tolerability of 
adjunctive ALKS 5461 2/2 taken sublingually (SL) once a day in male and female subjects with 
treatment refractory MDD (defined as having at least 2 inadequate responses to antidepressant 
therapies [ADT] in the current major depressive episode [MDE]). 
ALKS 5461 2/2 (plus current, approved ADT) or placebo (plus current, approved ADT) will be 
administered to subjects for 5 weeks in Stage 1 and for 6 weeks in Stage 2. During Stages 1 
and 2, subjects will return to the clinic every week for assessments. Subjects will return to the 
clinic for a Safety Follow-up Visit (Visit 14), 1 week after Visit 13. The total study duration for a 
given subject will be up to approximately 24 weeks, which includes a Screening Period of up to 
4 weeks, an 8-week Prospective Lead-in (PLI) period (if required as determined during 
Screening), two treatment periods of 5- and 6-weeks duration (Stages 1 and 2, respectively) and 
a 1-week Follow-up period. 
A schematic of the study design is provided in Figure 1. 
Figure 1: 
Study Design Schematic 
 


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1.3. 
Screening and Prospective Lead-in Period 
Potential subjects will be evaluated during a Screening Period (Visit 1) lasting up to 4 weeks. 
Screening will include an assessment of each subject’s history of inadequate response to ADT. 
Based on this assessment at Screening, qualifying subjects will either participate in an 8-week 
PLI Period (prospective inadequate responders [PIRs]) or will be eligible to bypass the PLI 
Period and proceed directly to Stage 1 (historic inadequate responders [HIRs]). 
Throughout the PLI Period, subjects will return to the clinic for brief assessments (Visits 1a-1f) 
that will occur weekly for the first 4 weeks and biweekly for the remainder of the PLI Period. At 
Visit 1f, subjects will be assessed for eligibility in an automated interactive voice or web 
response system (IxRS) using masked criteria. Based on this assessment, subjects will be 
classified as either being eligible to continue in the study or screen failures. 
1.4. 
Double-Blind Treatment Period 
The 11-week treatment period (Visits 2-13) will be divided into Stage 1 (Visits 2–7, 5 weeks) 
and Stage 2 (Visits 7-13, 6 weeks). At Visit 2, PIR and HIR subjects who meet all the entry 
criteria will be randomized in a 2:5 ratio to receive either ALKS 5461 2/2 or placebo for 5 
weeks, in addition to background ADT. 
At Visit 7, response to treatment will be calculated electronically based on Montgomery Åsberg 
Depression Rating Scale (MADRS) score change from baseline (Visit 2) to the end of Stage 1 
(Visit 7). Subjects in the Stage 1 placebo group will be categorized as either placebo responders 
or placebo nonresponders. The criteria for placebo nonresponders is defined in Unmasked 
Addendum Amendment 2.0. 
Subjects who fail to meet nonresponder criteria will be categorized as placebo responders. 
Subjects categorized as placebo nonresponders will be rerandomized in a 1:1 ratio to ALKS 5461 
2/2 or placebo for 6 weeks in Stage 2. Subjects categorized as placebo responders will not be 
rerandomized and will remain on placebo for 6 weeks in Stage 2. Subjects who received 
ALKS 5461 2/2 in Stage 1 will be switched to placebo for 6 weeks in Stage 2. All subjects will 
continue on the same background ADT as Stage 1. 
A study flow diagram is provided in Figure 2. 


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Figure 2: 
Study Flow Diagram 
 
1.5. 
Safety Follow-up Period 
Subjects who complete Stage 2 (Visit 13) or who prematurely discontinue during either 
Stage 1 or 2 should return to the clinic 1 week later for a Safety Follow-up Visit (Visit 14). 
1.6. 
Criteria for Evaluation 
Efficacy: 
Primary Efficacy Endpoint: 
• MADRS-10 score change from baseline to the end of treatment period 
Secondary Efficacy Endpoints: 
• Average of the differences in change from baseline at each Week from Week 3 
through the end of treatment period between ALKS 5461 vs placebo in MADRS-10 
• MADRS response, defined as a ≥50% reduction in MADRS-10 score from baseline 
to the end of treatment period 
• MADRS remission, defined as MADRS-10 score ≤10 at the end of treatment period 
Exploratory Endpoints: 
• Change over time in Clinical Global Impression-Severity (CGI-S) scores 
• Absolute Clinical Global Impression-Improvement (CGI-I) scores over time 


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• Change over time in Quality of Life Enjoyment and Satisfaction Questionnaire-Short 
Form (Q-LES-Q-SF) scores 
• Change over time in Brief Pain Inventory-Short Form (BPI-SF) scores 
• Change over time in Snaith-Hamilton Pleasure Scale (SHAPS) scores 
• Change over time in Connor-Davidson Resilience Scale (CD-RISC-25) scores 
Safety and Tolerability: 
The following assessment data will be collected to measure safety and tolerability throughout the 
study: 
• Adverse events (AEs) 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• Vital signs 
• Weight 
• Electrocardiogram (ECG) parameters 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Clinical Opiate Withdrawal Scale (COWS) 
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION 
Approximately 450 subjects are planned to be randomized in Stage 1 to have approximately 
200 subjects rerandomized to treatment in Stage 2. This will provide at least 80% power to show 
superiority for ALKS 5461 2/2 compared to placebo at the two-sided alpha level 0.05, for the 
primary endpoint, assuming an effect size of at least 0.20 in Stage 1, 0.44 in Stage 2 and 0.32 
overall (average of Stage 1 and Stage 2); and a standard deviation (SD) of 8.5 for MADRS-10 
scores. 
3. 
DATA ANALYSIS 
3.1. 
Study Population 
3.1.1. 
Definition of Analysis Populations (Analysis Sets) 
3.1.1.1. 
Safety Populations 
The primary safety populations for evaluation of safety of ALKS 5461 2/2 compared to placebo 
will be defined as follows and are illustrated in Figure 3. 
Stage 1 Safety Population will consist of all randomized subjects who received at least one dose 
of study drug (placebo or ALKS 5461 2/2) during Stage 1. 
Stage 2 Safety Population 1 will consist of Stage 1 placebo nonresponders who entered Stage 2 
and received at least one dose of study drug (placebo or ALKS 5461 2/2) during Stage 2. 


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Subjects in the above safety populations will be analyzed by the treatment group defined by the 
actual treatment received. 
Other safety populations will be defined as follows: 
Stage 2 Safety Population 2 will include Stage 1 placebo responders who continued on placebo 
in Stage 2, and subjects randomized to ALKS 5461 2/2 in Stage 1 and switched to placebo 
during Stage 2. Summary of disposition will be presented for this population. Safety data will not 
be summarized for this population separately, but will be included in data listings. 
Stage 2 Entire Safety Population will consist of subjects who received at least one dose of study 
drug (placebo or ALKS 5461 2/2) during Stage 2. This population comprises subjects in Stage 2 
Safety Population 1 and subjects in Stage 2 Safety Population 2. 
Subjects in Stage 2 Safety Population 2 will be summarized by the treatment group defined by 
the actual treatment received. Subjects in the Stage 2 Entire Safety Population will be 
summarized by the treatment sequence defined by the actual treatment received in each stage: 
• Placebo nonresponder - ALKS 5461 2/2 
• Placebo nonresponder - placebo 
• Placebo responder - placebo 
• ALKS 5461 2/2 - placebo 
Post-discontinuation Safety Population will consist of subjects in the Stage 1 Safety Population 
who have at least one post-discontinuation measurement. 
There will be three post-discontinuation safety populations, two will be used to analyze post-
discontinuation emergent adverse events (PDEAEs, defined as AEs that started or worsened after 
last dose date plus 1 day), and the other will be to analyze COWS scores, grouped by the last 
treatment received in the study. 
Stage 1 Post-discontinuation Safety Population for PDEAEs consists of subjects who were 
randomized and received at least one dose of study drug in Stage 1, grouped by the treatment 
received in Stage 1. 
Stage 2 Post-discontinuation Safety Population for PDEAEs consists of subjects who were 
Stage 1 placebo nonresponders, grouped by the last treatment received in Stage 2, and met any of 
the following criteria: 
• Subjects who entered the Post-discontinuation period and had a Post-discontinuation 
Visit 14 
• Subjects who did not enter the Post-discontinuation period, but had at least one 
PDEAE reported 
• Subjects who died after either completing the treatment or having an Early 
Termination (ET) Visit 
Stage 2 Post-discontinuation Safety Population for COWS consists of subjects who were Stage 1 
placebo nonresponders, grouped by the last treatment received in Stage 2, and had at least one 
postbaseline COWS assessment (Visit 14) that occurred from >2 to 16 days post last dose of 
study drug. 


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Prospective Lead-in Period Safety Population will consist of all PIR subjects who received at 
least one dose of ADT during the PLI Period. 
Figure 3: 
Primary Safety Populations 
Randomization Stage 1
ALKS 5461 
2/2
Placebo
Placebo
Placebo
Stage 1 
responders
Stage 1 non-responders
Stage 2 re-randomization
ALKS 5461 
2/2
Placebo
Stage 1
Stage 2
Stage 1 Safety Population
 
Randomization Stage 1
ALKS 5461 
2/2
Placebo
Placebo
Placebo
Stage 1 
responders
Stage 1 non-responders
Stage 2 re-randomization
ALKS 5461 
2/2
Placebo
Stage 1
Stage 2
Stage 2 Safety Population 1
 
3.1.1.2. 
Full Analysis Set Populations 
The FAS populations defined by stage are illustrated in Figure 4. 


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Stage 1 FAS will consist of subjects who received at least one dose of study drug (placebo or 
ALKS 5461 2/2) during Stage 1 and had at least one postbaseline assessment of MADRS-10 
score in Stage 1. 
Stage 2 FAS will consist of all subjects who were randomized and entered Stage 2 and received at 
least one dose of study drug (placebo or ALKS 5461 2/2) during Stage 2 and had at least one 
postbaseline assessment of MADRS-10 score in Stage 2. 
Subjects in the above populations will be analyzed by the treatment group into which they were 
randomized. 
Subjects identified as duplicate subjects (see Section 3.1.3) will not be included in the FAS 
Populations. 
Figure 4: 
Efficacy Populations 
Randomization Stage 1
ALKS 5461 
2/2
Placebo
Placebo
Placebo
Stage 1 
responders
Stage 1 non-responders
Stage 2 re-randomization
ALKS 5461 
2/2
Placebo
Stage 1
Stage 2
Stage 1 Full Analysis Set
 


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Figure 4: 
Efficacy Populations (Continued) 
Randomization Stage 1
ALKS 5461 
2/2
Placebo
Placebo
Placebo
Stage 1 
responders
Stage 1 non-responders
Stage 2 re-randomization
ALKS 5461 
2/2
Placebo
Stage 1
Stage 2
Stage 2 Full Analysis Set
 
3.1.1.3. 
Pharmacokinetic Population 
Stage 1 Pharmacokinetic Population will consist of all subjects who had at least one measurable 
plasma concentration of any analyte in Stage 1. 
Stage 2 Pharmacokinetic Population will consist of all subjects who had at least one measurable 
plasma concentration of any analyte in Stage 2. 
3.1.2. 
Disposition 
Subject disposition will be summarized for the following: 
For Stage 1, based on randomized subjects: 
• Subjects randomized 
• Subjects in the Stage 1 Safety Population 
• Subjects in the Stage 1 FAS Population 
• Subjects who completed Stage 1 treatment period 
• Subjects who discontinued the study during Stage 1 
• Subjects in the Post-discontinuation Safety Population 
• Subjects who entered Stage 2 
For Stage 2, based on Stage 2 Safety Population 1: 
• Subjects in the Stage 2 Safety Population 1 


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• Subjects in the Stage 2 FAS Population 
• Subjects who completed treatment 
• Subjects who completed study 
• Subjects who discontinued the study during Stage 2 
• Subjects in the Post-discontinuation Safety Population 
For Stage 2, based on the Stage 2 Entire Safety Population (summarized by treatment sequence): 
• Subjects in the Stage 2 Entire Safety Population 
• Subjects who completed the Stage 2 treatment period 
• Subjects who completed the study 
• Subjects who discontinued the study during Stage 2 
• Subjects in the Post-discontinuation Safety Population 
Disposition will be summarized by Stage 1 treatment group in Stage 1, and by Stage 2 treatment 
group in Stage 2. For subjects who prematurely discontinue from study, the reasons for 
discontinuation, as recorded on disposition page, will be presented. 
Subjects completing Stage 1 treatment period are defined as those who have assessments at Visit 
7. Subjects completing the treatment or completing the study are those with completion indicated 
on the disposition page in the case report form. 
In addition, disposition over the entire study will be summarized based on the treatment group 
subjects were assigned to when the disposition event occurred. Furthermore, disposition over the 
PLI period, based on the PLI Period Safety Population, will also be provided. 
Cumulative discontinuation rates will be provided by stage, by visit and by treatment arm. 
Supporting listings will be provided for subjects who enrolled in the PLI period, as well as for all 
randomized subjects. 
3.1.3. 
Protocol Deviations 
Subjects with major protocol deviations who fall into the following categories will be 
summarized by treatment group for each stage, along with supportive listings for each category: 
• Informed Consent - Informed consent not obtained prior to assessments 
• Violation of Enrollment Criteria - Subjects entered into the study even though they 
did not meet the eligibility criteria, including previous participation in the current 
study or another study in the FORWARD program and receipt of investigational 
drug, etc. 
• Prohibited Concomitant Medications - Use of a prohibited concomitant medication 
that may affect either efficacy or safety, including changes in ADT prescription or 
dosing during the treatment period 


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•
Nonadherence with Study Treatment - Lack of adherence defined as taking less than
70% or more than 130% of the protocol-specified amount of study drug during the
subject’s study participation
•
Randomization or Dosing Errors – Includes randomization errors and significant
dosing errors
•
Improper Collection of Primary Efficacy Assessment - MADRS assessment
conducted by a rater not certified for the ALK5461-217 study or other improper
collection of MADRS
•
Other - GCP violations or other unanticipated deviations not included in the
categories above that could potentially affect the scientific soundness of the research
plan or the rights, safety, or welfare of human subjects
Duplicate subjects include subjects who enrolled in multiple studies or multiple times in the same 
study, or other concurrent studies, despite clear instruction that prior participation is exclusionary 
per Study Protocol. These subjects put themselves at greater safety risk with inaccurate medical 
information misrepresenting disease symptoms and medical history to enroll more than once. 
These subjects violate the consent letter and spirit of the protocol regarding multiple 
participations (exclusion criteria 23 and 24). The data collected on these subjects are unreliable 
and are likely to misinform and adversely influence the interpretation of study results. 
During the conduct of this study, data (eCRF and other sources) will be reviewed to identify 
duplicate subjects and sites will be contacted to investigate and confirm duplicate enrollment. 
Upon confirmation, duplicate subjects will be prohibited from further participation in the study 
and will be discontinued from the study for exclusion criterion 2. Details of the procedure to be 
followed are summarized in ALKS 5461 Protocol Deviation Process. 
Data from these subjects will be included in the safety analyses, but excluded from the efficacy 
analyses. 
3.2. 
Demographic and Baseline Characteristics 
Demographics and other baseline characteristics (eg, age, gender, race, primary race, ethnicity, 
region [United States (US), non-US], HIR or PIR, duration of current MDE, current ADT, 
lifetime number of MDEs, lifetime number of antidepressants, number of ADT failures within 
the current MDE, total lifetime ADTs failed, ADT Class for current MDE, benzodiazepines 
(BDZ) use, opioid use, H1 antagonist use, weight, height, and body mass index [BMI]) at 
randomization (Stage 1 baseline Visit 2) will be summarized for the following populations: 
•
Stage 1 Safety Population by Stage 1 treatment group
•
Stage 2 Safety Population 1 by Stage 2 treatment group
Medical and psychiatric history (coded by MedDRA) will be summarized by Stage 1 treatment 
group using the number and percentage of subjects who reported each category for the Stage 1 
Safety Population as following: 
•
By System Organ Class and Preferred Term
•
By Preferred Term in decreasing frequency


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Baseline efficacy variables (MADRS-10, CGI-S, HAM-A, Q-LES-Q-SF, BPI-SF, SHAPS, and 
CD-RISC-25) will be summarized by Stage 1 treatment group for the Stage 1 FAS at 
randomization baseline at Visit 2, and summarized by Stage 2 treatment group for the Stage 2 
FAS at rerandomization baseline at Visit 7 to assess the comparability of the treatment groups. 
Continuous variables will be summarized by number of subjects, mean, SD, median, minimum, 
and maximum values. Categorical variables will be summarized by number and percentage of 
subjects in each category. Categories for missing data will be provided as necessary. 
Demographic and baseline characteristic listings will be provided for all subjects. 
3.3. 
Prior and Concomitant Medications 
Prior medications are defined as medications taken prior to the first dose of study drug. 
Concomitant medications are defined as medications taken during the period between the first 
dose date to the last dose date of study drug, inclusive. All medications, as documented by the 
Investigator, will be coded using the World Health Organization Anatomical Therapeutic 
Chemical (WHO-ATC) drug dictionary version WHODRUG_C / 171E+H/ CMCODE. 
Prior medications and concomitant medications will be summarized by ATC code and preferred 
term, by preferred term, and by corresponding treatment group and overall for the Safety 
Population. Prior medications will be summarized by Stage 1 treatment group for the Stage 1 
Safety Population. Concomitant medications will be summarized by treatment group in each 
stage as follows: concomitant medications that were taken during the period between the first 
dose date to the last dose date in Stage 1, inclusive, will be summarized by Stage 1 treatment 
group based on the Stage 1 Safety Population; concomitant medications that were taken during 
the period between the first dose date to the last dose date in Stage 2, inclusive, will be 
summarized by Stage 2 treatment group based on Stage 2 Safety Population 1. 
In addition, the concomitant ADTs by ADT class (selective serotonin reuptake inhibitor [SSRI], 
and serotonin-norepinephrine reuptake inhibitor [SNRI) and preferred term will be summarized 
similarly. 
Summary tables for benzodiazepine use, opioid use, and sedating H1 antagonist use (prior 
medication/concomitant medication) by preferred term will be summarized, respectively. 
All reported medications will be listed. A list of subjects taking ADTs, benzodiazepines (BDZ) 
and BDZ-like drugs, opioids, and sedating H1 antagonists will be provided. 
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 6.4. 
3.4. 
Treatment Adherence Rate and Extent of Exposure 
Treatment adherence to the daily dosing schedule of the study drug is measured as the rate of 
actual number of doses taken compared to intended number of doses to be taken. Percentage of 
treatment adherence will be calculated for study drug during the 5-week treatment period in 
Stage 1 and during the 6-week treatment period in Stage 2 as follows: 


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100 ×
Total tablets taken
Total tablets subject should have taken from the first dose date to the last dose date 
Duration of treatment of study drug is defined as the number of days from the date of the first 
dose of study drug taken to the date of the last dose taken, inclusive, for the relevant period. 
Treatment adherence and exposure will be summarized as follows: 
• During Stage 1 for Stage 1 Safety Population 
• During Stage 2 for Stage 2 Safety Population 1 
Treatment adherence and exposure to study drug will be summarized using descriptive statistics 
(number of subjects, mean, SD, minimum, median, and maximum). In addition, treatment 
adherence rate (rounded to the nearest whole number) will be categorized as <70%, ≥70 to 79%, 
≥80 to 89%, ≥90% to 100%, >100% to 110%, >110% to 120%, and >120%. 
The exposure to ADT will be summarized by ADT class (SSRI, SNRI, and other) and preferred 
term using descriptive statistics in a similar fashion. In addition, descriptive statistics of mean 
daily dose of ADT will be summarized by ADT class and preferred term for each stage. 
3.5. 
Efficacy Analyses 
3.5.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoint is: 
• MADRS-10 score change from baseline to the end of treatment period (Week 5 for 
Stage 1, Week 6 for Stage 2) 
The MADRS-10 score is the sum of all 10 items and ranges from 0 to 60. 
Analysis for the primary efficacy endpoint will be performed using a mixed model for repeated 
measures (MMRM) to evaluate changes from baseline in each stage. The primary efficacy 
analysis will be based on the combined estimates from Stage 1 and Stage 2 using MMRM. 
The estimate for Stage 1 will be the change from the baseline to end of Week 5 and the estimate 
for Stage 2 will be the change from baseline to the end of Week 6. 
3.5.2. 
General Consideration 
Efficacy endpoints will be evaluated during the defined treatment period. The entire 11 week 
treatment period is divided into two stage-specific treatment periods. The treatment period for 
Stage 1 is defined as the period spanning from the Stage 1 baseline (Visit 2) to the Stage 1 Week 
5 (Visit 7). The treatment period for Stage 2 is defined as the period spanning from the Stage 2 
baseline (Visit 7) to the Stage 2 Week 6 (Visit 13). 
Baseline for Stage 1 will be defined as the last nonmissing observation on or before the date of 
Visit 2. Baseline for Stage 2 will be defined as the last non-missing observation on or before the 
date of Visit 7. 
For continuous endpoints with repeated postbaseline measurements, a MMRM will be used for 
the analysis of changes from baseline for each stage. 


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Sensitivity analyses using the delta-adjusted pattern mixture model (PMM), analysis of 
covariance (ANCOVA) with last observation carried forward (LOCF) approach, and alternative 
stage-specific weights for combined MMRM analysis will be conducted for the primary efficacy 
endpoint (see Section 3.5.3). 
Using LOCF, a missing value at a visit will be imputed using the value from the most recent 
postbaseline visit within each stage, and the baseline value will not be carried forward to any 
postbaseline visit. The LOCF method will be used for efficacy endpoint total score or subscale 
score only; individual item scores will not be carried forward. For efficacy endpoints with a total 
score or subscale score derived from individual items, the postbaseline total or subscale will be 
imputed using the value from the most recent postbaseline visit; individual item score will not be 
carried forward. The derivation of the total score and subscale score are provided in Section 6.2. 
The overall treatment effect and associated standard error will be obtained from the 
stage-specific treatment effect estimates and standard errors, and the Wald test will be used to 
test the overall treatment effect. Stage-specific MMRM estimates and standard errors will be 
combined using equal weights to obtain the overall estimates and associated standard error across 
the two stages. 
For derived binary endpoints (ie, MADRS response and remission), normal approximation to 
binomial distributions will be used to obtain the difference in rates between active group and 
placebo by visit for each stage. The LOCF method will be used for imputation prior to the 
categorization of the treatment responder or remission status. The stage-specific rate differences 
and standard errors will be combined using equal weights to obtain the overall difference in 
responder or remission rate and corresponding standard error across the two stages. 
In addition, descriptive statistics will be provided for all efficacy variables by visit and Stage 1 
and Stage 2 treatment sequence throughout the entire study based on the Combined Stage FAS. 
Unless stated otherwise, all statistical hypothesis tests will be two-sided with α=0.05 and 95% 
confidence intervals (CIs), will be two-sided, and will be set at an alpha of 0.05. Source data used 
for the summary tables and statistical analyses will also be listed on the subject level. 
3.5.2.1. 
Pooling of Centers 
A five level variable for geographic region will be included in the statistical model. The five level 
categorical region variable representing geographic region will include 1 category for non-US 
and 4 categories for US site region (Table 1). The definition of the 4 US categories is based on 
the United States (US) Census Bureau regions with the inclusion of Puerto Rico in the Northeast 
category. Although Puerto Rico is not included in one of the US Census Bureau Regions, 
inclusion in the Northeast category is consistent with another established geographical 
classification system, the standard federal regions established by US Office of Management and 
Budget. 


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Table 1: 
The United States Census Bureau Regions 
Category Used in 
MMRM Model 
Census Bureau 
Regions 
Definition 
1 
Northeast 
Connecticut, Maine, Massachusetts, New Hampshire, 
Rhode Island, Vermont, New Jersey, New York, 
Pennsylvania, Puerto Rico 
2 
Midwest 
Illinois, Indiana, Michigan, Ohio, Wisconsin, Iowa, Kansas, 
Minnesota, Missouri, Nebraska, North Dakota, South Dakota 
3 
South 
Delaware, Florida, Georgia, Maryland, North Carolina, 
South Carolina, Virginia, District of Columbia, West Virginia, 
Alabama, Kentucky, Mississippi, Tennessee, Arkansas, 
Louisiana, Oklahoma, Texas 
4 
West 
Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, 
Utah, Wyoming, Alaska, California, Hawaii, Oregon, 
Washington 
5 
Non-US 
Australia 
3.5.2.2. 
Examination of Subgroups 
The following subgroups will be examined for the primary efficacy endpoints: 
• Sex (male, female) 
• Age (<55 years, ≥55 years) 
• Race (White, all other races) 
• Duration of current MDE (≤6 months, >6 months) 
• Number of ADT failures in the current MDE at randomization (2, >2) 
• ADT type (SSRI, SNRI, other) 
• Region (US [including Puerto Rico], Non-US) 
• MADRS-10 at randomization (<30, ≥30) 
• Subject type (HIR, PIR) 
The primary analysis for the primary efficacy endpoint will be repeated by subgroup. In addition, 
forest plots of the least squares mean difference, along with 95% CIs, from primary analysis (as 
described in Section 3.5.3.1) of the change from baseline to the end of treatment period in 
MADRS-10 score, as well as combined across stages, between ALKS 5461 and placebo, will be 
provided by the subgroup factors listed above. No p-values will be provided as the study is not 
powered to detect treatment effects within subgroups. 


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3.5.3. 
Efficacy Analysis for Primary Efficacy Endpoint 
3.5.3.1. 
Primary Efficacy Analysis 
Analysis for the primary efficacy endpoint will be performed using a MMRM to evaluate 
changes from baseline in each stage. The model will include variables for treatment group, visit, 
treatment group-by-visit interaction, and region as categorical fixed effects. Baseline value and 
baseline-by-visit interaction will be included as covariates in the model. The comparison 
(ALKS 5461 2/2 vs placebo) will be made using the combined weighted least squares mean 
difference from Stage 1 and Stage 2. These estimates, along with the corresponding 95% CIs, 
will be reported. 
An unstructured covariance matrix will be used to model the within-subject variability. The 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom 
(Kenward and Roger 1997). The analysis will be performed based on all observed postbaseline 
scores without any imputation of missing data. In the case when the MMRM fails to converge 
using an unstructured covariance matrix in any stage, a less stringent covariance matrix 
(eg, autoregressive 1) will be used. The same covariance matrix structure will be used across all 
treatment stages. 
The primary efficacy endpoint will be analyzed for each stage separately. The comparison of 
treatment effects between the ALKS 5461 2/2 and the placebo treatment group for each of the 
three primary endpoints in the two stages will be combined using the prespecified equal weights 
of 0.5 and 0.5 for Stage 1 and Stage 2. Specifically, let 𝜃𝜃(1) and 𝜃𝜃(2)denote the treatment effects 
between the ALKS 5461 2/2 and placebo treatment group in Stage 1 and Stage 2, respectively, 
and 𝜃𝜃෠(1)and 𝜃𝜃෠(2)denote the corresponding point estimates based on the MMRM analyses. 
These comparisons will be made through the following hypothesis of no treatment effect in both 
stages: 
H0: 𝑤𝑤𝜃𝜃(1) 
+ (1 −𝑤𝑤)𝜃𝜃(2) = 0    vs    Ha: 𝑤𝑤𝜃𝜃(1)  
+ (1 −𝑤𝑤)𝜃𝜃(2) > 0. 
The weighted test statistic for testing the above hypothesis is 
𝑤𝑤𝜃𝜃෠(1) + (1 −𝑤𝑤)𝜃𝜃෠(2)
ට𝑤𝑤2Var൫𝜃𝜃෠(1)൯+ (1 −𝑤𝑤)2Var൫𝜃𝜃෠(2)൯
, where 𝑤𝑤= 0.5. 
The SPCD analysis P-value is obtained by referring the above weighted test statistic to the 
standard normal distribution under the null hypothesis of no treatment effect in both stages. The 
validity of the weighted test statistic has been established (Chen et al, 2011). 
The hypothesis of no treatment effect in both stages, for an endpoint will be rejected if the SPCD 
analysis two-sided P-value is <0.05. 
In addition, descriptive statistics of MADRS-10 and individual item scores, and changes from 
baseline in MADRS-10 and individual item scores at each visit by treatment group for each stage 
will be presented based on observed data. 
The least squares mean change from baseline in MADRS-10 total score (± standard error) over 
time will be provided graphically by Stage 1 treatment group based on the Stage 1 FAS, and 
Stage 2 treatment group based on Stage 2 FAS. 


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Graphical subject profiles of MADRS-10 change from baseline by stage, by visit and treatment 
arm will be provided for all randomized subjects by stage to evaluate whether there is evidence 
of a trend in the profile for those who discontinued vs. those who completed the study across 
both treatment arms. 
3.5.3.2. 
Effect Size 
The effect size is defined as the difference in the reduction from baseline between active and 
placebo treatment groups divided by the SD, and is expressed as Hedges’ g of all three primary 
efficacy endpoints using the following formula: 
𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝑒𝑒𝑒𝑒′𝑔𝑔= 𝑀𝑀1 −𝑀𝑀2
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
 
Where 𝑀𝑀1 denotes the mean reduction from baseline of the active treatment group, 𝑀𝑀2 denotes 
the mean reduction from baseline of the placebo group, and 𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 denotes the pooled SD. 
Standard deviation will be calculated from model standard error with the following formula: 
𝑆𝑆𝑆𝑆= 𝑠𝑠𝑠𝑠∗√𝑛𝑛 
Where n is the sample size in Stage 1 and Stage 2 for the given treatment group and se is the 
model derived standard error associated with the least-squares mean derived from the MMRM 
model. 
The pooled SD will then be derived with the following formula: 
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝= ඨ(𝑛𝑛1 −1) ∗𝑆𝑆𝑆𝑆1
2 + (𝑛𝑛2 −1) ∗𝑆𝑆𝑆𝑆2
2
𝑛𝑛1 + 𝑛𝑛2 −2
, 
where n1 and n2 are the sample size from each treatment group (active vs placebo) and SD1 and 
SD2 are the associated SDs. 
Hedges’ g will be estimated for each stage of the treatment period first, assuming Hedges’ g is 
asymptotically independent between the two stages. The combined-stage effect size is defined as 
the average of the stage-specific effect sizes, and the combined-stage effect size is derived using 
the following formula 
,
)
ˆ
(
Var
)
1(
)
ˆ
(
Var
ˆ
)
1(
ˆ
= 
size
effect 
 
stage
-
Combined
)
2
(
2
)1(
2
)
2
(
)1(
θ
θ
θ
θ
w
w
w
w
−
+
−
+
 
where w=0.5, and 
)1(ˆθ
and 
)
2
(ˆθ
 refer to the effect sizes for the two stages. 
3.5.3.3. 
Sensitivity Analysis 
To assess the robustness of the primary MMRM results with equal weights for the primary 
efficacy endpoint, sensitivity analyses will be conducted using three approaches, the delta 
adjusted PMM, ANCOVA with LOCF, and alternative stage-specific weights for combined 
MMRM analysis approach, as described below. Additional sensitivity analysis may be performed 
to further explore the data. 


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Since the MMRM is valid only under the missing at random assumption, the PMM approach, 
which assumes missing not at random will be used as a sensitivity analysis. In particular, the 
delta-adjusted PMM, which incorporates the clinical assumption that subjects who discontinue at 
a given time point would have, on average, their unobserved efficacy score worsen by some 
amount (δ) compared with the observed efficacy score of subjects on the same treatment arm 
who continue to the next time point will be used. A sequential regression-based multiple 
imputation (MI) procedure will be used to incorporate the assumption and to allow uncertainty in 
the imputations to be reflected appropriately in the analysis. 
The imputation model will include the measurement at the current time point as the response 
variable, and the measurements at the previous time points and the baseline as covariates. The 
imputation will be performed separately for each treatment group. Twenty imputations will be 
carried out. For each imputed data set, an ANCOVA model will be fitted to the change from 
baseline to the end of the treatment period in MADRS-10 scores with treatment as a factor and 
baseline value as a covariate to obtain the treatment effect estimate and standard error. 
The imputation and ANCOVA model fitting will be done for each stage and an overall weighted 
estimate of treatment effect and associated standard error will be obtained from the stage-specific 
treatment effect estimates and standard errors with equal weights for the two stages. Rubin’s rule 
will be used to combine the treatment effect estimates and standard errors across imputations. 
The shift parameters in the two stages to be used in the sensitivity analysis are (0, 0), (0.6, 0.2), 
(1.5, 0.5), and (2, 1). In particular, the shift of (0, 0) corresponds to multiple imputation under the 
missing at random assumption. 
The ANCOVA using LOCF will also be conducted as a sensitivity analysis. The ANCOVA 
model will include the change from baseline to the end of the treatment period in MADRS-10 
scores as a dependent variable, treatment group as a factor, and baseline value as a covariate. The 
overall weighted estimate of treatment effect and associated standard error will be obtained from 
the stage-specific estimates and standard errors with equal weights for the two stages. 
Descriptive statistics for MADRS-10 score and change from baseline in MADRS-10 scores at 
each visit by treatment group will also be presented based on the LOCF approach. 
In addition, the treatment effect estimates based on the MMRM analyses in the two stages will be 
combined using weights proportional to the inverse of the associated variance estimates. 
Specifically, the weight for the Stage 1 treatment effect estimate is 
𝑤𝑤=
1/Var(
)1(ˆθ
)
1/Var൭
)1(ˆθ
൱+ 1/Var(
)
2
(ˆθ
)
 = 
Va𝑟𝑟(
)
2
(ˆθ
)
 Var
)
ˆ
(
)
1
(
θ
+ Va𝑟𝑟(
)
2
(ˆθ
)
, 
and the weight for the Stage 2 treatment effect estimate is 
1 −𝑤𝑤=
Var ቀ
)1(ˆθ
ቁ
 Var
)
ˆ
(
)
1
(
θ
+  Var ቀ
)
2
(ˆθ
ቁ
. 
The resulting linear combination test statistic is asymptotically normal due to the independence 
between the treatment effect estimate and the associated variance estimate within each stage. 


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An additional sensitivity analysis will employ bootstrap methodology for empirical estimation 
and inference of ALKS 5461 vs. placebo difference in MADRS-10 change from baseline. 
Results obtained from this approach (mean, standard error, empirical 95% CI and associated p-
value using 10,000 replicates) will be compared to those obtained from normal-based approach 
used in the primary analysis. In additional to the density plots of bootstrap treatment effects will 
be provided displaying ALKS 5461 vs. Placebo difference (x-axis) by density (y-axis). 
3.5.3.4. 
Supportive Analysis for Primary Endpoints 
As a supportive analysis, additional MMRM analyses will be conducted for the primary efficacy 
endpoint by including a more restricted nonresponder criterion of MADRS-10 score >15 at 
Visit 7 and <40% reduction in MADRS-10 score from Visit 2 to Visit 7. 
To evaluate the assumption of homogeneous variances across treatment arms two approaches 
will be used: (1) density plots will display change from baseline in MADRS-10 score by stage 
and treatment arm (x and y-axes will be change from baseline and density, respectively, where 
the sum of the area under the density plot for both treatment groups will equal one); and (2) a 
tabular display will present correlation (measured using the Pearson correlation coefficient) by 
visit and treatment arm within each stage for MADRS-10 scores. 
3.5.4. 
Efficacy Analysis for the Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Average of the differences in change from baseline at each Week from Week 3 
through the end of treatment period between ALKS 5461 vs placebo in MADRS-10 
• Proportion of subject who demonstrated MADRS treatment response, defined as a 
≥50% reduction in MADRS-10 score from randomization baseline to the end of 
treatment 
• Proportion of subjects who achieved remission, defined as MADRS-10 score ≤10 at 
the end of treatment 
The statistical testing of the three secondary endpoints will be done using a hierarchical testing 
approach, with the order of testing being the rank order in which the secondary endpoints are 
listed, only if the primary efficacy endpoint is significant at two sided α=0.05. 
The secondary hypotheses will be evaluated using a fixed sequence approach to adjust for 
multiple comparisons. 
Step 1: Testing ALKS 5461 2/2 relative to placebo using average of the differences in change 
from baseline at each Week from Week 3 to the end of treatment in MADRS-10. The average of 
the differences in change from baseline at each Week from Week 3 to the end of treatment in 
MADRS-10 will be tested using the combined effect of Stage 1 and Stage 2. Proceed to Step 2, 
only if significant at two-sided α=0.05. 
Step 2: Testing ALKS 5461 2/2 relative to placebo using MADRS treatment response. The 
MADRS treatment response will be tested using combined effect of Stage 1 and Stage 2. Proceed 
to Step 3, only if significant at two-sided α=0.05. 


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Step 3: Testing ALKS 5461 2/2 relative to placebo using remission. The remission will be tested 
using the combined effect of Stage 1 and Stage 2. 
3.5.4.1. 
Average of the Differences in Change from Vaseline at Each Week from Week 3 
to the End of Treatment Period in MADRS-10 
For this secondary endpoint, the estimate for Stage 1 will be the average of three time points (ie, 
the average of the change from baseline to Week 3, change from baseline to Week 4, and change 
from baseline to Week 5). The estimate for Stage 2 will be the average of four time points (ie, the 
average of the change from Baseline to Week 3, change from baseline to Week 4, change from 
baseline to Week 5 and change from baseline to Week 6). 
Analysis for this secondary efficacy endpoint will be performed using the same method as 
described for the primary efficacy analysis. 
3.5.4.2. 
Proportion of MADRS Treatment Responders at the End of Treatment Period 
A MADRS treatment responder is defined as a subject with a ≥50% reduction in MADRS score 
from baseline. 
The proportion of responders in each treatment group will be estimated using subject response 
(observed or imputed using LOCF if missing) at the end of the treatment period in each stage. A 
comparison between ALKS 5461 2/2 vs placebo will be conducted at the end of the treatment 
period in each stage, and the estimated difference in rates with 95% CIs and P-value will be 
reported for the comparison based on normal approximation to binomial distribution. 
Specifically, let 
𝑝𝑝1 = Pr(drug response in Stage 1) , 𝑞𝑞1 = Pr(placebo response in Stage 1),  
𝑝𝑝2 = Pr(drug response in Stage 2 | placebo non-responder in Stage 1), and 
𝑞𝑞2 = Pr(placebo response in Stage 2 | placebo non-responder in Stage 1). 
The treatment effect in Stage 1 is, ∆1= 𝑝𝑝1 −𝑞𝑞1,  
and the treatment effect in Stage 2 is ∆2= 𝑝𝑝2 −𝑞𝑞2. 
Let 𝑝𝑝̂𝑗𝑗=
𝑥𝑥𝑗𝑗
𝑛𝑛𝑗𝑗 𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞ො𝑗𝑗=
𝑦𝑦𝑗𝑗
𝑚𝑚𝑗𝑗 denote the estimated proportions of responders for the drug and 
placebo groups in stage j (j = 1, 2) respectively. The estimated rate difference in stage j is 
∆෠𝑗𝑗= 𝑝𝑝̂𝑗𝑗−𝑞𝑞ො𝑗𝑗 and the associated variance estimate is: 
Var (∆෠𝑗𝑗) = 
𝑝𝑝ො𝑗𝑗 (1−𝑝𝑝ො𝑗𝑗)
𝑛𝑛ො𝑗𝑗
+
𝑞𝑞ො𝑗𝑗 (1−𝑞𝑞ො𝑗𝑗)
𝑚𝑚ෝ𝑗𝑗
. 
Based on normal approximation to binomial distribution, the 95% CI for ∆෠𝑗𝑗 is: 
∆෠𝑗𝑗± 1.96ටVar (∆෠𝑗𝑗), 
and the P-value is obtained be referring the test statistic, 


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∆෠𝑗𝑗
ටVar (∆෠𝑗𝑗)
, 
to the standard normal distribution under the null hypothesis of no treatment effect in stage j for 
j = 1, 2. 
The comparison of treatment effect between the ALKS 5461 2/2 and placebo treatment groups in 
the two stages will be combined using the prespecified equal weights of 0.5 and 0.5 for Stage 1 
and Stage 2. Specifically, let ∆1 and ∆2 denote the treatment effects between ALKS 5461 2/2 and 
placebo in Stage 1 and Stage 2, respectively, and ∆෠1 and ∆෠2 denote the corresponding point 
estimates. The weighted test statistic is: 
𝑤𝑤∆෠1+(1−𝑤𝑤)∆෠2
ට𝑤𝑤2Var൫∆෠1൯+(1−𝑤𝑤2)Var൫∆෠2൯
 , where w = 0.5. 
The P-value will be obtained by referring the above weighted test statistic to the standard normal 
distribution under the null hypothesis of no treatment effect in both stages. For binary efficacy 
endpoints of MADRS responder and remission for this study, the validity of the above weighted 
test statistic relies on the independence of treatment effect estimates in the two stages, which is 
shown in Appendix 1. 
The proportion of MADRS treatment responders will be summarized at each visit by treatment 
group for each stage based on data with LOCF imputation. In addition, the bar graphs of the 
proportion of MADRS treatment responders will be provided by treatment group over time for 
each stage. The bar graphs for placebo-adjusted responder rate (ie, difference in responder rate 
between ALKS 5461 2/2 and placebo) during the treatment period will also be provided for each 
stage, as well as combined across stages. 
3.5.4.3. 
Proportion of Subjects Achieving Remission at the End of Treatment Period 
Remission is defined as a subject with a MADRS score ≤10. The remission analysis method will 
be the same as described for the MADRS responder analysis. 
3.5.5. 
Efficacy Analysis for the Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are: 
• Change from randomization baseline to the end of the treatment period in CGI-S scores 
• Absolute CGI-I scores from randomization baseline to the end of the treatment period 
• Change from randomization baseline to the end of the treatment period in the following 
efficacy measurements: 
− Q-LES-Q-SF scores 
− BPI-SF scores 
− SHAPS scores 
− CD-RISC-25 scores 


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For the efficacy endpoints listed above, analysis methods will be same as those describe for the 
primary analysis of the primary efficacy endpoints. In addition, descriptive statistics based on 
observed data will be provided by stage, by visit, and by treatment group for the the Stage 1 FAS 
and the Stage 2 FAS. 
3.6. 
Safety Analysis 
3.6.1. 
General Consideration 
Safety and tolerability of ALKS 5461 will be assessed throughout the study based on AEs, vital 
signs, weight, laboratory test results (chemistry, hematology, and urinalysis), ECG results, 
COWS scores, and C-SSRS scores. Criteria for evaluation will include incidence of 
treatment-emergent AEs (TEAEs), AEs of special interest (AESIs), the change from baseline in 
continuous variables, categorical analysis of potentially clinically significant (PCS) values of 
laboratory results, weight, vital sign, and ECG parameters, and the rate of suicidal ideation and 
behavior based on the C-SSRS. Subjects will be included in the C-SSRS analysis if they have at 
least one postbaseline assessment. Subjects will be included in the COWS analysis if they have 
an adequate baseline, at least one postbaseline assessment, and at least 4 weeks of study drug 
exposure. 
All safety analyses will be based on the safety populations defined in Section 3.1.1.1. 
Safety periods to be evaluated and associated definitions of baseline are described below: 
Stage 1 Treatment Period 
The Stage 1 treatment period for AEs includes the interval between the date of Visit 2 and the 
last dose date plus 1 day, inclusive, for subjects who did not enter Stage 2; or the interval 
between the date of Visit 2 and the date of Visit 7 minus 1 day, inclusive, for subjects who 
entered Stage 2. The baseline for AEs is defined as all data collected prior to the date of Visit 2. 
The Stage 1 treatment period for other safety endpoints covers the values collected at the baseline 
visit and the postbaseline visits throughout the Stage 1 treatment period starting from Visit 2 in 
Stage 1 to the last assessment visit date in Stage 1. The baseline for these other safety endpoints 
is defined as the last nonmissing value on or before the date of Visit 2. 
Stage 2 Treatment Period 
The Stage 2 treatment period for AEs includes the interval between the date of Visit 7 and the 
last dose date plus 1 day, inclusive. The baseline for AEs is defined as all data collected prior to 
Visit 7 for Stage 2 Safety Population 1. 
The Stage 2 treatment period for other safety endpoints covers the values collected at the Stage 2 
baseline visit and the postbaseline visits throughout the Stage 2 treatment period starting from 
Visit 7 in Stage 2 to the last assessment visit date in Stage 2. The Stage 2 treatment period will 
only be summarized for Stage 2 Population 1 and the baseline for these other safety endpoints is 
defined as the last nonmissing value on or before the date of Visit 7. 


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Post-discontinuation Safety Period 
Only AEs and COWS scores will be summarized for the Post-discontinuation Safety population. 
Post-discontinuation labs, vital signs and ECGs will be included in the descriptive summaries for 
the Stage 1 and Stage 2 treatment periods. 
For AEs, the Stage 1 Post-discontinuation Safety period is defined as the interval starting from 
the last dose date plus 2 days to the last study visit, inclusive, for early termination (ET) subjects 
during Stage 1, or starting from the date of Visit 7 to the last study visit, inclusive, for subjects 
who entered Stage 2. 
For AEs, the Stage 2 Post-discontinuation Safety period is defined as the interval starting from 
the last dose date plus 2 days to the last study visit, inclusive. 
For COWS scores, the Stage 2 post-discontinuation Safety period covers the values collected at 
Visit 13 through the post-discontinuation visit. The baseline for COWS assessments is the 
measurement at Visit 13. 
The general approach to summarize safety endpoints is illustrated in Table 2. Details are 
described in the relevant sections. 
All safety analyses will be based on observed data only; no missing values will be imputed. For 
the by-visit summary tables, the last assessment during the treatment period, defined as the value 
from the last scheduled postbaseline visit for the relevant treatment period, will also be included. 
Table 2: 
Summary Approach for Safety Endpoints 
Safety Population 
Safety Period 
Treatment to 
Summarize 
Safety Endpoint 
Stage 1 Safety Population 
Stage 1 Treatment Period 
Stage 1 Treatment 
AE (including AESI) 
Stage 1 Safety Population 
Stage 1 Treatment Period 
and Post-discontinuation 
Safety Period Combined 
Stage 1 Treatment 
Lab/VS/ECG, PCS, 
C-SSRS 
Stage 2 Safety Population 1 
Stage 2 Treatment Period 
Stage 2 Treatment 
AE (including AESI) 
Stage 2 Safety Population 1 
Stage 2 Treatment Period 
and Post-discontinuation 
Safety Period Combined 
Stage 2 Treatment 
Lab/VS/ECG, PCS, 
C-SSRS 
Stage 2 Entire Safety 
Population 
Entire Study 
Stage 1/Stage 2 
Treatment Sequence 
Lab/VS/ECG 
Post-discontinuation 
Population 
Post-discontinuation Safety 
Period 
Last treatmenta 
PDEAE (including AESI), 
COWS (Stage 2 re-
randomized) 
Stage 1 Safety Population 
who were not re-randomized 
in Stage 2 
Stage 2 Treatment Period 
Last treatment in 
Stage 1 
PDEAE (including AESI) 
a Last treatment is the last treatment subjects received. That is, Stage 1 treatment group for subjects who did not 
enter Stage 2; or Stage 2 treatment group for subjects who entered Stage 2. 
Abbreviations: ECG = electrocardiogram; Lab=laboratory results; VS=vital signs; PCS=potentially clinically 
significant; PDEAE=post-discontinuation emergent adverse events; AESI=adverse event of special interest; 
AE=adverse event; COWS= Clinical Opiate Withdrawal Scale; C-SSRS= Columbia-Suicide Severity Rating Scale 


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3.6.2. 
Adverse Events 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 20. The verbatim term will be included 
in the AE listings. 
An AE will be considered a TEAE if it starts or worsens (if present at baseline) on or after 
baseline during the relevant safety period. Adverse events will be identified as emerging in the 
Stage 1 treatment period, Stage 2 treatment period, or Post-discontinuation Safety period. For the 
determination of the TEAEs during the Stage 1 treatment period and Stage 2 treatment period, 
AEs with the greatest severity before the baseline of the respective safety period will be used as 
the benchmark for comparison with the AEs occurring during the respective safety period. In 
addition, PDEAEs, defined as AEs that start or worsen after the last dose date plus 1 day, will 
also be summarized. For PDEAEs, the greatest severity before or on the last dose date plus 1 day 
will be used as the benchmark for the comparison of the AEs occurring during the Post-
discontinuation Safety period. 
All AEs will be listed by subject, but only TEAEs, serious AEs (SAEs), AEs leading to study 
discontinuation, and PDEAEs will be included in the summary tables. Summary tables will be 
produced for the Stage 1 treatment period and Stage 2 treatment period. For AEs leading to study 
discontinuation, the AEs will be summarized in the safety period by the treatment group the 
subjects were in when the discontinuation occurred. 
An overview table, including the numbers of subjects with TEAEs, AEs leading to study 
discontinuation, SAEs, and study drug-related TEAEs will be provided for the Stage 1 treatment 
period and the Stage 2 treatment period. 
The following summary tables will be produced for the Stage 1 treatment period and the Stage 2 
treatment period: 
• TEAEs by System Organ Class and Preferred Term 
• TEAEs by Preferred Terms in decreasing frequency 
• TEAEs by System Organ Class, Preferred Term, and severity 
• TEAEs by System Organ Class, Preferred Term for drug-related TEAEs 
In addition, an AE overview table and AEs by system organ class and preferred term will be 
summarized for PDEAEs based on the Stage 1/Stage 2 Post-discontinuation Safety population, 
by the last treatment group in which subjects were included for their respective stages. 
An AE overview table and AEs by system organ class and preferred term will also be provided 
for AEs that started during the PLI period for the PLI Period Safety population. Furthermore, an 
AE overview table and TEAEs by system organ class and preferred term during the entire 
treatment period, defined as date of first dose up to the date of the last dose, will be summarized 
for the Stage 2 Safety population. 
All AE tables will be sorted by System Organ Class in alphabetical order and then Preferred 
Term in decreasing frequency of the number and percentage of subjects in the ALKS 5461 2/2 
treatment group. 


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A subject having the same AE (as determined by the coded MedDRA Preferred Term) more than 
once in a stage will be counted only once in the total number of subjects with that AE during the 
stage. Similarly, if a subject had more than one AE in a System Organ Class in a stage, the 
subject will be counted only once in the total number of subjects with the AE for that system 
organ class during the stage. If a subject has the same AE on multiple occasions, the highest 
severity (severe > moderate > mild) recorded for the event will be presented in the AE by 
severity summary. Similarly, if a subject has the same AE on multiple occasions, the closest 
relationship (related > not related, where related includes definitely related, probably related, and 
possibly related; and not related includes probably not related and definitely not related) recorded 
for the event will be presented in the AE by relationship summary. 
All AEs will be included in the listings. 
3.6.3. 
Deaths, Serious and Other Significant Adverse Events 
The number and percentage of subjects with at least one SAE will be summarized by treatment 
group, System Organ Class, and Preferred Term for the Stage 1 treatment period and the Stage 2 
treatment period. Adverse events leading to discontinuation will be summarized similarly and 
will be based on the the treatment group subjects were in when the discontinuation occurred. 
Supporting listings of SAEs and AEs leading to study discontinuations will be provided. Subjects 
who died during the study will also be listed. 
3.6.4. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) will be summarized by Preferred Term and treatment 
group during the Stage 1 treatment period and the Stage 2 treatment period for the Safety 
population/Follow-up Safety population for any TEAEs or PDEAEs of special interest. The 
following summaries will be created for AESIs: 
• TEAEs associated with abuse potential 
• TEAEs potentially associated with dependence 
• PDEAEs potentially associated with withdrawal 
• TEAEs potentially associated with suicidal ideation and behavior 
• TEAEs potentially associated with hypomania/mania 
• TEAEs potentially associated with central nervous system (CNS) depression and 
sedation 
• TEAEs potentially associated with respiratory depression 
• TEAEs potentially associated with orthostasis/hypotension 
• TEAEs potentially associated with hypersensitivity 
• TEAEs potentially associated with hepatic effects 
Treatment-emergent AEs potentially associated with abuse potential will be presented by ad hoc 
system organ class and preferred term, where ad hoc system organ class is manually classified by 
the Alkermes Medical Director as three categories: abuse behavior, euphoria-related, and non-
specific. 


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Treatment-emergent AEs associated with dependence will be presented for subjects with any 
exposure, ≥4 weeks exposure, and <4 weeks exposure, respectively. 
Post-discontinuation emergent AEs associated with withdrawal will be presented for subjects 
with any exposure, ≥4 weeks exposure, and <4 weeks exposure, respectively. Adverse events of 
special interest associated with withdrawal are PDEAEs that occur from >2 to 16 days post last 
dose, as this is the period during which physiological opioid withdrawal would be expected to 
present, based on the half-lives of both BUP and SAM. 
Supportive listings will be provided for each AESI group. Narratives will be provided for 
clinically meaningful events within each AESI group. 
3.6.5. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Only scheduled 
laboratory parameters will be included in the summaries. All laboratory data, including 
unscheduled assessments, will be included in the listings. 
Laboratory results (baseline and change from baseline) for chemistry and hematology parameters 
for each visit will be summarized by treatment group for the following populations and safety 
periods: the Stage 1 Safety population over the Stage 1 treatment period, Visit 8 (if any), and 
Post-discontinuation Safety period combined; Stage 2 Safety Population 1 over the Stage 2 
treatment period and Post-discontinuation Safety period combined; and the Stage 1 and Stage 2 
treatment sequence for the Stage 2 Entire Safety population over the entire study. For urinalysis, 
rate of abnormalities at any postbaseline visit will be summarized. In addition, the number and 
percentage of subjects with values considered PCS occurring at any postbaseline visit for select 
parameters will be summarized. The rate of abnormality of urinalysis and PCS summaries will be 
provided by treatment group for the Stage 1 Safety Population over the Stage 1 treatment period 
and Follow-up Safety period combined; and for Stage 2 Safety Population 1 over the Stage 2 
treatment period and Post-discontinuation Safety period combined. For PCS, the summary will 
also be provided for the Stage 2 Safety population over the entire study. 
Potentially clinically significant criteria for hematology, chemistry, and urinalysis parameters are 
presented in Table 3. The percentages will be calculated relative to the number of subjects with 
available non-PCS baseline values with respect to the specific criterion and at least one 
postbaseline assessment. The numerator is the total number of subjects with non-PCS baseline 
values and at least one postbaseline PCS value with respect to the specific criterion. Parameter 
order for summary tables and listings will be alphabetical. Supportive listings will present all 
values for a parameter for subjects with at least one PCS value for that parameter. Numbers and 
percentage of subjects with PCS values occurring at any postbaseline visit will be summarized by 
treatment group for the Stage 1 Safety population over the Stage 1 treatment period, for Stage 2 
Safety Population 1 over the Stage 2 treatment period, and for the Stage 2 Safety population over 
the entire study period by the Stage 1 and Stage 2 treatment sequence. 
In addition, the listing of subjects meeting Hy’s Law, defined as alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥3× ULN, along with total bilirubin ≥2× ULN and a 
nonelevated alkaline phosphatase (ALP) <2× ULN, with all values of relevant laboratory 
parameters will be provided. 
Pregnancy and drug screening data will be listed. 


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Table 3: 
Criteria of Potentially Clinically Significant Abnormality for Selected 
Analytes 
Category 
Parameter 
Criteria 
Hematology  
Eosinophils 
>1.0×103/µL 
Hematocrit  
≤32% and 3 point decrease from baseline (Female) 
≤37% and 3 point decrease from baseline (Male) 
Hemoglobin  
≤9.5 g/dL (Female) 
≤11.5 g/dL (Male) 
Leukocytes 
≤2.8×103/µL 
≥16×103/µL 
Neutrophils, Absolute 
<1.5×103/µL 
Platelets 
<75.1×103/µL 
≥700×103/µL 
Chemistry 
Alanine Aminotransferase 
≥3×ULN 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase 
≥3×ULN 
Aspartate Aminotransferase 
≥3×ULN 
Bicarbonate 
<15 mmol/L 
>31 mmol/L 
Blood Urea Nitrogen (BUN) 
>30 mg/dL 
Calcium 
<8.2 mg/dL 
>12 mg/dL 
Chloride 
≤90 mmol/L 
≥118 mmol/L 
Creatine Phosphokinase  
>3×ULN 
Creatinine 
≥2 mg/dL 
Gamma Glutamyltransferase 
≥3×ULN 
Glucose 
<50 mg/dL 
>200 mg/dL 
HDL Cholesterol 
≤30 mg/dL 
Lactate Dehydrogenase 
>3×ULN 
LDL Cholesterol 
≥160 mg/dL 
Phosphate 
<2 mg/dL 
>5 mg/dL 
Potassium 
<3 mmol/L 
>5.5 mmol/L 
Prolactin 
>1×ULN 


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Table 3: 
Criteria of Potentially Clinically Significant Abnormality for Selected 
Analytes (Continued) 
Category 
Parameter 
Criteria 
Chemistry 
Sodium 
<130 mmol/L 
>150 mmol/L 
Total Bilirubin 
≥2 mg/dL 
Total Cholesterol 
>300 mg/dL 
Triglycerides 
≥120 mg/dL (Female) 
≥160 mg/dL (Male) 
Uric Acid 
>9 mg/dL 
>8 mg/dL (Female) 
>10 mg/dL (Male) 
Urinalysis 
Glucose 
at least 2+ 
Protein 
at least 2+ 
Abbreviations: BUN=blood urea nitrogen; HDL=high density lipoproteins; LDL=low density lipoprotein; 
ULN=upper limit of normal reference range 
3.6.6. 
Vital Signs and Electrocardiogram 
3.6.6.1. 
Vital Signs 
Vital signs (supine systolic and supine diastolic blood pressure, heart rate, respiratory rate, oral 
temperature, weight, and BMI) and weight will be summarized (baseline and change from 
baseline) by treatment group for the following populations and safety periods: the Stage 1 Safety 
population over the Stage 1 treatment period, Visit 8 (if any), and Post-discontinuation Safety 
period combined; Stage 2 Safety Population 1 over the Stage 2 treatment period and Post-
discontinuation Safety period combined; and the Stage 1 and Stage 2 treatment sequence for the 
Stage 2 Entire Safety population over the entire study. All vital sign data will be presented in the 
subject data listings. 
Numbers and percentage of subjects with PCS values occurring at any postbaseline visit will be 
summarized by treatment group for the Stage 1 Safety population over the Stage 1 treatment 
period, for Stage 2 Safety Population 1 over the Stage 2 treatment period, and for the Stage 2 
Safety population over the entire study period by the Stage 1 and Stage 2 treatment sequence. 
Criteria for PCS are presented in Table 4 and will be presented for each criterion. The 
percentages will be calculated relative to the number of subjects with non-PCS baseline values 
with respect to the specific criterion and at least one postbaseline assessment in the relevant 
safety population. A supportive listing will present all values for a parameter for subjects with at 
least one PCS value for that parameter. 


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Table 4: 
Criteria for Potentially Clinically Significant Abnormal Vital Sign Values 
Parameter 
PCS Criteria 
Temperature 
Hyperthermia: ≥38.1°C 
Hypothermia: ≤35.0°C 
Supine Systolic Blood pressure 
Low: ≤90 mm Hg and decrease ≥20 mm Hg 
High: ≥140 mm Hg and increase ≥20 mm Hg 
Supine Diastolic Blood pressure 
Low: ≤50 mm Hg and decrease ≥10 mm Hg 
High: ≥90 mm Hg and increase ≥10 mm Hg 
Heart Rate 
Low: ≤50 bpm and decrease ≥15 bpm 
High: ≥100 bpm and increase ≥15 bpm 
Respiratory Rate 
Low: <12 breaths per minute 
High: >25 breaths per minute 
Body Weight 
Decrease from baseline ≥7% 
Increase from baseline ≥7% 
3.6.6.2. 
Electrocardiograms 
Electrocardiogram parameters (heart rate, RR interval, PR interval, QRS interval, QT interval, 
QTcB [QT interval corrected using Bazett’s method], and QTcF [QT interval corrected using 
Fridericia's method]) will be summarized (baseline and change from baseline) by treatment group 
for the following populations and safety periods: the Stage 1 Safety population over the Stage 1 
treatment period, Visit 8 (if any), and Post-discontinuation Safety period combined; Stage 2 
Safety Population 1 over the Stage 2 treatment period and Post-discontinuation Safety period 
combined; and the Stage 1 and Stage 2 treatment sequence for the Stage 2 Entire Safety 
population over the entire study. 
Numbers and percentage of subjects with PCS values occurring at any postbaseline visit will be 
summarized by treatment group for the Stage 1 Safety population over the Stage 1 treatment 
period, for Stage 2 Safety Population 1 over the Stage 2 treatment period, and for the Stage 2 
Safety population over the entire study period by the Stage 1 and Stage 2 treatment sequence. 
Potentially clinically significant criteria are presented in Table 5. A subject will be counted only 
once in the highest category for a given parameter based on the largest postbaseline value in the 
respective safety period. The percentages will be calculated relative to the number of subjects 
with non-PCS baseline values and at least one postbaseline assessment in the relevant safety 
population. A supportive listing will present all values for a parameter for subjects with at least 
one PCS value for that parameter. 


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Table 5: 
Criteria for Potentially Clinically Significant Abnormal ECG Values 
Parameter 
PCS Criteria 
PR Interval 
High: ≥220 msec 
QRS Interval 
High: ≥120 msec 
QTcF 
Low: <330 msec 
High: >450 msec; >480 msec; >500 msec  
Only cumulative incidence above the indicated limits 
QTcF 
Change from baseline increase: >30 msec; >60 msec 
Change from baseline decrease: >30 msec; >60 msec 
Heart Rate 
Low: ≤50 bpm and decrease ≥15 bpm 
High: ≥100 bpm and increase ≥15 bpm 
3.6.7. 
Clinical Opiate Withdrawal Scale (COWS) Scores 
Clinical Opiate Withdrawal Scale (COWS) scores will be analyzed for the Stage 2 
Post-discontinuation Safety population. Baseline COWS score is defined as the Visit 13 COWS 
score. Adequate COWS baseline is defined as COWS baseline assessment performed within (≤) 
2 days of the last dose of study drug. Subjects with inadequate baseline (ie, baseline COWS 
assessment performed more than (>) 2 days of the last dose) will be included in a supportive 
listing. 
Subjects will be included in the COWS analysis if they have an adequate EOT COWS 
assessment and at least 1 post-EOT COWS assessment in the Post-discontinuation Safety period. 
COWS scores will be summarized by: 
• Analysis of all post-EOT COWS assessments 
• Analysis of post-EOT COWS assessments that occurred from >2 to 16 days post last 
dose of study drug 
Subjects with inadequate EOT COWS (ie, EOT COWS assessment was performed more than (>) 
2 days of the last dose) will be included in a supportive listing. 
Although opioid withdrawal might not be expected in individuals with less than 4 weeks of drug 
exposure, COWS scores will be presented in all subjects with adequate baselines, and then 
COWS scores will be presented by subgroup of duration of study drug exposure. Three COWS 
analyses will be presented for the subjects with adequate baseline by the three exposure 
subgroups (any exposure, ≥4 week exposure, <4 week exposure): 
• Total COWS scores (baseline and change from baseline, and days between last dose 
and assessment date) will be summarized by visit (baseline, post-discontinuation 
visit) 
• Subject count and percentage will be provided by visit for each of the COWS total 
score categories indicated below: 
− No withdrawal: total score 0-4 


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− Mild withdrawal: total score 5-12 
− Moderate withdrawal: total score 13-24 
− Moderately severe withdrawal: total score 25–36 
− Severe withdrawal: total score >36 
• COWS category shift summary from baseline to postbaseline: the numerator is the 
number of subjects in each post-discontinuation COWS category with nonmissing 
baseline COWS scores. If there are more than one post-discontinuation COWS score 
(ie, a subject with an unscheduled visit), the highest value will be used. The 
denominator is the number of subjects in each baseline COWS category 
Narratives will be provided for any clinically meaningful COWS score shifts. 
3.6.8. 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used to measure the 
presence and intensity of suicidal ideation and behavior. 
Suicidal behavior and suicidal ideation will be summarized at baseline and postbaseline by 
treatment group for the Stage 1 Safety population over the Stage 1 treatment period and 
Post-discontinuation Safety period combined; the Stage 2 Safety Population 1 over the Stage 2 
treatment period and Post-discontinuation Safety period combined; and the Stage 1 and Stage 2 
treatment sequence for the Stage 2 Entire Safety population over the entire study. The proportion 
of subjects who met the criterion for each of these categories at any postbaseline visit will be 
summarized as described in Table 6. 
Any behaviors experienced will be listed with a brief narrative. Any completed suicides will be 
presented with a full narrative. 
Table 6: 
Columbia-Suicide Severity Rating Scale Categories for Analysis 
Category 
C-SSRS item response is "YES" 
Suicidal ideation 
1) Wish to be dead 
2) Non-specific active suicidal thoughts 
3) Active suicidal ideation with any methods (not plan) without intent to act 
4) Active suicidal ideation with some intent to act, without specific plan 
5) Active suicidal ideation with specific plan and intent 
Suicidal behavior 
6) Preparatory acts or behavior 
7) Aborted attempt 
8) Interrupted attempt 
9) Actual attempt 
10) Completed suicide 
Suicidal behavior or 
ideation 
Including 10 items above 
Self-injurious behavior 
without suicidal intent 
Purely for other reasons/without any intention of killing yourself 


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Summary of treatment-emergent suicide-related events based on the C-SSRS during the 
treatment period will be presented by treatment group for the Stage 1 Safety population over the 
Stage 1 treatment period; the Stage 2 Safety population 1 over the Stage 2 treatment period; and 
the Stage 1 and Stage 2 treatment sequence for the Stage 2 Entire Safety population over the 
entire study. The degree and type of treatment-emergent suicide-related events will be 
summarized in a table as defined in Table 7. Post-discontinuation assessments will not be 
included in this analysis. 
This analysis population consists of the safety population with nonmissing baseline and at least 
one postbaseline assessment during the treatment period. The percentage will be calculated for 
the treatment-emergent suicide-related event summary. The numerator is defined as the number 
of subjects with a nonmissing baseline and a post-baseline C-SSRS assessment that meets the 
treatment-emergent suicide-related numerator criteria defined in Table 7, and the denominator is 
defined as the number of subjects with a nonmissing baseline and at least one postbaseline 
C-SSRS assessment that meets the treatment-emergent suicide-related denominator criteria 
defined in Table 7 during the treatment period. 
Table 7: 
Treatment-Emergent Suicide-Related Events for Analysis 
Treatment 
Emergent Suicide-
related Events 
Denominator Criteria 
Numerator Criteria 
Increase in Suicidal 
Ideation from 
Baseline 
Baseline suicidal ideation 
(“No” to all ideation 
items 1-5, or “Yes” to 
any ideation item ≤4 and 
“No” to item 5)  
Baseline suicidal ideation (“No” to all ideation 
items 1-5, or “Yes” to any ideation item ≤4 and 
“No” to item 5) 
Post-baseline (increase in suicidal ideation 
severity from baseline at any post-baseline visit)  
Emergence of 
Serious Suicidal 
Ideation 
Baseline suicidal ideation 
(“No” to all ideation 
items 1-5, or “Yes” to 
any ideation item ≤3 and 
“No” to items 4 and 5) 
Baseline suicidal ideation (“No” to all ideation 
items 1-5, or “Yes” to any ideation item ≤3 and 
“No” to items 4 and 5) 
Post-baseline (“Yes” to ideation item 4 or 5 at 
any post-baseline visit) 
Emergence of 
Serious Suicidal 
Ideation in Subjects 
with no Suicidal 
Ideation at Baseline 
Baseline ideation (“No” 
to all ideation items 1-5) 
Baseline ideation (“No” to all ideation items 1-5) 
Post-baseline (“Yes” to ideation item 4 or 5 at 
any post-baseline visit)  
Decrease in Suicidal 
Ideation from 
Baseline 
Baseline ideation (“Yes” 
to any ideation items 1-5) 
Baseline ideation (“Yes” to any ideation items 1-
5) 
Post-baseline (decrease in suicidal ideation 
severity at any post-baseline visit compared to 
severity at baseline) 
Emergence of 
Suicidal Behavior in 
Subjects with no 
Suicidal Behavior at 
Baseline 
Baseline behavior (“No” 
to all behavior items 
6-10) 
Baseline behavior (“No” to all behavior items 
6-10) 
Post-baseline behavior (“Yes” to any behavior 
items 6-10 at any post-baseline visit) 


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3.7. 
Pharmacokinetic/ Pharmacodynamic Data Analysis 
For all subjects, plasma samples will be collected according to the schedule of events in order to 
quantify concentrations of SAM and its metabolites (RDC-9986 and RDC-1066), BUP and its 
metabolite (norbuprenorphine [nBUP]), and reported background ADTs. 
Descriptive statistics of concentration data for SAM, RDC-9986, BUP, and nBUP will be 
calculated based on nominal sample collection time. Please refer to Section 6.5 for the handling 
of concentration data that are below the lower limit of quantification (BLOQ). 
By-subject listings of plasma concentrations, including SAM, BUP, and their metabolites, and 
analytes from background ADTs will be provided. 
Pharmacokinetic data may be used in a subsequent population pharmacokinetic evaluation 
conducted outside of this study. 
4. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE 
No interim analysis is planned for this study. 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
The analyses specified here are consistent with those specified in the Study Protocol 
Amendment 3.0 (dated 02 Oct 2019) and the associated Unmasked Addendum Amendment 2.0 
(dated 25 Jan 2018). 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Every attempt must be made to collect complete data for every subject. In cases where complete 
data cannot be collected, the principles to assign the analysis visits for inclusion in summary 
tables described in this section will be followed for data handling and analyses. 
Early termination visits for efficacy measurements will be mapped to the next scheduled visit. 
For example, a subject who terminates shortly after Day 43 (eg, has assessments at baseline 
through Day 43, and Day 78 or early termination) would have assessments at early termination 
mapped to the next scheduled visit for each assessment. In this example, the MADRS scores 
from the early termination visit would be mapped to Day 50. For visits other than early 
termination/ Day 78, the visit number indicated on the case report form will be used as the 
analysis visit. Results from this mapping will be considered observed data and the mapping will 
be performed prior to any imputation. 


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Early termination visits for safety measurements will not be mapped to any scheduled 
postbaseline visit, but will be used as the last assessment during the treatment period. 
Measurements collected from unscheduled visits will not be included in the by-visit summary 
tables or mean change analyses, but will be included in the analysis of PCS values and in the 
subject listings. 
6.2. 
Efficacy Data Handling 
The MADRS-10 is the sum of the 10 items from the MADRS. If only one of the items of the 
MADRS for a given visit is missing, then the MADRS-10 score will be calculated as follows: 
(sum of nonmissing items) × (total number of items) / (number of nonmissing items). If more 
than one of the items is missing, the MADRS-10 score will be set to missing. 
For the LOCF on the total score, if a subject misses a postbaseline visit for a given stage, a record 
for the scheduled visit will be imputed using the value from the most recent postbaseline visit 
from the same stage. Individual items will not be carried forward. 
6.3. 
Safety Data Handling 
All efforts should be made to obtain the missing information from the investigator. For COWS 
scores, C-SSRS scores, vital signs, laboratory testing (chemistry, hematology, urinalysis), and 
12-lead ECGs, only observed data will be used for analyses, and missing data will not be 
imputed. 
6.4. 
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 available partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the available partial 
date. In the case of a completely missing stop date, medication will be assumed to be ongoing. 
6.5. 
Pharmacokinetic Data Handling 
Pharmacokinetic concentration values BLOQ will be treated as zero for the determination of 
summary and order statistics. Individual values that are BLOQ will be presented as “BLOQ” in 
the concentration data listing. For the presentation of summary and order statistics, if at least 1 
subject has a concentration value BLOQ for the time point, then the minimum value will be 
displayed as “BLOQ”. If more than 50% of the subjects have a concentration data value BLOQ 
for the time point, then the minimum and median values will be displayed as “BLOQ”. If all 
subjects have concentration data values BLOQ for the time point, then all order statistics 
(minimum, first quartile [Q1], median, third quartile [Q3], and maximum) will be displayed as 
“BLOQ”. If the mean is less than the lower limit of quantification, the mean values will be 
displayed as “BLOQ”. 


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7. 
GENERAL STATISTICAL METHODOLOGY 
7.1. 
Statistical Conventions 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of subjects in each category for categorical variables) will 
be provided by treatment group. All summary tables will be based on observed data, and missing 
values will not be imputed unless otherwise indicated. Measurements collected from unscheduled 
visits or repeated assessments will not be included in the by-visit summary tables or figures, but 
will be included in the derivation of the last postbaseline value during treatment, the analyses for 
the PCS postbaseline values, and subject listings. Source data for the summary tables and 
statistical analyses will be presented as subject data listings. 
7.2. 
Reporting Precision 
Summary statistics will be presented to the degree of precision in Table 8, unless otherwise 
specified. 
Table 8: 
Degree of Precision  
Statistics 
Degree of Precision 
Mean, Geometric Mean, Median, 
Quartiles, Confidence limit boundaries 
One more than the raw data, up to three decimal places 
Standard deviation, Standard error 
One more than the mean, up to three decimal places 
Minimum, Maximum 
The same as the raw data, up to two decimal places 
P-value 
Rounded to three decimal places and therefore presented as 
0.xxx; P-values smaller than 0.001 as “<0.001”; P-values 
greater than 0.999 as “>0.999”. 
Percentage 
One decimal place. A percentage of 100% will be reported 
as 100.0%. Percentages of zero will be reported as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12 – 0.30). 
For weight, height, and BMI, one decimal place will be used for summary statistics. 
8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
9. 
MOCK TABLES, LISTINGS AND FIGURES 
Mock tables, listings, and figures will be provided in a separate document. 


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10. 
REFERENCES 
Chen YF, Yang Y, Hung HM, Wang SJ. Evaluation of performance of some enrichment designs 
dealing with high placebo response in psychiatric clinical trials. Contemp Clin Trials. 
2011;32(4):592-604. doi: 10.1016/j.cct.2011.04.006. 
Ivanova A, Qaqish B, Schoenfeld DA. Optimality, sample size, and power calculations for the 
sequential parallel comparison design. Stat Med. 2011;30(23):2793-2803. doi: 10.1002/sim.4292. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-997. 
Little RJ, Rubin DB. Statistical Analysis with Missing Data. 2nd ed. New York. John Wiley & 
Sons; 2002. 
 


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APPENDIX 1. INDEPENDENCE OF ESTIMATED TREATMENT 
EFFECTS IN 2 STAGES FOR SPCD WITH BINARY 
ENDPOINTS 
Table 9 displays subject accounting by response status in the two stages according to the SPCD 
with rerandomization of placebo nonresponders at the start of Stage 2. The construction of the 
table is similar to Table I in (Ivanova et al, 2011). In Table 9, s is the probability of placebo 
nonresponders in Stage 1 being rerandomized into Stage 2, and the rerandomization ratio is 1:1. 
Rerandomization occurs only for placebo nonresponders in Stage 1 who complete Stage 1 and 
meet additional criteria for rerandomization into Stage 2. 
Table 9: 
Subject Accounting by Response Status in 2 Stages of SPCD 
Treatment in 
Stage 1 
Response in 
Stage 1 
Treatment in 
Stage 2 
Response in 
Stage 2 
Count 
Probability 
ALKS 5461 
2/2 
Yes 
NA 
NA 
z1 
p1 
No 
NA 
NA 
l1 – z1 
1 – p1 
Placebo 
Yes 
NA 
NA 
y1 
q1 
No 
ALKS 5461 
2/2 
Yes 
z2 
1
2 (1 −𝑞𝑞1 )𝑠𝑠𝑝𝑝2 
No 
l2 – z2 
1
2 (1 −𝑞𝑞1 )𝑠𝑠(1 −𝑝𝑝2) 
Placebo 
Yes 
y2 
1
2 (1 −𝑞𝑞1 )𝑠𝑠𝑞𝑞2 
No 
m2 – y2 
1
2 (1 −𝑞𝑞1 )𝑠𝑠(1 −𝑞𝑞2) 
Not Re-
randomized 
NA 
k1 
(1 −𝑞𝑞1 )(1 −𝑠𝑠) 
Abbreviation: NA= not applicable for inference. 
The notation is as follows: 
p1: response probability in Stage 1 for subjects randomized to ALKS 5461 2/2in Stage 1 
q1: response probability in Stage 1 for subjects randomized to placebo in Stage 1 
s: probability of re-randomization for placebo nonresponders in Stage 1 
p2: response probability in Stage 2 for subjects rerandomized to ALKS 5461 2/2 in Stage 2 
q2: response probability in Stage 2 for subjects rerandomized to placebo in Stage 2 
Let m1 = y1 + l2 + m2 + k1 denote the total number of placebo subjects on Stage 1. The joint 
likelihood for (p1, q1, s, p2, q2) is: 
L(p1, q1, s, p2, q2) ∝ 𝑝𝑝1
𝑧𝑧1(1 −𝑝𝑝1)𝑙𝑙1−𝑧𝑧1𝑞𝑞1
𝑦𝑦1 
× ((1 −𝑞𝑞1)𝑠𝑠𝑝𝑝2)𝑧𝑧2((1 −𝑞𝑞1)𝑠𝑠(1 −𝑝𝑝2))𝑙𝑙2−𝑧𝑧2 


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× ((1 −𝑞𝑞1)𝑠𝑠𝑞𝑞2)𝑦𝑦2((1 −𝑞𝑞1)𝑠𝑠(1 −𝑞𝑞2))𝑚𝑚2−𝑦𝑦2 
 × (1 −𝑞𝑞1 )(1 −𝑠𝑠)𝑚𝑚1−𝑦𝑦1− 𝑙𝑙2−𝑚𝑚2  
= 𝑝𝑝1
𝑧𝑧1(1 −𝑝𝑝1)𝑙𝑙1−𝑧𝑧1𝑞𝑞1
𝑦𝑦1(1 −𝑞𝑞1)𝑚𝑚1−𝑦𝑦1 
× 𝑠𝑠𝑙𝑙2+𝑚𝑚2(1 −𝑠𝑠)𝑚𝑚1−𝑦𝑦1−𝑙𝑙2−𝑚𝑚2 
× 𝑝𝑝2 𝑧𝑧2൫1 −𝑝𝑝2൯ 𝑙𝑙2−𝑧𝑧2𝑞𝑞2 𝑦𝑦2(1 −𝑞𝑞2)
𝑚𝑚2−𝑦𝑦2 
Since the joint loglikelihood decomposes into the sum of the loglikelihoods of the component 
parameters, the maximum likelihood estimates of the component parameters are mutually 
independent (Little and Rubin 2002). In particular, (𝑝𝑝̂1, 𝑞𝑞ො1) is independent of (𝑝𝑝̂2, 𝑞𝑞ො2). For the 
comparison of ALKS 5461 2/2 versus placebo, the treatment effect estimate for Stage 1 ∆෠1 is a 
function of (𝑝𝑝̂1, 𝑞𝑞ො1) and for Stage 2 ∆෠2 is a function of (𝑝𝑝̂2, 𝑞𝑞ො2). ∆෠1 is independent of ∆෠2. This 
establishes the validity of the linear combination test statistic for the SPCD design with binary 
endpoints. 


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APPENDIX 2. AESI – ABUSE POTENTIAL 
Preferred Term 
Ad hoc SOC 
Accidental overdose 
AP_abuse behavior 
Drug abuser 
AP_abuse behavior 
Drug diversion 
AP_abuse behavior 
Drug level above therapeutic 
AP_abuse behavior 
Drug level increased 
AP_abuse behavior 
Drug screen 
AP_abuse behavior 
Drug screen positive 
AP_abuse behavior 
Intentional overdose 
AP_abuse behavior 
Intentional product misuse 
AP_abuse behavior 
Intentional product use issue 
AP_abuse behavior 
Maternal use of illicit drugs 
AP_abuse behavior 
Needle track marks 
AP_abuse behavior 
Neonatal complications of substance abuse 
AP_abuse behavior 
Overdose 
AP_abuse behavior 
Prescription drug used without a prescription 
AP_abuse behavior 
Prescription form tampering 
AP_abuse behavior 
Product tampering 
AP_abuse behavior 
Substance abuse 
AP_abuse behavior 
Substance abuser 
AP_abuse behavior 
Substance use 
AP_abuse behavior 
Substance-induced mood disorder 
AP_abuse behavior 
Substance-induced psychotic disorder 
AP_abuse behavior 
Toxicity to various agents 
AP_abuse behavior 
Acute psychosis 
AP_non-specific 
Aggression 
AP_non-specific 
Cognitive disorder 
AP_non-specific 
Confusional state 
AP_non-specific 
Delirium 
AP_non-specific 
Delusional disorder, unspecified type 
AP_non-specific 
Depersonalisation/derealisation disorder  
AP_non-specific 
Disorientation 
AP_non-specific 


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Preferred Term 
Ad hoc SOC 
Dissociation 
AP_non-specific 
Disturbance in attention 
AP_non-specific 
Disturbance in social behaviour 
AP_non-specific 
Dizziness 
AP_non-specific 
Dopamine dysregulation syndrome 
AP_non-specific 
Emotional disorder 
AP_non-specific 
Flight of ideas 
AP_non-specific 
Medication overuse headache 
AP_non-specific 
Mental impairment 
AP_non-specific 
Mood altered 
AP_non-specific 
Mood swings 
AP_non-specific 
Narcotic bowel syndrome 
AP_non-specific 
Paranoia 
AP_non-specific 
Psychotic behaviour 
AP_non-specific 
Psychotic disorder 
AP_non-specific 
Sedation 
AP_non-specific 
Somnolence 
AP_non-specific 
Stupor 
AP_non-specific 
Euphoric mood 
AP-euphoria related 
Feeling abnormal 
AP-euphoria related 
Feeling drunk 
AP-euphoria related 
Feeling of relaxation 
AP-euphoria related 
Hallucination 
AP-euphoria related 
Hallucination, auditory 
AP-euphoria related 
Hallucination, gustatory 
AP-euphoria related 
Hallucination, mixed 
AP-euphoria related 
Hallucination, olfactory 
AP-euphoria related 
Hallucination, synaesthetic 
AP-euphoria related 
Hallucination, tactile 
AP-euphoria related 
Hallucination, visual 
AP-euphoria related 
Inappropriate affect 
AP-euphoria related 
Thinking abnormal 
AP-euphoria related 


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APPENDIX 3. AESI – DEPENDENCE 
Preferred Term 
Dependence 
Drug dependence 
Drug dependence, antepartum 
Drug dependence, postpartum 
Drug tolerance 
Drug tolerance decreased 
Drug tolerance increased 
Substance dependence 


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APPENDIX 4. AESI – WITHDRAWAL 
Preferred Term 
Drug detoxification 
Reversal of opiate activity 
Drug rehabilitation 
Drug withdrawal convulsions 
Drug withdrawal headache 
Drug withdrawal maintenance therapy 
Drug withdrawal syndrome 
Drug withdrawal syndrome neonatal 
Rebound effect 
Steroid withdrawal syndrome 
Withdrawal arrhythmia 
Withdrawal syndrome 
Anhedonia 
Depressed mood 
Depression 
Dysphoria 
Feeling of despair 
Morose 
Negative thoughts 
Persistent depressive disorder 
Dyssomnia 
Headache 
Insomnia 
Obsessive thoughts 
Poor quality sleep 
Syncope 
Terminal insomnia 
Agitation 
Irritability 
Anxiety 
Chills 


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Preferred Term 
Hyperhidrosis 
Nausea 
Nervousness 
Pain 
Tremor 
Vomiting 
Abdominal pain 
Arthralgia 
Diarrhoea 
Mydriasis 
Piloerection 
Restlessness 
Rhinorrhoea 
Tachycardia 
Yawning 


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APPENDIX 5. AESI – SUICIDAL IDEATION AND BEHAVIOR 
Preferred Term 
Depression suicidal 
Suicidal ideation 
Suicide threat 
Suicidal behavior 
Suicide attempt 
Intentional overdose 
Multiple drug overdose 
Multiple drug overdose intentional 
Overdose 
Poisoning deliberate 
Completed suicide 
Intentional self-injury 
Self injurious behavior 
Self mutilation 
Self-injurious ideation 
Columbia suicide severity rating scale abnormal 


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APPENDIX 6. AESI – HYPOMANIA/ MANIA 
Preferred Term 
Affective ambivalence 
Affect lability 
Agitation 
Aggression 
Anger 
Bipolar disorder 
Bipolar I disorder 
Bipolar II disorder 
Cyclothymic disorder 
Delusion 
Energy increased 
Euphoric mood 
Flight of ideas 
Frustration tolerance decreased 
Grandiosity 
Hallucination 
Hostility 
Hypomania 
Inappropriate affect 
Irritability 
Mania 
Mood swings 
Sexually inappropriate behavior 


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APPENDIX 7. AESI – CNS DEPRESSION AND SEDATION 
Preferred Term 
Apathy  
Asthenia  
Bradyphrenia  
Decreased activity  
Decreased interest  
Depressed level of consciousness 
Fatigue  
Hypersomnia  
Hypersomnia related to another mental condition  
Hypokinesia neonatal  
Hyporesponsive to stimuli 
Hypotonic-hyporesponsive episode 
Lethargy  
Listless  
Loss of consciousness 
Neonatal oversedation  
Prostration  
Psychomotor retardation  
Sedation  
Sense of oppression  
Sleep disorder due to general medical condition, hypersomnia type  
Sluggishness 
Somnolence 
Somnolence neonatal  
Sopor  
Unresponsive to stimuli 


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APPENDIX 8. AESI – RESPIRATORY DEPRESSION 
Preferred Term 
Acute respiratory failure 
Apnoea 
Apnoeic attack 
Bradypnoea 
Breath holding 
Breath sounds abnormal 
Breath sounds absent 
Central-alveolar hypoventilation 
Hypopnoea 
Hypoventilation 
Hypoventilation neonatal 
Infantile apnoea 
Lung hypoinflation 
Neonatal respiratory arrest 
Neonatal respiratory depression 
Neonatal respiratory failure 
Postoperative respiratory failure 
Respiratory arrest 
Respiratory depression 
Respiratory depth decreased 
Respiratory failure 
Respiratory paralysis 
Respiratory rate decreased 


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APPENDIX 9. AESI – ORTHOSTATIC HYPOTENSION 
Preferred Term 
Autonomic nervous system imbalance 
Blood pressure abnormal 
Blood pressure ambulatory abnormal 
Blood pressure ambulatory decreased 
Blood pressure decreased 
Blood pressure diastolic abnormal 
Blood pressure diastolic decreased 
Blood pressure fluctuation 
Blood pressure immeasurable 
Blood pressure orthostatic 
Blood pressure orthostatic decreased 
Blood pressure systolic abnormal 
Blood pressure systolic decreased 
Circulatory collapse 
Circulatory failure neonatal 
Diastolic hypotension 
Dizziness exertional 
Dizziness 
Dizziness postural 
Hypoperfusion 
Hypotension 
Labile blood pressure 
Mean arterial pressure decreased 
Neonatal hypotension 
Neurogenic shock 
Orthostatic heart rate response increased 
Orthostatic hypotension 
Orthostatic intolerance 
Peripheral circulatory failure 
Postural orthostatic tachycardia syndrome 
Presyncope 


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Preferred Term 
Procedural hypotension 
Shock 
Shock symptom 
Syncope 


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APPENDIX 10. AESI – HYPERSENSITIVITY 
Preferred Term 
Acute generalised exanthematous pustulosis 
Acute haemorrhagic oedema of infancy 
Administration site dermatitis 
Administration site eczema 
Administration site hypersensitivity 
Administration site rash 
Administration site recall reaction 
Administration site urticaria 
Administration site vasculitis 
Allergic bronchitis 
Allergic colitis 
Allergic cough 
Allergic cystitis 
Allergic eosinophilia 
Allergic gastroenteritis 
Allergic granulomatous angiitis 
Allergic hepatitis 
Allergic keratitis 
Allergic myocarditis 
Allergic oedema 
Allergic otitis externa 
Allergic otitis media 
Allergic pharyngitis 
Allergic respiratory disease 
Allergic respiratory symptom 
Allergic sinusitis 
Allergic transfusion reaction 
Allergy alert test positive 
Allergy test positive 
Allergy to immunoglobulin therapy 
Allergy to surgical sutures 


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Preferred Term 
Allergy to vaccine 
Alveolitis allergic 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Anaphylaxis treatment 
Angioedema 
Antiallergic therapy 
Antiendomysial antibody positive 
Anti-neutrophil cytoplasmic antibody positive vasculitis 
Aortitis 
Application site dermatitis 
Application site eczema 
Application site hypersensitivity 
Application site rash 
Application site recall reaction 
Application site urticaria 
Application site vasculitis 
Arteritis 
Arteritis coronary 
Arthritis allergic 
Aspirin-exacerbated respiratory disease 
Atopy 
Behcet's syndrome 
Blepharitis allergic 
Blood immunoglobulin E abnormal 
Blood immunoglobulin E increased 
Bromoderma 
Bronchospasm 
Capillaritis 


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Preferred Term 
Catheter site dermatitis 
Catheter site eczema 
Catheter site hypersensitivity 
Catheter site rash 
Catheter site urticaria 
Catheter site vasculitis 
Cerebral arteritis 
Chronic eosinophilic rhinosinusitis 
Chronic hyperplastic eosinophilic sinusitis 
Chronic pigmented purpura 
Circulatory collapse 
Circumoral oedema 
Cogan's syndrome 
Conjunctival oedema 
Conjunctivitis allergic 
Contact stomatitis 
Contrast media allergy 
Contrast media reaction 
Corneal oedema 
Cutaneous vasculitis 
Dennie-Morgan fold 
Dermatitis 
Dermatitis acneiform 
Dermatitis allergic 
Dermatitis atopic 
Dermatitis bullous 
Dermatitis contact 
Dermatitis exfoliative 
Dermatitis exfoliative generalised 
Dermatitis herpetiformis 
Dermatitis infected 
Dermatitis psoriasiform 


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Preferred Term 
Device allergy 
Diabetic arteritis 
Dialysis membrane reaction 
Diffuse vasculitis 
Distributive shock 
Documented hypersensitivity to administered product 
Drug cross-reactivity 
Drug eruption 
Drug hypersensitivity 
Drug provocation test 
Drug reaction with eosinophilia and systemic symptoms 
Eczema 
Eczema infantile 
Eczema nummular 
Eczema vaccinatum 
Eczema vesicular 
Eczema weeping 
Encephalitis allergic 
Encephalopathy allergic 
Epidermal necrosis 
Epidermolysis 
Epidermolysis bullosa 
Epiglottic oedema 
Erythema induratum 
Erythema multiforme 
Erythema nodosum 
Exfoliative rash 
Eye allergy 
Eye oedema 
Eye swelling 
Eyelid oedema 
Face oedema 


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Preferred Term 
Fixed drug eruption 
Giant papillary conjunctivitis 
Gingival oedema 
Gingival swelling 
Gleich's syndrome 
Granulomatosis with polyangiitis 
Haemorrhagic urticaria 
Haemorrhagic vasculitis 
Hand dermatitis 
Henoch-Schonlein purpura 
Henoch-Schonlein purpura nephritis 
Heparin-induced thrombocytopenia 
Hereditary angioedema 
Hypersensitivity 
Hypersensitivity vasculitis 
Idiopathic angioedema 
Idiopathic urticaria 
Immediate post-injection reaction 
Immune thrombocytopenic purpura 
Immune tolerance induction 
Immune-mediated adverse reaction 
Implant site dermatitis 
Implant site hypersensitivity 
Implant site rash 
Implant site urticaria 
Incision site dermatitis 
Incision site rash 
Infusion site dermatitis 
Infusion site eczema 
Infusion site hypersensitivity 
Infusion site rash 
Infusion site recall reaction 


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Preferred Term 
Infusion site urticaria 
Infusion site vasculitis 
Injection site dermatitis 
Injection site eczema 
Injection site hypersensitivity 
Injection site rash 
Injection site recall reaction 
Injection site urticaria 
Injection site vasculitis 
Instillation site hypersensitivity 
Instillation site rash 
Instillation site urticaria 
Interstitial granulomatous dermatitis 
Intestinal angioedema 
Iodine allergy 
Kaposi's varicelliform eruption 
Kawasaki's disease 
Kounis syndrome 
Langerhans' cell histiocytosis 
Laryngeal oedema 
Laryngitis allergic 
Laryngospasm 
Laryngotracheal oedema 
Limbal swelling 
Lip oedema 
Lip swelling 
Lupus vasculitis 
Mast cell degranulation present 
Medical device site dermatitis 
Medical device site eczema 
Medical device site hypersensitivity 
Medical device site rash 


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Preferred Term 
Medical device site recall reaction 
Medical device site urticaria 
Medical device site vasculitis 
Microscopic polyangiitis 
Mouth swelling 
Mucocutaneous rash 
Multiple allergies 
Nephritis allergic 
Nikolsky's sign 
Nodular rash 
Nodular vasculitis 
Ocular vasculitis 
Oculomucocutaneous syndrome 
Oculorespiratory syndrome 
Oedema mouth 
Oral allergy syndrome 
Oropharyngeal blistering 
Oropharyngeal spasm 
Oropharyngeal swelling 
Palatal oedema 
Palatal swelling 
Palisaded neutrophilic granulomatous dermatitis 
Palpable purpura 
Pathergy reaction 
Periorbital oedema 
Pharyngeal oedema 
Polyarteritis nodosa 
Polymyalgia rheumatica 
Pruritus allergic 
Pseudovasculitis 
Pulmonary vasculitis 
Radiation vasculitis 


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Preferred Term 
Radioallergosorbent test positive 
Rash 
Rash erythematous 
Rash follicular 
Rash generalised 
Rash macular 
Rash maculo-papular 
Rash maculovesicular 
Rash morbilliform 
Rash neonatal 
Rash papulosquamous 
Rash pruritic 
Rash pustular 
Rash rubelliform 
Rash scarlatiniform 
Rash vesicular 
Reaction to azo-dyes 
Reaction to colouring 
Reaction to drug excipients 
Reaction to preservatives 
Red man syndrome 
Renal arteritis 
Renal vasculitis 
Retinal vasculitis 
Rheumatoid vasculitis 
Rhinitis allergic 
Scleral oedema 
Scleritis allergic 
Scrotal oedema 
Segmented hyalinising vasculitis 
Serum sickness 
Serum sickness-like reaction 


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Preferred Term 
Shock 
Shock symptom 
Skin necrosis 
Skin reaction 
Skin test positive 
Solar urticarial 
Solvent sensitivity 
Stevens-Johnson syndrome 
Stoma site hypersensitivity 
Stoma site rash 
Swelling face 
Swollen tongue 
Takayasu's arteritis 
Temporal arteritis 
Thromboangiitis obliterans 
Tongue oedema 
Toxic epidermal necrolysis 
Toxic skin eruption 
Tracheal oedema 
Type 2 lepra reaction 
Type I hypersensitivity 
Type II hypersensitivity 
Type III immune complex mediated reaction 
Type IV hypersensitivity reaction 
Urticaria 
Urticaria cholinergic 
Urticaria chronic 
Urticaria contact 
Urticaria papular 
Urticaria physical 
Urticaria pigmentosa 
Urticaria vesiculosa 


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Preferred Term 
Urticarial vasculitis 
Vaccination site dermatitis 
Vaccination site eczema 
Vaccination site exfoliation 
Vaccination site hypersensitivity 
Vaccination site rash 
Vaccination site recall reaction 
Vaccination site urticaria 
Vaccination site vasculitis 
Vaccination site vesicles 
Vaginal exfoliation 
Vaginal ulceration 
Vascular purpura 
Vasculitic rash 
Vasculitis 
Vessel puncture site rash 
Vessel puncture site vesicles 
Vulval ulceration 
Vulvovaginal rash 
Vulvovaginal ulceration 


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APPENDIX 11. AESI – HEPATIC EFFECTS 
Preferred Term 
Acute hepatic failure 
Acute on chronic liver failure 
Acute yellow liver atrophy 
Ascites 
Asterixis 
Bacterascites 
Biliary cirrhosis 
Biliary cirrhosis primary 
Biliary fibrosis 
Cholestatic liver injury 
Chronic hepatic failure 
Coma hepatic 
Cryptogenic cirrhosis 
Diabetic hepatopathy 
Drug-induced liver injury 
Duodenal varices 
Gallbladder varices 
Gastric variceal injection 
Gastric variceal ligation 
Gastric varices 
Gastric varices haemorrhage 
Hepatectomy 
Hepatic atrophy 
Hepatic calcification 
Hepatic cirrhosis 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic failure 
Hepatic fibrosis 
Hepatic hydrothorax 
Hepatic infiltration eosinophilic 


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Preferred Term 
Hepatic lesion 
Hepatic necrosis 
Hepatic steato-fibrosis 
Hepatic steatosis 
Hepatitis fulminant 
Hepatobiliary disease 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatotoxicity 
Intestinal varices 
Intestinal varices haemorrhage 
Liver and small intestine transplant 
Liver dialysis 
Liver disorder 
Liver injury 
Liver operation 
Liver transplant 
Lupoid hepatic cirrhosis 
Minimal hepatic encephalopathy 
Mixed liver injury 
Nodular regenerative hyperplasia 
Non-alcoholic fatty liver 
Non-alcoholic steatohepatitis 
Non-cirrhotic portal hypertension 
Oedema due to hepatic disease 
Oesophageal varices haemorrhage 
Peripancreatic varices 
Portal fibrosis 
Portal hypertension 


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Preferred Term 
Portal hypertensive enteropathy 
Portal hypertensive gastropathy 
Portal vein cavernous transformation 
Portal vein dilatation 
Portopulmonary hypertension 
Renal and liver transplant 
Retrograde portal vein flow 
Reye's syndrome 
Reynold's syndrome 
Splenic varices 
Splenic varices haemorrhage 
Steatohepatitis 
Subacute hepatic failure 
Varices oesophageal 
Varicose veins of abdominal wall 
Anorectal varices 
Anorectal varices haemorrhage 
Intrahepatic portal hepatic venous fistula 
Peritoneovenous shunt 
Portal shunt 
Portal shunt procedure 
Small-for-size liver syndrome 
Spider naevus 
Splenorenal shunt 
Splenorenal shunt procedure 
Spontaneous intrahepatic portosystemic venous shunt 
Stomal varices