A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 5461 in Treatment Refractory Major Depressive Disorder
Phase: PHASE3
Conditions: Major Depressive Disorder
Sponsor: Alkermes, Inc.

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 
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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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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)