Clinical trial NCT02141399
Conditions: Major Depressive Disorder
Sponsor: Alkermes, Inc.
Start date: 2014-05-01; Completion date: 2017-11-20
Enrollment: 1485 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a 52-week open-label study to evaluate the safety and tolerability of ALKS 5461.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: ALKS 5461
Intervention descriptions: intervention 1: Sublingual tablet, taken daily

Protocol documents:
Prot_000.pdf: 
A Phase 3 Multicenter Study of the Long-term Safety and 
Tolerability of ALKS 5461 for the Adjunctive Treatment of 
Major Depressive Disorder in Adults who Have an 
Inadequate Response to Antidepressant Therapy (the 
FORWARD-2 Study) 
 
 
Unique Protocol ID: 
ALK5461-208 
NCT Number: 
NCT02141399 
EudraCT Number:  
2014-000380-41 
Date of Protocol:  
03 March 2016 
 


1. 
 TITLE PAGE 
 
 
 
CLINICAL STUDY PROTOCOL 
ALK5461-208 
EudraCT Number: 2014-000380-41 
 
Study Title 
A Phase 3 Multicenter Study of the Long-term Safety and 
Tolerability of ALKS 5461 for the Adjunctive Treatment of 
Major Depressive Disorder in Adults who Have an Inadequate 
Response to Antidepressant Therapy (the FORWARD-2 Study) 
Document Status 
Final 
Document Date 
Amendment #3: 03 March 2016 
Amendment #2: 12 May 2015 
Amendment #1: 17 April 2014 
Original Protocol: 16 December 2013 
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 
Role in Study 
Name 
Address and Telephone 
Alkermes Medical Monitor  
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Telephone: 
 
Mobile Phone: 
 
Alkermes Drug Safety 
Representative 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 USA 
Telephone: 
  
 Medical Monitor 
and 24-hour Emergency Contact 
 
 
 
Raleigh, NC 27604 USA 
Telephone: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Alkermes, Inc. 
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2. 
SYNOPSIS 
Name of Sponsor/ Company: 
Alkermes, Inc 
Name of Study Drug: 
ALKS 5461 
Name of Active Ingredients: 
buprenorphine (BUP) and samidorphan 
Title of Study: 
A Phase 3 Multicenter Study of the Long-term Safety and Tolerability of ALKS 5461 for the 
Adjunctive Treatment of Major Depressive Disorder in Adults who Have an Inadequate Response to 
Antidepressant Therapy (the FORWARD-2 Study) 
Investigators: 
This will be a multicenter, multinational study.  
Study Period: 
First subject consented: Q2 2014 
Last subject completed: 2017 
Phase of development: 
3 
Objective: 
• 
To assess the long-term safety and tolerability of ALKS 5461 for use as an adjunctive therapy 
to antidepressants for the treatment of major depressive disorder (MDD) 
Methodology: 
ALKS 5461 is a fixed-dose combination product consisting of BUP and samidorphan in a 
1:1 (weight/weight) ratio. Throughout this protocol ALKS 5461 dose levels will be referred to as dose 
of BUP/samidorphan expressed as weight in mg (eg, a 2 mg BUP:2 mg samidorphan dose will be 
expressed as ALKS 5461 2/2). 
This study will evaluate the safety and tolerability, and explore the treatment effect of ALKS 5461 
administered for 52 weeks as an adjunctive therapy to antidepressants for the treatment of MDD in 
subjects who have had 1 to 2 inadequate responses to an approved antidepressant therapy (ADT). 
Subjects will have been treated with an adequate dose of an approved ADT for at least 8 weeks, with a 
stable dose over the last 4 weeks prior to study entry. An adequate dose is defined as a dose that is 
greater than or equal to the minimum effective dose on the Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (ATRQ), inclusive of up to 3 weeks for titration 
into the adequate dose range. 
Subjects will enter into the study in one of the following 3 ways, based on their previous experience 
with ALKS 5461: 
1. New Subjects:
2. 
 those who have not been randomized in a prior study of ALKS 5461 within 
2 years 
Continuing Subjects:
3. 
 those who have completed the treatment period of study ALK5461-205, 
ALK5461-206, ALK5461-207, or ALK5461-210 within the past 10 days 
Lead-in Subjects: those who participated in study ALK5461-205, ALK5461-206, or 
ALK5461-207 within the past 10 days, and met the criteria for response to ADT during the 
prospective lead-in (PLI) period of that antecedent study, but did not meet the criteria for 


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remission 
All New Subjects will be initially evaluated for eligibility at screening (Visit 1), to occur up to 28 days 
prior to Visit 2. Continuing Subjects and Lead-in Subjects will not have a separate screening visit and 
will begin participation in this study at Visit 2. 
At Visit 2, all eligible, consenting subjects will begin the treatment period. Subjects who are not 
receiving ALKS 5461 at study entry will require a 1-week titration period. Subjects entering the study 
already receiving ALKS 5461 will not require a titration period. To maintain the blinded dosing 
scheme in ALK5461-206 and ALK5461-207, Continuing Subjects from those studies will be blinded to 
whether or not they receive a 1-week titration. 
Starting on Day 8 (Visit 3), the target dose for the remaining 51 weeks for all participating subjects will 
be ALKS 5461 2/2. Attempts should be made to achieve and maintain the ALKS 5461 2/2 dose 
throughout that period, if it is tolerated. However, flexible down-titration to ALKS 5461 1/1 or 0.5/0.5 
is permitted at the investigator’s discretion, if tolerability issues persist. Once a subject has stabilized 
after down-titration, attempts should again be made to achieve and maintain the target dose of 
ALKS 5461 2/2 over the course of treatment, dependent on the individual subject’s experience with 
study drug tolerability. 
Dose adjustment of ADT during the treatment period is permitted for optimal therapeutic effect within 
the recommended dose range, however ADT dose adjustment should not be made within the same 
week as ALKS 5461 dose adjustment. Furthermore, subjects are not permitted to change ADTs during 
the course of the study period. 
During the 52-week treatment period, subjects will return to the clinic for periodic scheduled visits 
(Visits 2-14) at which safety, tolerability, and treatment effect over time will be assessed. 
A 4-week safety follow-up period will occur following the ALKS 5461 treatment period. During the 
4-week follow-up period, there are a total of 4 clinic visits (Visits 15-18), as well as 7 safety 
assessments by phone. The clinic visits will occur 1 day, 1 week, 2 weeks, and 4 weeks following the 
end of treatment visit (Visit 14). The phone assessments will occur daily for the first week between 
visits, and weekly during the second and third week. 
If any adverse events (AEs) are reported that relate to opioid withdrawal (eg, nausea, vomiting, 
restlessness, hyperhidrosis) during a phone assessment in the follow-up period, the subject will be 
asked to come into the clinic as soon as possible to receive a Clinical Opiate Withdrawal Scale 
(COWS) assessment. 
Number of Subjects (planned): 
It is estimated that approximately 1,500 subjects will be enrolled in this study.  
Main Criteria for Inclusion: 
The main criteria for study eligibility are as follows: 
• 
New Subjects must have a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, 
Text Revision (DSM-IV-TR) MDD diagnosis and an inadequate response to current 
approved ADT. They will not have participated in a prior trial of ALKS 5461 within 2 years. 
• 
Continuing Subjects must have completed the treatment period of ALK5461-205, 
ALK5461-206, ALK5461-207, or ALK5461-210 within 10 days of the baseline visit for this 
study. 
• 
Lead-in Subjects must have completed the PLI period of ALK5461-205, ALK5461-206, or 
ALK5461-207 within 10 days of the baseline visit for this study and met the criteria for 
response to ADT during the PLI, but not for remission. 


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Study Drug, Dosage, Duration, and Mode of Administration: 
ALKS 5461 consists of buprenorphine (BUP), a United States Drug Enforcement Administration 
(US DEA) Schedule III narcotic, and samidorphan, a US DEA Schedule II controlled substance. 
The following doses will be used in the study: 
• 
ALKS 5461 0.5/0.5 (0.5 mg BUP:0.5 mg samidorphan) 
• 
ALKS 5461 1/1 (1 mg BUP:1 mg samidorphan) 
• 
ALKS 5461 2/2 (2 mg BUP:2 mg samidorphan) 
Tablets will be administered sublingually, daily for up to 52 weeks. 
Reference Therapy, Dosage, Duration and Mode of Administration: 
This safety study has no reference therapy. 
Study and Treatment Duration: 
For New Subjects, the study duration will be up to 60 weeks, which includes up to 4 weeks for the 
screening period, 52 weeks for the dosing period, and 4 weeks for the follow-up period. 
For Continuing Subjects and Lead-in Subjects, the study duration will be up to 56 weeks, which 
includes 52 weeks for the dosing period, and 4 weeks for the follow-up period. 
Criteria for Evaluation: 
Safety and Tolerability: 
The following assessments will be collected to evaluate safety and tolerability throughout the study: 
• 
AEs 
• 
clinical laboratory tests (chemistry, hematology, and urinalysis) 
• 
vital signs 
• 
body weight 
• 
electrocardiogram (ECG) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
COWS 
Efficacy: The following assessments will be made for exploratory evaluation of treatment effect over 
time: 
• 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
• 
Hamilton Rating Scale for Anxiety (HAM-A) 
• 
Clinical Global Impression – Severity (CGI-S) 
Pharmacokinetics: 
Plasma samples will be collected at specified time points from consenting subjects enrolled in the US 
only. These samples will be used to quantify concentrations of BUP, samidorphan, and relevant 
metabolites. Concentrations of background ADTs that subjects report taking during the study may be 
quantified, as appropriate. 
Statistical Methods: 
Safety: Safety and tolerability analyses will be performed using data from the safety population, 
defined as all subjects who receive at least 1 dose of ALKS 5461. Reported AE terms will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA®) preferred terms and system organ 
class categories. 
Safety assessments will be summarized using descriptive statistics along with supportive listings. 


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Efficacy: Exploratory evaluation of treatment effect over time will be performed using data from the 
full analysis set (FAS), defined as all subjects who receive at least 1 dose of ALKS 5461 and complete 
at least 1 post-baseline efficacy assessment (MADRS). 
Pharmacokinetics: 
Plasma concentration data for BUP, samidorphan, and relevant metabolites as well as background 
ADTs will be listed and summarized. Additionally, concentration data obtained from this study may be 
combined with data from other studies for population PK analysis, which will be reported separately.  
Sample Size Considerations: 
It is estimated that approximately 1,500 subjects will be enrolled in order to ensure that a minimum of 
100 subjects achieve 12 months of exposure to ALKS 5461 and a minimum of 300 subjects achieve 
6 months of exposure.  


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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 ......................................................................................................14 
5.1. 
Study Rationale ...........................................................................................................15 
5.2. 
Dose Selection ............................................................................................................15 
6. 
OBJECTIVE ...............................................................................................................16 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................17 
7.1. 
Subject Inclusion Criteria ...........................................................................................17 
7.1.1. 
All Subjects .................................................................................................................17 
7.1.2. 
New Subjects ..............................................................................................................17 
7.1.3. 
Continuing Subjects ....................................................................................................18 
7.1.4. 
Lead-in Subjects .........................................................................................................18 
7.2. 
Subject Exclusion Criteria ..........................................................................................18 
7.2.1. 
All Subjects .................................................................................................................18 
7.2.2. 
New Subjects ..............................................................................................................18 
7.3. 
Subject Withdrawal ....................................................................................................21 
7.4. 
Replacement of Subjects .............................................................................................22 
8. 
STUDY DESIGN .......................................................................................................23 
8.1. 
Overall Study Design and Plan ...................................................................................23 
8.2. 
Schedule of Visits and Assessments ...........................................................................25 
8.3. 
Study Procedures Descriptions ...................................................................................31 
8.3.1. 
Informed Consent .......................................................................................................31 
8.3.2. 
Confirmation of Eligibility .........................................................................................31 
8.3.3. 
Demographics .............................................................................................................31 
8.3.4. 
Medical and Psychiatric History .................................................................................31 
8.3.5. 
Physical Examination .................................................................................................31 
8.3.6. 
Height .........................................................................................................................31 


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8.3.7. 
Weight .........................................................................................................................31 
8.3.8. 
Vital Signs ..................................................................................................................32 
8.3.9. 
12-Lead Electrocardiogram ........................................................................................32 
8.3.10. 
Concomitant Medication Review ...............................................................................32 
8.3.11. 
Illicit Substances Review ............................................................................................33 
8.3.12. 
Emergency Treatment Cards ......................................................................................33 
8.3.13. 
Pharmacokinetic Assessments ....................................................................................33 
8.3.14. 
Adverse Event Monitoring .........................................................................................33 
8.3.15. 
Laboratory Assessments .............................................................................................33 
8.3.15.1. 
Serology Testing .........................................................................................................33 
8.3.15.2. 
Breath Alcohol Test ....................................................................................................34 
8.3.15.3. 
Urine Drug Screening .................................................................................................34 
8.3.15.4. 
Pregnancy Testing ......................................................................................................34 
8.3.15.5. 
Hematology, Biochemistry, and Urinalysis ................................................................34 
8.3.16. 
Structured Interviews and Questionnaires ..................................................................36 
8.3.16.1. 
Assessments for Study Eligibility ...............................................................................36 
8.3.16.2. 
Safety Assessments .....................................................................................................37 
8.3.16.3. 
Efficacy Assessments .................................................................................................37 
8.4. 
Study Requirements and Restrictions .........................................................................37 
8.4.1. 
Contraception and Pregnancy .....................................................................................37 
8.4.2. 
Concomitant and Prohibited Medications ..................................................................38 
8.4.2.1. 
Concomitant Medications ...........................................................................................38 
8.4.2.2. 
Prohibited Medications ...............................................................................................39 
8.4.3. 
Pain Management .......................................................................................................39 
9. 
TREATMENT OF SUBJECTS ..................................................................................41 
9.1. 
Study Drug Dose and Administration .........................................................................41 
9.1.1. 
Description of ALKS 5461 .........................................................................................41 
9.1.2. 
Study Drug Dose and Dosing Regimen ......................................................................41 
9.2. 
Treatment Adherence ..................................................................................................41 
9.3. 
Method of Assigning Subjects to Treatment ..............................................................41 
9.4. 
Blinding ......................................................................................................................42 
9.5. 
Study Drug Dose Adjustment and Stopping Rules .....................................................42 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 


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10.1. 
Packaging and Labeling ..............................................................................................43 
10.2. 
Storage ........................................................................................................................43 
10.3. 
Accountability .............................................................................................................43 
10.4. 
Handling and Disposal ................................................................................................44 
11. 
ASSESSMENT OF EFFICACY ................................................................................45 
12. 
ASSESSMENT OF PHARMACOKINETICS ...........................................................46 
13. 
ASSESSMENT OF SAFETY .....................................................................................47 
13.1. 
Definition of Adverse Event .......................................................................................47 
13.2. 
Definition of Serious Adverse Event ..........................................................................47 
13.3. 
Relationship to Study Drug ........................................................................................48 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................50 
13.5. 
Reporting of Serious Adverse Events .........................................................................50 
14. 
STATISTICS ..............................................................................................................51 
14.1. 
Sample Size Considerations .......................................................................................51 
14.2. 
General Statistical Methodology ................................................................................51 
14.2.1. 
Study Population .........................................................................................................51 
14.2.1.1. 
Efficacy Population ....................................................................................................51 
14.2.1.2. 
Safety Population ........................................................................................................51 
14.2.1.3. 
Pharmacokinetic Population .......................................................................................51 
14.3. 
Subject Disposition .....................................................................................................51 
14.4. 
Demographics and Baseline Data ...............................................................................51 
14.5. 
Efficacy Analyses .......................................................................................................52 
14.6. 
Pharmacokinetic Analyses ..........................................................................................52 
14.7. 
Safety and Tolerability Analyses ................................................................................52 
14.7.1. 
Adverse Events ...........................................................................................................52 
14.7.2. 
Concomitant Medications ...........................................................................................52 
14.7.3. 
Columbia Suicide Severity Rating Scale ....................................................................52 
14.7.4. 
Laboratory Data ..........................................................................................................52 
14.7.5. 
Weight and Body Mass Index .....................................................................................53 
14.7.6. 
Vital Signs ..................................................................................................................53 
14.7.7. 
12-Lead Electrocardiograms .......................................................................................53 
14.7.8. 
Clinical Opiate Withdrawal Scale ..............................................................................53 
15. 
DIRECT ACCESS TO SOURCE DATA/ DOCUMENTS........................................54 


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15.1. 
Study Monitoring ........................................................................................................54 
15.2. 
Audits and Inspections ................................................................................................54 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................54 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55 
16.1. 
Case Report Forms .....................................................................................................55 
16.2. 
Confidentiality of Data ...............................................................................................55 
17. 
ETHICAL CONSIDERATIONS................................................................................56 
17.1. 
Ethics Review .............................................................................................................56 
17.2. 
Ethical Conduct of the Study ......................................................................................56 
17.3. 
Written Informed Consent ..........................................................................................56 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
18.1. 
Data Capture ...............................................................................................................58 
18.2. 
Inspection of Records .................................................................................................58 
18.3. 
Retention of Records ..................................................................................................58 
18.4. 
Use of Information and Publication Policy ................................................................59 
19. 
REFERENCES ...........................................................................................................60 
20. 
APPENDICES ............................................................................................................61 
 
 
LIST OF TABLES 
Table 1: 
Week 1 Titration and Blinding by Entry Dose and Antecedent Study
 
 .......................24
Table 2: 
Schedule of Visits and Assessments, Screening and Treatment Period
 
 .....................26
Table 3: 
Schedule of Assessments, Safety Follow-up Period
 
 ...................................................29
Table 4: 
Clinical Laboratory Assessments
 
 ...............................................................................35
Table 5: 
Adverse Event Causality Guidelines
 
 ..........................................................................49
 


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LIST OF APPENDICES 
Appendix A. 
Prohibited Cytochrome P450 3A4 (CYP3A4) Inducers and Moderate-to-Strong 
Inhibitors 
Appendix B. 
Maximum Daily Dose Table for Antidepressant Therapy Taken During the Study  
Appendix C. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(ATRQ) - Sample 
Appendix D. 
Mini International Neuropsychiatric Interview (MINI) - Sample 
Appendix E. 
Structured Interview Guide for the 17-Item Hamilton Rating Scale for Depression 
(SIGH-D) - Sample 
Appendix F. 
Columbia Suicide Severity Rating Scale (C-SSRS) - Samples 
• 
“Baseline” Version 
• 
“Since Last Visit” Version 
Appendix G. 
Clinical Opiate Withdrawal Scale (COWS) - Sample 
Appendix H. 
Structured Interview Guide for the Montgomery-Åsberg Depression Rating Scale 
(SIGMA) - Sample 
Appendix I. 
Structured Interview Guide for the Hamilton Rating Scale for Anxiety (SIGH-A) - 
Sample 
Appendix J. 
Clinical Global Impression Scale - Severity (CGI-S) - Sample 


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4. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation or specialist term 
Explanation 
ADT 
antidepressant therapy 
AE 
adverse event 
ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
BMI 
body mass index 
BUP 
buprenorphine 
CGI-S 
Clinical Global Impression–Severity 
COWS 
Clinical Opiate Withdrawal Scale 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSA 
Clinical Study Agreement  
CST 
Clinical Surveillance Team 
CYP 
cytochrome P450 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, 
Text Revision  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
17-item Hamilton Rating Scale for Depression 
HbA1c 
glycosylated hemoglobin 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
interactive response technology 


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Abbreviation or specialist term 
Explanation 
IUD 
intrauterine device 
MADRS 
Montgomery-Åsberg Depression Rating Scale  
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
OTC 
over-the-counter 
PCS 
potentially clinically significant  
PK 
pharmacokinetic(s) 
PLI 
prospective lead-in  
QTcB 
corrected QT interval – Bazett’s formula 
QTcF 
corrected QT interval – Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SL 
sublingual 
SIGH-A 
Structured Interview Guide for the Hamilton Rating Scale for 
Anxiety 
SIGH-D 
Structured Interview Guide for the Hamilton Rating Scale for 
Depression 
SIGMA 
Structured Interview Guide for the Montgomery-Åsberg 
Depression Rating Scale 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor  
TEAE 
treatment-emergent adverse event 
WHO-ATC 
World Health Organization Anatomical Therapeutic Chemical 


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5. 
INTRODUCTION 
Alkermes is developing ALKS 5461, a fixed-dose combination tablet consisting of 
buprenorphine (BUP) and samidorphan in a 1:1 (weight/weight) ratio for once-daily sublingual 
administration for use as an adjunctive therapy to antidepressants for the treatment of major 
depressive disorder (MDD). 
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, 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. These conditions and other side effects of the atypical antipsychotics commonly 
lead to discontinuation of treatment [Spielmans, 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. ALKS 5461 offers a unique mechanism of action for the 
treatment of MDD, modulation of the opioid system. From 1982 to the present, there have been 
at least 8 published studies of BUP in depressed patients [Spielmans, 2013]. 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 is a fixed-dose combination of BUP (a μ-opioid receptor partial agonist) and 
samidorphan (a μ-opioid receptor antagonist). Samidorphan is a new chemical entity optimized 
for high potency and high sublingual (SL) bioavailability to facilitate co-formulation with BUP 
for SL administration. ALKS 5461 was specifically designed to confer therapeutic benefits in the 
treatment of MDD through modulation of the opioid system. The inclusion of samidorphan in the 
ALKS 5461 combination is intended to counteract the subjective, rewarding and addictive 
properties of BUP and thus address the risk of abuse and dependence. 
Subjects treated with ALKS 5461 in Phase 1 and the Phase 2 studies showed substantial and 
clinically important improvements in depressive symptoms compared with those treated with 
placebo. Safety and tolerability data from these studies showed that ALKS 5461 was safe and 
generally well tolerated, and further no evidence has been found that ALKS 5461 is associated 
with motor disorders or metabolic dysregulation, the important toxicities associated with atypical 
antipsychotics. All together these findings indicate that ALKS 5461 has the potential to address 
an unmet medical need in this serious and in some cases life-threatening, condition. 
Full summaries of nonclinical and clinical results available to date on the pharmacokinetics (PK), 
safety, and efficacy of ALKS 5461, as well as of samidorphan and buprenorphine as individual 
and co-administered therapeutic agents are summarized in the Investigator’s Brochure (IB). 


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5.1. 
Study Rationale 
Subjects with MDD and an inadequate response to concomitant ADT who were treated with 
ALKS 5461 in both a Phase 1 study (ALK33BUP-201) and a Phase 2 study (ALK5461-202) 
showed substantial and clinically important improvements in depressive symptoms compared 
with those who received placebo. Safety and tolerability data from these studies showed that 
ALKS 5461 was safe and generally well tolerated, and further showed no evidence that ALKS 
5461 is associated with motor disorders or metabolic dysregulation, the important toxicities 
associated with atypical antipsychotics. 
In the clinical trials of ALKS 5461 to date, however, only data on the short-term safety and 
tolerability of ALKS 5461 have been collected. This study is designed to assess long-term safety 
and tolerability of ALKS 5461, as well as to explore treatment effect over time. 
5.2. 
Dose Selection 
Note: Throughout this protocol ALKS 5461 dose levels will be referred to as dose of 
BUP/samidorphan expressed as weight in mg (eg, a 2 mg BUP:2 mg samidorphan dose will be 
expressed as ALKS 5461 2/2). 
Doses for the current study were identified based on completed studies of ALKS 5461 including 
a drug-drug interaction study of BUP with samidorphan (ALK33-008), and a Phase 2 
(ALK5461-202) study in adults with MDD and inadequate response to concomitant ADT. 
Study ALK33-008, the drug-drug interaction study, showed that a 1:1 ratio of BUP and 
samidorphan in doses up to 8/8 provided maximal blockade of objective and subjective µ opioid 
agonist effects of BUP. Thus doses in the current study, which use a 1:1 ratio, are expected to 
mitigate BUP’s subjective, rewarding, and addictive effects. 
Study ALK5461-202 was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
sequential-parallel-comparison-design clinical trial which evaluated ALKS 5461 at doses of 2/2 
and 8/8. The ALKS 5461 2/2 dose was shown to be safe, well tolerated, and efficacious. After 
4 weeks of dosing, statistically significant improvements from baseline were found for the 
ALKS 5461 2/2 group versus the placebo group for the primary efficacy endpoint (change in the 
17-item Hamilton Rating Scale for Depression [HAM-D] total score), as well as several 
secondary endpoints, (change in Montgomery-Åsberg Depression Rating Scale [MADRS] total 
score and Clinical Global Impression - Severity [CGI-S] score). Additionally, the rate of 
treatment response and the rate of remission as defined by MADRS scores were significantly 
higher in the ALKS 5461 2/2 group versus the placebo group. 
The selection of the ALKS 5461 2/2 dose is further supported by its improved tolerability profile 
compared with results for the ALKS 5461 8/8 dose. 


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Alkermes, Inc. 
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6. 
OBJECTIVE 
The objective of this study is to assess the long-term safety and tolerability of ALKS 5461 for 
use as an adjunctive therapy to antidepressants for the treatment of MDD. 


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Alkermes, Inc. 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
7.1.1. 
All Subjects 
In order to qualify for participation in this study, all subjects must meet all of the following 
criteria: 
1. Be willing and able to provide informed consent 
2. Be willing and able to follow the study procedures as outlined in the protocol, including 
adherence with both approved antidepressant therapy (ADT) and study drug regimen 
3. Agree to use an approved method of contraception for the duration of the study unless 
surgically sterile or postmenopausal (See Section 8.4.1 for details) 
4. Have the potential to safely benefit from the administration of ALKS 5461, in the opinion 
of the investigator 
7.1.2. 
New Subjects 
In order to qualify for participation in this study, in addition to meeting the criteria for all 
subjects presented in Section 7.1.1, New Subjects must also meet all of the following criteria: 
5. Be between 18 and 70 years of age, inclusive 
6. Have a body mass index (BMI) 18.0 - 40.0 kg/m2 
7. Have not been randomized in a prior study of ALKS 5461 within 2 years 
8. Have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision (DSM-IV-TR) MDD diagnosis at screening, as assessed and confirmed by the 
Mini International Neuropsychiatric Interview (MINI) administered by qualified site 
staff. The diagnosis of MDD must be considered by the investigator as the primary 
source of current distress and functional impairment 
9. Have a current major depressive episode (MDE) lasting 8 weeks to 24 months 
10. Have been treated with an adequate dose of an approved ADT during the current MDE 
for at least 8 weeks, with the same, adequate dose over the last 4 weeks, which is 
expected to remain stable throughout the study 
11. Have an inadequate response to current ADT and up to 1 prior ADT during the 
current MDE. An inadequate response is defined as less than a 50% reduction in 
depressive symptom severity during a course of treatment at least 8 weeks in duration 
with an adequate dose of an approved ADT, as assessed on-site using the Massachusetts 
General Hospital Antidepressant Treatment Questionnaire (ATRQ) 
(NOTE: If a subject had an adequate response to an ADT in the past, but now has 
relapsed on the same ADT at the same or lower dose and is experiencing a new MDE, 
this would not represent an adequate trial of an ADT for this new MDE) 


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Alkermes, Inc. 
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12. Have a HAM-D total score of ≥14 at Visit 1 and ≥10 at Visit 2 
7.1.3. 
Continuing Subjects 
In order to qualify for participation in this study, in addition to meeting the criteria for all 
subjects presented in Section 7.1.1, Continuing Subjects must also meet the following criterion: 
13. Have completed the treatment period of ALK5461-205, ALK5461-206, ALK5461-207, 
or ALK5461-210 within 10 days of Visit 2 
7.1.4. 
Lead-in Subjects 
In order to qualify for participation in this study, in addition to meeting the criteria for all 
subjects presented in Section 7.1.1, Lead-in Subjects must also meet all of the following criteria: 
14. Have completed the prospective lead-in (PLI) of study ALK5461-205, ALK5461-206, or 
ALK5461-207 within the past 10 days; criteria for completion of the PLI includes 1) at 
least 8 weeks of ADT with at least 5 weeks at the minimally effective dose and 2) 
completion of Visits 1a through 1f 
15. Have demonstrated a treatment response during the PLI of the antecedent study, but 
failed to achieve remission from MDD, as determined in an interactive voice or web 
response system (IxRS) using masked criteria 
7.2. 
Subject Exclusion Criteria 
7.2.1. 
All Subjects 
No individuals may participate in this trial if they meet any of the following criteria: 
1. Have any finding that in the view of the investigator or medical monitor would compromise 
the safety of the subject or affect their ability to fulfill the protocol visit schedule or visit 
requirements 
2. Have a positive test for drugs of abuse at screening or Visit 2 (exception: a positive screen 
for benzodiazepine may not be exclusionary when such medication is medically indicated 
for insomnia) 
3. Are pregnant, planning to become pregnant, or breastfeeding during the study 
7.2.2. 
New Subjects 
New Subjects will be excluded from participation in this trial if they meet any of the following 
criteria: 
4. Have any current “primary” Axis I diagnosis other than MDD, where “primary” is defined by 
the investigator as the primary source of current distress and functional impairment 
5. Have any of the following psychiatric conditions per DSM-IV-TR criteria, as assessed by the 
MINI. Conditions not assessable by the MINI should be assessed by clinical judgment: 
a. Lifetime history of an Axis I diagnosis of dementia, schizophrenia or other psychotic 
disorder (including psychotic depression), or bipolar disorder (I or II) 


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Alkermes, Inc. 
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b. History within the past 12 months of an Axis I diagnosis of eating disorder, 
posttraumatic stress disorder, or acute stress disorder 
c. Clinically significant current Axis II diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal, or histrionic personality disorder 
d. Current diagnosis or clinical evidence of any cognitive disorder at screening 
6. Have experienced hallucinations, delusions, or any psychotic symptoms in the current MDE 
7. Have initiated psychotherapy within 6 weeks of screening 
8. Have received adjunctive therapy at an adequate dose and duration in combination with their 
approved ADT for the purpose of augmenting the effects of the ADT at any time during 
the current MDE (such adjunctive therapies include, but are not restricted to: atypical 
antipsychotics, monoamine oxidase inhibitors, lithium, tricyclic antidepressants, 
psychostimulants, bupropion, and BUP) 
9. Have been hospitalized for MDD within 3 months prior to screening 
10. Have used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid 
antagonists (eg, naloxone, naltrexone) within 14 days before screening, or have an 
anticipated need for opioid use at any point during the study (eg, planned surgery) 
11. Have used an extended-release formulation of an opioid antagonist within 2 months prior to 
screening 
12. Have initiated a hypnotic agent for insomnia (eg, benzodiazepines, zolpidem, trazodone) 
within 30 days prior to screening. Have used a hypnotic agent for insomnia >3 
times/week within 30 days of screening, or expect to use any of these agents at >3 
times/week at any time during the study. Have used a hypnotic agent for any indication 
other than insomnia within 30 days prior to screening (see Section 8.4.2.2 for further 
details) 
13. Have initiated or had dose adjustment to hormone replacement therapy (including 
testosterone) or an oral contraceptive within 30 days of screening 
14. Have used inducers or moderate to strong inhibitors of cytochrome P450 (CYP) 3A4 
(prescription medications, over-the-counter medications [OTC], or dietary supplements) 
within 30 days prior to screening (see Appendix A for examples of prohibited CYP3A4 
modulators) 
15. Have received electroconvulsive therapy treatment within the last 2 years, or received more 
than 1 course of electroconvulsive treatment during their lifetime 
16. Pose a current suicide risk, as evidenced by any of the following: 
a. it is the opinion of the investigator that 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 Columbia Suicide Severity Rating Scale 
(C-SSRS), if the most recent episode occurred within the past 12 months 
c. the subject has attempted suicide within the past 2 years 


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Alkermes, Inc. 
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17. Have a QT interval >450 msec for men and >470 msec for women, assessed in a relaxed 
state, as corrected by the Fridericia formula (QTcF) observed at Visit 1 or Visit 2 
18. Have an aspartate aminotransferase or alanine transaminase measurement of >2 times the 
upper limit of normal at Visit 1. 
19. Have 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 or human immunodeficiency virus (HIV) infection 
e. myasthenia gravis 
f. any contraindicated medical condition as per the approved labeling for buprenorphine 
20. Have current evidence of, or a history in the past 12 months of, alcohol or substance 
abuse or dependence (excluding nicotine) per DSM-IV-TR criteria as assessed by the 
MINI 
21. Have a positive breath alcohol test at screening 
22. Have a history of intolerance, allergy or hypersensitivity to BUP or opioid antagonists 
(eg, naltrexone, naloxone) 
23. Have 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 trial 
24. Have participated in any of the following: 
a. clinical studies of more than 2 distinct investigational products with a central nervous 
system indication in the past 4 years 
b. any clinical study of an investigational product given as an adjunctive treatment for 
MDD at any time during the current MDE 
c. any clinical study of an investigational product and/or have received an 
investigational drug or device within 30 days of screening 
25. Are an employee of the investigator or study center, or immediate family* of such 
employees or the investigator 
26. Are an employee or an immediate family member* of an employee (permanent, 
temporary contract worker, or designee responsible for the conduct of the study) of 
Alkermes or the contract research organization (CRO) executing this study or any prior 
ALKS 5461 study 
* Immediate family is defined as a spouse, parent, child, or sibling, whether biological or 
legally adopted 


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Alkermes, Inc. 
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7.3. 
Subject Withdrawal 
Any subject who signs the informed consent form for this study but does not qualify for ALKS 
5461 dosing will be considered a screen failure. 
A subject may be discontinued from the study at any time if the subject, investigator, or sponsor 
determines that it is not in the best interest of the subject to continue participation. 
Examples of reasons for subject discontinuation may include, but are not limited to, the 
following: 
• Failure to meet eligibility criteria 
• Adverse Event 
• Lack of Efficacy 
• Physician’s decision 
• Pregnancy (see Section 8.4.1) 
• Protocol violation 
• Non-compliance with study drug 
• Withdrawal of consent 
• Lost to follow-up 
• Study terminated by Sponsor 
• Other 
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) and/or IxRS. The reason for discontinuation will be documented. If a 
subject is lost to follow-up, a reasonable attempt to contact the subject must be made and 
documented. 
If a subject withdraws from the study for any reason
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 to do so. Subjects will be asked to return to the clinic for an early termination visit and 
follow-up visits. The early termination visit should be scheduled within 24 hours of the subject’s 
last dose and will mirror the assessments scheduled to be collected at Visit 14. Following the 
early termination visit, subjects will be asked to participate in the safety follow-up period as 
detailed in 
, any ongoing adverse events (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 period, 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. 
Table 3. If the subject fails or refuses to return to the study center for clinic visits, an 
attempt must be made to contact the subject by telephone in order to assess as many safety and 


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Alkermes, Inc. 
(Amendment #3)  
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efficacy parameters as possible. All data collected over the telephone must be documented and 
kept in the subject’s record. 
7.4. 
Replacement of Subjects 
Subjects who withdraw after receiving the first dose of study drug in this study will not be 
replaced. 


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Alkermes, Inc. 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a multicenter, multinational, study to evaluate the long-term safety and tolerability, and to 
explore treatment effect of 52 weeks of ALKS 5461 administration for use as an adjunctive 
therapy to antidepressants for the treatment of MDD in subjects who have had 1 to 2 inadequate 
responses to an approved ADT. All subjects in the study will have been treated with an adequate 
dose of an approved ADT for at least 8 weeks, at a stable dose over the last 4 weeks prior to 
study entry. An adequate dose is defined as the minimum effective dose or higher according to 
the applicable current approved label, inclusive of up to 1 week for titration into the adequate 
dose range. 
Subjects will enter into the study in one of three ways, based on their previous experience with 
ALKS 5461: 
1. New Subjects:
2. 
 those who have not randomized in a prior study of ALKS 5461 within 
2 years 
Continuing Subjects:
3. 
 those who have completed the treatment period of study 
ALK5461-205, ALK5461-206, ALK5461-207, or ALK5461-210 within the past 10 days 
Lead-in Subjects:
All New Subjects will be initially evaluated for eligibility at screening (Visit 1), to occur up to 
28 days prior to Visit 2. 
 those who participated in study ALK5461-205, ALK5461-206, or 
ALK5461-207 and have completed the PLI within the past 10 days, and met the criteria 
for response to ADT during the PLI period of that antecedent study, but did not meet the 
criteria for remission. Criteria for completion of the PLI includes 1) at least 8 weeks of 
ADT with at least 5 weeks at the minimally effective dose and 2) completion of Visits 1a 
through 1f. 
For Lead-in and Continuing Subjects, Visit 2 will be the first visit of this study and there will not 
be a separate screening visit. 
While completion of Visit 2 of the antecedent study for Lead-In Subjects is not required, if a 
subject has completed a Visit 2 of the antecedent study, completed assessments taken at Visit 2 
of the antecedent study do not need to be repeated at Visit 2 of this study unless more than 
10 days elapses between these visits. 
For Continuing Subjects, Visit 2 of this study must occur within 10 days of the subject’s end of 
treatment visit in the prior study. Completed assessments taken at the end of treatment visit of 
the antecedent study do not need to be repeated at Visit 2 of this study. At Visit 2, all eligible, 
consenting subjects will begin the treatment period. Subjects entering the study already receiving 
ALKS 5461 will not require titration; all other subjects will require a 1-week ALKS 5461 
titration period. Depending on the antecedent study, the titration may be blinded. Regardless of 
method of entry, all subjects will have been taking an SSRI, SNRI, or bupropion for at least 
8 weeks at the beginning of the treatment period (Visit 2), and at an adequate dose for at least 


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Alkermes, Inc. 
(Amendment #3)  
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Page 24 
5 weeks. Table 1 below shows the Week 1 titration and blinding schemes for the subjects 
entering by each path. 
Table 1: 
Week 1 Titration and Blinding by Entry Dose and Antecedent Study 
Dose Upon 
Study Entry 
Antecedent Study 
Week 1 
Blinding 
Week 1 Dosing Scheme 
No study drug 
being given 
• 
New Subjects 
• 
Lead-in Subjects 
• 
ALK5461-205 (after 1-week 
discontinuation period) 
Unblinded 
1-Week Titration 
• 
Days 1–3: ALKS 5461 
0.5/0.5 
• 
Days 4–7: ALKS 5461 1/1 
• 
Days 8–364: ALKS 5461 
2/2 
Placebo 
• 
ALK5461-206 
• 
ALK5461-207  
Blinded 
ALKS 5461 1/1  
• 
ALK5461-207 
Blinded 
No Titration 
• 
Days 1–364: ALKS 5461 
2/2 
ALKS 5461 2/2 
• 
ALK5461-206 
• 
ALK5461-207 
Blinded 
• 
ALK5461-210 
Unblinded 
Dosing is described in detail in Section 9.1.2. From Week 2 to 52, all participating subjects will 
take ALKS 5461 2/2 and an approved ADT, with allowable dose adjustments for tolerability as 
described in Section 9.5. 
Study staff will administer the first dose of ALKS 5461 at Visit 2 (Day 1). From that point on 
during the treatment period, according to the schedule of visits as shown in Table 2, the staff will 
dispense ALKS 5461 for subjects’ self-administration. Subjects will be advised to take the study 
drug at bedtime. 
During the 52-week treatment period, subjects will return to the clinic for periodic scheduled 
visits (Visits 2-14) at which safety, tolerability, and treatment effect over time will be assessed. 
A 4-week safety follow-up period will occur following the ALKS 5461 treatment period. During 
the 4-week follow-up period, there are a total of 4 clinic visits (Visits 15-18), as well as 7 safety 
assessments by phone. The clinic visits will occur 1 day, 1 week, 2 weeks, and 4 weeks 
following the end of treatment visit (Visit 14). The phone assessments will occur daily for the 
first week between visits, and weekly during the second and third week. See Table 3 for the 
schedule of assessments during the follow-up period. 
If any AEs are reported that relate to opioid withdrawal (eg nausea, vomiting, restlessness, 
hyperhidrosis) during a phone assessment in the follow-up period, the subject will be asked to 
come into the clinic as soon as possible to receive a Clinical Opiate Withdrawal Scale (COWS) 
assessment. 
After completing the study, ADT may be continued for up to 3 months, as appropriate, based on 
the investigator’s clinical judgment. 


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8.2. 
Schedule of Visits and Assessments 
The schedule of visits and assessments is shown in Table 2 for screening through the treatment 
period, and in Table 3 for the safety follow-up period. 
For a missed visit, the site should attempt to contact the subject to reschedule. 
Subjects who discontinue from the study prematurely will be encouraged to return for an early 
termination (ET) visit and to participate in a subsequent follow-up period. The Visit 14 
assessments will serve as early termination assessments for any subject who withdraws prior to 
completion. The safety follow-up period for subjects who discontinue early should mirror the 
visits displayed in Table 3. 


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Table 2: 
Schedule of Visits and Assessments, Screening and Treatment Period 
Evaluation 
Screening
a 
ALKS 5461 Treatment Period 
Base-
line 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
14 
Week 
20 
Week 
26 
Week 
32 
Week 
38 
Week 
44 
Week 
52 
Study Day: 
-28 to -1 
1 
8 
(±1) 
15 
(±1) 
29 
(±3) 
43 
(±3) 
57 
(±3) 
99 
(±3) 
141 
(±3) 
183 
(±3) 
225 
(±3) 
267 
(±3) 
309 
(±3) 
ET/365b 
(±3) 
Visit Number: 
1 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Informed Consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
Qualification/ Diagnostic Assessments 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ Psychiatric History 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
Serology Testingf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol Testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAM-D 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/ Vital Signs h 
Qualification/ Safety Assessments 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Xe 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Drug Screeningi 
X 
Xe 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
Pregnancy Testingj 
X 
Xe 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Symptom-Directed Physical 
Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 


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Alkermes, Inc. 
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Table 2: 
Schedule of Visits and Assessments, Screening and Treatment Period (Continued) 
Evaluation 
Screeninga 
ALKS 5461 Treatment Period 
Base-
line 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
14 
Week 
20 
Week 
26 
Week 
32 
Week 
38 
Week 
44 
Week 
52 
Study Day: 
-28 to -1 
1 
8 
(±1) 
15 
(±1) 
29 
(±3) 
43 
(±3) 
57 
(±3) 
99 
(±3) 
141 
(±3) 
183 
(±3) 
225 
(±3) 
267 
(±3) 
309 
(±3) 
ET/365b 
(±3) 
Visit Number: 
1 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Blood and Urine Samples for 
Safety Labs 
X 
Xe 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
C-SSRSk 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWSl 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Illicit Substances Review n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-A 
Exploratory Efficacy Assessments 
 
Xe 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
CGI-S 
 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRSo 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drugp 
Additional Study Procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Adherence Reviewq 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADT Adherence Review r 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample – PK s 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Emergency Treatment Card t 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADT=antidepressant therapy; ATRQ=Massachusetts General Hospital Antidepressant Treatment Questionnaire; CGI-S=Clinical Global Improvement – 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; MADRS=Montgomery-Åsberg Depression Rating 
Scale; MINI=Mini International Neuropsychiatric Interview; PK=pharmacokinetic. 


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a Only New Subjects will participate in the screening visit. Screening may be repeated in some cases for Potential New Subjects, but only after approval by the 
medical monitor 
b Visit 14/ET should occur within 24 hours of the subject's last dose of ALKS 5461 
c For Continuing Subjects and Lead-in Subjects, identical assessments taken at the subject’s Visit 2 of the antecedent study for Lead in Subjects and last 
treatment visit of the antecedent study for continuing subjects do not need to be repeated at Visit 2 unless ,more than 10 days elapses between these visits. If 
more than 10 days elapses between visits, all assessments must be performed at Visit 2 (ie data cannot be carried forward). 
d Eligible, consenting New Subjects will give written consent at the screening visit. Eligible, consenting Continuing Subjects and Lead-in Subjects will give 
written consent prior to participating in any study-specific procedures on Visit 2 
e To be conducted predose on Visit 2 
f For hepatitis B surface antigen, anti-hepatitis C antibodies, and human immunodeficiency virus 
g Breath alcohol test may be repeated for any participating subject at any point during the study based on investigator's judgment 
h Vital sign measurements include oral temperature, respiratory rate, blood pressure, and heart rate. Blood pressure, respiratory rate, and heart rate will be 
measured after the subject has been in a supine position for at least 5 minutes 
i Centralized drug screen testing at screening, local drug screen testing (via dipstick) for all other time points. The urine drug screen at Visit 1 may be repeated 
based on investigator judgment. The test can also be repeated at any time during the study, should the investigator feel it is warranted 
j Serum pregnancy testing at screening; urine pregnancy testing at all other visits 
k At screening the “Baseline” version of the C-SSRS will be administered and at all other visits the “Since Last Visit” version will be administered 
l COWS to be administered by a medical professional 
m All medications (prescription and non-prescription, including vitamins and herbal supplements) including ADT taken within 30 days will be recorded at 
screening. Any changes will be recorded at subsequent visits 
n Subject will be queried at screening on illicit substances used within 30 days, with updates made at each subsequent visit 
Note: additional dispensation visits may be required based on country specific regulatory requirements. No other activities or assessments are done on these days. 
o The MADRS should be administered prior to the HAM-D, CGI-S and HAM-A on visits when multiple assessments are scheduled 
p First dose of ALKS 5461 (at Visit 2) to be administered on-site; ALKS 5461 to be dispensed at each indicated visit for subjects to self-administer starting on 
Day 2. Self-administration should be recommended to occur at bedtime 
q Via pill count and subject query 
r Via subject query 
s One PK blood sample will be collected during each indicated visit from consenting subjects enrolled in the United States only. When PK and safety blood 
samples are scheduled to be collected on the same day, efforts should be made to collect both samples during the same draw. 
t Dispense card on Visit 2; confirm possession of card at each subsequent visit and re-dispense if necessary  


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Table 3: 
Schedule of Assessments, Safety Follow-up Period 
Evaluation 
Safety Follow-up Period 
Days post end of 
treatment: 
1 (+1) 
2 (+1) 
3 (+1) 
4 (+1) 
5 (+1) 
6 (+1) 
7 (+1) 
10 (+2) 
14 (±2) 
21 (+2) 
28 (±2) 
Study Day: 
366 
367 
368 
369 
370 
371 
372 
375 
(+2) 
379 
(±2) 
386 
(+2) 
393 
(±2) 
Visita 
15 
Phone 
Phone 
Phone 
Phone 
Phone 
16 
Phone 
17 
Phone 
18 
Adverse Event Monitoringb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Med Reviewc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Illicit Substances Reviewc 
X 
 
 
 
 
 
X 
 
X 
 
X 
Emergency Treatment Cardd 
X 
 
 
 
 
 
X 
 
X 
 
X 
ADT Adherence Reviewe 
X 
 
 
 
 
 
X 
 
X 
 
X 
Brief Symptom-Directed 
Physical Exam 
X 
 
 
 
 
 
X 
 
X 
 
X 
Weight/ Vital Signsf 
X 
 
 
 
 
 
X 
 
X 
 
X 
C-SSRSg 
X 
 
 
 
 
 
X 
 
X 
 
X 
Drug Screenh 
X 
 
 
 
 
 
X 
 
X 
 
X 
COWSi 
X 
 
 
 
 
 
X 
 
X 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
X 
Blood and Urine Samples 
for Safety Labs 
 
 
 
 
 
 
 
 
 
 
X 
CGI-S 
 
 
 
 
 
 
X 
 
X 
 
X 
ADT=antidepressant therapy; CGI-S=Clinical Global Impression Scale – Severity; COWS=clinical opiate withdrawal scale; C-SSRS=Columbia Suicide Severity 
Rating Scale; ECG=electrocardiogram. 
a Visits labeled “Phone” should occur by telephone whenever possible. In regions where local privacy restrictions do not permit contact by telephone, alternative 
forms of contact are acceptable 


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b If any AEs are reported that relate to opioid withdrawal (eg, nausea, vomiting, restlessness, hyperhidrosis) during a phone assessment, the subject will be asked 
to come into the clinic as soon as possible to receive a COWS assessment 
c Any changes since last visit to be recorded 
d Possession of card to be confirmed at each clinic visit until Visit 18 when card should be collected 
e Via subject query 
f Vital sign measurements at all visits to include oral temperature, respiratory rate, blood pressure and heart rate. Respiratory rate, blood pressure and heart rate 
to be measured in the supine position 
g “Since Last Visit” version to be administered 
h Local drug screen via dipstick 
i COWS to be administered by a medical professional 


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8.3. 
Study Procedures Descriptions 
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. 
Confirmation of Eligibility 
For New Subjects, eligibility for participation in the study will be confirmed at the screening 
visit and reconfirmed at Visit 2 predose, on the first day of dosing. 
Continuing Subjects and Lead-in Subjects will not attend a screening visit. Their eligibility will 
be confirmed at Visit 2. Identical assessments collected at Visit 2 for Lead-In Subjects (if 
performed) and the last treatment visit of the antecedent study for Continuing Subject their last 
visit of the antecedent ALKS 5461 study in which they participated will not be repeated at Visit 
2 unless more than 10 days elapses between visits. 
8.3.3. 
Demographics 
For New Subjects only, demographic data will be reviewed and documented at screening. 
For Continuing Subjects and Lead-in Subjects, demographic information will be carried over 
from information recorded in the antecedent ALKS 5461 study in which they participated. 
8.3.4. 
Medical and Psychiatric History 
For New Subjects, medical and psychiatric history will be reviewed and documented at 
screening. Information collected for psychiatric history should include duration of current MDE, 
number of lifetime MDEs, number of prior ADT failures and number of ADT failures within the 
current MDE. For all participating subjects, this information will be carried over from 
information recorded in the antecedent ALKS 5461 study in which they participated. 
8.3.5. 
Physical Examination 
For New Subjects, a full physical examination will be performed at screening. All participating 
subjects will have brief, symptom-directed physical examinations at all other time points 
specified in Table 2 and Table 3. 
8.3.6. 
Height 
For New Subjects only, height will be measured at the screening visit. 
8.3.7. 
Weight 
For New Subjects, weight will be measured at the screening visit. All participating subjects will 
be weighed at all other time points shown in Table 2 and Table 3. 


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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. 
8.3.8. 
Vital Signs 
Vital signs will be measured at each visit and include oral body temperature, respiratory rate, 
blood pressure, and heart rate. Blood pressure, respiratory rate and heart rate will be measured 
after the subject has been 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, heart rate will be measured in the brachial 
artery for at least 30 seconds. 
As specified in Table 2, on the first day of dosing, vital signs are to be measured predose. 
8.3.9. 
12-Lead Electrocardiogram 
A 12-lead ECG will be conducted at the time points specified in Table 2 and Table 3. All 
scheduled ECGs must be performed after the subject has rested quietly for at least 5 minutes in 
the supine position. 
ECGs 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 will be automatically calculated by the 
ECG machine. 
ECGs will be additionally evaluated by a central reader. 
8.3.10. 
Concomitant Medication Review 
At screening all New Subjects will be asked about the medications they have taken in the last 
30 days. For a potential subject to qualify for the study, those exclusions outlined in 
Section 8.4.2.2 must be ruled out. At each subsequent study visit, review of concomitant 
medications will be repeated for all participating subjects. Concomitant medications to be 
reviewed at each study visit include: 
• prescription medications (including ADT) 
• nonprescription/ over-the-counter (OTC) medications 
• vitamins and supplements 
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. 


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8.3.11. 
Illicit Substances Review 
For New Subjects, all illicit substances consumed/used within 30 days will be reviewed and 
recorded at the screening visit, including name, amount, frequency and start and stop dates. 
Changes at each subsequent study visit will be recorded for all participating subjects. 
8.3.12. 
Emergency Treatment Cards 
An emergency treatment card will be distributed to each subject prior to first dosing. The card 
will indicate that the subject will be receiving BUP, a partial opioid receptor agonist, and 
samidorphan, an opioid receptor antagonist. The card will include the investigator’s contact 
information, a suggested pain management plan, and information regarding opioid blockade and 
withdrawal. Subjects will be instructed to keep the emergency treatment card with them at all 
times. See Table 2 and Table 3 for details on card distribution, confirmation of possession, and 
collection. 
8.3.13. 
Pharmacokinetic Assessments 
Plasma samples for PK will be collected according to the schedule of events (Table 2), from 
consenting subjects enrolled in the US only. 
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 samidorphan 
concentrations, as well as relevant metabolites. Concentrations of background ADTs that 
subjects report taking during the study may be quantified, as appropriate. 
8.3.14. 
Adverse Event Monitoring 
The monitoring of adverse events will begin once informed consent is obtained and will be 
performed at each visit (see Section 13). Adverse events will be monitored continuously until the 
completion of the final study visit. 
Adverse events and serious adverse events (SAEs) are defined in Section 13.1 and Section 13.2, 
respectively. 
Section 13.4 provides guidance on the monitoring and reporting requirements for adverse events. 
Section 13.5 provides guidance on the reporting requirements for SAEs. 
8.3.15. 
Laboratory Assessments 
8.3.15.1. Serology Testing 
New Subjects will provide a blood sample for a serology panel testing for hepatitis B surface 
antigen, anti-hepatitis C antibodies, and HIV at screening. Results must be negative for a subject 
to be eligible for the study. 


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8.3.15.2. Breath Alcohol Test 
New subjects will undergo an alcohol test at screening via breathalyzer. A negative breath 
alcohol will be required for a New Subject to enter into the study. However, the test at Visit 1 
may be repeated based on investigator judgment. 
The breath alcohol test may be repeated for any participating subject at any time during the 
study, should the investigator feel it is warranted. 
8.3.15.3. Urine Drug Screening 
New Subjects will undergo urine drug screening for drugs of abuse at Visit 1 and laboratory 
analysis will be centralized. At all other time points specified in Table 2 and Table 3, all 
participating study subjects will have urine drug screening via dipstick; results will be analyzed 
by the local laboratory. 
Drug screening will be performed for amphetamines, barbiturates, benzodiazepines, cocaine 
(metabolite), tetrahydrocannabinol, opioids, and phencyclidine. The opioid panel to be 
performed at screening for New Subjects (analyzed centrally) will include BUP, codeine, 
hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Drug 
screens administered at all other visits as specified in Table 2 and Table 3 (analyzed locally) will 
include all aforementioned opioids. 
Negative urine drug screening at Visit 1 and Visit 2 will be required for a subject to enter in the 
study. However, an exception may be made for a benzodiazepine, when such medication is 
medically indicated for insomnia. 
The urine drug test at screening may be repeated based on investigator judgment. The test can 
also be repeated 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. 
8.3.15.4. Pregnancy Testing 
A serum pregnancy test will be administered to all female New Subjects at screening. Results 
must be negative for a female subject to be eligible for the study. 
A urine pregnancy test will be administered to all participating female subjects predose, on the 
first day of dosing. Results must be negative prior to administration of study drug. 
At all other time point(s) specified in Table 2 and 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. Additional follow-up may be required as detailed in Section 8.4.1. 
8.3.15.5. Hematology, Biochemistry, and Urinalysis 
Blood and urine samples for laboratory safety assessments will be collected at the time points 
specified in Table 2 and Table 3. Specific hematology, biochemistry, and urinalysis assessments 
are listed in Table 4. 


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Table 4: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
• 
Glycosylated hemoglobin 
(HbA1c )a 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelets 
• 
Red blood cell count 
• 
Total and differential 
(absolute) white blood cell 
count 
• 
Alanine transferase (ALT) 
• 
Albumin 
• 
Alkaline phosphatase 
(ALK-P) 
• 
Aspartate transferase (AST) 
• 
Bicarbonate 
• 
Blood urea nitrogen (BUN) 
• 
Calcium 
• 
Chlorine 
• 
Creatine phosphokinase 
(CPK) 
• 
Creatinine 
• 
Gamma-glutamyl transferase 
(GGT) 
• 
High-density lipoprotein 
(HDL) 
• 
Lactic dehydrogenase (LDH) 
• 
Low-density lipoprotein 
(LDL) 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Prolactinb 
• 
Random Glucose 
• 
Sodium 
• 
Thyroid-stimulating hormone 
c 
• 
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 
a HbA1c to be analyzed at Visits 2, 8, 10, 12, and 14/ET 
b Prolactin to be analyzed at Visits 1, 2, 10, and 14/ET 
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. 


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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. 
Results of clinical laboratory testing will appear on electronically produced laboratory reports 
submitted directly to the site from the central laboratory, if applicable. 
8.3.16. 
Structured Interviews and Questionnaires 
Brief descriptions of each of the structured interviews and questionnaires to be administered are 
provided below. Table 2 and Table 3 provide details on the time points during which each 
measure should be administered. All structured interviews and questionnaires will be 
administered by trained and qualified study personnel. 
At screening, the medical and psychiatric history and MINI diagnostic interview must be 
conducted prior to the HAM-D and MADRS. 
The MADRS should be administered prior to the HAM-D, CGI-S and HAM-A on visits when 
multiple assessments are scheduled. 
8.3.16.1. Assessments for Study Eligibility 
8.3.16.1.1. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
The ATRQ is a clinician-administered scale used to document history of antidepressant treatment 
and to determine treatment resistance in MDD. A sample of the ATRQ can be found in 
Appendix C. 
8.3.16.1.2. Mini International Neuropsychiatric Interview 
The MINI is a short, clinician-administered, structured diagnostic interview, with an 
administration time of approximately 15 minutes. The MINI has been validated against the much 
longer Structured Clinical Interview for DSM diagnoses. A sample of the MINI can be found in 
Appendix D. 
8.3.16.1.3. 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. A sample of the SIGH-D can be found in Appendix E. 
8.3.16.1.4. Clinical Surveillance Team Eligibility Review for New Subjects 
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 
enrolling new subjects will complete the CST Pre-Baseline Packet at screening and forward the 
data to the CST so that review may be completed as soon as possible after screening and before 
the next study visit. The investigator may use the results of this tool at his or her discretion. 
PPD


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8.3.16.2. Safety Assessments 
8.3.16.2.1. Columbia Suicide Severity Rating Scale 
The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior 
[Posner, 2011]. The “Baseline” version of the instrument will be administered to New Subjects at 
the screening visit. The “Since Last Visit” version will be administered to all participating 
subjects at all other visits. A sample of the C-SSRS can be found in Appendix F. 
8.3.16.2.2. Clinical Opiate Withdrawal Scale 
The COWS is an 11-item questionnaire designed to measure an individual’s level of opiate 
withdrawal [Wesson and Ling 2003]. The COWS should be administered by a medical 
professional. A sample of the COWS can be found in Appendix G. 
8.3.16.3. Efficacy Assessments 
8.3.16.3.1. 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. A sample of the SIGMA can be 
found in Appendix H. 
8.3.16.3.2. 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. A sample of the SIGH-A can be found in Appendix I. 
8.3.16.3.3. 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. A sample of the CGI-S can be found in Appendix J. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study unless they are surgically sterile or post-menopausal (see below). At a 
minimum subjects must agree to use one of the following. Additional restrictions, if required, 
will be clarified in the locally approved informed consent form (ICF). 
• Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
• Intrauterine device (IUD) 


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• Hormonal contraceptives (eg, birth control pills, a vaginal ring, contraceptive patch, 
contraceptive implant; must be initiated and at a stable dose for at least 30 days prior 
to screening; see Section 8.4.2.2). 
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. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female subject. 
Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to screening in women who are 45 years of age or older. 
If any female subject becomes or is found to be pregnant while participating in the study, she 
will be discontinued immediately. The investigator must fill out a Pregnancy Report Form and 
submit the information to the sponsor within 24 hours of awareness of the pregnancy, 
irrespective of whether an adverse event has occurred. The end-of-treatment and safety follow-
up visits will be scheduled. 
The investigator will follow the pregnancy until completion or until pregnancy termination and 
notify the outcome to the sponsor. If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE, the investigator should follow the procedure of reporting 
SAEs (See Section 13.2). 
8.4.2. 
Concomitant and Prohibited Medications 
8.4.2.1. 
Concomitant Medications 
All medications taken by a given subject within 30 days of screening through follow-up will be 
recorded as detailed in Section 8.3.10. The concomitant medication review on each visit will 
include all prescription medications including ADT, OTC medications, and vitamins and dietary 
supplements. Concomitant medications will be reviewed at all clinic visits and all phone 
assessments. 
Subjects will be permitted to continue taking concomitant medications during the study provided 
that these medications are not prohibited (see Sections 7.2 and 8.4.2.2). 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. 
Dose adjustment of approved ADT during the treatment period is permitted for optimal 
therapeutic effect within the recommended dose range, however ADT dose adjustment should 
not be made within the same week as ALKS 5461 dose adjustment. Further, subjects are not 
permitted to change ADTs during the course of the study period. 


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See Section 9.5 for complete details of ALKS 5461 dose adjustments. 
8.4.2.2. 
Prohibited Medications 
The use of any kind of adjunctive therapy, other than ALKS 5461, at an adequate dose and 
duration in combination with an ADT at any time during the current MDE for the purpose of 
augmenting the effects of the ADT is prohibited. Adjunctive therapy other than ALKS 5461 is 
prohibited from screening through the final follow-up visit. Prohibited adjunctive therapies 
include, but are not restricted to the following: 
• atypical antipsychotics (eg, aripiprazole, quetiapine, olanzapine) 
• monoamine oxidase inhibitors (eg, phenelzine, tranylcypromine, selegiline) 
• lithium 
• tricyclic antidepressants (eg, amitriptyline, nortriptyline, desipramine) 
• psychostimulants (eg, methylphenidate, dextroamphetamine/ amphetamine) 
• bupropion 
• BUP 
The use of opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists 
(eg, naloxone, naltrexone) within 14 days before screening through the final follow-up visit is 
prohibited. Use of extended-release opioid antagonists within 2 months prior to screening 
through the final follow-up visit is prohibited. 
The initiation or dose adjustment of hormone replacement therapy (including testosterone) or an 
oral contraceptive within 30 days of screening is prohibited. Such therapy is permissible if a 
stable dose of hormone replacement therapy or oral contraceptive is taken for at least 30 days 
prior to screening and the same stable dose is expected to be taken throughout the study. 
Hypnotic agents for insomnia (eg, benzodiazepines, zolpidem, trazodone) are not permitted if 
started within 30 days of screening or if started at any time during the study. Such agents are 
permitted if they have been used stably for at least 30 days before screening not more than 
3 times/week, and are expected to be used stably at ≤ 3 times/week throughout the study. For an 
insomnia indication, benzodiazepine is permissible if equivalent to ≤2 mg/day of lorazepam, 
trazodone up to 100 mg/day, zolpidem or zaleplon up to 10 mg/day, or Ambien CR up to 12.5 
mg/day. Hypnotic agents are not permitted within 30 days prior to screening through the final 
follow-up visit if prescribed for an indication other than insomnia. 
Use of inducers or moderate to strong inhibitors of CYP3A4 (prescription medications, OTC 
medications, or dietary supplements) within 30 days before screening through the final follow-up 
visit is prohibited. See Appendix A for a list of prohibited inducers and moderate to strong 
inhibitors of CYP3A4. 
8.4.3. 
Pain Management 
Because the ALKS 5461 co-formulation contains samidorphan, a μ-opioid receptor antagonist, 
patients 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. 


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In the event of an emergency, pain management of the subject should include the following: 
• Regional analgesia or use of non-opioid analgesics 
• If opiate anesthesia or analgesia is required, the subject should be continuously 
monitored in an anesthesia care setting, by persons not involved in the conduct of the 
surgical or diagnostic procedure. The opioid therapy must be provided by individuals 
specifically trained in the use of anesthetic drugs and the management of the 
respiratory effects of potent opioids, specifically the establishment and the 
maintenance of a patent airway and assisted ventilation 
• Close monitoring by appropriately trained personnel in a setting equipped and staffed 
for cardiopulmonary resuscitation 
For subjects requiring emergency opioid analgesics prior to dosing, the study drug should not be 
administered. If opioid analgesics are required after the study drug has been dosed, it may take 
several days for opiate sensitivity to be restored, since samidorphan is an opioid antagonist and 
could interfere with opioid-mediated pain management. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
9.1.1. 
Description of ALKS 5461 
The ALKS 5461 drug product will be formulated as tablets for sublingual (SL) administration 
and will contain a ratio of 1:1 BUP: samidorphan as free base equivalents by weight. BUP is a 
Schedule III narcotic and samidorphan is a Schedule II controlled substance. Thus, ALKS 5461 
should be treated as a Schedule II controlled substance in 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 study drug formulation contains common pharmaceutical excipients that are listed in the US 
as “GRAS” (Generally Recognized As Safe [GRAS]) and accepted for use as food additives in 
Europe: lactose monohydrate, microcrystalline cellulose, crospovidone, sucralose, citric acid, 
sodium citrate, and magnesium stearate. 
9.1.2. 
Study Drug Dose and Dosing Regimen 
Dosing begins at Visit 2, with a 1-week titration for subjects not already taking ALKS 5461 upon 
study entry. The 1-week titration will be blinded for Continuing Subjects entering from 
ALK5461-206 and ALK5461-207. See Section 8.1 and Table 1 for details on Week 1 titration 
and blinding. 
One tablet will be taken sublingually on each dosing day. The tablet should be placed under the 
tongue and kept under the tongue until completely dissolved. The tablet must not be 
swallowed. Eating and drinking should be avoided for 15 minutes after dosing. At Visit 2, study 
site personnel will administer the tablet and visually confirm that the tablet has dissolved 
completely. From Day 2 on, subjects will self-administer the daily SL dose; it is recommended 
that subjects take ALKS 5461 at bedtime. 
9.2. 
Treatment Adherence 
According to the schedule in Table 2 and Table 3, at each specified dispensing visit, subjects will 
receive a supply of ALKS 5461 to last until the following visit. Subjects will be instructed to 
bring the bottle or blister pack (as applicable, see Section 10.1) with them to each subsequent 
visit. Subjects will also be instructed to bring in containers of their ADT. Drug adherence will be 
reviewed with subjects at each visit. 
9.3. 
Method of Assigning Subjects to Treatment 
Three different groups of subjects will be enrolled in this study, some of whom will require a 
1-week ALKS 5461 titration, as described in Section 8.1. From Day 8 on, all participating 
subjects will receive ALKS 5461 2/2. 


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9.4. 
Blinding 
Subjects who are not already taking ALKS 5461 on study entry will begin treatment with a 
1-week titration period. As explained in Section 8.1 and Table 1, to maintain the blinded dosing 
scheme in antecedent studies ALK5461-206 and ALK5461-207, subjects entering from those 
studies will be blinded to whether or not they will participate in the 1-week titration. Study 
subjects, investigators, site staff and the sponsor will remain blinded to the treatment assignment 
in all applicable antecedent studies. 
Beginning on Day 8, all participating subjects will receive open-label ALKS 5461 2/2, as 
tolerability allows. 
9.5. 
Study Drug Dose Adjustment and Stopping Rules 
Starting on Day 8 (Visit 3), attempts should be made to achieve and maintain the target dose of 
ALKS 5461 2/2 over the course of treatment, if tolerated. However, at any time during the study, 
flexible down-titration to ALKS 5461 1/1 and then to ALKS 5461 0.5/0.5 is permitted at the 
investigator’s discretion, if tolerability issues persist. Once a subject has stabilized after down-
titration, attempts should again be made to achieve and maintain the target dose of 
ALKS 5461 2/2 over the course of treatment, dependent on the individual subject’s experience 
with study drug tolerability. 
Dose adjustment of approved ADT during the treatment period is permitted for optimal 
therapeutic effect within the recommended approved dose range, however ADT dose adjustment 
should not be made within the same week as ALKS 5461 dose adjustment. Furthermore, subjects 
are not permitted to change ADTs during the course of the study period. 
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. 
Packaging and Labeling 
A subset of subjects in North America may receive ALKS 5461 in child-resistant bottles. 
Otherwise, 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. 
Dosing for Week 1 will be in accordance with Table 1. During this period subjects will receive 
either child-resistant bottles or child-resistant blister packs containing 9 tablets to cover the week 
from Visit 2 to Visit 3 (+2 day visit window). During Week 1, titration packaging will be either 
blinded or unblinded dependent on the antecedent study, as outlined in Table 1. 
All subjects will receive open-label child-resistant bottles or open-label child-resistant blister 
packs of ALKS 5461 on Visit 3 through Visit 13, each containing 9 tablets. The number of 
bottles or blister packs distributed to the subject at each visit will be dependent upon the number 
of days between the specific scheduled visits. 
Subjects should follow the dosing instructions as printed on the packaging. 
10.2. 
Storage 
ALKS 5461 contains BUP and samidorphan. Under the US Controlled Substances Act, 
buprenorphine is a Schedule III narcotic. Samidorphan is considered a Schedule II controlled 
substance, derived from opium alkaloids. Therefore, 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. 
10.3. 
Accountability 
The investigator will be responsible for the oversight of recording the receipt and administration 
of ALKS 5461, and for insuring the supervision of the storage and allocation of these supplies. 
The investigator is required to maintain current drug dispensing and accountability logs 
throughout the study. The investigator may delegate accountability duties to an appropriate and 
qualified pharmacist or staff member who is under the supervision of the investigator. 
The investigator or designee must allow the Clinical Research Associate or equivalent to perform 
drug reconciliation during each study monitoring visit. All unused supplies will be checked 
against the study drug movement records before investigational drug is returned or destroyed. 
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 


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containing controlled substances. These actions may include but are not limited to re-training 
subject on adherence or discontinuation of subject from the trial. 
10.4. 
Handling and Disposal 
All unused study drug, which contains the controlled substances buprenorphine and 
samidorphan, must be handled and disposed of in accordance with the Good Clinical Practice 
(GCP), Good Manufacturing Practice (GMP), and controlled substance requirements. The 
sponsor will provide additional instruction as to the disposition of unused investigational 
product. Until instructions have been provided, each study site must store unused materials on 
site in the manner described in Section 10.2. All study drug must be accounted for on the study 
drug accountability logs. 


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11. 
ASSESSMENT OF EFFICACY 
ALKS 5461 treatment effect over time will be assessed in an exploratory manner based on 
change from baseline in MADRS total score, HAM-A score, and CGI-S score. 


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12. 
ASSESSMENT OF PHARMACOKINETICS 
Concentrations of BUP, samidorphan, their relevant metabolites, and reported background ADTs 
will be quantified in consenting subjects enrolled in the US only. Plasma samples will be 
collected at time points shown in Table 2. 


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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 (ie, hematology, chemistry, and urinalysis) 
• vital sign measurements (ie, oral body temperature, respiratory rate, blood pressure, 
and pulse) 
• weight 
• ECG findings 
• C-SSRS results 
• COWS 
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product. The occurrence, which may or may not have a causal 
relationship with the investigational treatment, may include any clinical or laboratory change that 
does not commonly occur in that subject and is considered clinically significant. 
Illnesses present prior to the subject signing the informed consent form (ICF) are considered to 
be pre-existing conditions (which may include AEs from a previous ALKS 5461 study for 
Continuing Subjects or Lead-in Subjects) and are documented on the medical history eCRF. 
Pre-existing conditions that worsen during the study are entered on the AE eCRF. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the investigator. Clinically significant values will be considered AEs and recorded 
as such on the eCRFs. 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy must be reported to Alkermes 
and additional follow-up may be required. 
13.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• 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. Hospital 
admission for elective surgery scheduled prior to study entry is not considered an 
SAE 


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• Results in disability/ incapacity (eg, a substantial disruption of a person’s ability to 
conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered 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. 
Some outcomes of pregnancy may meet the criteria of an SAE. These include: spontaneous 
abortion (including miscarriage or missed abortion), stillbirth, neonatal death, or congenital 
anomaly (including that in an aborted fetus, stillbirth, neonatal death). All neonatal deaths that 
occur within 1 month of birth should be reported as an SAE, without regard to causality. In 
addition, any infant death occurring more than 1 month after birth that the investigator assesses 
as possibly related to the in utero exposure to the study drug should be reported. See 
Section 8.4.1 for details on reporting pregnancies. 
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 
sub-investigator) according to his/her best clinical judgment. The criteria listed in Table 5 should 
be used to guide this assessment. Please note that not all criteria must be present to be indicative 
of a particular drug relationship. All study drugs are considered “test drugs” for the purposes of 
the definitions listed in the table. 


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Table 5: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for assessment 
Definitely related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Rechallenge (if feasible) is positive. 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class. 
Probably related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Possibly related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE could have been due to another equally likely cause. 
Dechallenge (if performed) is positive. 
Probably not 
related 
There is evidence of exposure to the test drug. 
AND 
There is another more likely cause of the AE. 
Dechallenge (if performed) is negative or ambiguous. 
Rechallenge (if performed) is negative or ambiguous. 
Definitely not 
related 
The subject did not receive the test drug. 
OR 
Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable. 
OR 
There is another obvious cause of the AE. 


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13.4. 
Monitoring and Recording of Adverse Events 
AE data collection will begin after a subject signs the ICF and will continue until completion of 
the final safety follow-up visit. Any AE or SAE having an onset after the final 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 IB will be used as the 
reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE and any therapeutic measures that are taken shall 
be at the discretion of the investigator. If a subject withdraws from the study for any reason
13.5. 
Reporting of Serious Adverse Events 
, 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. 
All SAEs must be reported to 
 within 1 business day 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 should be submitted on the SAE form provided for this purpose. The 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. 
PPD
PPD
PPD
PPD


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14. 
STATISTICS 
14.1. 
Sample Size Considerations 
Approximately 1,500 subjects will be enrolled in order to achieve at least 100 subjects with 
12 months and 300 subjects with 6 months of exposure to ALKS 5461. 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
statistical analysis plan (SAP)to be finalized before database lock. 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables, and number and percentage of subjects in each category for 
categorical variables) will be provided by treatment group for evaluated variables. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
14.2.1. 
Study Population 
14.2.1.1. Efficacy Population 
The exploratory efficacy endpoints to assess treatment effect over time will be analyzed using 
data from the full analysis set (FAS), defined as all subjects who receive at least 1 dose of 
ALKS 5461 and receive 1 post-baseline efficacy assessment (MADRS). 
14.2.1.2. Safety Population 
The safety population, defined as all subjects who receive at least 1 dose of ALKS 5461, will be 
used in the safety analyses. 
14.2.1.3. Pharmacokinetic Population 
The pharmacokinetic population is defined as all subjects who have at least 1 measurable plasma 
concentration of any analyte during the treatment period. 
14.3. 
Subject Disposition 
The number (percentage) of subjects completing or prematurely discontinuing from the study 
will be tabulated for all subjects enrolled. The reasons for discontinuation will also be tabulated. 
14.4. 
Demographics and Baseline Data 
For all participating subjects, baseline is defined as Visit 2. 
Demographics and baseline characteristics such as gender, age, race, weight, and baseline 
physical examination reports, vital signs, and clinical laboratory data will be summarized. 


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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. 
14.5. 
Efficacy Analyses 
As stated in Section 11, treatment effect over time will be assessed in an exploratory manner 
based on change from baseline in MADRS total score, HAM-A total score, and CGI-S score. 
Results will be presented as described in Section 14.2 and the SAP. 
14.6. 
Pharmacokinetic Analyses 
Plasma concentrations of BUP, samidorphan, their relevant metabolites, and reported 
background ADTs will be summarized by visit. Concentration data may be used in a subsequent 
population PK evaluation conducted outside of this study. 
14.7. 
Safety and Tolerability Analyses 
Safety and tolerability will be evaluated throughout the study with the assessments described 
below, at the time points presented in Table 2 and Table 3. 
Potentially clinically significant (PCS) values for each relevant parameter will be defined in the 
SAP. 
14.7.1. 
Adverse Events 
Reported AE terms will be coded using MedDRA® preferred terms and system organ classes. 
TEAEs are defined as adverse events that occur or worsen after the first dose of study drug. The 
incidence of TEAEs will be summarized for all TEAEs and for categories defined by preferred 
term and system organ class. Subjects with SAEs or AEs leading to discontinuation will also be 
summarized. 
14.7.2. 
Concomitant Medications 
Concomitant medications (defined as medications taken between 30 days before screening 
through the follow-up visit) will be coded using the World Health Organization Anatomical 
Therapeutic Chemical (WHO-ATC) class. The number and percentage of subjects using 
concomitant medications will be summarized. 
14.7.3. 
Columbia Suicide Severity Rating Scale 
Individual items and summary scores of the C-SSRS will be summarized by visit. 
14.7.4. 
Laboratory Data 
For hematology and blood chemistry assessments, baseline, value, and change from baseline will 
be summarized by visit. The number (percentage) of subjects with PCS values will be 
summarized. 


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14.7.5. 
Weight and Body Mass Index 
Weight (kg) and BMI (kg/m2) measurements will be summarized by visit for baseline, value, and 
change from baseline. The number (percentage) of subjects with PCS values will be summarized. 
14.7.6. 
Vital Signs 
Vital signs assessments will be summarized by visit for baseline, value, and change from 
baseline. 
14.7.7. 
12-Lead Electrocardiograms 
ECG parameters will be summarized for baseline, value, and change from baseline by visit. 
In addition, the number and percentages of subjects with post-baseline results QTcB and QTcF 
values >450, 480, or 500 msec and an increase from baseline of >30 or 60 msec from baseline 
will be summarized. 
14.7.8. 
Clinical Opiate Withdrawal Scale 
The number (percentage) of subjects will be summarized for COWS total score categories (mild, 
moderate, moderately severe, and severe opioid withdrawal) by visit. 


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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 
ICH, and any applicable regulatory requirements. 
The investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
15.3. 
Institutional Review Board/Independent Ethics Committee 
The investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval as 
well as all materials approved by the IRB/IEC for this study, including the subject consent form 
and recruitment materials, must be maintained by the investigator and made available for 
inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness and compliance, the study site should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 15.2 for details regarding the audit process. 
16.1. 
Case Report Forms 
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data ( eg, 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. 
All substantial protocol changes will be submitted to the respective competent authority and the 
IRB/IEC according to local procedures and will be implemented only after approval. All SAE 
reports will be submitted immediately to the competent authority and IRB/IEC per local 
requirements. 
All relevant correspondence from the IRB/IEC will be forwarded by the respective study site to 
the sponsor in a timely fashion. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. GCP is an international ethical and scientific quality 
standard used for designing, conducting, recording, and reporting studies involving the 
participation of human subjects. Alkermes is committed to complying with this standard to 
provide assurance that the rights, safety, and well-being of study subjects will be protected, 
consistent with the principles having their origin in the Declaration of Helsinki. 
17.3. 
Written Informed Consent 
The investigator (or authorized designee) at each center will ensure that the subject is given full 
and adequate oral and written information about the nature, purpose, potential and possible risks 
and benefits of the study. Each prospective subject will receive an IRB-approved ICF that 
summarizes 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 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 monitor 
and/or aforementioned parties 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 date that informed consent is obtained must be documented. The investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 


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18. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, this study will use eCRFs for capturing data. All entries, corrections, 
and alterations will be made by the investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail. 
All laboratory reports will remain with the source documents at the study site. All out-of-range 
laboratory values will be deemed as clinically significant or not clinically significant by the 
investigator. Clinically significant values will be considered AEs and recorded as such on the 
eCRFs. 
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 essential clinical study documents (eg, worksheets, drug accountability 
forms, and other administrative documentation) shall be governed by the terms and conditions of 
the site’s CSA. If the CSA does not state specific document retention terms, then the site shall 
keep essential clinical study documentation for the longer of: 
• Ten years after discontinuation of the study, or 
• Two years following the date a marketing application is approved for the study drug 
for the indication for which it is being investigated pursuant to the study, or 
• If no application is to be filed or if the application is not approved for such indication, 
until 2 years after the date the study is terminated 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 


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


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19. 
REFERENCES 
Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M (2010) RESEARCH: Validation 
of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). 
CNS Neurosci Ther 16:322-325 
Guy W (2000) Clinical Global Impressions (CGI) Scale. In: Rush J, Pincus HA, First MB, 
Blacker D, Endicott J, Keith SJ, Ryan ND, Smith GR, Tsuang MT, Widiger TA, Zarin DA eds. 
Handbook of Psychiatric Measures. APA, Washington, DC, pp. 100-102 
Hamilton M (1959) The assessment of anxiety states by rating., pp. 50-55 
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62 
Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. 
Br J Psychiatry 134:382-389 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ (2011) The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 168:1266-1277 
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, 
Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, 
Luther J, Fava M (2006) Acute and longer-term outcomes in depressed outpatients requiring one 
or several treatment steps: A STAR*D report. Am J Psychiatry 163:1905-1917 
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC (2013) Adjunctive 
atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, 
quality of life, and safety outcomes. PLoS Med 10:e1001403 
Wesson DR, Ling W (2003) The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs 35:253-259 
 
 


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20. 
APPENDICES 
Appendix A. 
Prohibited Cytochrome P450 3A4 (CYP3A4) Inducers and Moderate-to-Strong 
Inhibitors 
Appendix B. 
Maximum Daily Dose Table for Antidepressant Therapy Taken During the Study 
Appendix C. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(ATRQ) - Sample 
Appendix D. 
Mini International Neuropsychiatric Interview (MINI) - Sample 
Appendix E. 
Structured Interview Guide for the 17-Item Hamilton Rating Scale for Depression 
(SIGH-D) - Sample 
Appendix F. 
Columbia Suicide Severity Rating Scale (C-SSRS) - Samples 
• 
“Baseline” Version 
• 
“Since Last Visit” Version 
Appendix G. 
Clinical Opiate Withdrawal Scale (COWS) - Sample 
Appendix H. 
Structured Interview Guide for the Montgomery-Åsberg Depression Rating Scale 
(SIGMA) - Sample 
Appendix I. 
Structured Interview Guide for the Hamilton Rating Scale for Anxiety (SIGH-A) - 
Sample 
Appendix J. 
Clinical Global Impression Scale - Severity (CGI-S) - Sample 
 


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APPENDIX A. PROHIBITED CYTOCHROME P450 3A4 (CYP3A4) 
INDUCERS AND MODERATE-TO-STRONG 
INHIBITORS 
Page 62


 
 
 
Partial List of CYP3A4 Inhibitors and Inducers  
 
This is not an all inclusive list. 
 
 
Partial List of Moderate to Strong CYP3A4 inhibitors: 
 
• 
Amprenavir 
• 
Aprepitant 
• 
Atazanavir 
• 
Boceprevir 
• 
Ciprofloxacin 
• 
Clarithromycin 
• 
Conivaptan 
• 
Crizotinib 
• 
Darunavir/ritonavir 
• 
Diltiazem 
• 
Erythromycin 
• 
Fosamprenavir 
• 
Fluconazole 
• 
Imatinib 
• 
Indinavir 
• 
Itraconazole 
• 
Ketoconazole 
• 
Lopinavir/ritonavir 
• 
Nefazodone 
• 
Nelfinavir 
• 
Posaconazole 
• 
Ritonavir 
• 
Saquinavir 
• 
Telaprenavir 
• 
Telithromycin 
• 
Troleandomycin 
• 
Verapamil 
• 
Voriconazole 
 
 
Partial List of Moderate to Strong CYP3A4 inducers: 
 
• 
Bosentan 
• 
Carbamazepine 
• 
Efavirenz 
Page 63


 
• 
Etravirine 
• 
Modafinil 
• 
Nafcillin 
• 
Nevirapine 
• 
Phenobarbital 
• 
Phenytoin 
• 
Rifampin 
• 
Rifabutin 
• 
St. John’s Wort 
Page 64


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX B. MAXIMUM DAILY DOSE TABLE FOR 
ANTIDEPRESSANT THERAPY TAKEN DURING THE 
STUDY 
Page 65


Maximum Daily Dose Allowed for Antidepressant Therapy Taken During the Trial
Drug Class
Selective Serotonin Reuptake Inhibitors (SSRIs)
Brand Name 
Generic Name
Maximum Daily Dose 
Permitted for PIR 
Subjects?
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Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Brand Name
Generic Name
Maximum Daily Dose
Permitted for PIR 
Subjects?
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Other Antidepressants
Brand Name
Generic Name
Maximum Daily Dose
Permitted for PIR 
Subjects?
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Page 66


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX C. MASSACHUSETTS GENERAL HOSPITAL 
ANTIDEPRESSANT TREATMENT RESPONSE 
QUESTIONNAIRE (ATRQ) - SAMPLE 
Page 67


Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
  
   
 :   
  
 
Yes □ 
No □
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
     _/  
   
 
1 
CONFIDENTIAL 
  
MGH CTNI 
MGH ANTIDEPRESSANT TREATMENT RESPONSE QUESTIONNAIRE (ATRQ) 
 
 
Please indicate the correct answer to the following questions: 
 
1. Have you received any treatment with medications since the beginning of THIS CURRENT episode or 
period of depression? Please circle the correct answer. 
YES 
 
NO
2. If YES, please review the list on pages 2-3 and put a check next to any medication(s) that you have taken 
for at least 8 or 10 weeks during THIS episode or period of depression. 
3. Of those medication(s) that you have checked from the list on pages 2-3, please put a second check next to 
those that you have taken at a dosage equal to or greater than the minimum dosage listed for that 
medication. 
4. Of those medication(s) that you have checked from the list on pages 2-3, please put a third check next to 
those that you have 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. 
5. Of the medications that you have checked on pages 2-3, please write below the name of the one that 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? Please put a check next to the answer that best applies to you. 
_____ a) less than 25% improved 
_____ b) between 25% and 49% improved 
_____ c) between 50% and 75% improved 
_____ d) more than 75% improved 
AMPLE - DO NOT USE
RQ)
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RQ)
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Page 68


Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
  
   
 :   
  
 
Yes □ 
No □
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
     _/  
   
 
2 
CONFIDENTIAL 
  
MGH CTNI 
List of Antidepressant Medications 
INSTRUCTIONS:  Please check the names of any medications that you have taken for at least 8 or 10 weeks since the beginning of THIS EPISODE or period of depression. 
Please also check if your daily dosage of the medication was equal to or greater than the minimum dose listed below. Finally, please check whether a drug [e.g., buspirone, 
lithium, psychostimulants such as methylphenidate, atypical antipsychotics such as olanzapine] was added to augment or boost the antidepressant effect. 
Drug Class  
Brand Name 
Generic Name 
At least 
8 weeks 
or 
At least 
10 weeks 
Minimum** 
Dose 
Equal to or 
greater than 
Minimum** 
Dose 
Equal to or 
greater than 
Added to 
augment or 
boost effect?
Tricyclic Antidepressants 
Adapin
doxepin
_____
 
_____
150 mg/d
_____
250 mg/d
_____
_____
Anafranil 
clomipramine 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Asendin
amoxapine 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Endep/Elavil 
amitriptyline 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Ludiomil 
maprotiline 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Norpramin 
desipramine 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Pamelor
nortriptyline 
_____ 
 
_____ 
75 mg/d
_____ 
125 mg/d 
_____ 
_____ 
Sinequan 
doxepin 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Surmontil
trimipramine 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Tofranil 
imipramine 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Vivacti 
protriptyline 
_____ 
 
_____ 
30 mg/d
_____ 
60 mg/d 
_____ 
_____ 
Azafen 
pipofezine 
_____ 
_____ 
150 mg/d 
_____ 
300 mg/d 
_____ 
_____ 
Agedal/Elronon 
noxiptiline 
_____ 
 
_____ 
100 mg/d 
_____ 
200 mg/d 
_____ 
_____ 
Monoamine Oxidase Inhibitors (MAOIs) 
Marplan 
isocarboxazid 
_____ 
 
_____ 
30 mg/d
_____ 
60 mg/d 
_____ 
_____ 
Nardil 
phenelzine 
_____ 
 
_____ 
45 mg/d
_____ 
90 mg/d 
_____ 
_____ 
Parnat 
tranylcypromine 
_____ 
 
_____ 
30 mg/d
_____ 
60 mg/d 
_____ 
_____ 
Emsam
selegiline patch 
_____ 
 
_____ 
6 mg/24 hrs 
_____ 
12 mg/24 hrs 
_____ 
_____ 
Aurorix 
moclobemide 
_____ 
 
_____ 
300 mg/d 
_____ 
600 mg/d 
_____ 
_____ 
Pirazidol 
pirlindole 
_____ 
 
_____ 
200 mg/d 
_____ 
300 mg/d 
_____ 
_____ 
** Note = The left column (minimum dose) shows the dose that is minimally adequate; the right column (minimum dose) shows the minimal dose of the drug at an optimized level. Patients have 
adequate dosing as long as the dose is equal or greater than the dose on the left. 
 
 
SAMPLE - DO NOT USE
ministration
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Visit No
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50 mg/d
150 mg/d
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150 mg/d
150 mg/d
DO
150 mg/d
150 mg/d
DO
150 mg/d
_
D
_
150 mg/d
DO
150 mg/d
___
D
___
75 mg/
D
75 mg/
_____
D
_____
150 
D
150 
_____
_____
1
D
1
_____
-
_____
_____
E
_____
_____
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_____
___
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mum dose) shows the
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dose is equal or grea
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Page 69


Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
  
   
 :   
  
 
Yes □ 
No □
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
     _/  
   
 
3 
CONFIDENTIAL 
  
MGH CTNI 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
Luvox 
fluvoxamine 
_____ 
 
_____ 
50 mg/d
_____ 
150 mg/d 
_____ 
_____ 
Paxil 
paroxetine 
_____ 
 
_____ 
20/25 mg/d 
_____ 
60/75 mg/d 
_____ 
_____ 
Prozac 
fluoxetine 
_____ 
 
_____ 
20 mg/d
_____ 
60 mg/d 
_____ 
_____ 
Zoloft 
sertraline 
_____ 
 
_____ 
50 mg/d
_____ 
150 mg/d 
_____ 
_____ 
Celexa 
citalopram 
_____ 
 
_____ 
20 mg/d
_____ 
60 mg/d 
_____ 
_____ 
Lexapro
escitalopram 
_____ 
 
_____ 
10 mg/d
_____ 
30 mg/d 
_____ 
_____ 
Viibryd  
vilazodone 
_____ 
 
_____ 
40 mg/d
_____ 
80 mg/d 
_____ 
_____ 
Brintellix  
vortioxetine 
_____ 
 
_____ 
10 mg/d
_____ 
20 mg/d 
_____ 
_____ 
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) 
Effexor 
venlafaxine 
_____ 
 
_____ 
150 mg/d 
_____ 
250 mg/d 
_____ 
_____ 
Cymbalta 
duloxetine 
_____ 
 
_____ 
60 mg/d
_____ 
120 mg/d 
_____ 
_____ 
Pristiq 
desvenlafaxine 
_____ 
 
_____ 
50 mg/d
_____ 
100 mg/d 
_____ 
_____ 
Savella 
milnacipran 
_____ 
 
_____ 
100 mg/d 
_____ 
200 mg/d 
_____ 
_____ 
Fetzima 
levomilnacipran 
_____ 
 
_____ 
40 mg/d
_____ 
120 mg/d 
_____ 
_____ 
Other Antidepressants 
Desyrel 
trazodone 
_____ 
 
_____ 
300 mg/d 
_____ 
600 mg/d 
_____ 
_____ 
Serzone 
nefazodone 
_____ 
 
_____ 
300 mg/d 
_____ 
600 mg/d 
_____ 
_____ 
Wellbutrin
bupropion 
_____ 
 
_____ 
300 mg/d 
_____ 
450 mg/d 
_____ 
_____ 
Remeron
mirtazapine 
_____ 
 
_____ 
15 mg/d
_____ 
45 mg/d 
_____ 
_____ 
Valdoxan 
agomelatine 
_____ 
 
_____ 
25 mg/d
_____ 
50 mg/d 
_____ 
_____ 
Stablon 
tianeptine 
_____ 
 
_____ 
37.5 mg/d 
_____ 
75 mg/d 
_____ 
_____ 
Edronax 
reboxetine 
_____ 
 
_____ 
4 mg/d 
_____ 
8 mg/d 
_____ 
_____ 
Bolvidon/Depnon/ 
Norval/Tolvon 
mianserin 
_____ 
 
_____ 
30 mg/d
_____ 
90 mg/d 
_____ 
_____ 
Insidon
opipramol 
_____ 
 
_____ 
150 mg/d 
_____ 
300 mg/d 
_____ 
_____ 
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 
** Note = The left column (minimum dose) shows the dose that is minimally adequate; the right column (minimum dose) shows the minimal dose of the drug at an optimized level. Patients have 
adequate dosing as long as the dose is equal or greater than the dose on the left. 
AMPLE - DO NOT USE
ministration
E
ministration
ment to
SE
ment to th
SE
this sub
E
is sub
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Visit No
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Visit No
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SE
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S
150 mg
T U
150 mg
__
O
__
60/7
T 
60/7
____
O
____
6
T
6
_____
O
_____
_____
NO
_____
_____
NO
_____
_____
NO
_____
_____
N
_____
150 mg/d
O
150 mg/d
60 mg/d
DO
60 mg/d
50 mg/d
DO
50 mg/d
_
D
_
SAM
100 mg/d
DO
100 mg/d
____
D
____
40 mg/
D
40 mg/
_____
E
_____
_____
E
_____
___
E
___
__
L
__
_
E
_
____
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____
_____
PL
_____
_____
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_____
_____
MP
_____
____
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____
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AM
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M
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SA
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SA
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Page 70


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX D. MINI INTERNATIONAL NEUROPSYCHIATRIC 
INTERVIEW (MINI) - SAMPLE 
Page 71


 

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;;;;;;;;;;
7 0
S
7 0
Page 101


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 78





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966&08





 78



 

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PQ
 78


 
 
 
&$966&08


 

 
 
MOOD DISORDER DUE TO A GENERAL MEDICAL CONDITION
966&08PX<&&-7Q





 78


 
 
 
SUBSTANCE INDUCED MOOD DISORDER
966&08PX<&&-7Q





 78




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966&08





 
 
 
 
 78


 
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 78


 
 
 
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 78

 
 
 
 
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 78

 
 
 
 
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 78





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 78


 
 
 
MANIC EPISODE DUE TO A GENERAL MEDICAL CONDITION
966&08PX<&&-7Q




 78


 
 
 
HYPOMANIC EPISODE DUE TO A GENERAL MEDICAL CONDITION966&08PX<&&-7Q




 78


 
 
 
SUBSTANCE INDUCED MANIC EPISODE
966&08PX<&&-7Q




 78


 
 
 
 
 
SAMPLE - DO NOT USE
T U
OT 
OT
OT
NOT
NO
NO
NO
N
O N
O N
O N
DO 
&&-7Q
O
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Page 102


7
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SUBSTANCE INDUCED HYPOMANIC EPISODE
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 78




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ANXIETY DISORDER WIITH PANIC ATTACKS DUE TO


A GENERAL MEDICAL CONDITION
966&08


 
 
 
SUBSTANCE INDUCED ANXIETY DISORDER WITH PANIC ATTACKS966&08


 


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OCD DUE TO A GENERAL MEDICAL CONDITION
966&08





 
SUBSTANCE INDUCED OCD
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NOT
NO
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DO
DO
&
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PLE
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AM
AM
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AM
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SA
SA
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Page 103


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SE
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US
US
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OT
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NOT
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NO
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O N
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Page 104


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX E. STRUCTURED INTERVIEW GUIDE FOR THE 17-ITEM 
HAMILTON RATING SCALE FOR DEPRESSION (SIGH-
D) - SAMPLE 
Page 105


©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
 
 
 
Page 1 of 9 
STRUCTURED INTERVIEW GUIDE  
FOR THE HAMILTON DEPRESSION SCALE (SIGH-D) 
 
 
Janet B.W. Williams, PhD  
 
 
  
INTERVIEWER 
The first question for each item should be asked exactly as written.  Often this question will elicit enough 
information about the severity and frequency of a symptom for you to rate the item with confidence.  Follow-up 
questions are provided, however, for use when further exploration or additional clarification of symptoms is 
necessary.  The specified questions should be asked until you have enough information to rate the item 
confidently.  In some cases, you may also have to add your own follow-up questions to obtain necessary 
information. 
 
 
Time period
 
.  The interview questions indicate that the ratings should be based on the patient's condition in the 
past week. 
 
Referent of "usual" or "normal" condition
 
.  Several of the interview questions in the HAM-D refer to the 
patient's usual or normal functioning.  In some cases, such as when the patient has Dysthymia or Seasonal 
Affective Disorder, the referent should be to the last time they felt OK (i.e., not depressed or high) for at least a 
few weeks. 
 
This instrument provides an interview guide for the Hamilton Depression Scale (Hamilton, Max:  A rating scale for depression. J Neurol 
Neurosurg Psychiat 23:56-61, 1960).  The anchor point descriptions, with very minor modifications, have been taken from the ECDEU 
Assessment Manual (Guy, William, ECDEU Assessment Manual for Psychopharmacology, Revised 1976, DHEW Publication No. (ADM) 
76-338).  Additional designators were added in parentheses to the depression scale anchor points by Kobak, Lipsitz and Williams to 
further standardize ratings.  A reliability study of the SIGH-D (interview guide for the HAM-D alone) was published in the Archives of 
General Psychiatry
 
 (1988;45:742-747). 
 
For further information contact 
 at 
                                                                                                                                   
 
 
 
Revised 21 February 2007. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAMPLE DO NOT USE
nough
E
nough
ce.  Follow
E
ce.  Follow
E
symptoms is 
SE
symptoms is 
rate the item 
SE
rate the item 
obtain necessary 
USE
obtain necessary 
ed on the patient
T U
ed on the patient
iew questions in 
OT
iew questions in 
hen the patient h
NO
hen the patient h
felt OK (i.e., not 
NO
felt OK (i.e., not 
ression Scale (Hami
O N
ression Scale (Hami
ptions, with very mino
O
ptions, with very mino
anual for Psychopha
DO 
anual for Psychopha
O
es to the depression
DO
es to the depression
GH
D
GH-
D
-D (interview guid
DO
D (interview guid
at
at
Page 106
PPD
PPD


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
 
 
 
  
   
:   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
     _/  
   
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 2 of 9 
STRUCTURED INTERVIEW GUIDE FOR THE HAMILTON DEPRESSION SCALE (SIGH-D) 
 
 
OVERVIEW:  I’d like to ask you some questions about the past week.  How have you been feeling since 
last (DAY OF WEEK)?  IF OUTPATIENT:  Have you been working?  IF NOT:  Why not? 
 
What’s your mood been like this past week 
(compared to when you feel OK)? 
 
Have you been feeling down or depressed? 
 
IF YES: Can you describe what this feeling has been 
like for you? How bad is the feeling? 
 
Does the feeling lift at all if something good happens?  
 
How are you feeling about the future? 
 
In the last week, how often have you felt (OWN 
EQUIVALENT)?  Every day?  All day? 
 
Have you been crying at all? 
 
 
 
 
DEPRESSED MOOD (sadness, hopeless, helpless, 
worthless): 
 
0 -  absent 
1 -  indicated only on questioning (occasional, mild 
depression) 
2 -  spontaneously reported verbally (persistent, 
mild to moderate depression) 
3 -  communicated non-verbally, i.e., facial 
expression, posture, voice, tendency to weep  
       (persistent, moderate to severe depression) 
 
4 -  VIRTUALLY ONLY those feeling states reported 
in spontaneous verbal and non-verbal 
communication (persistent, very severe 
depression, with extreme hopelessness or 
tearfulness) 
IF SCORED 1-4 ABOVE, ASK: How long have you been feeling this way? 
NOTES: 
 
 
 
 
USE
eling since 
SE
eling since 
E
DO NOT US
dness, hopeless, 
US
dness, hopeless, 
nly on questioning
OT 
nly on questioning
on)
O
on)
aneously reported
OT
aneously reported
d to moderate dep
NO
d to moderate dep
ommunicated no
NO
ommunicated no
expression, pos
NO
expression, pos
(persistent, m
N
(persistent, m
4
O
4 -
O
-
O
VIRTUA
O N
VIRTUA
in sp
O 
in sp
E
DO
co
O
co
US
DO
SAMPLE 
How long have yo
E
How long have yo
Page 107


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 3 of 9 
How have you been spending your time this past 
week (when not at work)? 
 
Have you felt interested in doing (THOSE THINGS), or do 
you feel you have to push yourself to do them?   
 
How much less interested in these things have you been 
this past week compared to when you’re not depressed?  
How hard do you have to push yourself to do them? 
 
Have you stopped doing anything you used to do?  (What 
about hobbies?)  IF YES:  Why? 
 
About how many hours a day do you spend doing things 
that interest you? 
 
Is there anything you look forward to? 
 
IF WORKING (IN OR OUT OF THE HOME):  Have you 
been able to get as much (work) done as you usually do? 
 
How much less productive or efficient are you compared 
to before you were depressed? 
 
WORK AND ACTIVITIES: 
 
0 -  no difficulty 
1 -  thoughts and feelings of incapacity, fatigue or 
weakness related to activities, work or hobbies 
(Mild reduction in interest or pleasure; no clear 
impairment in functioning)  
2 -  loss of interest in activity, hobbies or work - by 
direct report of the patient or indirect in 
listlessness, indecision and vacillation (feels he 
has to push self to work or do activities; Clear 
reduction in interest, pleasure or functioning) 
3 -  decrease in actual time spent in activities or 
decrease in productivity.  In hospital, patient  
spends less than 3 hours/day in activities 
(hospital job or hobbies) exclusive of ward 
chores (Profound reduction in interest, pleasure, 
or functioning)  
4 -  stopped working because of present illness.  In 
hospital, no activities except ward chores, or 
fails to perform ward chores unassisted (Unable 
to work or fulfill primary role because of illness, 
and total loss of interest ) 
 
Now let’s talk about your sleep.  What were your usual hours of going to sleep and waking up, before this 
began?   
 
When have you been falling asleep and waking up over the past week? 
 
Have you had any trouble falling asleep at the 
beginning of the night?  (Right after you go to bed, how 
long has it been taking you to fall asleep?) 
 
How many nights this week have you had trouble falling 
asleep? 
 
Have you changed the time at which you try to get to 
sleep since you’ve been depressed? 
 
INSOMNIA EARLY (INITIAL INSOMNIA): 
 
0 -  no difficulty falling asleep 
1 -  complains of occasional difficulty falling asleep 
(i.e., more than 1/2 hour, 2-3 nights) 
2 -  complains of nightly difficulty falling asleep (i.e., 
more than ½ hour, 4 or more nights) 
 
AMPLE DO NOT USE
o?
O
o?
mpared
DO
mpared
acity, fatigue or 
SE
acity, fatigue or 
s, work or hobbie
SE
s, work or hobbie
or pleasure; no c
USE
or pleasure; no c
ng)
U
ng)
tivity, hobbies or 
US
tivity, hobbies or 
e patient or indire
U
e patient or indire
decision and vac
T U
decision and vac
self to work or do
T U
self to work or do
in interest, pleas
OT 
in interest, pleas
se
O
se in actual time 
OT
in actual time 
ease in productiv
OT
ease in productiv
pends less than 3
NO
pends less than 3
(hospital job or h
NO
(hospital job or h
chores (
NO
chores (Profo
NO
Profo
or functioni
N
or functioni
4 
O
4 -
O N
-
O N
stopped
O N
stopped
hospit
O N
hospit
fail
O 
fail
t
O
t
O
sleep.  What we
LE
sleep.  What we
een falling aslee
PL
een falling aslee
E
SAM
you had any tro
AM
you had any tro
ginning of the ni
SAM
ginning of the ni
S
ong 
S
ong has it been ta
SA
has it been ta
How many n
SA
How many n
leep?
S
leep?
AM
S
Page 108


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 4 of 9 
During the past week, have you been waking up in 
the middle of the night?  IF YES:  Do you get out of 
bed?  What do you do?  (Only go to the bathroom?) 
 
When you get back in bed, are you able to fall right 
back asleep? How long does it take you to fall back 
asleep? 
 
Do you wake up more than once during the night?  (IF 
YES: How long does it take for you to fall back to 
sleep each time?) 
 
Have you felt your sleeping has been restless or 
disturbed some nights? 
 
How many nights this week have you had that kind of 
trouble? 
 
 
 
INSOMNIA MIDDLE: 
 
0 -  no difficulty 
1 -  complains of being restless and disturbed during 
the night (or Occasional difficulty, i.e., 2-3 nights,  
more than ½ hr) 
2 -  waking during the night - any getting out of bed 
(except to void) (Often i.e., 4 or more nights of 
difficulty, more than ½ hr) 
What time have you been waking up in the 
morning for the last time, this past week? 
 
IF EARLY:  Is that with an alarm clock, or do you just 
wake up yourself?  What time do you usually wake up 
(that is, when you feel well)? 
 
How many mornings this past week have you 
awakened early? 
  
 
INSOMNIA LATE (TERMINAL INSOMNIA): 
 
0 -  no difficulty 
1 -  waking in early hours of morning but goes back 
to sleep (occasional, i.e., 2-3 nights difficulty) 
2 -  unable to fall asleep again if gets out of bed     
(often, i.e., 4 or more nights difficulty) 
 
 
Sometimes, along with depression or anxiety, 
people might lose interest in sex.  This week, how 
has your interest in sex been?  (I’m not asking 
about actual sexual activity, but about your interest in 
sex.) 
 
Has there been any change in your interest in sex 
(from when you were feeling OK)? 
 
IF YES: How much less interest do you have 
compared to when you’re not depressed? (Is it a little 
less or a lot less?) 
 
 
GENITAL SYMPTOMS (such as loss of libido, 
menstrual disturbances): 
 
0 -  absent 
1 -  mild (Somewhat less interest than usual) 
2 -  severe (A lot less interest than usual) 
 
 
 
 
 
PLE DO NOT USE
 disturbed durin
SE
 disturbed durin
culty, i.e., 2
SE
culty, i.e., 2-
SE
-3 nigh
SE
3 nigh
U
any getting out 
US
any getting out 
n i.e., 4 or more n
US
n i.e., 4 or more n
n ½ hr)
U
n ½ hr)
O
r do you just
D
r do you just
usually wake up 
D
usually wake up 
week have you 
E
week have you 
DO
DO
DO
INSO
O
INSO
O
SAMPL
 with depressio
PL
 with depressio
ose interest in se
MP
ose interest in se
erest in sex been
MP
erest in sex been
al sexual activity, 
MP
al sexual activity, 
s there been any 
SAM
s there been any 
SA
from when you w
SA
from when you w
IF YES: How
SA
IF YES: How
ompared
S
ompared
or
S
or
PL
S
Page 109


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 5 of 9 
 
How has your appetite been this past week?  
(What about compared to your usual appetite?) 
IF LESS: How much less than usual? 
 
Have you had to force yourself to eat? 
 
Have other people had to urge you to eat?  (Have you 
skipped meals?) 
 
 
 
 
SOMATIC SYMPTOMS GASTROINTESTINAL: 
 
0 -  none 
1 -  loss of appetite but eating without 
encouragement (Appetite somewhat less than 
usual) 
2 -  difficulty eating without urging (or Appetite 
significantly less than usual) 
Have you lost any weight since this 
(DEPRESSION) began?  IF YES:  Did you lose any 
weight this last week?  (Was it because of feeling 
depressed or down?)  How much did you lose? 
 
IF NOT SURE:  Do you think your clothes are any 
looser on you? 
 
AT FOLLOW-UP:  Have you gained any of the weight 
back? IF YES: How much? 
 
NOTE:  RATE 1 OR 2 ONLY IF PATIENT LOST 
WEIGHT AND HAS NOT BEGUN TO GAIN IT BACK. 
 
LOSS OF WEIGHT (Rate either A or B): 
 
A.  When rating by history: 
0 -  no weight loss 
1 -  probable weight loss due to current depression 
2 -  definite (according to patient) weight loss due to 
depression 
  
 
B.  On weekly ratings by ward staff, when actual 
weight changes are measured: 
0 -  less than 1 lb. loss in week 
1 -  more than 1 lb. loss in week 
2 -  more than 2 lb. loss in week 
  
 
  
 
 
 
 
OT USE
TINAL
E
TINAL
hout 
S
hout 
somewhat less th
USE
somewhat less th
ut urging
US
ut urging (or 
US
(or App
US
App
han usual
U
han usual)
U
)l)l
U
l)l
E
O NOT
WEIGHT (Rate eit
OT
WEIGHT (Rate eit
en rating b
NO
en rating by histo
O
y histo
no weight loss
NO
no weight loss
N
probable weigh
NO
probable weigh
2 
2 -
N
definite (acc
N
definite (acc
depressio
O N
depressio
O
B.  O
O
B.  O
OT
PLE DO
ht 
O
ht 
OST
D
OST
N IT BACK.
D
N IT BACK.
SAMPL
PL
O
Page 110


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 6 of 9 
How has your energy been this past week? 
 
IF LOW ENERGY: Have you felt tired?  (How much 
of the time? How bad has it been?) 
 
This week, have you had any aches or pains?  (What 
about backaches or muscle aches?) 
(How much of the time?  How bad has it been?) 
 
Have you felt any heaviness in your limbs, back, or 
head? 
 
 
 
 
 
 
 
SOMATIC SYMPTOMS GENERAL: 
 
0 -  none 
1 -  heaviness in limbs, back, or head.  Backaches, 
muscle aches.  Loss of energy and fatiguability. 
(Somewhat less energy than usual; mild, 
intermittent loss of energy or muscle 
aches/heaviness) 
2 -  any clear-cut symptoms (Persistent, significant 
loss of energy or muscle aches/heaviness) 
 
 
 
 
 
 
 
Have you been putting yourself down this past 
week, feeling you’ve done things wrong, or let 
others down? 
IF YES: What have your thoughts been? 
Have you been feeling guilty about anything that 
you’ve done or not done?  IF YES:  What have your 
thoughts been? 
What about things that happened a long time ago? 
IF UNKNOWN: How often have you thought about 
this the past week? 
 
Have you thought that you’ve brought (THIS 
DEPRESSION) on yourself in some way? 
 
(Have you been hearing voices or seeing visions in 
the last week?  IF YES: Tell me about them.) 
 
FEELINGS OF GUILT: 
 
0 -  absent 
1 -  self-reproach, feels he has let people down 
2 -  ideas of guilt or rumination over past errors or 
sinful deeds (feelings of guilt, remorse or shame) 
3 -  present illness is a punishment.  Delusions of 
guilt. (severe, pervasive feelings of guilt) 
4 -  hears accusatory or denunciatory voices and/or 
      experiences threatening visual hallucinations 
AMPLE DO NOT USE
ad.  Backaches,
SE
ad.  Backaches,
gy and fatiguabilit
SE
gy and fatiguabilit
an usual; mild,
USE
an usual; mild,
gy or muscle
US
gy or muscle
ptoms
U
ptoms (Persistent
U
(Persistent
r muscle aches/h
T U
r muscle aches/h
O
ng that 
D
ng that 
hat have your 
D
hat have your 
d a long time ago
E
d a long time ago
ve you thought a
LE 
ve you thought a
t you’ve brought (
PL
t you’ve brought (
yourself in some
PL
yourself in some
en hearing voices
MP
en hearing voices
ek?  IF YES: Tell
MP
ek?  IF YES: Tell
O 
FEELING
O
FEELING
0
O
0 -
O
-
1
O
1
SAM
O
AM
O
Page 111


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 7 of 9 
This past week, have you had thoughts that life 
is not worth living?  IF YES: What about 
thinking you’d be better off dead?  Have you 
had thoughts of hurting or killing yourself? 
  
 
IF YES:  What have you thought about?  Have you 
actually done anything to hurt yourself? 
 
SUICIDE: 
0 -  absent 
1 -  feels life is not worth living 
2 -  wishes he were dead or any thoughts of possible     
      death to self 
3 -  suicidal ideas or gesture 
4 -  attempts at suicide 
Have you been feeling especially tense this past 
week?  IF YES:  Is this more than is normal for 
you? 
 
Have you been unusually argumentative or 
impatient? 
 
Have you been worrying a lot about little things, 
things you don’t ordinarily worry about?   
IF YES:  Like what, for example? 
 
How often have you felt this way the past week? 
Has this caused you any problems or difficulties?  
 IF YES:  Like what, for example? 
 
ANXIETY PSYCHIC: 
0 -  no difficulty 
1 -  subjective tension and irritability (Mild,  
      occasional) 
2 -  worrying about minor matters (Moderate, causes  
      some distress) 
3 -  apprehensive attitude apparent in face or speech  
     (Severe; significant impairment in functioning due  
      to anxiety) 
4 -  fears expressed without questioning (Symptoms 
       incapacitating) 
OT USE
ughts of possibl
SE
ughts of possibl
O NO
ETY PSYCHIC:
NO
ETY PSYCHIC:
no difficulty
NO
no difficulty
-
N
subjective ten
NO
subjective ten
O N
occasional)
O N
occasional)
2
O
2 -
O
-
O N
worrying
O N
worrying
O
some
O
some
3 
O
3 -
O
-
O
app
O 
app
O
(
O
(
O
PLE DO
st week?
D
st week?
r difficulties? 
r difficulties? 
SAMP
O
Page 112


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 8 of 9 
Tell me if you’ve had any of the following 
physical symptoms in the past week.  (READ 
LIST) 
 
FOR EACH SX ACKNOWLEDGED AS PRESENT: 
How much has (THE SX) been bothering you this 
past week?   (How bad has it gotten?  How much of 
the time, or how often, have you had it? Did (the 
symptom) interfere at all with your functioning or 
your usual activities?)  
 
NOTE: DO NOT RATE SXS THAT ARE CLEARLY 
RELATED TO A DOCUMENTED PHYSICAL 
CONDITION. 
 
 
 
ANXIETY SOMATIC (physiologic concomitants of 
anxiety, such as 
Gastrointestinal - dry mouth, gas, indigestion, 
diarrhea, stomach cramps, belching 
CV - heart palpitations, headaches 
Respiratory - hyperventilating, sighing 
Urinary frequency 
Sweating): 
 
0 -  not present 
1 -  mild (Symptom(s) present only infrequently, no 
impairment, minimal distress) 
2 -  moderate (Symptom(s) more persistent, or some 
interference with usual activities, moderate 
distress) 
3 -  severe (Significant impairment in functioning) 
4 -  incapacitating 
In the last week, how much have your thoughts 
been focused on your physical health or how 
your body is working (compared to your normal 
thinking)?  (Have you worried a lot about being or 
becoming physically ill?  Have you really been 
preoccupied with this?) 
 
Have you worried a lot that you had a specific 
medical illness?     
 
Do you complain much about how you feel 
physically? 
 
Have you seen a doctor about these problems? 
 
What did the doctor say? 
 
 
 
 
HYPOCHONDRIASIS: 
 
0 - not present 
1 - self-absorption (bodily) (Some inappropriate 
worry about his/her health OR slightly concerned 
despite reassurance) 
2 - preoccupation with health (Often has excessive 
worries about his/her health OR definitely 
concerned has specific illness despite medical 
reassurance) 
3 - frequent complaints, requests for help, etc. (Is 
certain there is a physical problem which the 
doctors cannot confirm; exaggerated or unrealistic 
concerns about body and physical health) 
4 - hypochondriacal delusions 
 
SAMPLE DO NOT USE
an
E
an
gestion, 
E
gestion, 
g
S
g
s
S
s
sighing
US
sighing
m(s) present only
T U
m(s) present only
t, minimal distres
OT 
t, minimal distres
te (
O
te (Symptom(s) m
OT
Symptom(s) m
erence with usua
OT
erence with usua
tress
NO
tress)
NO
)
s)
s
NO
s)
s
severe 
NO
severe (Significa
NO
(Significa
N
incapacitating
NO
incapacitating
O
ughts 
D
ughts 
r how 
D
r how 
our normal 
D
our normal 
bout being or 
bout being or 
really been
E
really been
you had a specif
LE
you had a specif
uch about how y
PL
uch about how y
een a doctor abo
MP
een a doctor abo
did the doctor sa
AM
did the doctor sa
DO
DO
DO
H
O
H
O
SA
SA
O
Page 113


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
    _/  
   
 
 
©All rights reserved.  Janet B.W. Williams, 2007 
Clintara Version 1.0 January, 2012 
Page 9 of 9 
RATING BASED ON OBSERVATION DURING 
INTERVIEW 
 
 
INSIGHT: 
 
0 - acknowledges being depressed and ill OR not 
currently depressed 
1 - acknowledges illness but attributes cause to bad 
food, overwork, virus, need for rest, etc. 
2 - denies being ill at all 
RATING BASED ON OBSERVATION DURING 
INTERVIEW 
AGITATION:
 
0 -  none 
1 -  fidgetiness (slight agitation or mild restlessness) 
2 -  playing with hands, hair, etc. (moderate to 
marked restlessness or agitation) 
3 -  moving about, can’t sit still (cannot remain 
seated) 
4 -  hand-wringing, nail biting, hair-pulling, biting of 
lips (interview cannot be conducted; severe 
agitation) 
 
 
RATING BASED ON OBSERVATION DURING 
INTERVIEW 
 
RETARDATION (slowness of thought and speech; 
impaired ability to concentrate; decreased motor 
activity): 
 
0 -  normal speech and thought  
1 -  slight retardation at interview (mild psychomotor 
retardation) 
2 -  obvious retardation at interview (moderate; some     
difficulty with interview, noticeable pauses and 
slowness of thought) 
3 -  interview difficult (severe psychomotor retardation; 
very long pauses) 
4 -  complete stupor (extreme retardation; interview 
barely possible) 
 
 
 
 
TOTAL HAM-D SCORE:                                                          ___________ 
 
 
 
Rater Signature: _______________________ 
Date: _________________________
 
SAMPLE DO NOT USE
d ill OR not 
E
d ill OR not 
butes cause to ba
SE
butes cause to ba
for rest, etc
USE
for rest, etc.
S
.
:
O
:
ne
N
ne
fidgetiness
NO
fidgetiness (sligh
O
(sligh
-
N
playing with ha
NO
playing with ha
marked res
N
marked res
3 
O
3 -
O
-
O N
moving a
O N
moving a
seated
O N
seated
4
O
4 -
O
-
O
han
O 
han
li
O
li
OT
O
DURING 
D
DURING 
D
SA
TAL 
S
TAL 
S
Page 114


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX F. COLUMBIA SUICIDE SEVERITY RATING SCALE 
(C-SSRS) - SAMPLES 
• “Baseline” Version 
• “Since Last Visit” Version 
Page 115


© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Page 1 of 4 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Baseline Version 
 
 
 
Version 1/14/09 
 
 
 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; Burke, A.; 
Oquendo, M.; Mann, J.
 
 
 
 
 
 
 
 
 
Disclaimer: 
 
 
 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in  The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 
 
For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
 
 
 
 
 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
SAMPLE - DO NOT USE
elazny, J
SE
elazny, J.;
SE
.; Bur
E
Bur
ed
ed training in i
O N
 training in i
d 
d 
d
ts
N
ts a
N
a
d
O
d pro
O
probes. Ultim
O N
bes. Ultima
N
a
udgment 
O
udgment of
O N
of the in
O N
the in
f
O N
f
u
P
uic
P
icidal 
PL
idal eve
PL
even
PL
nts
L
ts in 
L
in 
nn, 
MP
nn, MD
P
MD and Maria
MPL
and Maria
Sta
M
State
MP
te P
MP
Psyc
MP
sychi
P
hiatr
P
atr
iai
P
iai
i
P
i
P
i
M
M
Ma
M
ann
M
nn J. J
MP
J. J.,
MP
., Risk fa
MP
Risk fa
zed Evalu
AM
zed Evaluat
M
ati
M
itit
M
tit on
M
on in
M
in
pri
S
prints
SA
nts of
SA
of t
SA
t
f f
SA
f f he C-SS
SA
he C-SS
k,
S
k, New
SA
New Y
SA
 Yor
SA
ork, 1003
SA
k, 1003
Page 116
PPD
PPD


© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Page 2 of 4 
 
 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
            :   
 
Yes □ 
No □ 
N/A  □ 
1st administration of 
this instrument to this 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
           /_               /_      
  
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes,” ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, 
complete “Intensity of Ideation” section below. 
Lifetime: 
Time He/She 
Felt Most 
Suicidal 
Past 12 Months 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and 
not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
Yes 
No 
Yes 
No 
2. Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about 
killing myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during 
the assessment period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
Yes 
No 
Yes 
No 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act Subject 
endorses thoughts of suicide and has thought of at least one method during the assessment 
period. This is different than a specific plan with time, place or method details worked out (e.g., 
thought of method to kill self but not a specific plan). Includes person who would say, “I thought 
about taking an overdose but I never made a specific plan as to when, where or how I would 
actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
 
If yes, describe: 
Yes 
No 
Yes 
No 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such 
thoughts, as opposed to “I have the thoughts but I definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
Yes 
No 
Yes 
No 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some 
intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you 
intend to carry out this plan? 
 
If yes, describe: 
Yes 
No 
Yes 
No 
AMPLE - DO NOT USE
T U E
S
S
She 
S
he 
st
S
st
da
U
dal
U
l
P
SE
Pas
SE
ast 1
E
t 1
E
SE
Yes
U
Yes
No
U
No
US
OT
S
I’ve
N
I’ve thou
NO
though
NO
ght 
NO
t abo
O
abou
O
ut
O
t
en
N
ent,
N
t, or p
NO
or pla
NO
lan dur
NO
n durin
O
ing
O
g
OT
OT
OT
OT
t
D
thout I
DO
hout Int
DO
nte
DO
ent
DO
nt to A
O
to A
e
D
e me
D
met
D
tho
DO
hod
DO
d du
DO
during t
DO
ring t
ce or method deta
D
e or method deta
nc
nclud
ludes person wh
D
es person wh
fic plan as to w
D
fic plan as to when
D
hen
wh
w
D
wh
w
h it”.
it”.
gh
E
ght do this?
E -
t do this?
DO
S
P
Som
PL
ome Inte
PLE
e Intent
LE
nt to Ac
LE
to Ac
g on
P
g ones
PL
eself and
PL
elf and sub
L
subj
L
jbjb
L
bjb
ve
P
ve th
P
the t
P
e tho
PL
ho
th
t
P
th
t
u
PL
ugh
PL
ghts 
PL
ts bu
L
bu
ughts a
MP
ughts and
MP
nd had som
P
 had som
d 
d
P
d 
d
LE
SAM
da
A
dal Id
A
l Idea
AM
eation with
AM
tion with
ki
A
kil
A
llin
A
ling 
SA
g on
A
oneself 
AM
eself wi
AM
with
M
th
a
S
arry it
SA
rry it ou
SA
out.
SA
t.
you sta
SA
you start
SA
rted 
SA
ed to wor
SA
to wor
d
S
d to
S
to
d
S
d
ca
S
carry o
SA
rry ou
SA
ut
SA
t th
SA
th
t
SA
t
S
ribe:
S
ribe:
AM
Page 117


Subject ID No.  
 
© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Page 3 of 4 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, 
with 1 being the least severe and 5 being the most severe ). Ask about time he/she was feeling the most 
suicidal. 
Lifetime - Most Severe Ideation: 
       
               
                      
                                                                         Type # (1-5) 
    Description of Ideation 
Past 12 Months - Most Severe Ideation:   
                                                          
                                                                        Type # (1-5)          Description of Ideation 
Most Severe 
Most Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week   (2) Once a week   (3) 2-5 times in week 
(4) Daily or almost daily       (5) Many times each day 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes 
(4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty   (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty  (0) Does not attempt to control thoughts 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                        (5) Deterrents definitively did not stop you 
(3) Uncertain that deterrents stopped you                      (0) Does not apply 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end 
the pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or 
how you were feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others (4) Mostly to end or stop the pain (you 
(2) Mostly to get attention, revenge or a reaction from others 
couldn’t go on living with the pain or how 
(3) Equally to get attention, revenge or a reaction from others 
you were feeling 
and to end/stop the pain 
(5) Completely to end or stop the pain (you 
couldn’t go on living with the pain or how 
you were feeling) 
(0) Does not apply 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past 12 Months 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought 
of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, 
then it can be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential 
for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered 
an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but 
they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died?    
What did you do? 
 Did you   
as a way to end your life? 
 Did you want to die (even a little) when you   
? 
Yes 
Total # of att
No 
empts 
Yes 
Total # of att
No 
empts 
 
 
 
  Were you trying to end your life when you   
? 
 Or did you think it was possible you could have died from   
? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel       
better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes 
No 
Yes 
No 
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LE
Page 118


Subject ID No.  
 
© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Page 4 of 4 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not 
for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to 
fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: 
Person has noose around neck but has not yet started to hang - is stopped from doing so. 
 
Yes 
No 
Yes 
No
Has there been a time when you started to do something to end your life but someone or something 
stopped you before you actually did anything? 
If yes, describe: 
Total # of 
interrupted 
Total # of 
interrupted 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually 
have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being 
stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped 
 
Yes 
No 
Yes 
No 
yourself before you actually did anything? 
If yes, describe: 
Total # of aborted 
Total # of aborted 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or 
preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as 
collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes 
No 
Yes 
No 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
No 
Yes 
No 
Answer for Actual Attempts Only 
Most Recent 
Attempt Date: 
Most Lethal 
Attempt Date: 
Initial/First Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; 
sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, 
somewhat responsive; second-degree burns; bleeding of major vessel). 
 
Enter Code 
 
Enter Code 
 
Enter Code 
3. Moderately severe physical damage; medical hospitalization and likely intensive care 
  
 
required (e.g., comatose with reflexes intact; third-degree burns less than 20% of body; 
extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (e.g., 
comatose without reflexes; third degree burns over 20% of body; extensive blood loss with 
unstable vital signs; major damage to a vital area). 
5. Death 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having 
no actual medical damage, had potential for very serious lethality: put gun in mouth and 
pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with 
oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
Enter Code 
Enter Code 
Rater Signature:   
Date:   
 
SAMPLE - DO NOT USE
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Page 119


Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Since Last Visit 
 
 
 
Version 1/14/09 
 
 
 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; Burke, A.; 
Oquendo, M.; Mann, J. 
 
 
 
 
 
 
 
 
 
Disclaimer: 
 
 
 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in  The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 
 
For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
 
 
 
 
 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Clintara Version 1.6 June, 2011 
 
Page 1 of 4 
SAMPLE - DO NOT USE
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Page 120
PPD
PPD


© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Clintara Version 1.6 June, 2011 
Subject ID Number:  
Visit Number  
Page 2 of 4
Rater 
I i i l
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
  
 :   
 
Yes □ 
No □ 
           N/A □ 
1st administration of 
this instrument to this 
Subject Initials: 
Site No./ Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
/  
/  
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is 
“yes,” ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” 
section below. 
Since Last Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
 
If yes, describe: 
Yes 
No 
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
Yes 
No 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This 
is different than a specific plan with time, place or method details worked out (e.g., thought of method to kill self 
but not a specific plan). Includes person who would say, “I thought about taking an overdose but I never made a 
specific plan as to when, where or how I would actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
 
If yes, describe: 
Yes 
No 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as 
opposed to “I have the thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
Yes 
No 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it 
out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out 
this plan? 
 
If yes, describe: 
Yes 
No 
- DO NOT USE
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Page 121


© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Clintara Version 1.6 June, 2011 
Subject ID Number:  
Visit Number  
Page 3 of 4
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the 
least severe and 5 being the most severe ). 
Most Severe Ideation:  
  
 
  
 
 
Type # (1-5) 
 
Description of Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes 
(4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or 
acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide    (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                           (5) Deterrents definitively did not stop you 
(3) Uncertain that deterrents stopped you                                   (0) Does not apply 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or stop 
the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to 
get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others (4) Mostly to end or stop the pain (you couldn’t 
(2) Mostly to get attention, revenge or a reaction from others 
go on living with the pain or how you were 
(3) Equally to get attention, revenge or a reaction from others 
feeling 
and to end/stop the pain 
(5) Completely to end or stop the pain (you 
couldn’t go on living with the pain or how 
you were feeling) 
(0) Does not apply 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as 
method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be 
considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If 
person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. 
For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to 
head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could 
be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you  
 as a way to end your life? 
Did you want to die (even a little) when you  
  ? 
Were you trying to end your life when you  
? 
Or did you think it was possible you could have died from  
? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes 
No 
Total # of attempts 
Yes 
No 
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it m
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arly not an accident
oor/story
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PL
). Also,
PLE
Also, if
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if so
LE
so
f
LE
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pt?
P
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a
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arm you
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rm your
MP
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MPL
self?
rs
r
MP
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MP
rous
MP
ous
ro
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MP
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where
MP
where y
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 yo
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a way to end yo
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 to end yo
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y
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 (even a litt
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to end 
AM
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AM
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AM
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do it 
SA
do it purely
SAM
purely for
AM
for o
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SA
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describe:
SA
describe:
ng
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D
Page 122


© 2008 The Research Foundation for Mental Hygiene, Inc. Version 1/14/19. 
Clintara Version 1.6 June, 2011 
Subject ID Number:  
Visit Number  
Page 4 of 4
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual 
attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather 
than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow 
prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised 
to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is 
stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
Yes 
No 
Total # of interrupted 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in 
any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something 
else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
No 
Total # of aborted 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, 
such as assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving 
things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes 
No 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
No 
Completed Suicide: 
Yes 
No 
Answer for Actual Attempts Only 
Most Lethal Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5. Death 
Enter Code 
  
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on 
train tracks with oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
Rater Signature:   
 
Date:   
 
AMPLE - DO NOT USE
SE
S
ed in 
US
ed in 
something
US
something
be
T
bef
T
fore
T U
ore
fo
f
T
fo
f
yo
T U
you
U
u
Yes 
S
Yes 
SE
US
e
N
eyo
N
yond a verbalization
NO
nd a verbalization
one’s death by suicid
NO
one’s death by suicid
yourse
N
yourself (s
N
lf (such
N
uch as c
N
 as c
OT
O
D
E -
r physical damage (e
PL
r physical damage (e
thargic speech;
PL
thargic speech; first
L
first
L
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M
medical attention nee
MPL
edical attention nee
sel).
M
sel).
sical damage;
MP
sical damage; medic
MP
medic
ns
M
ns less than 20% of b
MP
less than 20% of b
amage; 
AM
amage; medical 
AM
medical hos
M
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f body; 
AM
f body; ext
AM
exte
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nsive blo
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LE
SA
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ethality:
SA
hality: On
SA
Only Answ
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ly Answ
hality 
S
hality of ac
SA
of actual
SA
tual attem
SA
 attem
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very serious le
SA
ry serious le
ks with 
S
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S
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not 
S
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S
lik
A
Page 123


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX G. CLINICAL OPIATE WITHDRAWAL SCALE (COWS) - 
SAMPLE 
Page 124


Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
  
   
/_       
     _/  
   
 
 
From: Wesson DR, Ling W J Psychoactive Drugs 2003 Apr-June; 35(2): 253-9 
Clinical Opiate Withdrawal Scale 
For each item, circle the number that best describes the patient’s signs or symptom. Rate on just the apparent 
relationship to opiate withdrawal. For example, if heart rate is increased because the patient was jogging just prior 
to assessment, the increase pulse rate would not add to the score. 
 
Resting Pulse Rate: 
  
beats/minute 
Measured after patient is sitting or lying for one minute 
0 pulse rate 80 or below 
1 pulse rate 81-100 
2 pulse rate 101-120 
4 pulse rate greater than 120 
GI Upset: over last ½ hour 
0 no GI symptoms 
1 stomach cramps 
2 nausea or loose stool 
3 vomiting or diarrhea 
5 Multiple episodes of diarrhea or vomiting 
Sweating: over past ½ hour not accounted for by room 
temperature or patient activity. 
0 no report of chills or flushing 
1 subjective report of chills or flushing 
2 flushed or observable moistness on face 
3 beads of sweat on brow or face 
4 sweat streaming off face 
Tremor observation of outstretched hands 
0 No tremor 
1 tremor can be felt, but not observed 
2 slight tremor observable 
4 gross tremor or muscle twitching 
Restlessness Observation during assessment 
0 able to sit still 
1 reports difficulty sitting still, but is able to do so 
3 frequent shifting or extraneous movements of legs/arms 
5 Unable to sit still for more than a few seconds 
Yawning Observation during assessment 
0 no yawning 
1 yawning once or twice during assessment 
2 yawning three or more times during assessment 
4 yawning several times/minute 
Pupil size 
0 pupils pinned or normal size for room light 
1 pupils possibly larger than normal for room light 
2 pupils moderately dilated 
5 pupils so dilated that only the rim of the iris is visible 
Anxiety or Irritability 
0 none 
1 patient reports increasing irritability or anxiousness 
2 patient obviously irritable anxious 
4 patient so irritable or anxious that participation in 
the assessment is difficult 
Bone or Joint aches If patient was having pain 
previously, only the additional component attributed 
to opiates withdrawal is scored 
0 not present 
1 mild diffuse discomfort 
2 patient reports severe diffuse aching of joints/ muscles 
4 patient is rubbing joints or muscles and is unable to sit 
still because of discomfort 
Gooseflesh skin 
0 skin is smooth 
3 piloerrection of skin can be felt or hairs standing up 
on arms 
5 prominent piloerrection 
Runny nose or tearing Not accounted for by cold 
symptoms or allergies 
0 not present 
1 nasal stuffiness or unusually moist eyes 
2 nose running or tearing 
4 nose constantly running or tears streaming down cheeks 
Total Score    
 
The total score is the sum of all 11 items 
Initials of person 
completing Assessment: 
  
 
 
Score: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal 
 
PLE - DO NOT USE
ren
SE
rent 
SE
t 
ng just 
SE
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SE
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SE
ior 
SE
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OT
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OT
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trt etc
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r can be fel
NO
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NO
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NO
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NO
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NO
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O N
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O N
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LE
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 wit
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ent 
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dif
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 sever
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atient 
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Run
SA
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no
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p
S
p
mp
m
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mp
m
0
S
0 not 
S
not p
S
p
SA
S
Page 125


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX H. STRUCTURED INTERVIEW GUIDE FOR THE 
MONTGOMERY-ÅSBERG DEPRESSION RATING 
SCALE (SIGMA) - SAMPLE 
Page 126


© Williams & Kobak, 2008, v.2 
Clintara Version 1.6 June, 2011 
Page 1 of 5 
STRUCTURED INTERVIEW GUIDE FOR THE MONTGOMERY AND ASBERG DEPRESSION RATING 
SCALE (SIGMA) 
  
 
 
Janet B.W. Williams, D.S.W. and Kenneth A. Kobak, Ph.D. 
 
 
 
 
INTERVIEWER: The questions in bold for each item should be asked exactly as written. Often these questions will 
elicit enough information about the severity and frequency of a symptom for you to rate the item with confidence. 
Follow-up questions are provided, however, for use when further exploration or additional clarification of symptoms is 
necessary. The specified questions should be asked until you have enough information to rate the item confidently. In 
some cases, you may also have to add your own follow-up questions to obtain necessary information. Note that 
questions in parentheses are optional, for use, for example if information is unknown.  
 
 
 
 
 
NOTES:  
 
Time period. The ratings should be based on the patient's condition in the past week.  
 
Change from baseline. In general, a symptom is rated as present only when it reflects a change from before the 
depression began (baseline). The interviewer must identify a 2-month period of non-depressed functioning and use 
this as a reference point. In some cases, such as when the patient has dysthymia the referent should be to the last 
time the person felt all right (i.e. not depressed or high) for at least a few weeks. When a clear baseline cannot be 
established because of chronic depressive symptoms, current symptoms should be rated as observed over the past 7 
days. 
 
 
 
 
 
This interview guide is based on the Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery SA, 
Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry ;1979 134: 382-9). The scale 
itself has been retained in its original form, except for reversing the order of the first two items. This guide adds 
interview questions to aid in the assessment and application of the MADRS. Previous versions of this guide appeared 
in 1988, 1992, 1996, and 2005. 
 
 
 
 
 
  
©2008 The Royal College of Psychiatrists. The SIGMA may be copied by individual researchers or clinicians for their 
own use without seeking permission from the publishers. The scale must be copied in full and all copies must 
acknowledge the following source: Williams JBW, Kobak KA. Development and reliability of a structured interview 
guide for the Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry 2008; 192: 52-58. Written 
permission must be obtained from the Royal College of Psychiatrists for copying and distribution to others or for 
replication (in print, online or by any other medium). Correspondence should be addressed to 
 at 
 To inform an ongoing survey, researchers and clinicians are asked to notify 
 of their 
intention to use the SIGMA. 
 
 
 
 
LE - DO NOT USE
questi
SE
questions will 
SE
ons will 
h confidence. 
SE
h confidence. 
ation of symptom
USE
ation of symptom
e the item confide
US
e the item confide
nformation. Note 
US
nformation. Note 
n in the past wee
NO
n in the past wee
sent only when it
O N
sent only when it
a 2
O
a 2-
O
-month period 
O N
month period 
e patient has dys
O 
e patient has dys
for at least a few
DO
for at least a few
ms, current sympto
DO
ms, current sympto
he Mo
LE
he Montgomery
LE
ntgomery
SAMPLE
-A
cale designed to 
LE
cale designed to 
original form, ex
PLE
original form, ex
in the assessmen
PL
in the assessmen
d 2005.
P
d 2005.
8 The Royal Col
SA
8 The Royal Col
 use without se
SA
 use without se
S
owledge the
S
owledge the
r the M
S
r the M
S
Page 127
PPD
PPD
PPD


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
 
 
___ ___ : ___ ___ 
Yes □                         No □                         N/A □ 
   
Subject Initials: 
Site No. / Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
 
 
 
 
 
 
 
 
 
 
 
 
___ ___/___ ___ ___/___ ___ ___ ___ 
 
 
 
© Williams & Kobak, 2008, v.2 
Clintara Version 1.6 June, 2011
Page 2 of 5
OVERVIEW:  
I’d like to ask you some questions about the past week. How have you been feeling since last (DAY OF WEEK)? IF OUT-
PATIENT: Have you been working? (What kind of work do you do?) IF NOT: Why not?  
In the past week, have you been feeling sad or 
unhappy? (Depressed at all?) IF YES: Can you describe 
what this has been like for you? (IF UNKNOWN: How bad 
has that been?)  
 
IF DEPRESSED: Does the feeling lift at all if something 
good happens? How much does your mood lift? Does the 
feeling ever go away completely? (What things have made 
you feel better?) 
  
How often did you feel (depressed/OWN EQUIVALENT) 
this past week? (IF UNKNOWN: How many days this week 
did you feel that way? How much of each day?)  
 
In the past week, how have you been feeling about the 
future? (Have you been discouraged or pessimistic?) What 
have your thoughts been? How (discouraged or 
pessimistic) have you been? How often have you felt that 
way? Do you think things will ever get better for you?  
 
IF ACKNOWLEDGES DEPRESSED MOOD, TO GET 
CONTEXT ASK: How long have you been feeling this way?  
 
 
1. REPORTED SADNESS. Representing reports of 
depressed mood, regardless of whether it is reflected in 
appearance or not. Includes low spirits, despondency or the 
feeling of being beyond help and without hope. Rate 
according to intensity, duration, and the extent to which the 
mood is reported to be influenced by events.  
 
0 – Occasional sadness in keeping with the circumstances  
1 –  
2 – Sad or low but brightens up without difficulty 
3 – 
4 – Pervasive feelings of sadness or gloominess. The mood 
is still influenced by external circumstances 
5 –  
6 – Continuous or unvarying sadness, misery, or 
despondency 
 
RATING BASED ON OBSERVATION DURING 
INTERVIEW AND THE FOLLOWING QUESTIONS.  
 
In the past week, do you think you have looked sad or 
depressed to other people? Did anyone say you looked 
sad or down?  
 
How about when you’ve looked in the mirror? Did you look 
gloomy or depressed?  
 
IF YES: How sad or depressed do you think you have 
looked? How much of the time over the past week do you 
think you have looked depressed or down?  
 
IF APPEARANCE WAS DEPRESSED IN PAST WEEK: 
Have you been able to laugh or smile at all during the past 
week? IF YES: How hard has it been for you to laugh or 
smile, even if you weren’t feeling happy inside?  
 
 
2. APPARENT SADNESS. Representing despondency, 
gloom and despair. (More than just ordinary transient low 
spirits) reflected in speech, facial expressions, and posture. 
Rate by depth and inability to brighten up.  
 
0 – No sadness  
1 – 
2 – Looks dispirited but does brighten up without difficulty 
3 – 
4 – Appears sad and unhappy most of the time 
5 – 
6 – Looks miserable all the time. Extremely despondent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMPLE - DO NOT USE
?
D
?
ected in
SE
ected in
ndency or t
SE
ndency or the
E
he
ope. Rate
SE
ope. Rate
extent to which the
US
extent to which the
events.
US
events.
ng with the
U
ng with the circums
U
circums
s up withou
T U
s up without difficu
T U
t difficu
of sadness or gloo
OT 
of sadness or gloo
external
OT
external circumsta
OT
circumsta
s or unvarying sadn
NO
s or unvarying sadn
cy
N
cy
E
D
E
IONS.
IONS.
looked sad or 
E -
looked sad or 
ne say you looked
E
ne say you looked
d in the mirror? Di
LE
d in the mirror? Di
epressed do you th
PL
epressed do you th
of the time over th
MP
of the time over th
oked depressed o
MP
oked depressed o
ANCE WAS DEPR
AM
ANCE WAS DEPR
SAM
u been able to laug
AM
u been able to laug
IF YES: How hard
AM
IF YES: How hard
e, even if you were
SA
e, even if you were
2. A
D
2. A
gl
D
gl
D
S
D
S
D
Page 128


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
 
 
___ ___ : ___ ___ 
Yes □                         No □                         N/A □ 
   
Subject Initials: 
Site No. / Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
 
 
 
 
 
 
 
 
 
 
 
 
___ ___/___ ___ ___/___ ___ ___ ___ 
 
 
 
© Williams & Kobak, 2008, v.2 
Clintara Version 1.6 June, 2011
Page 3 of 5
Have you felt tense or edgy in the last week? Have you 
felt anxious or nervous?  
IF YES: Can you describe what that has been like for you? 
How bad has it been? (Have you felt panicky?)  
 
What about feeling fearful that something bad is about to 
happen?  
 
How hard has it been to control these feelings? (What has it 
taken to help you feel calmer? Has anything worked to calm 
you down?)  
 
How much of the time have you felt this way over the past 
week?  
3. INNER TENSION. Representing feelings of ill defined 
discomfort, edginess, inner turmoil, mental tension 
mounting to either panic, dread, or anguish. Rate according 
to intensity, frequency, duration and the extent of 
reassurance called for.  
 
0 – Placid. Only fleeting inner tension 
1 – 
2 – Occasional feelings of edginess and ill-defined 
discomfort 
3 – 
4 – Continuous feelings of inner tension or intermittent 
panic which the patient can master with some difficulty 
5 –   
6 – Unrelenting dread or anguish. Overwhelming panic 
 
 
 
How has your sleeping been in the last week? (How 
many hours have you been sleeping, compared to 
usual?)  
 
Have you had trouble falling asleep? (How long has it 
been taking you to fall asleep this past week?)  
 
Have you been able to stay asleep through the night? 
(Have you been waking up at all in the middle of the night? 
How long does it take you to fall back to sleep?)  
 
Has your sleeping been restless or disturbed?  
 
 
4. REDUCED SLEEP. Representing the experience of 
reduced duration or depth of sleep compared to the 
subject’s own normal pattern when well.  
 
0 – Sleeps as usual 
1 – 
2 – Slight difficulty dropping off to sleep or slightly reduced, 
light, or fitful sleep 
3 –  
4 – Sleep reduced or broken by at least 2 hours 
5 – 
6 – Less than 2 or 3 hours sleep 
 
How has your appetite been this past week? (What 
about compared to your usual appetite?)  
 
Have you been less interested in food? (How much less?)  
 
Does food taste as good as usual? IF LESS: How much 
less?  
 
Have you had to force yourself to eat?  
 
Have other people had to urge you to eat?  
 
 
5. REDUCED APPETITE. Representing the feeling of a 
loss of appetite compared with when well. Rate by loss of 
desire for food or the need to force oneself to eat.  
 
0 – Normal or increased appetite 
1 –  
2 – Slightly reduced appetite 
3 – 
4 – No appetite. Food is tasteless 
5 – 
6 – Needs persuasion to eat at all 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOT USE
rdin
E
rdin
d ill
U
d ill-
U
-defined 
US
defined 
r tension or 
T U
r tension or interm
U
interm
master with some d
T U
master with some d
or anguish. Overwh
OT 
or anguish. Overwh
O
E
DO NO
 SLEEP. 
NO
 SLEEP. Represe
NO
Represe
uration or depth of 
NO
uration or depth of 
s own normal patte
NO
s own normal patte
Sleeps as us
O N
Sleeps as usual
N
ual
1
O
1 –
O
–
2
O
2 –
O
– Slight difficu
DO 
Slight difficu
light, or fitful 
DO
light, or fitful 
3
DO
3 –
DO
–
4
DO
4 –
D
– Slee
DO
Slee
E - D
ght?
D
ght?
ed?
ed?
SAMPLE 
5
D
5 –
D
–
6
D
6
NO
E
D
past week?
E
past week? (What
E
(What
petite?)
LE
petite?)
ed in food? (How m
PLE
ed in food? (How m
d as usual? IF LES
PL
d as usual? IF LES
o force yourself to 
MP
o force yourself to 
r people had to urg
AM
r people had to urg
E
SA
SA
Page 129


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
 
 
___ ___ : ___ ___ 
Yes □                         No □                         N/A □ 
   
Subject Initials: 
Site No. / Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
 
 
 
 
 
 
 
 
 
 
 
 
___ ___/___ ___ ___/___ ___ ___ ___ 
 
 
 
© Williams & Kobak, 2008, v.2 
Clintara Version 1.6 June, 2011
Page 4 of 5
 
Have you had trouble concentrating or collecting your 
thoughts in the past week? (How about at home or at 
work?) IF YES: Can you give me some examples? (Have 
you been able to concentrate on reading a newspaper or 
magazine? Do you need to read things over and over 
again?)  
 
How often has that happened in the past week? Has this 
caused any problems for you? IF YES: Can you give me 
some examples?  
 
Has your trouble concentrating been so bad at any time in 
the past week that it has been difficult to follow a 
conversation? (IF YES: How bad has that been? How often 
has that happened this past week?)  
 
NOTE: ALSO CONSIDER BEHAVIOR DURING 
INTERVIEW. 
 
 
6. CONCENTRATION DIFFICULTIES. Representing 
difficulties in collecting one’s thoughts mounting to 
incapacitating lack of concentration. Rate according to 
intensity, frequency, and degree of incapacity produced.  
 
0 – No difficulties in concentration 
1 – 
2 – Occasional difficulties in collecting one’s thoughts 
3 –  
4 – Difficulties in concentrating and sustaining thought 
which reduces ability to read or hold a conversation 
5 – 
6 – Unable to read or converse without great difficulty 
 
Have you had any trouble getting started at things in 
the past week? IF YES: What things?  
 
Have you had to push yourself to do things?  
IF YES: What things? How hard have you had to push 
yourself? Are you OK once you get started or is it still more 
of an effort to get something done? What about getting 
started at simple routine everyday things (like getting 
dressed)?  
 
Have you done everyday things more slowly than 
usual? (Have you been sluggish?) IF YES: Like what, for 
example? How bad has that been? 
 
7. LASSITUDE. Representing a difficulty getting started, or 
slowness initiating and performing everyday activities.  
 
0 – Hardly any difficulty in getting started. No sluggishness  
1 – 
2 – Difficulties in starting activities 
3 – 
4 – Difficulties in simple routine activities, which are carried 
out with effort 
5 – 
6 – Complete lassitude. Unable to do anything without help 
 
 
 
Have you been less interested in things around you, or 
in activities you used to enjoy? IF YES: What things? 
How bad has that been? How much less interested in 
(those things) are you now compared to before?  
 
Have you been less able to enjoy the things you usually 
enjoy?  
 
Has there been any change in your ability to feel emotions? 
(Do you feel things less intensely than you used to, things 
like anger, grief, pleasure?) IF YES: Can you tell me more 
about that? (IF UNKNOWN: Are you able to feel any 
emotions at all?)  
 
How do you feel toward your family and friends? Is that 
different from usual? IF REDUCED: Do you feel less than 
you used to towards them?  
8. INABILITY TO FEEL. Representing the subjective 
experience of reduced interest in the surroundings, or 
activities that normally give pleasure. The ability to react 
with adequate emotion to circumstances or people is 
reduced.  
 
0 – Normal interest in the surroundings and in other people 
1 – 
2 – Reduced ability to enjoy usual interests 
3 – 
4 – Loss of interest in the surroundings. Loss of feelings for 
friends and acquaintances 
5 – 
6 – The experience of being emotionally paralyzed, inability 
to feel anger, grief or pleasure, and a complete or even 
painful failure to feel for close relatives and friends 
 
 
 
 
 
 
 
 
 
 
NOT USE
o
E
o
uced.
E
uced.
ne’s t
US
ne’s thoughts
US
houghts
 sustaining though
US
 sustaining though
hold a conversatio
U
hold a conversatio
erse without great 
T U
erse without great 
N
E
DO N
ASSITUDE. 
O N
ASSITUDE. Repre
N
Repre
lowness initiating a
O N
lowness initiating a
0
DO
0 –
DO
– Hardly any
DO
Hardly any
1
DO
1 –
DO
–
2
DO
2 –
DO
– Diffi
DO
Diffic
O
c
3
D
3 –
D
–
4
D
4 –
D
–
LE - D
 more
D
 more
tting
D
tting
etting
etting
 slowly than
E -
 slowly than
YES: Like what, f
E
YES: Like what, f
LE
o
D
o
N
LE
D
SAMPLE
ested in things ar
PL
ested in things ar
o enjoy?
PL
o enjoy? IF YES: 
PL
IF YES: 
n? How much less
PL
n? How much less
ou now 
MP
ou now compared
MP
compared
n less able to enjo
AMP
n less able to enjo
ere been any chan
SAM
ere been any chan
you feel things les
SA
you feel things les
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SA
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about that? (IF U
SA
about that? (IF U
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otions at al
S
otions at al
S
LE
Page 130


 
Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
 
 
___ ___ : ___ ___ 
Yes □                         No □                         N/A □ 
   
Subject Initials: 
Site No. / Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
 
 
 
 
 
 
 
 
 
 
 
 
___ ___/___ ___ ___/___ ___ ___ ___ 
 
 
 
© Williams & Kobak, 2008, v.2 
Clintara Version 1.6 June, 2011
Page 5 of 5
 
Have you been putting yourself down, or feeling that 
you’re a failure in some way, over the past week? (Have 
you been blaming yourself for things that you’ve done, or not 
done?) IF YES: What have your thoughts been? How often 
have you felt that way?  
 
Have you been feeling guilty about anything in the past 
week? What about feeling as if you have done 
something bad or sinful? IF YES: What have your 
thoughts been? How often have you felt that way?  
 
ALSO CONSIDER RESPONSES TO QUESTIONS ABOUT 
PESSIMISM FROM ITEM 1. 
 
 
9. PESSIMISTIC THOUGHTS. Representing thoughts of 
guilt, inferiority, self-reproach, sinfulness, remorse, and ruin. 
 
0 – No pessimistic thoughts 
1 – 
2 – Fluctuating ideas of failure, self-reproach, or self 
depreciation 
3 – 
4 – Persistent self-accusations, or definite but still rational 
ideas of guilt or sin. Increasingly pessimistic about the future  
5 – 
6 – Delusions of ruin, remorse, or unredeemable sin. Self-
accusations which are absurd and unshakeable 
 
This past week, have you felt like life isn’t worth living? 
IF YES: Tell me about that. IF NO: What about feeling as if 
you're tired of living?  
 
This week, have you thought that you would be better 
off dead? IF YES: Tell me about that. 
 
Have you had thoughts of hurting or even killing 
yourself this past week? IF YES: What have you thought 
about? How often have you had these thoughts? How long 
have they lasted? Have you actually made plans? IF YES: 
What are these plans? Have you made any preparations to 
carry out these plans? (Have you told anyone about it?) 
 
 
10. SUICIDAL THOUGHTS. Representing the feeling that 
life is not worth living, that a natural death would be 
welcome, suicidal thoughts, and preparation for suicide. 
Suicidal attempts should not in themselves influence this 
rating.  
 
0 – Enjoys life or takes it as it comes 
1 – 
2 – Weary of life. Only fleeting suicidal thoughts 
3 – 
4 – Probably better off dead. Suicidal thoughts are 
common, and suicide is considered as a possible solution, 
but without specific plans or intention 
5 –  
6 – Explicit plans for suicide when there is an opportunity. 
Active preparations for suicide 
 
 
TOTAL MADRS SCALE SCORE: 
 
 
_____________ 
 
Rater Signature: _______________________ 
Date: _________________________ 
 
OT USE
ru
E
ru
, or self 
SE
, or self 
finite but still ration
US
finite but still ration
essimistic about th
US
essimistic about th
e, or unredeemabl
T U
e, or unredeemabl
urd and unshakea
T U
urd and unshakea
OT
E
DO NOT
HOUGHTS.
OT
HOUGHTS. Repre
OT
Repre
th living, that a nat
NO
th living, that a nat
suicidal thoughts, a
NO
suicidal thoughts, a
attempts should n
NO
attempts should n
0 
O
0 –
O
– Enjoy
O
Enjoys life or ta
O N
s life or ta
1
O
1 –
O
–
2
DO
2 –
DO
– Weary of 
DO
Weary of 
3
DO
3 –
DO
–
4
DO
4
E - D
ong
D
ong
YES:
D
YES:
ations to
D
ations to
bout it?)
D
bout it?)
E
–
DO
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DO
Prob
comm
D
comm
but
D
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5
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OT
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SAMPLE 
E:
L
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E
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____________
P
____________
Page 131


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX I. STRUCTURED INTERVIEW GUIDE FOR THE 
HAMILTON RATING SCALE FOR ANXIETY (SIGH-A) - 
SAMPLE 
Page 132


 
 
STRUCTURED INTERVIEW GUIDE FOR THE HAMILTON ANXIETY SCALE 
(SIGH-A) 
 
 
Janet B.W. Williams, D.S.W. 
 
 
INTERVIEWER: The first question for each item should be asked exactly as written. Often this 
question will elicit enough information about the severity and frequency of a symptom for you to 
rate the item with confidence. Follow-up questions are provided, however, for use when further 
exploration or additional clarification of symptoms is necessary. The specified questions should be 
asked until you have enough information to rate the item confidently. In some cases, you may also 
have to add your own follow-up questions to obtain necessary information. For some of the HAM-
A items, you may find you have already asked about some of the symptoms (for a previous item). 
You do not need to 
repeat questions about these symptoms unless you need additional information to rate the 
severity. 
All of the items have the same anchor points. The following may be useful as guides to rating 
item severity: 
 
 
MILD: 
Occurs irregularly and for short periods of time. 
MODERATE: 
Occurs more constantly and of longer duration, requiring 
considerable effort on the part of the subject to cope with it. 
SEVERE: 
Continuous and dominates the subject’s life. 
VERY SEVERE: 
Incapacitating. 
 
 
Interviewers may find it helpful to ask the patient the following questions to help clarify the 
severity of a symptom: How much time does (the symptom) take up? Has (the symptom) been 
irregular or constant? Has it been easily manageable? How severe has it been when you get it? 
How much time over the last week has it been bothering you? 
 
 
NOTES: Time period. The ratings should be based on the patient’s condition in the past week. 
 
 
Panic Attacks. If the patient has panic attacks, this will affect the ratings of many of the 
symptoms. It is recommended that you consider the total amount of time during the past week that 
the panic attack symptoms occurred, as well as their severity. Therefore, for example, a patient who 
has few severe but short–lived panic attacks during the week, but who otherwise does not have 
many anxiety symptoms, would probably not have a very high total HAM-A score. 
 
This instrument provides an interview guide for the Hamilton Anxiety Scale (Hamilton M: The assessment of anxiety states by rating. Brit 
J of Med Psychol 32:50-55, 1959; Hamilton M: The diagnosis and rating of anxiety, In Studies of Anxiety, MM Lader, Ed., Meedley 
Bros., Kent, 1969). The anchor point descriptions for the scale have been taken from the ECDEU Assessment Manuel (Guy, William, 
ECDEU Assessment Manual for Psychopharmacology, Revised 1976,  DMEW Publication No. (ADM) 76-338), except that “sighing” 
and “dyspnea,” which appear twice in that version, have been taken out of the item “cardiovascular symptoms,” and left under 
“respiratory symptoms.” It has been demonstrated that an interview guide strengthens the reliability of individual scale items of the Ham- 
D (Williams J&W: A structured guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 45:742-767, 1988). This work was 
supported in part by NIMN Grant #1 P50 MH 43520. Andrea Gitow, M.S.W. contributed to the current revision of the SIGH-A. 
 
For further information contact 
 at 722 West 168 St., Box 74, N.Y., N.Y. 10032 (Telephone: 
 Revised 3/12/93 
E - DO NOT USE
u
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u to
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SE
rther 
s should be 
SE
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US
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useful as 
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NO
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and of 
O N
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for
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DO
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k k ththe 
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D
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the
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time e doe
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SAMPLE 
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- 
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st week has it bee
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PL
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AM
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AM
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Page 133
PPD
PPD


 
 
 
STRUCTURED INTERVIEW GUIDE FOR THE HAMILTON ANXIETY SCALE 
(SIGH-A) 
 
OVERVIEW: I’d like to ask you some questions about the past week. How have you been 
feeling since last (DAY OF THE WEEK)? IF OUTPATIENT: Have you been working? IF 
NOT: Why not? 
 
MILD: 
Occurs irregularly and for short periods of time. 
MODERATE: 
Occurs more constantly and of longer duration, requiring 
considerable effort on the part of the subject to cope with it. 
SEVERE: 
Continuous and dominates the subject’s life. 
VERY SEVERE: 
Incapacitating. 
 
In the last week, how much have you been 
worrying? 
ANXIOUS MOOD (worries, anticipation of the worst, 
fearful anticipation, irritability): 
 
How much have you been thinking about the worst 
that can happen, or been afraid of what’s going to 
happen? 
 
 
Have you been feeling especially irritable this past 
week? 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
 
IF SCORED 1-4 ABOVE, ASK: How long have you been feeling this way? 
 
In the past week, how much have you felt tense? 
Have you gotten tired easily? 
 
How much have you been bothered by any of these 
things: being startled easily, crying easily, 
trembling, feeling restless, not being able to relax? 
For each SX: How bad has that been this past 
week? 
TENSION (feelings of tension, fatigability, startle 
response, moved to tears easily, trembling, feelings of 
restlessness, inability to relax): 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
 
This past week, have you been afraid of the dark, 
of strangers, of being left alone, of animals, of 
traffic, or of crowds? IF YES:  How afraid? 
FEARS (of the dark, of strangers, of being left alone, 
of animals, of traffic, of crowds): 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
SAMPLE - DO NOT USE
ing
S
ing
p
S
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S
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S
with
S
h it.
SE
it.
rries
T
rries,
T U
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T U
anticipatio
rritability):
T U
rritability):
te
NO
te
re
N
re
r
N
ry 
N
y severe
NO
severe
o
D
ou 
O
u bee
O
been
O
n feelin
O
feeling
O 
g t
ense?
D
ense?
by
by an
any of 
- D
y of these 
D
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g 
E
g easily,
E
easily,
bein
E
being 
E
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E
able to
E
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rel
ha
E
hat 
E
t bee
E
been
E
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E
this
E
s pas
E
pas
TENS
DO
TENS
res
D
res
r
D
r
av
P
ave 
P
e yo
P
you 
PL
u bee
PL
been
PL
n afr
L
afr
M
bein
MP
being
MP
g lef
MP
left 
P
t 
ftf
P
ftf alone
P
alone
crowds
MP
crowds? IF
MP
? IF YES
P
YES
Page 134


 
SIGH-A 
MILD: 
Occurs irregularly and for short periods of time. 
MODERATE: 
Occurs more constantly and of longer duration, requiring 
considerable effort on the part of the subject to cope with it. 
SEVERE: 
Continuous and dominates the subject’s life. 
VERY SEVERE: 
Incapacitating. 
In the last week, have you had trouble falling 
asleep, or had broken sleep, unsatisfying sleep and 
being tired when you wake up, bad dreams, or 
nightmares? FOR EACH SX: How bad has that 
been? 
 
INSOMNIA (difficulty in falling asleep, broken sleep, 
unsatisfying sleep and fatigue on waking, dreams, 
nightmares, night terrors): 
 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
In the last week, have you had trouble 
concentrating, or trouble remembering things? 
How much? 
INTELLECTUAL (difficulty in concentrating, poor 
memory): 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
In the past week, have you felt depressed? 
DEPRESSED MOOD (loss of interest, lack of 
pleasure in hobbies, depression, early waking, 
diurnal swing): 
Have you been less interested in things, or not 
enjoying things you usually enjoy doing? 
This past week, what time have you been waking 
up in the morning for the last time? (Is that with 
an alarm clock, or do you just wake up yourself?) 
This past week, have you been feeling better or 
worse at any particular time of day – morning or 
evening? IF VARIATION: How much worse do 
you feel in the (MORNING OR EVENING)? IF 
UNSURE: A little bit worse or a lot worse? 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
SAMPLE - DO NOT USE
,
S
, broke
SE
broken
SE
n sleep,
E
sleep,
king
S
king, 
S
, dreams,
SE
dreams,
CTUA
NO
CTUAL
NO
L (difficu
O
(difficu
y):
N
y):
 no
not 
N
t present
O N
present
1 –
O
1 – mild
O N
mild
2 – 
O
2 – moderate
O
moderate
3 – 
DO
3 – severe
O
severe
4 – 
DO
4 – ver
O
very
O
y
d? ? 
DE
D
DE
in 
E
in things
E
things, or 
E
, or not
not
enjo
LE
enjoy 
LE
y doing?
LE
doing?
eek
M
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M
, wha
MP
what 
MP
t tim
MP
time 
P
e h
P
h
morning
AM
morning fo
M
for
M
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M
th
r
A
rm 
A
m clock
AM
clock, or do 
AM
, or do 
hi
S
his
SA
s pas
SA
past 
SA
t wee
SA
week,
A
k, h
A
h
wors
SA
worse at 
SA
e at an
SA
any 
A
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p
evening
SA
evening? IF
SA
? IF
you 
S
you fee
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NSU
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NSU
Page 135


 
SIGH-A 
MILD: 
Occurs irregularly and for short periods of time. 
MODERATE: 
Occurs more constantly and of longer duration, requiring 
considerable effort on the part of the subject to cope with it. 
SEVERE: 
Continuous and dominates the subject’s life. 
VERY SEVERE: 
Incapacitating. 
In the last week, have you been bothered by aches 
and pains, muscle twitching, stiffness or sudden 
muscle jerks? 
 
SOMATIC (MUSCULAR) (pain and aches, 
twitching, stiffness, myoclonic jerk, grinding of 
teeth, unsteady voice, increased muscular tone): 
How about grinding your teeth, having an unsteady 
voice, or your muscles being tense? 
IF YES: How bad has that been? (How much has it 
bothered you?) 
In the past week, have you had ringing in your 
ears, blurred vision, hot or cold flashes, feelings of 
weakness, or pricking sensation? IF YES: How bad 
has that been? (How much has it bothered you?) 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
 
 
 
 
SOMATIC (SENSORY) (tinnitus, blurring of vision, 
hot and cold flushes, feelings of weakness, pricking 
sensation): 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
In the past week, has your heart raced, skipped, or 
pounded? Have you had pain in your chest, 
throbbing blood vessels, or fainting feelings? IF 
YES: How bad has that been? 
CARDIOVASCULAR SYMPTOMS (tachycardia, 
palpitations, missing beats, pain in chest, throbbing of 
vessels, fainting feelings): 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
In the last week, have you had pressure or 
tightness in your chest, or choking feelings? IF 
YES: How bad has that been? 
RESPIRATORY SYMPTOMS (pressure or 
constriction in chest, choking feelings, sighing, 
dyspnea): 
What about sighing, or shortness of breath? IF 
YES: How bad has that been? 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe
SAMPLE - DO NOT USE
din
E
ding of 
E
g of 
a
S
ar
S
r tone):
SE
tone):
SENSORY
OT
SENSORY)
OT
) (tinn
OT
(tinn
l
N
ld 
N
d flushes
NO
flushes, 
O
, feelin
O
feelin
on):
N
on):
 no
not 
N
t present
O N
present
1 – 
O
1 – mi
O
mil
O N
ld
O N
d
2 – 
O
2 – moderate
O
moderate
3 – 
DO
3 – severe
O
severe
4 – 
DO
4 – ver
O
very
O
y
kipped
D
kipped, 
D
, or
D
or
chest, 
chest, 
feelings
-
feelings?
- D
? IF
D
IF
CA
D
CA
hav
P
have
P
e yo
PL
you 
PL
u ha
PL
had 
PL
d pr
L
pr
ou
M
our
M
r chest
MP
chest, or 
MP
, or chok
P
chok
ba
M
bad
M
d ha
M
has
MP
s tha
MP
that 
MP
t been
P
been
abou
AM
about 
AM
t sighing
AM
sighing, o
M
, o
: 
A
: Ho
A
How 
AM
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AM
bad 
AM
d ha
AM
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M
s t
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t
Page 136


 
SIGH-A 
MILD: 
Occurs irregularly and for short periods of time. 
MODERATE: 
Occurs more constantly and of longer duration, requiring 
considerable effort on the part of the subject to cope with it. 
SEVERE: 
Continuous and dominates the subject’s life. 
VERY SEVERE: 
Incapacitating. 
In the last week, have you had trouble swallowing? 
Have you had stomach pain or fullness, gas, 
nausea, vomiting, burning or rumbling in your 
stomach, loose bowels, or constipation. IF YES: 
How bad has that been? 
Have you lost weight in the past week? IF YES: 
How much? Have you been trying to lose weight? 
DO NOT RATE LOSS OF WEIGHT DUE TO 
DIETING. 
GASTROINTESTINAL SYMPTOMS (difficulty in 
swallowing, wind, abdominal pain, burning sensations, 
abdominal fullness, nausea, borborygmi, looseness of 
bowels, loss of weight, constipation): 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
In the past week, have you had to urinate 
frequently? Have you had the urge to? 
GENITOURINARY SYMPTOMS (frequency of 
micturition, urgency of micturition, amenorrhea, 
menorrhagia, development of frigidity, premature 
ejaculation, loss of libido, impotence): 
 
How has your interest in sex been in the past 
week? (Here, I’m not asking about performance 
but about your interest in sex.  How much did 
you think about it?). 
FOR WOMEN: Have you had trouble having an 
orgasm in the past week? (When did that start?) 
Have you had your period in the last month or so? 
IF NOT: Do you know why not? IF YES: Was it 
especially heavy? 
FOR MEN: Have you had trouble with premature 
ejaculation (coming too soon) in the past week? 
How about trouble keeping an erection? (When did 
that start?) 
In the past week, has your mouth been dry? Have 
you had any flushing in your face, or have you been 
pale? Have you felt lightheaded, or had any tension 
headaches? How about feeling the hair rise on your 
arms, the back of your neck, or your head? Have 
you tended to sweat a lot in the past week? FOR 
EACH SX: How bad has that been? 
 
 
 
 
 
 
 
 
 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
 
 
 
 
 
 
 
 
 
 
 
AUTONOMIC SYMPTOMS (dry mouth, flushing, 
pallor, tendency to sweat, giddiness, tension headache, 
raising of hair): 
 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
SAMPLE - DO NOT USE
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Hav
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rms,
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0 – 
O
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O N
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present
1 – 
O
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3 – 
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Page 137


 
 
 
 
SIGH-A 
MILD: 
Occurs irregularly and for short periods of time. 
MODERATE: 
SEVERE: 
Occurs more constantly and of longer duration, requiring 
considerable effort on the part of the subject to cope with it. 
Continuous and dominates the subject’s life. 
VERY SEVERE: 
Incapacitating. 
 
 
RATING BASED ON OBSERVATION 
BEHAVIOR AT INTERVIEW (fidgeting, restless or 
pacing, tremor of hands, furrowed brow, strained face, 
sighing or rapid respiration, facial pallor, swallowing, 
belching, brisk tendon jerks, dilated pupils, 
exophthalmos, etc.) 
0 – not present 
1 – mild 
2 – moderate 
3 – severe 
4 – very severe 
 
TOTAL 14-ITEM HAMILTON ANXIETY 
SCORE 
___ ___ 
SAMPLE - DO NOT USE
fidgeting
US
fidgeting,
S
, restles
SE
restles
we
U
wed
U
d brow
US
brow,
US
, strain
S
strain
facia
U
facial 
U
l pallor
US
pallor, 
US
, swa
S
swa
ks
ks, , dilate
U
dilated 
U
d pupils
U
pupils
evere
NO
evere
_
O
__ 
O
_ ___
O N
___
Page 138


Revised Clinical Study Protocol 
CONFIDENTIAL 
Alkermes, Inc. 
(Amendment #3) 
 
ALK5461-208 
APPENDIX J. CLINICAL GLOBAL IMPRESSION SCALE - SEVERITY 
(CGI-S) - SAMPLE 
Page 139


Rater Initials 
Time Performed (24 hours) 
Has the rater changed from the previous assessment? 
 
  
   
 :   
  
 
Yes □ 
No □ 
N/A □ 
1st administration of this 
instrument to this subject 
Subject Initials: 
Subject ID No. 
Date of Assessment (DD/MMM/YYYY) 
Visit No. 
 
  
   
/_       
     _/  
   
 
 
 
 
Clinical Global Impression – Severity (CGI-S) Scale 
 
Considering your total clinical experience with this particular population, how mentally ill is the patient at 
this time? 
□ 
0 = Not assessed 
□ 
1 = Normal, not at all ill 
□ 
2 = Borderline mentally ill 
□ 
3 = Mildly ill 
□ 
4 = Moderately ill 
□ 
5 = Markedly ill 
□ 
6 = Severely ill 
□ 
7 = Among the most extremely ill patients 
 
 
Rater Signature:   
 
Date:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6Busner, J., Targum, S., The Clinical Global Impressions scale: Applying a 
Research Tool in Clinical Practice. Psychiatry, 2007; 4(7):28-37 as adapted 
from Kay, Stanley R., Positive and Negative Symptoms in Schizophrenia: 
Assessment and Research. Clinical and Experimental Psychiatry, 
Monograph No. 5. Brunner/Mazel, 1991. 
 
 
Clintara Version 1.6 June, 2011 
 
 
 
Page 1 of 1 
SAMPLE - DO NOT USE
y
U
y ill
U
ill is
U
is the
US
the pa
US
patien
S
tien
extremely
DO
extremely ill
DO
ill pat
DO
pat
-
Page 140

SAP_001.pdf: 
A Phase 3 Multicenter Study of the Long-term Safety and 
Tolerability of ALKS 5461 for the Adjunctive Treatment of 
Major Depressive Disorder in Adults who Have an 
Inadequate Response to Antidepressant Therapy (the 
FORWARD-2 Study) 
 
Unique Protocol ID: 
ALK5461-208 
NCT Number: 
NCT02141399 
EudraCT Number:  
2014-000380-41 
Date of Statistical Analysis 
Plan:  
15 September 2017 
 


 
 
STATISTICAL ANALYSIS PLAN  
PHASE III 
ALK5461-208 
 
Study Title: 
A Phase 3 Multicenter Study of the Long-term Safety and 
Tolerability of ALKS 5461 for the Adjunctive Treatment of 
Major Depressive Disorder in Adults who Have an 
Inadequate Response to Antidepressant Therapy (the 
FORWARD-2 Study) 
Document Status: 
Final 
Document Date: 
15 September 2017 
Based on: 
Study protocol amendment 3 (dated 03 March 2016) 
Study protocol amendment 2 (dated 12 May 2015) 
Study protocol amendment 1 (dated 17 April 2014) 
Original study protocol (dated 16 December 2013) 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA  02451 
USA 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 
 
 
 


Alkermes, Inc. 
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Page 2 of 57 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Study Objectives ...........................................................................................................7 
1.2. 
Summary of the Study Design and Schedule of Assessments ......................................7 
1.3. 
Criteria for Evaluation ..................................................................................................9 
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION .......................10 
3. 
DATA ANALYSIS ....................................................................................................10 
3.1. 
General Statistical Methodology ................................................................................10 
3.2. 
Study Population .........................................................................................................10 
3.2.1. 
Definitions of Analysis Populations (Analysis Sets) ..................................................10 
3.2.2. 
Disposition ..................................................................................................................13 
3.2.3. 
Protocol Deviations ....................................................................................................13 
3.3. 
Demographics and Baseline Characteristics ...............................................................14 
3.4. 
Prior and Concomitant Medications ...........................................................................14 
3.5. 
Treatment Adherence Rate and Extent of Exposure ...................................................15 
3.6. 
Efficacy Analysis ........................................................................................................16 
3.6.1. 
General Considerations ...............................................................................................16 
3.6.1.1. 
Pooling of Centers ......................................................................................................16 
3.6.1.2. 
Multiple Comparisons/Multiplicity ............................................................................16 
3.6.1.3. 
Examination of Subgroups .........................................................................................16 
3.6.2. 
Efficacy Analysis ........................................................................................................16 
3.6.2.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................16 
3.6.2.2. 
Hamilton Rating Scale for Anxiety (HAM-A) ...........................................................17 
3.6.2.3. 
Clinical Global Impression – Severity (CGI-S) ..........................................................17 
3.7. 
Safety Analysis ...........................................................................................................18 
3.7.1. 
General Considerations ...............................................................................................18 
3.7.2. 
Adverse Events ...........................................................................................................18 
3.7.3. 
Adverse Events of Special Interest .............................................................................20 
3.7.4. 
Clinical Laboratory Parameters ..................................................................................21 
3.7.4.1. 
Descriptive Analysis of Laboratory Parameters .........................................................21 
3.7.4.2. 
Outlier Analyses of Laboratory Parameters ...............................................................22 


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3.7.4.3. 
Hepatic Effects ............................................................................................................25 
3.7.5. 
Vital Signs ..................................................................................................................26 
3.7.6. 
Electrocardiograms .....................................................................................................27 
3.7.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................28 
3.7.8. 
Clinical Opiate Withdrawal Scale (COWS) Scores ....................................................31 
4. 
INTERIM ANALYSES ..............................................................................................32 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................32 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........32 
6.1. 
Analysis Visit Windows .............................................................................................32 
6.2. 
Efficacy Data Handling ..............................................................................................32 
6.3. 
Handling of Partial Dates of Prior and Concomitant Medications .............................33 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................33 
7.1. 
Statistical Conventions ...............................................................................................33 
7.2. 
Reporting Precision ....................................................................................................33 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................34 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................34 
10. 
REFERENCES ...........................................................................................................34 
APPENDIX 1. AESI – ABUSE POTENTIAL ...........................................................................35 
APPENDIX 2. AESI – DEPENDENCE .....................................................................................37 
APPENDIX 3. AESI – WITHDRAWAL ...................................................................................38 
APPENDIX 4. AESI – SUICIDAL IDEATION AND BEHAVIOR .........................................40 
APPENDIX 5. AESI – HYPOMANIA/MANIA ........................................................................41 
APPENDIX 6. AESI – CNS DEPRESSION AND SEDATION................................................42 
APPENDIX 7. AESI – RESPIRATORY DEPRESSION ...........................................................43 
APPENDIX 8. AESI – ORTHOSTASIS HYPOTENSION .......................................................44 
APPENDIX 9. AESI – HYPERSENSITIVITY ..........................................................................45 
APPENDIX 10. AESI – SLOWING OF VENTRICULAR REPOLARIZATION ....................53 
APPENDIX 11. AESI – HEPATIC EFFECTS ...........................................................................54 
APPENDIX 12. AESI – SEXUAL DYSFUNCTION ................................................................57 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Safety Assessments ...................................................................................9 
Table 2: 
Baseline and Study Period for Safety Endpoints ........................................................12 
Table 3: 
Definitions to Define Study Drug Cumulative Exposure ...........................................15 
Table 4: 
Potentially Clinically Significant Abnormal Laboratory Values ................................23 
Table 5: 
Shift Criteria and Denominator for Alanine Aminotransferase (ALT) ......................25 
Table 6: 
Shift Criteria and Denominator for Aspartate Aminotransferase (AST) ....................26 
Table 7: 
Shift Criteria and Denominator for Total Bilirubin (TBILI) ......................................26 
Table 8: 
Potentially Clinically Significant Abnormal Vital Sign Values .................................27 
Table 9: 
Potentially Clinically Significant Abnormal ECG Values .........................................28 
Table 10: C-SSRS Summary Categories for Analysis ................................................................29 
Table 11: Treatment Emergent Suicide-related Events for Analysis ..........................................30 
Table 12: Degree of Precision .....................................................................................................33 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................8 
 


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LIST OF ABBREVIATIONS 
The following abbreviations are used in the statistical analysis plan. 
Abbreviation 
Definition 
ADT 
Antidepressant Therapy 
AE  
Adverse Event  
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BDZ 
Benzodiazapine 
BMI  
Body Mass Index  
BUP 
Buprenorphine 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DILI 
Drug Induced Liver Injury 
ECG  
Electrocardiogram  
eDISH 
Evaluation of Drug-induced Serious Hepatotoxicity 
EOT 
End of Treatment  
ET 
Early Termination 
FAS 
Full Analysis Set 
HAM-A 
Hamilton Rating Scale for Anxiety 
LLRR 
Lower Limit of Reference Range  
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAOI 
Moclobemide 
MDD 
Major Depressive Disorder 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
PCS 
Potentially Clinically Significant  


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Page 6 of 57 
Abbreviation 
Definition 
PDEAE 
Post-discontinuation Emergent Adverse Event 
PLI 
Prospective Lead-in  
PT 
Preferred Term 
QTcF 
QTcF – Fridericia’s Correction Formula 
SAE 
Serious Adverse Event 
SAM 
Samidorphan 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SNRI 
Serotonin-norepinephrine Reuptake Inhibitor 
SOC 
System Organ Class 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TBILI 
Total Bilirubin 
TCA 
Tricyclic Antidepressant 
TEAE 
Treatment Emergent Adverse Events 
ULRR 
Upper Limit of Reference Range  
VS 
Vital Sign 
WHO-ATC 
World Health Organization Anatomical Therapeutic Chemical 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data presentation to be 
used for analyzing and reporting efficacy and safety data for study ALK5461-208 for the 
adjunctive treatment of Major Depressive Disorder (MDD) at study completion. This document 
has been prepared based on Alkermes ALK5461-208 study protocol amendment 3 (dated 03 
March 2016) [1]. 
1.1. 
Study Objectives 
The objective of this study is to assess the long-term safety and tolerability of ALKS 5461 for 
use as an adjunctive therapy to antidepressants for the treatment of MDD.  
1.2. 
Summary of the Study Design and Schedule of Assessments 
This is a Phase 3, multicenter, multinational, study to evaluate the long-term safety and 
tolerability, and to explore treatment effect of 52 weeks of ALKS 5461 administration for use as 
an adjunctive therapy to antidepressants (ADT) for the treatment of MDD in subjects who have 
had 1 or 2 inadequate response to an approved ADT in the current MDE.  
ALKS 5461 was studied at a dose of 2 mg buprenorphine (BUP):2 mg samidorphan (SAM). 
Note that ALKS 5461 dose levels are referred to as doses of BUP/SAM expressed as weight in 
mg (eg, a 2 mg BUP:2 mg SAM dose is expressed as ALKS 5461 2/2). 
All subjects in the study had been treated with an adequate dose of an approved ADT for at least 
8 weeks, at a stable dose over the last 4 weeks prior to study entry.  
Subjects will enter into the study in one of three ways, based on their prior experience with an 
ALKS 5461 study:  
1. New Subjects: those who have not participated in a prior study of ALKS 5461 within 2 
years. 
2. Continuing Subjects: those who have completed the treatment period of study 
ALK5461-205, ALK5461-206, ALK5461-207, or ALK5461-210 within the past 10 days. 
Since some of these antecedent studies were randomized placebo-controlled studies, 
these subjects may or may not have received ALKS 5461 in the prior study. 
3. Lead-in Subjects: those who participated in study ALK5461-205, ALK5461-206, or 
ALK5461-207 within the past 10 days, and met the criteria for response to ADT during 
the prospective lead-in (PLI) period of that antecedent study, but did not meet the criteria 
for remission. These subjects were not eligible for entry into the double-blind treatment 
period in the antecendent and received neither placebo nor ALKS 5461 in the antecedent 
study. 
All New Subjects will be initially evaluated for eligibility at screening (Visit 1), to occur up to 28 
days prior to Visit 2. 
For Continuing Subjects and Lead-in Subjects, Visit 2 will be the first visit of this study and 
there will not be a separate screening visit. Identical assessments taken at the subject’s last visit 


Alkermes, Inc. 
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Page 8 of 57 
of the antecedent study do not need to be repeated at Visit 2 of this study unless more than 10 
days elapses between these visits. 
At Visit 2, all eligible, consenting subjects will begin the treatment period. Subjects entering the 
study already receiving ALKS 5461 will not require titration; all other subjects will require a 
1-week ALKS 5461 titration period. Depending on the antecedent study, the titration may be 
blinded per blinding schemes as described in the protocol. From Week 2 to 52, all participating 
subjects will take ALKS 5461 2/2 and an approved ADT, with allowable ALKS 5461 dose 
adjustments for tolerability as described in the protocol.  
During the 52-week treatment period, subjects will return to the clinic for periodic scheduled 
visits (Visits 2-14) at which safety, tolerability, and treatment effect over time will be assessed. 
A 4-week safety follow-up period will occur following the ALKS 5461 treatment period. During 
the 4-week follow-up period, there are a total of 4 clinic visits (Visits 15-18), as well as 7 safety 
assessments by phone. Please refer to the protocol for a detailed schedule of assessments. A brief 
schematic of study design is provided in Figure 1. A summary of the schedule of safety 
assessments is presented in Table 1.  
Figure 1: 
Study Design Schematic 
 


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Page 9 of 57 
Table 1: 
Schedule of Safety Assessments  
Study 
Number 
Dosing 
Schedule 
(Days) 
Vital 
Signsa 
Clinical 
Laboratory 
Testingb 
12-Lead 
ECG 
C-SSRSd 
COWSe AEs 
ALK5461-
208 
Treatment:  
1-365 (1 
year) 
Titration: 
1-7 (1 
week) 
Safety 
Follow 
Up: 366-
393 (1 
month) 
Screening, 
Days 1c, 8, 
15, 29, 43, 
57, 99, 141, 
183, 225, 
267, 309, 
365, 366, 
372, 379, 
393 
Screening, 
Days 1c, 8, 
99, 183, 
267, 365, 
393 
Screening, 
Days 1c, 
8, 183, 
365, 393 
Screening, 
Days 1c, 8, 
15, 29, 43, 
57, 99, 141, 
183, 225, 
267, 309, 
365, 366, 
372, 379, 
393 
Days 
365, 
366, 
372, 
379, 
393e 
Throughout 
Abbreviations: ECG=electrocardiogram; C-SSRS=Columbia-Suicide Severity Rating Scale; COWS=Clinical Opiate 
Withdrawal Scale; AEs=Adverse Events 
a Vital signs included weight, oral temperature, supine respiratory rate, blood pressure, and heart rate.   
b Chemistry, hematology, and urinalysis.  
c Conducted predose. 
d At screening the “Baseline” version of the C-SSRS was administered and at all other visits the “Since Last Visit” 
version was administered. 
e  COWS was administered by a medical professional. 
1.3. 
Criteria for Evaluation 
Safety and Tolerability: 
The following assessments will be collected to measure safety and tolerability throughout the 
study: 
• Adverse events (AEs) 
• Vital signs (VS) 
• Weight 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• Electrocardiogram (ECG) parameters 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Clinical Opiate Withdrawal Scale (COWS) 
Efficacy: 
The following assessments will be collected to measure treatment effect throughout the study: 
• Montgomery-Asberg Depression Rating Scale (MADRS) 
• Hamilton Rating Scale for Anxiety (HAM-A) 
• Clinical Global Impression - Severity (CGI-S) 


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Page 10 of 57 
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION 
Approximately 1,500 subjects will be enrolled in order to achieve at least 100 subjects with 
12 months and 300 subjects with 6 months of exposure to ALKS 5461. Subjects will enter from 
four feeder studies or enter de novo. The antecedent studies included ALK5461-205, ALK5461-
206, ALK5461-207, and ALK5461-210. 
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology  
The safety and efficacy endpoints will be summarized by prior ALKS 5461 exposure: no prior 
exposure to ALKS 5461 and prior exposure to ALKS 5461, as well as overall.  
Subjects with no prior exposure to ALKS 5461 come from three sources: De Novo (i.e., New 
Subjects), PLI Failures (i.e., antecedent study Prospective Lead-in Subjects Failures) and 
Placebo (i.e., those who did not receive any active treatment in an antecedent study).  
Prior exposure to ALKS 5461 subjects include Continuing Subjects who received active 
treatment (doses ALKS 5461 0.5/0.5, ALKS 5461 1/1, or ALKS 5461 2/2) in an antecedent 
study. Subjects with prior exposure are designated as such independent of the duration of 
exposure in the antecedent trial.  
In general, summary statistics (n, mean, standard deviation [SD], median, minimum, and 
maximum for continuous variables, and number and percentage of subjects in each category for 
categorical variables) based on observed data will be provided by prior ALKS 5461 exposure 
and overall. Measurements collected from unscheduled visits or repeated assessments will not be 
included in the by-visit summary tables or figures, but will be included in categorical outlier 
analyses of post-baseline values and subject listings.  
In general, only data collected during the ALK5461-208 study will be summarized even though 
the baseline may come from an antecedent study. 
Last assessment during treatment period, defined as the last non-missing value from scheduled 
post-baseline visit during the treatment period (i.e., from Visit 2 to Visit 14, inclusive), will be 
included in the by-visit summary tables for both efficacy and safety endpoints as appropriate.  
Source data for the summary tables will be presented as subject data listings. Please refer to 
Section 6.1 on the handling of data collected at an early termination visit.  
3.2. 
Study Population 
3.2.1. 
Definitions of Analysis Populations (Analysis Sets)  
Safety Population consists of all subjects who receive at least 1 dose of study drug in the 
ALK5461-208 study.  
An AE will be considered as a treatment emergent adverse event (TEAE) if it starts or worsens 
(if present at baseline) on or after the baseline during treatment period.  An AE will be 


Alkermes, Inc. 
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Page 11 of 57 
considered as a post-discontinuation emergent adverse events (PDEAE) if it starts or worsens 
after the last dose date plus 1 day. 
Post-discontinuation Safety Population consists of subjects in the Safety Population who have at 
least 1 post-discontinuation measurement. There will be two Post-discontinuation Safety 
Populations, one is used to analyze PDEAE, and the other is to analyze COWS, grouped by 
whether having had exposure to study drug in a prior controlled trial or had no prior exposure. 
Post-discontinuation Safety Population for PDEAE consists of subjects who received at least 1 
dose of study drug, and met one of the following criteria: 
• Subjects who entered the Post-discontinuation Period and had a Post-discontinuation 
Visit  
• Subjects who did not enter the Post-discontinuation Period, but had at least 1 PDEAE 
reported 
• Subjects who died after either completing the treatment or having an Early 
Termination (ET) Visit 
Post-discontinuation Safety Population for COWS consists of subjects who received at least 1 
dose of study drug, had an adequate COWS baseline (defined as end of treatment [EOT] COWS 
assessment) and had at least 1 post-EOT COWS assessment,  where an adequate EOT COWS is 
defined as having been performed within (≤) 2 days of last dose of study drug. 
Full Analysis Set (FAS) consists of subjects in the Safety Population who have at least 1 post-
baseline complete MADRS assessment. 
The baseline for efficacy endpoints is defined as the last non-missing observation on or before 
the date of baseline visit (Visit 2) of ALKS 5461-208 study for subjects who are new to ALKS 
5461 (ie, De Novo, PLI Failures, and Continuing Subjects who received placebo in antecedent 
study); or the last non-missing observation on or before the first dose of ALKS 5461 in 
antecedent study for Continuing Subjects who received any dose of ALKS 5461 (i.e., ALKS 
5461 0.5/0.5, ALKS 5461 1/1, or ALKS 5461 2/2) in antecedent study.  
The baseline and study period are defined in Table 2 for each safety endpoint. Visit 2 is the first 
scheduled visit during treatment period and Visit 14 is the last scheduled visit including ET visit 
during treatment. Please refer to Protocol for detailed schedule of assessments. 


Alkermes, Inc. 
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Table 2: 
Baseline and Study Period for Safety Endpoints 
Safety Endpoint 
Population 
Study Period and Baseline 
AE 
Safety Population 
For AEs, treatment period will include the interval 
between the date of Visit 2 and the last dose date plus 
1 day, inclusive. 
For new subjects, the baseline for TEAEs is defined 
as all AE data collected prior to Visit 2 in Study 
ALK5461-208. For all other subjects, Visit 2 will be 
their first visit of this study, so all the AEs occurred 
or worsened after Visit 2 during treatment period are 
considered as TEAE. 
Lab, VS , ECG 
and C-SSRS 
Safety Population 
For safety endpoints lab, VS, ECG and C-SSRS, the 
treatment period will include assessments collected at 
the Visit 2 baseline visit and all post-baseline visits 
throughout the entire treatment period starting from 
Visit 2 to the last assessment visit date. 
The baseline for these safety endpoints is defined as 
the last non-missing value on or before the date of 
Visit 2. 
PDEAE 
Post-discontinuation 
Safety Population 
for PDEAE 
For PDEAEs, the Post-discontinuation Safety Period 
will be defined as the interval starting from the last 
dose date plus 2 days to the end of study date.  
The baseline for PDEAEs is defined as all data 
collected prior to last dose date plus 2 days. 
COWS 
Post-discontinuation 
Safety Population 
for COWS 
For COWS, Post-discontinuation Safety Period 
covers the values collected from the EOT visit (Visit 
14) through the post-discontinuation visits. 
The post-discontinuation baseline for COWS is 
defined as EOT COWS assessment (Visit 14), and an 
adequate post-discontinuation baseline is defined as 
EOT COWS having been performed within (≤) 2 days 
of last dose of study drug.  


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3.2.2. 
Disposition 
Subject disposition will be summarized for all subjects and for subjects categorized as having 
prior ALKS 5461 exposure and no prior ALKS 5461 exposure. Subjects with no prior 
ALKS 5461 exposure will be further summarized by the following sub-categories: De Novo (i.e., 
New Subjects), PLI Failures (i.e., Lead-in Subjects), and Placebo (i.e., Continuing subjects who 
received only placebo in the antecendent study). The number and percentage of subjects will be 
summarized for the following: 
• Subjects who enrolled in the study 
• Subjects in the Safety Population 
• Subjects in the FAS population 
• Subject who completed treatment (as indicated on the case report form, CRF) 
• Subjects who completed the study (as indicated on the CRF)  
• Subjects who discontinued from the study  
For subjects who prematurely discontinue from the study, the reasons for discontinuation as 
recorded on the disposition CRF will be presented. Percentage will be calculated based on Safety 
Population. Disposition for those subjects who had a down-titratration from the ALKS 5461 2/2 
mg dose will be summarized similarly.  
A listing of disposition will be provided for all subjects. 
Additional analysis will include analysis of time to treatment discontinuation for subjects who 
discontinue from the study. Time to treatment discontinuation will be summarized for those with 
study discontinuation due to any cause and due to AE as indicated on the disposition CRF. For 
those subjects who discontinued due to AE or due to any other reason, time to discontinuation 
will be calculated from the date of the first dose of ALKS 5461 in the ALK5461-208 study (Visit 
2), to the EOT visit date. In analysis of time to treatment discontinuation due to AE, subjects 
who discontinue for other reasons will be censored by day of EOT. The distribution of time to 
treatment discontinuation will be estimated and graphically displayed by prior ALKS 5461 
experience and overall using Kaplan-Meier methods. Time to treatment discontinuation will also 
be summarized by descriptive statistics.  
3.2.3. 
Protocol Deviations 
Subjects with major protocol deviations will be summarized by prior ALKS 5461 exposure and 
overall along with supportive listings for each of the following categories: 
• Did not meet the inclusion / exclusion criteria 
• Received prohibited medications  
• Lack of adherence with study medication, as defined by subjects taking less than 70% 
of the protocol specified amount of study medication  
• Dosing error 
• Other major protocol deviation 


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3.3. 
Demographics and Baseline Characteristics 
For New Subjects only, demographic and baseline characteristics data (including MDD history) 
will be collected at screening visit. For Continuing Subjects and Lead-in Subjects, these data will 
be carried over from information recorded in the antecedent ALKS 5461 study in which they 
participated.  
Demographics and baseline characteristics (age, gender, primary race, ethnicity, region (United 
States [US], non-US), duration of current MDE, ADT Class for current MDE, number of 
inadequate responses to ADT in the current MDE, lifetime number of MDEs, lifetime number of 
antidepressants,  benzodiazepines (BDZ) use, opioid use, H1 antagonist use, height, weight, body 
mass index [BMI]) will be summarized by prior exposure to ALKS 5461, no prior exposure to 
ALKS 5461, and overall for the Safety Population. For no prior exposure to ALKS 5461, the 
group is divided further into 3 subgroups of De Novo, PLI Failures, and Placebo, as well as 
overall. Categories for missing data will be provided as necessary.  
Baseline characteristics for efficacy measurments (MADRS-10 score,  MADRS-6 score, HAM-
A total score, CGI-S score and HAM-D total score) will be summarized by prior exposure to 
ALKS 5461, no prior exposure to ALKS 5461, and overall for the FAS Population. For no prior 
exposure to ALKS 5461, the group is divided further into three subgroups of De Novo, PLI 
Failures, and Placebo, as well as overall. The baseline for efficacy measurements is defined as 
the last non-missing value on or before the date of initiation of ALKS 5461 at any dose.   
Medical and psychiatric history will be summarized using the number of observations and 
percentage of subjects reporting each category by prior ALKS 5461 exposure and overall for the 
Safety Population. 
Demographic and baseline listings will be provided for all subjects.  
3.4. 
Prior and Concomitant Medications 
Prior medications are defined as medications started prior to the first dose of study drug. 
Concomitant medications are defined as medications taken during the period between the first 
dose date and the last dose date of study drug, inclusive. All medications as documented by the 
investigator will be coded using the World Health Organization Anatomical Therapeutic 
Chemical (WHO-ATC) drug dictionary version June 2016.  
Prior medications and concomitant medications will be summarized by ATC code and Preferred 
Term, by Preferred Term, and by prior ALKS 5461 exposure and overall for the Safety 
Population. For the summary tables, if a subject has taken a prior or concomitant medication 
more than once, the subject will be counted only once for the medication.  
In addition, the prior and concomitant ADTs by ADT class (selective serotonin reuptake 
inhibitor [SSRI], serotonin-norepinephrine reuptake inhibitor [SNRI], Tricyclic Antidepressant 
[TCA], Moclobemide [MAOI] and other) and Preferred Term will be summarized similarly.  
Summary tables for benzodiazepines use, opioid use, and sedating H1 antagonist use (prior 
medication / concomitant medication) by Preferred Term and by prior ALKS 5461 exposure and 
overall for the Safety Population will be produced, respectively.   


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A list of subjects taking ADTs, Benzodiazepines (BDZ) and BDZ-like drugs, Opioids, and 
sedating H1 antagonists will be provided. 
3.5. 
Treatment Adherence Rate and Extent of Exposure 
Treatment adherence to the daily dosing schedule of study drug is measured as the rate of actual 
compared to intended number of doses to be taken during the ALK5461-208 study. Percentage 
of treatment adherence will be calculated during 52-week treatment period for the Safety 
Population as follows:  
100 ×
Total tablets taken
Total tablets subject should have taken from the first dose date to the last dose date, inclusive 
Duration of exposure to study drug is defined as the number of days from the first dose date of 
study drug taken to the date of the last dose taken during the ALK5461-208 study, inclusive.    
Treatment adherence and exposure of study drug will be summarized by prior ALKS 5461 
exposure and overall for the Safety Population.  
Treatment adherence will be summarized as a continuous measure using descriptive statistics 
(number of subjects, mean, SD, median, minimum, and maximum) and as a categorical measure 
using the number and percentage of subjects in each adherence rate category (rounded to the 
whole number): <70%; ≥70% to 80%; >80% to 90%; >90% to 100%; >100% to 110%; >110% 
to 119%; and ≥120%.  
The number of subjects exposed to study drug and the average days of treatment will be 
summarized as a continuous measure using descriptive statistics (number of subjects, mean, SD, 
median, minimum, and maximum).    
The exposure to ADT will be summarized by ADT class (SSRI, SNRI, TCA, MAOI and other) 
and Preferred Term (ADT name) using descriptive statistics in a similar fashion. In addition, 
descriptive statistics of mean daily dose of ADT will be summarized by ADT class and Preferred 
Term. 
The descending cumulative exposure of study drug will be categorized as ≥1 day, ≥1 month, ≥3 
months, ≥6 months, ≥9 months and ≥12 months, and will be summarized as a categorical 
measure using the number and percentage of subjects in each category.  
The definitions in Table 3 will be used to define cumulative exposure. 
Table 3: 
Definitions to Define Study Drug Cumulative Exposure 
 
Definition 
Programming Derivation 
≥ 1 day 
≥ 1 day 
 
≥ 1 month 
≥ 23 days (3 weeks) 
≥ (365.25/12)-7 days 
≥ 3 months 
≥ 84 days (12 weeks) 
≥ [(365.25/12)x3]-7 days 
≥ 6 months 
≥ 169 days (24 weeks) 
≥ [(365.25/12)x6]-14 days 
≥ 9 months 
≥ 260 days (37 weeks) 
≥ [(365.25/12)x9]-14 days 
≥ 12 months 
≥ 351 days (50 weeks) 
≥ 365.25 -14 days 


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3.6. 
Efficacy Analysis 
3.6.1. 
General Considerations 
All efficacy analyses will be based on the FAS. Descriptive statistics will be summarized by 
prior ALKS 5461 exposure and overall based on observed data. 
3.6.1.1. 
Pooling of Centers 
No plan to pool study centers.  
3.6.1.2. 
Multiple Comparisons/Multiplicity 
Not applicable. 
3.6.1.3. 
Examination of Subgroups 
No subgroup analysis for efficacy is planned. 
3.6.2. 
Efficacy Analysis  
3.6.2.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS measures the severity of depressive symptoms and consists of 10 items. The 
MADRS-10 is the sum of all 10 items and ranges from 0 to 60. The MADRS-6 is 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 and ranges from 0 to 36. 
Section 6.2 describes the handling of MADRS-10 if any of the items of the MADRS is missing.  
The following endpoints will be assessed: 
• Change from baseline in MADRS-10 and MADRS-6 score 
• Proportion of subjects demonstrating MADRS treatment response, defined as a ≥50%   
reduction in MADRS-10 from baseline  
• Proportion of subjects achieving remission, defined as a MADRS-10 of ≤10 
Descriptive summary statistics of baseline MADRS-10 and MADRS-6 score and change from 
baseline at each visit including the last assessment during treatment period will be provided by 
prior ALKS 5461 exposure and overall based on observed data. In addition, the figures of 
MADRS-10 and MADRS-6 score (including standard error), mean change from baseline 
(including standard error) over time including the last assessment during treatment period will be 
provided by prior ALKS 5461 exposure and overall based on observed data. 
The responder and remission endpoints are derived based on the observed MADRS-10. The 
number and percentage of subjects demonstrating MADRS-10 treatment response and remission 
by visit including the last assessment during treatment period will be provided based on FAS. 
The figures of MADRS-10 responder rate and MADRS-10 remission rate over time including 
the last assessment during treatment period will be provided by prior ALKS 5461 exposure and 
overall.  


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The individual MADRS item scores will not be summarized but will be included in the subject 
listing. 
3.6.2.2. 
Hamilton Rating Scale for Anxiety (HAM-A) 
The HAM-A is a clinician-administered 14-item scale developed to measure the severity of 
anxiety symptoms. The HAM-A total score is the sum of all 14 items and ranges from 0 to 56. 
Section 6.2 describes the handling of total score if any of the items of the HAM-A is missing.  
The following endpoints will be assessed 
• Change from baseline in HAM-A total score 
• Change from baseline in HAM-A psychic subscale, where the psychic subscale is the 
sum of HAM-A items 1 to 6, and item 14 
• Change from baseline in HAM-A somatic subscale, where the somatic subscale is the 
sum of HAM-A items 7 to 13 
Descriptive summary statistics of baseline, HAM-A total score and change from baseline at each 
visit including the last assessment during treatment period will be provided by prior ALKS 5461 
exposure and overall based on observed data. The HAM-A psychic subscale and somatic 
subscale will be summarized in a similar way. In addition, a figure of HAM-A total score 
(including standard error), mean change from baseline (including standard error)  over time 
including the last assessment during treatment period will be provided by prior ALKS 5461 
exposure and overall. 
The individual HAM-A item score will not be summarized but will be included in the subject 
listing. 
3.6.2.3. 
Clinical Global Impression – Severity (CGI-S) 
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the subject's illness 
at the time of assessment, relative to the clinician's past experience with subjects who have the 
same diagnosis. Considering total clinical experience, a subject is assessed on severity of mental 
illness at the time of rating 0=not assessed; 1=normal, not at all ill; 2=borderline mentally ill; 3= 
mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill. The rating of 0 
(not assessed) will be considered as missing.  
Descriptive summary statistics of baseline,  CGI-S score and change from baseline at each visit 
including the last assessment during treatment period and follow up period will be provided by 
prior ALKS 5461 exposure and overall based on observed data.  The number and percentage of 
subjects for each CGI-S category at each visit including the last assessment during treatment 
period and follow up period will also be summarized. In addition, figures of CGI-S score 
(including standard error) and mean change from baseline (including standard error)over time 
including the last assessment during treatment period and follow up period will be provided by 
prior ALKS 5461 exposure and overall based on observed data. 


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3.7. 
Safety Analysis 
3.7.1. 
General Considerations 
All safety endpoints will be summarized by prior ALKS 5461 exposure and overall based on 
observed data for the Safety Population.  
3.7.2. 
Adverse Events 
Adverse events will be coded by System Organ Class and Preferred Term using the Medical 
Dictionary for Regulatory Activities MedDRA version 19.0. The verbatim term will be included 
in the AE listings. An AE will be considered as a treatment emergent adverse event (TEAE) if it 
starts or worsens (if present at baseline) on or after the baseline during treatment period. An AE 
will be considered as a PDEAE if it starts or worsens during the Post-discontinuation Safety 
Period which is after the last dose date plus 1 day. For the determination of TEAEs during the 
treatment period, AEs with the greatest severity before the baseline will be used as the 
benchmark for the comparison of the AEs occurring during the treatment period. For PDEAEs, 
the greatest severity before or on the last dose date plus 1 day will be used as the benchmark for 
the comparison of the AEs occurring during the Post-discontinuation Safety Period.  
All AEs will be listed by subject. TEAEs / PDEAEs, deaths, serious adverse events (SAEs), AEs 
leading to study discontinuation will be included in the summary tables. Summary tables will be 
provided by prior ALKS 5461 exposure and overall for the Safety Population. For AEs leading 
to study discontinuation or deaths, the AEs will be summarized in the period in which the 
discontinuation or death occurred. Drug related TEAEs include those scored as definitely related, 
probably related, and possibly related by the investigator. 
The following summary tables will be produced for the treatment period / Post-discontinuation 
Safety Period by prior ALKS 5461 exposure and overall for the Safety Population: 
• Overview AE summary tables (TEAEs / PDEAEs) 
• TEAEs / PDEAEs by System Organ Class and Preferred Term 
• TEAEs / PDEAEs by Preferred Term in decreasing frequency 
• TEAEs / PDEAEs experienced by ≥5% of subjects (in any group) by Preferred Term  
• TEAEs / PDEAEs by System Organ Class, Preferred Term, and Severity 
• Drug-related TEAEs by System Organ Class and Preferred Term 
• SAEs (fatal and non-fatal) by System Organ Class and Preferred Term 
• SAEs (fatal and non-fatal) by Preferred Term in decreasing frequency  
• AEs leading to study discontinuation by System Organ Class and Preferred Term 
• AEs leading to study discontinuation by Preferred Term in decreasing frequency  
• TEAEs by System Organ Class, Preferred Term, and Duration of Exposure 
• TEAEs by Preferred Term in decreasing frequency and Duration of Exposure 
• Duration of TEAEs experienced by ≥5% of All Subjects by Preferred Term 


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• Incidence of TEAEs experienced by ≥5% of All Subjects by Preferred Term and 
Exposure Interval 
A subject having the same AE (as determined by the coded MedDRA preferred term) more than 
once will be counted only once in the calculation of the number and percentage of subjects for 
that AE. Similarly, if a subject has more than one AE in a System Organ Class, the subject will 
be counted only once in the number of subjects with an AE for that System Organ Class. If a 
subject has the same AE on multiple occasions, the highest severity (severe > moderate > mild) 
recorded for the event will be presented in the AE by severity summary. Similarly, if a subject 
has the same AE on multiple occasions, the closest relationship (related > not related, where 
related includes definitely related, probably related, and possibly related; and not related includes 
probably not related and definitely not related) recorded for the event will be presented in the AE 
by relationship summary. If a subject has the same AE on multiple occasions, the first 
presentation will be used in the incidence table and the longest duration will be used in the 
duration table.  
The number and percentage of subjects with TEAE during the ALK5461-208 study will be 
summarized by System Organ Class, Preferred Term, and duration of exposure since the first 
dose of the study drug in the ALK5461-208 study (1 day to <1 month, ≥1 to <3 months, ≥3 to <6 
months, ≥6 to <9 months, ≥9 to <12 months, and ≥12 months). For each exposure interval, the 
percentage will be calculated as the number of subjects with a new TEAE that started during the 
exposure interval, relative to the number of subjects exposed during the interval. Separate tables 
for prior ALKS 5461 exposure and overall will be provided.  
Descriptive statistics (number of subjects, mean, SD, median, 10th percentile, 90th percentile, 
minimum, and maximum) of duration (days) of TEAEs experienced by ≥5% of All Subjects will 
be provided by Preferred Term during treatment period for the Safety Population. The duration is 
defined as number of days from the TEAE start date to the TEAE stop date during the 
ALK5461-208 study, inclusive.  If a TEAE is ongoing at the end of the treatment period, the 
TEAE stop date is imputed by last dose date plus 1 day. For those subjects who have the same 
event (same PT term) that is treatment emergent on multiple occasions, we will choose the 
longest duration as stated above. For partial TEAE start or stop date: 
• If only day is missing but month available, TEAE start date will be imputed as the 
first day of the month and TEAE stop date will be imputed as the last day of the 
month. 
• If both month and day are missing, TEAE start date will be imputed as the Visit 2 
date or January 1st whenever applicable, and TEAE stop date will be imputed as the 
last dose date or December 31st whenever applicable. 
The Incidence (%) of TEAEs experienced by ≥5% of All Subjects by Preferred Term and 
Exposure Interval (1 day to <1 month, ≥1 to <3 months, ≥3 to <6 months, ≥6 to <9 months, ≥9 to 
<12 months, and ≥12 months) will be presented by prior ALKS 5461 exposure and overall 
during treatment period for the Safety Population. For those subjects who have the same event 
(same PT term) that is treatment emergent on multiple occasions, the first instance where that 
event was treatment emergent will be used, as stated above. The incidence (%) is calculated by 
n/m x 100%, where n is defined as the number of subjects with newly emergent or worsened 
adverse events during the exposure interval; m is defined as the number of subjects who had 


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treatment exposure during the exposure interval. The incidence (%) of TEAE over time will also 
be presented graphically. For each preferred term, a bar graph will be presented by prior ALKS 
5461 exposure and overall. The number of n/m of three groups will be listed below the figure.   
Subgroup analyses are planned for TEAEs only. Subgroups to include:  
• Demographics (age [<55 years, ≥55 years], race [white, all other races], gender 
[female, male]) 
• Region (US, non-US) 
• ADT class (SSRI, SNRI, and other)  
• Benzodiazepines use (yes, no) 
• Opioid use (yes, no) 
A subject is considered as having used a Benzodiazepine (BDZ) or BDZ-like drug (“yes” 
subgroup) if the subject was taking any concomitant medication in the Benzodiazepine group for 
any duration in the treatment period of interest. A subject is considered as not having used a 
Benzodiazepine (BDZ) or BDZ-like drug (“no” subgroup) if the subject was not taking any 
concomitant medication in the Benzodiazepine group and sedating H1 antagonist group.  
Similarly, a subject is considered as having used an opioid drug (“yes” subgroup) if the subject 
was treated with any concomitant medication in the opioid classification for any duration in the 
treatment period of interest. A subject is considered as not having used an opioid drug (“no” 
subgroup) if the subject was not treated with any concomitant medication in the opioid 
classification. A table of SAE by System Organ Class and Preferred Term for opioid use will be 
presented. 
Subject listings for AEs will be included. 
3.7.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) will be summarized by Preferred Term and by prior 
ALKS 5461 exposure and overall during treatment period for the Safety Population / Post-
discontinuation Safety Population for any TEAEs or PDEAEs of special interest. The following 
summaries will be created for AESI: 
• TEAEs associated with abuse potential  
• TEAEs associated with dependence  
• PDEAEs associated with withdrawal 
• TEAEs associated with suicidal ideation and behavior  
• TEAEs associated with hypomania / mania  
• TEAEs associated with central nervous system (CNS) depression and sedation  
• TEAEs associated with respiratory depression  
• TEAEs associated with orthostasis / hypotension  
• TEAEs associated with hypersensitivity  


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• TEAEs associated with slowing of ventricular repolarization  
• TEAEs associated with hepatic effects  
• TEAEs associated with sexual dysfunction 
TEAEs associated with abuse potential will be presented by Adhoc System Organ Class and 
Preferred Term, where Adhoc System Organ Class is manually classified by Alkermes medical 
director as 3 categories: abuse behavior, euphoria related, and non-specific. 
TEAEs associated with dependence will be presented for subjects with any exposure, ≥4 weeks 
exposure, and <4 weeks exposure, respectively. 
PDEAEs associated with withdrawal will be preseneted for subjects with any exposure, ≥4 
weeks exposure, and <4 weeks exposure, respectively. AESIs associated with withdrawal are 
PDEAEs that occur from >2 to 16 days post last dose as this is the period during which 
physiological opioid withdrawal presents by considering half-lives of both BUP and SAM.   
Supportive AE listings will be provided for each special interest group. Narratives will be 
provided for clinically meaningful events within each AESI group. 
3.7.4. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional units. Only scheduled laboratory 
assessments will be included in the summaries of mean and change from baseline descriptive 
analyses. Laboratory assessments from both scheduled and unscheduled visits will be included in 
outlier analyses. Outlier analyses will not include post-discontinuation assessments. All 
laboratory data will be included in the listings. Parameter order for summary tables and listings 
will be by system (renal, hepatic, etc.).  
3.7.4.1. 
Descriptive Analysis of Laboratory Parameters 
Numerical laboratory results (baseline and change from baseline) for chemistry and hematology 
parameters and urinalysis (pH and Specific Gravity) for each visit during the entire study 
(including last assessment during treatment period and visits in Post-discontinuation Safety 
Period) will be summarized (number of subjects, mean, SD, median, minimum, and maximum) 
by prior ALKS 5461 exposure and overall for the Safety Population.  
In addition, baseline and post-baseline observed values (lowest, highest, last assessment during 
treatment period), and change from baseline to lowest, highest and last assessment values during 
the treatment period for chemistry and hematology parameters, urinalysis (pH and Specific 
Gravity), will be summarized by prior ALKS 5461 exposure and overall for the Safety 
Population. 


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The following graphical displays for laboratory parameters (chemistry, hematology, and 
urinalysis) will be presented during the entire study (including last assessment during treatment 
period and Post-discontinuation Safety Period) by prior ALKS 5461 exposure and overall for the 
Safety Population: 
• Line graphs for mean change from baseline along with the corresponding standard 
error (SE; including Post-discontinuation Safety Period)  
• Box-and-Whisker figures for baseline and post-baseline observed values (lowest, 
highest, last assessment during treatment period)  
• Box-and-Whisker figures for change from baseline to the lowest post-baseline value, 
the highest post-baseline value, and the last scheduled post-baseline value during 
treatment period 
• Scatter plots for baseline and post-baseline observed values (lowest, highest, last 
assessment during treatment period) 
3.7.4.2. 
Outlier Analyses of Laboratory Parameters 
The number and percentage of subjects with values considered potentially clinically significant 
(PCS) occurring at any post-baseline visit during treatment period for selected parameters will be 
summarized. For PCS, the summary will be provided by prior ALKS 5461 exposure and overall 
for the Safety Population. These analyses do not include Post-discontinuation Safety Period. 
Clinical laboratory test values, scheduled or unscheduled, will be considered PCS if they meet 
the PCS criteria listed in Table 4. The percentage will be calculated relative to the number of 
subjects with available non-PCS baseline values with respect to the specific criterion and at least 
1 post-baseline assessment. The numerator is the total number of subjects with a non-PCS 
baseline value with respect to the specific criterion and at least 1 post-baseline PCS value. A 
supportive listing will present all values for a parameter for subjects with at least 1 PCS value for 
that parameter. 
Shift tables for shift from within normal reference limits / high to low and shift from within 
normal reference limits / low to high during treatment period will be provided for chemistry, 
hematology, and urinalysis parameters with conventional reference limits (limits provided by the 
performing laboratories) by prior ALKS 5461 exposure and overall for the Safety Population. 
For parameters which have gender and / or age specific limits, the categories will be based on the 
specific limits. High is defined as values greater than the upper limit of the reference range 
(ULRR). Low is defined as values less than the lower limit of the reference range (LLRR). 
Normal reference limits is defined as values within normal range. The analysis population 
consists of subjects in the Safety Population with a baseline value outside the specific shift 
direction. All laboratory values collected during the treatment period will be considered in this 
analysis.  


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The percentages  will be calculated for the shift summary as follows: 
• For the shifts from within normal reference limits / high to low: the numerator is 
defined as the number of subjects with a post-baseline result below the LLRR, and 
the denominator is defined as the number of subjects with a baseline value within the 
limits or above the ULRR. 
• For the shifts from within  normal reference limits / low to high: the numerator is 
defined as the number of subjects with a post-baseline results above the ULRR, and 
the denominator is defined as the number of subjects with a baseline value within the 
limits or below the LLRR.  
Pregnancy and drug screening data will be listed. For urinalysis, rate of abnormalities at any 
post-baseline visit during treatment period will be summarized.  
Table 4: 
Potentially Clinically Significant Abnormal Laboratory Values 
Category 
Parameter 
Criteria 
Hematology  
Eosinophils 
>1.0x103/µL 
Hematocrit  
≤32% and 3 point decrease from baseline (Female) 
≤37% and 3 point decrease from baseline (Male) 
Hemoglobin  
≤9.5 g/dL (Female) 
≤11.5 g/dL (Male) 
Leukocytes 
≤2.8x103/µL 
≥16x103/µL 
Neutrophils, Absolute 
<1.5x103/µL 
Platelets  
<75.1x103/µL 
≥700x103/µL 
Chemistry 
 
Alanine Aminotransferase 
≥3xULRR 
Albumin 
<2.5 g/dL 
Alkaline Phosphatase 
≥3xULRR 
Aspartate Aminotransferase 
≥3xULRR 
Bicarbonate 
<15 mmol/L 
>31 mmol/L 
Blood Urea Nitrogen (BUN) 
>30 mg/dL 
Calcium 
<8.2 mg/dL 
>12 mg/dL 
Chloride 
≤90 mmol/L  
≥118 mmol/L 
Creatine Phosphokinase  
>3xULRR 
Creatinine 
≥2 mg/dL 


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Table 4: 
Potentially Clinically Significant Abnormal Laboratory Values (Continued) 
Category 
Parameter 
Criteria 
 
Gamma Glutamyltransferase 
≥3xULRR 
Glucose 
<50 mg/dL  
>200 mg/dL 
HDL Cholesterol 
≤30 mg/dL 
Lactate Dehydrogenase 
>3xULRR 
LDL Cholesterol 
≥160 mg/dL 
Phosphate 
<2 mg/dL 
>5 mg/dL 
Potassium 
<3 mmol/L 
>5.5 mmol/L 
Prolactin 
>1xULRR 
Sodium 
<130 mmol/L 
>150 mmol/L 
Total Bilirubin 
≥2 mg/dL 
Total Cholesterol 
>300 mg/dL 
Triglycerides 
≥120 mg/dL (Female) 
≥160 mg/dL (Male) 
Uric Acid 
>9 mg/dL 
>8 mg/dL (Female) 
>10 mg/dL (Male) 
Urinalysis 
Glucose 
Protein 
at least 2+ 
Abbreviations: BUN=blood urea nitrogen; HDL=high density lipoproteins; LDL=low density lipoprotein; 
ULRR=upper limit of referene range  
 


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3.7.4.3. 
Hepatic Effects 
Analyses on hepatic analytes will be performed on some laboratory measures to assess potential 
hepatic effects and will include alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP),  and total bilirubin (TBILI).  Hepatic effects will be 
explored using drug induced liver injury (DILI) criteria from the FDA guidance as well as Hy’s 
Law criteria and through individual frequencies of abnormalities compared to reference limits. 
Summaries will be presented by prior ALKS 5461 exposure and overall for the Safety 
Population. DILI and Hy’s Law criteria are defined relative to the ULRR as follows:  
• ((ALT or AST) ≥3xULRR) & (TBILI≥1.5xULRR) 
• ((ALT or AST) ≥3xULRR) & (TBILI≥1.5xULRR) & (ALP<2xULRR) 
• ((ALT or AST) ≥3xULRR) & (TBILI≥2xULRR) 
• ((ALT or AST) ≥3xULRR) & (TBILI≥2xULRR) & (ALP<2xULRR) 
To complement the DILI and Hy’s Law analyses described above, an “evaluation of drug-
induced serious hepatotoxicity” (eDISH) plot will present maximum TBILI versus maximum 
ALT / AST by study group during treatment period for the Safety Population. Individual subject 
values for the maximum ALT / AST value expressed as the multiple of the ULRR versus the 
maximum TBILI value also expressed as the multiple of the ULRR will be presented. Reference 
lines will indicate values that fall within the range of DILI or Hy’s Law criteria. 
The listing of subjects meeting the DILI or Hy’s Law citeria with all values of relevant 
laboratory parameters will be provided. 
The number and percentage of subjects with certain baseline values for ALT, AST, TBILI and 
who have any post-baseline values meeting the shift criteria specified in Table 5, Table 6 and 
Table 7 during treatment period will be summarized, respectively. The numerator is the number 
of subjects with baseline meeting the specific baseline criterion and at least 1 post-baseline 
assessment. The denominator is the number of subjects with baseline meeting the specific 
baseline criterion and at least 1 post-baseline ALT / AST / TBILI elevation value. 
Table 5: 
Shift Criteria and Denominator for Alanine Aminotransferase (ALT)  
 
ALT Elevations 
During Treatment 
Period 
Denominator  
All Subjects 
Subjects with Baseline 
Values ≤1xULRR 
Subjects with Baseline 
Values >1xULRR 
 ≥3xULRR  
Baseline <3xULRR 
Baseline ≤1xULRR 
Baseline >1xULRR 
 ≥5xULRR  
Baseline <5xULRR 
 ≥10xULRR  
Baseline <10xULRR 
 ≥20xULRR  
Baseline <20xULRR 
Abbreviations:  ULRR=upper limit of reference range  


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Table 6: 
Shift Criteria and Denominator for Aspartate Aminotransferase (AST)  
 
AST Elevations 
During Treatment 
Period 
Denominator  
All Subjects 
Subjects with Baseline 
Values ≤1xULRR 
Subjects with Baseline 
Values >1xULRR 
 ≥3xULRR  
Baseline <3xULRR 
Baseline ≤1xULRR 
Baseline >1xULRR 
 ≥5xULRR  
Baseline <5xULRR 
 ≥10xULRR  
Baseline <10xULRR 
 ≥20xULRR  
Baseline <20xULRR 
Abbreviations:  ULRR=upper limit of reference range  
Table 7: 
Shift Criteria and Denominator for Total Bilirubin (TBILI)  
Total Bilirubin Elevations During 
Treatment Period 
Denominator  
 ≥2xULRR  
All Subjects with Baseline <2xULRR 
 ≥2xULRR  
Baseline ≤1xULRR 
 ≥2xBaseline  
Baseline >1xULRR 
Abbreviations:  ULRR=upper limit of reference range  
3.7.5. 
Vital Signs 
Vital signs (supine systolic and supine diastolic blood pressure, heart rate, respiratory rate, 
temperature, weight, and BMI) will be summarized for baseline and change from baseline (BMI 
baseline only) by prior ALKS 5461 exposure and overall for the Safety Population, and will 
include post-discontinuation assessments.  
In addition, baseline and post-baseline observed values (lowest, highest, last assessment during 
treatment period), and change from baseline to lowest, highest and last assessment values during 
treatment period for vital sign parameters will be summarized by prior ALKS 5461 exposure and 
overall for the Safety Population, and will not include post-discontinuation assessments. 
The following graphical displays for vital sign parameters will be presented by prior ALKS 5461 
exposure and overall for the Safety Population: 
• Line graphs for mean change from baseline along with the corresponding SE 
(including Post-discontinuation Safety Period)  
• Box-and-Whisker figures for baseline and post-baseline observed values (lowest, 
highest, and last assessment during treatment period)  
• Box-and-Whisker figures for change from baseline to the lowest post-baseline value, 
the highest post-baseline value, and the last scheduled post-baseline value during 
treatment period 
• Scatter plots for baseline and post-baseline observed values (lowest, highest, and last 
assessment during treatment period) 


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Vital signs will also be evaluated using PCS criteria as indicated in Table 8 and summarized by 
prior ALKS 5461 exposure and overall for the Safety Population. Post-discontinuation 
assessments will not be included in this analysis.  
Table 8: 
Potentially Clinically Significant Abnormal Vital Sign Values 
Parameter 
PCS Criteria 
Temperature 
 
Hyperthermia: ≥38.1°C 
Hypothermia: ≤35.0°C  
Supine Systolic Blood Pressure 
Low: ≤90 mm Hg and decrease ≥20 mm Hg 
High: ≥140 mm Hg and increase ≥20 mm Hg 
Supine Diastolic Blood Pressure 
Low: ≤50 mm Hg and decrease ≥10 mm Hg 
High: ≥90 mm Hg and increase ≥10 mm Hg 
Heart Rate 
Low: ≤50 bpm and decrease ≥15 bpm 
High: ≥100 bpm and increase ≥15 bpm 
Respiratory Rate 
 
Low: <12 breaths per minute 
High: >25 breaths per minute 
Body Weight 
Decrease from baseline ≥7% 
Increase from baseline ≥7% 
A supportive listing will present for subjects and parameter for cases where at least 1 value was 
potentially significant. 
3.7.6. 
Electrocardiograms 
Electrocardiogram (ECG) parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTcF [QT interval corrected using Fridericia's method]) will be summarized 
(baseline and change from baseline) for each visit during the entire study, including last 
assessment during treatment period and post-discontinuation assessments. 
In addition, baseline and post-baseline observed values (lowest, highest, last assessment during 
treatment period), and change from baseline to lowest, highest and last assessment values during 
treatment period for ECG parameters will be summarized by prior ALKS 5461 exposure and 
overall for the Safety Population. These analyses will not include post-discontinuation values. 


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The following graphical displays for ECG will be presented by prior ALKS 5461 exposure and 
overall for the Safety Population: 
• Line graphs for mean change from baseline along with the corresponding SE 
(including Post-discontinuation Safety Period)  
• Box-and-Whisker figures for baseline and post-baseline observed values (lowest, 
highest, last assessment during treatment period)  
• Box-and-Whisker figures for change from baseline to the lowest post-baseline value, 
the highest post-baseline value, and the last scheduled post-baseline value during 
treatment period 
• Scatter plots for baseline and post-baseline observed values (lowest, highest, last 
assessment during treatment period) 
ECG will be evaluated using PCS criteria as indicated in Table 9 by prior ALKS 5461 exposure 
and overall for the Safety Population. These analyses will not include post-discontinuation 
assessments. 
Table 9: 
Potentially Clinically Significant Abnormal ECG Values 
ECG Parameter 
PCS Criteria 
PR Interval 
High: ≥220 msec 
QRS Interval 
High: ≥120 msec 
QTcF 
 
Low: <330 msec 
High: >450 msec;  >480 msec;  >500 msec   
Only cumulative incidence above the indicated limits 
QTcF 
Change from baseline increase/decrease >30 msec 
Change from baseline increase/decrease >60 msec 
Heart Rate 
Low: ≤50 bpm and decrease ≥15 bpm 
High: ≥100 bpm and increase ≥15 bpm 
A supportive listing will present all values for a parameter for subjects with at least 1 PCS value 
for that parameter. 
3.7.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Columbia Suicide Severity Rating Scale items of suicidal behavior and suicidal ideation will be 
summarized at baseline and post-baseline by prior ALKS 5461 exposure and overall for the 
Safety Population. The proportion of subjects who meet the criterion for each of these categories 
will be summarized as described in Table 10. Each item will be presented separately within each 
category (suicidal behavior, suicidal ideation, self-injurious behavior without suicidal intent). 
Any suicide attempt (aborted, interrupted, and actual) will also be summarized as a category. 
Data will be presented for baseline, any post-baseline (i.e. on treatment), and any post-
discontinuation values. 


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Any behaviors experienced will be listed with a brief narrative. Any completed suicides will be 
presented with full narrative.  
Table 10: 
C-SSRS Summary Categories for Analysis 
Category 
C-SSRS item response is "YES"  
Suicidal ideation 
1) Wish to be dead 
2) Non-specific active suicidal thoughts  
3) Active suicidal ideation with any methods (not 
plan) without intent to act  
4) Active suicidal ideation with some intent to 
act, without specific plan 
5) Active suicidal ideation with specific plan and 
intent 
Suicidal behavior 
6) Preparatory acts or behavior 
7) Aborted attempt  
8) Interrupted attempt  
9) Actual attempt 
10) Completed suicide 
Suicidal behavior or ideation 
Including 10 items above 
Self-injurious behavior without suicidal intent 
Purely for other reasons / without any intention of 
killing yourself 
Summary of treatment emergent suicide-related events based on the C-SSRS during treatment 
period will be presented by prior ALKS 5461 exposure and overall for the Safety Population. 
The degree and type of treatment emergent suicide-related events will be summarized in a table 
as defined in Table 11. Post-discontinuation assessments will not be included in this analysis. 
This analysis population consists of safety population with non-missing baseline and at least 1 post-
baseline assessment during treatment period. The percentage will be calculated for the treatment 
emergent suicide-related event summary. The numerator is defined as the number of subjects 
with a non-missing baseline and a post-baseline C-SSRS assessment meeting the treatment 
emergent suicide-related numerator criteria defined in Table 11, and the denominator is defined 
as the number of subjects with a non-missing baseline and at least 1 post-baseline C-SSRS 
assessment meeting the treatment emergent suicide-related denominator criteria defined in 
Table 11 during treatment period. 


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Table 11: 
Treatment Emergent Suicide-related Events for Analysis 
Treatment Emergent Suicide-
related Events 
Denominator Criteria 
Numerator Criteria 
Increase in Suicidal Ideation from 
Baseline 
Baseline suicidal ideation 
(“No” to all ideation items 1-
5,  or “Yes” to any ideation 
item ≤4 and “No” to item 5)  
Baseline suicidal ideation (“No” 
to all ideation items 1-5,  or “Yes” 
to any ideation item ≤4 and “No” 
to item 5) 
Post-baseline (increase in suicidal 
ideation severity from baseline at 
any post-baseline visit)  
Emergence of Serious Suicidal 
Ideation 
Baseline suicidal ideation 
(“No” to all ideation items 1-
5, or “Yes” to any ideation 
item≤3 and “No” to items 4 
and 5)  
 
Baseline suicidal ideation (“No” 
to all ideation items 1-5, or “Yes” 
to any ideation item ≤3 and “No” 
to items 4 and 5) 
Post-baseline (“Yes” to ideation 
item 4 or 5 at any post-baseline 
visit) 
Emergence of Serious Suicidal 
Ideation in Subjects with no 
Suicidal Ideation at Baseline 
Baseline ideation (“No” to all 
ideation items 1-5) 
Baseline ideation (“No” to all 
ideation items 1-5)  
Post-baseline (“Yes” to ideation 
item 4 or 5 at any post-baseline 
visit)  
Decrease in Suicidal Ideation from 
Baseline 
Baseline ideation ( “Yes” to 
any ideation items 1-5) 
Baseline ideation ( “Yes” to any 
ideation items 1-5) 
Post-baseline (decrease in suicidal 
ideation severity at any post-
baseline visit compared to severity 
at baseline) 
Emergence of Suicidal Behavior in 
Subjects with no Suicidal Behavior 
at Baseline 
Baseline behavior (“No” to all 
behavior items 6-10)  
 
Baseline behavior (“No” to all 
behavior items 6-10)  
Post-baseline behavior (“Yes” to 
any behavior items 6-10 at any 
post-baseline visit) 


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3.7.8. 
Clinical Opiate Withdrawal Scale (COWS) Scores 
COWS will be administered only at EOT and post-discontinuation visits, so COWS will be 
analyzed for Post-discontinuation Safety Population.  For Post-discontinuation Safety 
Population, baseline COWS is defined as EOT COWS assessment. Adequate COWS baseline is 
defined as EOT COWS assessment being performed within (≤) 2 days of last dose of study drug.   
Subjects will be included in the COWS analysis if they have an adequate EOT COWS and at 
least 1 post-EOT COWS in the post-discontinuation safety period. COWS will be summarized 
by:  
• Analysis of all post-EOT COWS assessments   
• Analysis of post-EOT COWS assessments that occurred from >2 to 16 days post last 
dose of study drug 
Subjects with inadequate EOT COWS, i.e. EOT COWS assessment was performed more than 
(>) 2 days of last dose, will be included in a supportive listing. 
Although opioid withdrawal might not be expected in individuals with less than 4 weeks of drug 
exposure, COWS will be presented in all subjects with adequate EOT COWS, and then COWS 
will be subset by duration of study drug exposure. Three COWS analyses will be presented for 
the subjects with adequate EOT COWS by the 3 exposure subgroups (any exposure, ≥4 weeks 
exposure, <4 weeks exposure):  
• Total COWS scores (baseline and change from baseline, and days between last dose 
and assessment date) will be summarized by visit (baseline, post-discontinuation 
visits)  
• Subject count and incidence will be provided by visit for each of the COWS total 
score categories indicated below:  
− No withdrawal: total score 0-4 
− Mild withdrawal: total score 5-12 
− Moderate withdrawal: total score 13-24 
− Moderately severe withdrawal: total score 25-36 
− Severe withdrawal: total score >36 
• COWS category shift summary from baseline to post-baseline: the numerator is the 
number of subjects in each post-discontinuation COWS category with non-missing 
baseline COWS. If there are more than one post-discontinuation COWS, i.e. a subject 
with an unscheduled visit, the highest value will be used. The denominator is the 
number of subjects in each baseline COWS category.  
Data listing of COWS scores at each visit will be provided. Narratives will be provided for any 
clinically meaningful COWS shifts.  


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4. 
INTERIM ANALYSES  
No interim analysis is planned.   
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
N/A. 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Every attempt must be made to provide complete data. In cases where complete data cannot be 
collected, the principles to assign the analysis visits for inclusion in summary tables described in 
this section will be followed for data handling and analyses. 
Early termination visits for efficacy measurements will be mapped to the next scheduled visit. 
For example, a subject who terminates shortly after Day 29 (e.g., has assessments at baseline 
through Day 29, and Day 365 or early termination) would have assessments at early termination 
mapped to the next scheduled visit for each assessment. In this example, the MADRS and CGI-S 
from the early termination visit would be mapped to Day 43; and the HAM-A results would be 
mapped to Day 57. For other visits other than early termination / Day 365, the visit number 
indicated on the CRF (i.e., CRF visit) will be used as the analysis visit. 
Early termination visits for safety measurements will not be mapped to any scheduled post-
baseline visit, but will be used as the last assessment during treatment period.  
Measurements collected from unscheduled visits will not be included in the by-visit summary 
tables or mean change analyses but will be included in the analysis of outlier and PCS values and 
in the subject listings. 
6.2. 
Efficacy Data Handling 
MADRS-10 is the sum of the 10 items from the MADRS. HAM-A total score is the sum of 14 
items from the HAM-A. If only one of the items of the MADRS, or HAM-A for a given visit is 
missing, then the total score will be calculated using (sum of non-missing items) × (total number 
of items) / (number of non-missing items). If more than one of the items are missing, the total 
score will be set to missing. The MADRS-6 and HAM-A subscale scores will be set to missing if 
any item is missing. 


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6.3. 
Handling of Partial Dates of Prior and Concomitant Medications 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. In the 
case of completely missing stop date, medication will be assumed to be ongoing. 
7. 
GENERAL STATISTICAL METHODOLOGY 
7.1. 
Statistical Conventions 
In general, summary statistics (n, mean, standard deviation [SD], median, minimum and 
maximum for continuous variables, and number and percentage of subjects in each category for 
categorical variables) will be provided by study group. All summary tables will be based on 
observed data, and missing values will not be imputed unless otherwise indicated. Measurements 
collected from unscheduled visits or repeated assessments will not be included in the by-visit 
summary or mean change tables or figures, but will be included in the analyses for the outlier / 
PCS post-baseline values, and subject listings. Source data for the summary tables and statistical 
analyses will be presented as subject data listings. 
7.2. 
Reporting Precision 
Summary statistics will be presented to the degree of precision in Table 12, unless otherwise 
specified. 
Table 12: 
Degree of Precision 
Statistics 
Degree of Precision 
Mean, Median, Quartiles, Confidence 
limit boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 3 decimal places and therefore presented 
as 0.xxx; p-values smaller than 0.001 as ‘<0.001’; p-
values greater than 0.999 as ‘>0.999’. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12–0.30).  
For weight, height, and BMI, one decimal place will be used for summary statistics. 


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8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 
9. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) 
Mock-up tables, listings, and figures will be provided in a separate document. 
10. 
REFERENCES 
1. Alkermes ALK5461-208 Study Protocol Amendment 3 (dated 03 March 2016).  
 


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APPENDIX 1. AESI – ABUSE POTENTIAL 
Preferred Term 
Adhoc SOC 
Accidental overdose 
AP_abuse behavior 
Drug abuser 
AP_abuse behavior 
Drug diversion 
AP_abuse behavior 
Drug level above therapeutic 
AP_abuse behavior 
Drug level increased 
AP_abuse behavior 
Drug screen 
AP_abuse behavior 
Drug screen positive 
AP_abuse behavior 
Intentional overdose 
AP_abuse behavior 
Intentional product misuse 
AP_abuse behavior 
Intentional product use issue 
AP_abuse behavior 
Maternal use of illicit drugs 
AP_abuse behavior 
Needle track marks 
AP_abuse behavior 
Neonatal complications of substance abuse 
AP_abuse behavior 
Overdose 
AP_abuse behavior 
Prescription drug used without a prescription 
AP_abuse behavior 
Prescription form tampering 
AP_abuse behavior 
Product tampering 
AP_abuse behavior 
Substance abuse 
AP_abuse behavior 
Substance abuser 
AP_abuse behavior 
Substance use 
AP_abuse behavior 
Substance-induced mood disorder 
AP_abuse behavior 
Substance-induced psychotic disorder 
AP_abuse behavior 
Toxicity to various agents 
AP_abuse behavior 
Acute psychosis 
AP_non-specific 
Aggression 
AP_non-specific 
Cognitive disorder 
AP_non-specific 
Confusional state 
AP_non-specific 
Delirium 
AP_non-specific 
Delusional disorder, unspecified type 
AP_non-specific 
Depersonalisation/derealisation disorder  
AP_non-specific 
Disorientation 
AP_non-specific 
Dissociation 
AP_non-specific 
Disturbance in attention 
AP_non-specific 
Disturbance in social behaviour 
AP_non-specific 
Dizziness 
AP_non-specific 
Dopamine dysregulation syndrome 
AP_non-specific 
Emotional disorder 
AP_non-specific 
Flight of ideas 
AP_non-specific 
Medication overuse headache 
AP_non-specific 


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Preferred Term 
Adhoc SOC 
Mental impairment 
AP_non-specific 
Mood altered 
AP_non-specific 
Mood swings 
AP_non-specific 
Narcotic bowel syndrome 
AP_non-specific 
Paranoia 
AP_non-specific 
Psychotic behaviour 
AP_non-specific 
Psychotic disorder 
AP_non-specific 
Sedation 
AP_non-specific 
Somnolence 
AP_non-specific 
Stupor 
AP_non-specific 
Euphoric mood 
AP-euphoria related 
Feeling abnormal 
AP-euphoria related 
Feeling drunk 
AP-euphoria related 
Feeling of relaxation 
AP-euphoria related 
Hallucination 
AP-euphoria related 
Hallucination, auditory 
AP-euphoria related 
Hallucination, gustatory 
AP-euphoria related 
Hallucination, mixed 
AP-euphoria related 
Hallucination, olfactory 
AP-euphoria related 
Hallucination, synaesthetic 
AP-euphoria related 
Hallucination, tactile 
AP-euphoria related 
Hallucination, visual 
AP-euphoria related 
Inappropriate affect 
AP-euphoria related 
Thinking abnormal 
AP-euphoria related 
 


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APPENDIX 2. AESI – DEPENDENCE 
Preferred Term 
Dependence 
Drug dependence 
Drug dependence, antepartum 
Drug dependence, postpartum 
Drug tolerance 
Drug tolerance decreased 
Drug tolerance increased 
Substance dependence 


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APPENDIX 3. AESI – WITHDRAWAL 
Preferred Term 
Drug detoxification 
Reversal of opiate activity 
Drug rehabilitation 
Drug withdrawal convulsions 
Drug withdrawal headache 
Drug withdrawal maintenance therapy 
Drug withdrawal syndrome 
Drug withdrawal syndrome neonatal 
Rebound effect 
Steroid withdrawal syndrome 
Withdrawal arrhythmia 
Withdrawal syndrome 
Anhedonia 
Depressed mood 
Depression 
Dysphoria 
Feeling of despair 
Morose 
Negative thoughts 
Persistent depressive disorder 
Dyssomnia 
Headache 
Insomnia 
Obsessive thoughts 
Poor quality sleep 
Syncope 
Terminal insomnia 
Agitation 
Irritability 
Anxiety 
Chills 
Hyperhidrosis 
Nausea 
Nervousness 
Pain 
Tremor 
Vomiting 
Abdominal pain 
Arthralgia 


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Preferred Term 
Diarrhoea 
Mydriasis 
Piloerection 
Restlessness 
Rhinorrhoea 
Tachycardia 
Yawning 


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APPENDIX 4. AESI – SUICIDAL IDEATION AND BEHAVIOR 
Preferred Term 
Depression suicidal 
Suicidal ideation 
Suicide threat 
Suicidal behavior 
Suicide attempt 
Intentional overdose 
Multiple drug overdose 
Multiple drug overdose intentional 
Overdose 
Poisoning deliberate 
Completed suicide 
Intentional self-injury 
Self injurious behavior 
Self mutilation 
Self-injurious ideation 
Columbia suicide severity rating scale abnormal 


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APPENDIX 5. AESI – HYPOMANIA/MANIA 
Preferred Term 
Affective ambivalence 
Affect lability 
Agitation 
Aggression 
Anger 
Bipolar disorder 
Bipolar I disorder 
Bipolar II disorder 
Cyclothymic disorder 
Delusion 
Energy increased 
Euphoric mood 
Flight of ideas 
Frustration tolerance decreased 
Grandiosity 
Hallucination 
Hostility 
Hypomania 
Inappropriate affect 
Irritability 
Mania 
Mood swings 
Sexually inappropriate behavior 


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APPENDIX 6. AESI – CNS DEPRESSION AND SEDATION 
Preferred Term 
Apathy  
Asthenia  
Bradyphrenia  
Decreased activity  
Decreased interest  
Depressed level of consciousness 
Fatigue  
Hypersomnia  
Hypersomnia related to another mental condition  
Hypokinesia neonatal  
Hyporesponsive to stimuli 
Hypotonic-hyporesponsive episode 
Lethargy  
Listless  
Loss of consciousness 
Neonatal oversedation  
Prostration  
Psychomotor retardation  
Sedation  
Sense of oppression  
Sleep disorder due to general medical condition, hypersomnia type  
Sluggishness 
Somnolence 
Somnolence neonatal  
Sopor  
Unresponsive to stimuli 


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APPENDIX 7. AESI – RESPIRATORY DEPRESSION 
Preferred Term 
Acute respiratory failure 
Apnoea 
Apnoeic attack 
Bradypnoea 
Breath holding 
Breath sounds abnormal 
Breath sounds absent 
Central-alveolar hypoventilation 
Hypopnoea 
Hypoventilation 
Hypoventilation neonatal 
Infantile apnoea 
Lung hypoinflation 
Neonatal respiratory arrest 
Neonatal respiratory depression 
Neonatal respiratory failure 
Postoperative respiratory failure 
Respiratory arrest 
Respiratory depression 
Respiratory depth decreased 
Respiratory failure 
Respiratory paralysis 
Respiratory rate decreased 


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APPENDIX 8. AESI – ORTHOSTASIS HYPOTENSION 
Preferred Term 
Autonomic nervous system imbalance 
Blood pressure abnormal 
Blood pressure ambulatory abnormal 
Blood pressure ambulatory decreased 
Blood pressure decreased 
Blood pressure diastolic abnormal 
Blood pressure diastolic decreased 
Blood pressure fluctuation 
Blood pressure immeasurable 
Blood pressure orthostatic 
Blood pressure orthostatic decreased 
Blood pressure systolic abnormal 
Blood pressure systolic decreased 
Circulatory collapse 
Circulatory failure neonatal 
Diastolic hypotension 
Dizziness exertional 
Dizziness 
Dizziness postural 
Hypoperfusion 
Hypotension 
Labile blood pressure 
Mean arterial pressure decreased 
Neonatal hypotension 
Neurogenic shock 
Orthostatic heart rate response increased 
Orthostatic hypotension 
Orthostatic intolerance 
Peripheral circulatory failure 
Postural orthostatic tachycardia syndrome 
Presyncope 
Procedural hypotension 
Shock 
Shock symptom 
Syncope 


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APPENDIX 9. AESI – HYPERSENSITIVITY 
Preferred Term 
Acute generalised exanthematous pustulosis 
Acute haemorrhagic oedema of infancy 
Administration site dermatitis 
Administration site eczema 
Administration site hypersensitivity 
Administration site rash 
Administration site recall reaction 
Administration site urticaria 
Administration site vasculitis 
Allergic bronchitis 
Allergic colitis 
Allergic cough 
Allergic cystitis 
Allergic eosinophilia 
Allergic gastroenteritis 
Allergic granulomatous angiitis 
Allergic hepatitis 
Allergic keratitis 
Allergic myocarditis 
Allergic oedema 
Allergic otitis externa 
Allergic otitis media 
Allergic pharyngitis 
Allergic respiratory disease 
Allergic respiratory symptom 
Allergic sinusitis 
Allergic transfusion reaction 
Allergy alert test positive 
Allergy test positive 
Allergy to immunoglobulin therapy 
Allergy to surgical sutures 
Allergy to vaccine 
Alveolitis allergic 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Anaphylaxis treatment 


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Preferred Term 
Angioedema 
Antiallergic therapy 
Antiendomysial antibody positive 
Anti-neutrophil cytoplasmic antibody positive vasculitis 
Aortitis 
Application site dermatitis 
Application site eczema 
Application site hypersensitivity 
Application site rash 
Application site recall reaction 
Application site urticaria 
Application site vasculitis 
Arteritis 
Arteritis coronary 
Arthritis allergic 
Aspirin-exacerbated respiratory disease 
Atopy 
Behcet's syndrome 
Blepharitis allergic 
Blood immunoglobulin E abnormal 
Blood immunoglobulin E increased 
Bromoderma 
Bronchospasm 
Capillaritis 
Catheter site dermatitis 
Catheter site eczema 
Catheter site hypersensitivity 
Catheter site rash 
Catheter site urticaria 
Catheter site vasculitis 
Cerebral arteritis 
Chronic eosinophilic rhinosinusitis 
Chronic hyperplastic eosinophilic sinusitis 
Chronic pigmented purpura 
Circulatory collapse 
Circumoral oedema 
Cogan's syndrome 
Conjunctival oedema 
Conjunctivitis allergic 
Contact stomatitis 
Contrast media allergy 
Contrast media reaction 


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Preferred Term 
Corneal oedema 
Cutaneous vasculitis 
Dennie-Morgan fold 
Dermatitis 
Dermatitis acneiform 
Dermatitis allergic 
Dermatitis atopic 
Dermatitis bullous 
Dermatitis contact 
Dermatitis exfoliative 
Dermatitis exfoliative generalised 
Dermatitis herpetiformis 
Dermatitis infected 
Dermatitis psoriasiform 
Device allergy 
Diabetic arteritis 
Dialysis membrane reaction 
Diffuse vasculitis 
Distributive shock 
Documented hypersensitivity to administered product 
Drug cross-reactivity 
Drug eruption 
Drug hypersensitivity 
Drug provocation test 
Drug reaction with eosinophilia and systemic symptoms 
Eczema 
Eczema infantile 
Eczema nummular 
Eczema vaccinatum 
Eczema vesicular 
Eczema weeping 
Encephalitis allergic 
Encephalopathy allergic 
Epidermal necrosis 
Epidermolysis 
Epidermolysis bullosa 
Epiglottic oedema 
Erythema induratum 
Erythema multiforme 
Erythema nodosum 
Exfoliative rash 
Eye allergy 


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


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Preferred Term 
Injection site recall reaction 
Injection site urticaria 
Injection site vasculitis 
Instillation site hypersensitivity 
Instillation site rash 
Instillation site urticaria 
Interstitial granulomatous dermatitis 
Intestinal angioedema 
Iodine allergy 
Kaposi's varicelliform eruption 
Kawasaki's disease 
Kounis syndrome 
Langerhans' cell histiocytosis 
Laryngeal oedema 
Laryngitis allergic 
Laryngospasm 
Laryngotracheal oedema 
Limbal swelling 
Lip oedema 
Lip swelling 
Lupus vasculitis 
Mast cell degranulation present 
Medical device site dermatitis 
Medical device site eczema 
Medical device site hypersensitivity 
Medical device site rash 
Medical device site recall reaction 
Medical device site urticaria 
Medical device site vasculitis 
Microscopic polyangiitis 
Mouth swelling 
Mucocutaneous rash 
Multiple allergies 
Nephritis allergic 
Nikolsky's sign 
Nodular rash 
Nodular vasculitis 
Ocular vasculitis 
Oculomucocutaneous syndrome 
Oculorespiratory syndrome 
Oedema mouth 
Oral allergy syndrome 


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Preferred Term 
Oropharyngeal blistering 
Oropharyngeal spasm 
Oropharyngeal swelling 
Palatal oedema 
Palatal swelling 
Palisaded neutrophilic granulomatous dermatitis 
Palpable purpura 
Pathergy reaction 
Periorbital oedema 
Pharyngeal oedema 
Polyarteritis nodosa 
Polymyalgia rheumatica 
Pruritus allergic 
Pseudovasculitis 
Pulmonary vasculitis 
Radiation vasculitis 
Radioallergosorbent test positive 
Rash 
Rash erythematous 
Rash follicular 
Rash generalised 
Rash macular 
Rash maculo-papular 
Rash maculovesicular 
Rash morbilliform 
Rash neonatal 
Rash papulosquamous 
Rash pruritic 
Rash pustular 
Rash rubelliform 
Rash scarlatiniform 
Rash vesicular 
Reaction to azo-dyes 
Reaction to colouring 
Reaction to drug excipients 
Reaction to preservatives 
Red man syndrome 
Renal arteritis 
Renal vasculitis 
Retinal vasculitis 
Rheumatoid vasculitis 
Rhinitis allergic 


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Preferred Term 
Scleral oedema 
Scleritis allergic 
Scrotal oedema 
Segmented hyalinising vasculitis 
Serum sickness 
Serum sickness-like reaction 
Shock 
Shock symptom 
Skin necrosis 
Skin reaction 
Skin test positive 
Solar urticarial 
Solvent sensitivity 
Stevens-Johnson syndrome 
Stoma site hypersensitivity 
Stoma site rash 
Swelling face 
Swollen tongue 
Takayasu's arteritis 
Temporal arteritis 
Thromboangiitis obliterans 
Tongue oedema 
Toxic epidermal necrolysis 
Toxic skin eruption 
Tracheal oedema 
Type 2 lepra reaction 
Type I hypersensitivity 
Type II hypersensitivity 
Type III immune complex mediated reaction 
Type IV hypersensitivity reaction 
Urticaria 
Urticaria cholinergic 
Urticaria chronic 
Urticaria contact 
Urticaria papular 
Urticaria physical 
Urticaria pigmentosa 
Urticaria vesiculosa 
Urticarial vasculitis 
Vaccination site dermatitis 
Vaccination site eczema 
Vaccination site exfoliation 


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


Alkermes, Inc. 
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Page 53 of 57 
APPENDIX 10. AESI – SLOWING OF VENTRICULAR 
REPOLARIZATION 
Preferred Term 
Electrocardiogram QT interval abnormal 
Electrocardiogram QT prolonged 
Long QT syndrome 
Long QT syndrome congenital 
Torsade de pointes 
Ventricular tachycardia 


Alkermes, Inc. 
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Page 54 of 57 
APPENDIX 11. AESI – HEPATIC EFFECTS 
Preferred Term 
Acute hepatic failure 
Acute on chronic liver failure 
Acute yellow liver atrophy 
Ascites 
Asterixis 
Bacterascites 
Biliary cirrhosis 
Biliary cirrhosis primary 
Biliary fibrosis 
Cholestatic liver injury 
Chronic hepatic failure 
Coma hepatic 
Cryptogenic cirrhosis 
Diabetic hepatopathy 
Drug-induced liver injury 
Duodenal varices 
Gallbladder varices 
Gastric variceal injection 
Gastric variceal ligation 
Gastric varices 
Gastric varices haemorrhage 
Hepatectomy 
Hepatic atrophy 
Hepatic calcification 
Hepatic cirrhosis 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic failure 
Hepatic fibrosis 
Hepatic hydrothorax 
Hepatic infiltration eosinophilic 
Hepatic lesion 
Hepatic necrosis 
Hepatic steato-fibrosis 
Hepatic steatosis 
Hepatitis fulminant 
Hepatobiliary disease 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 


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Page 55 of 57 
Preferred Term 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatotoxicity 
Intestinal varices 
Intestinal varices haemorrhage 
Liver and small intestine transplant 
Liver dialysis 
Liver disorder 
Liver injury 
Liver operation 
Liver transplant 
Lupoid hepatic cirrhosis 
Minimal hepatic encephalopathy 
Mixed liver injury 
Nodular regenerative hyperplasia 
Non-alcoholic fatty liver 
Non-alcoholic steatohepatitis 
Non-cirrhotic portal hypertension 
Oedema due to hepatic disease 
Oesophageal varices haemorrhage 
Peripancreatic varices 
Portal fibrosis 
Portal hypertension 
Portal hypertensive enteropathy 
Portal hypertensive gastropathy 
Portal vein cavernous transformation 
Portal vein dilatation 
Portopulmonary hypertension 
Renal and liver transplant 
Retrograde portal vein flow 
Reye's syndrome 
Reynold's syndrome 
Splenic varices 
Splenic varices haemorrhage 
Steatohepatitis 
Subacute hepatic failure 
Varices oesophageal 
Varicose veins of abdominal wall 
Anorectal varices 
Anorectal varices haemorrhage 
Intrahepatic portal hepatic venous fistula 


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Page 56 of 57 
Preferred Term 
Peritoneovenous shunt 
Portal shunt 
Portal shunt procedure 
Small-for-size liver syndrome 
Spider naevus 
Splenorenal shunt 
Splenorenal shunt procedure 
Spontaneous intrahepatic portosystemic venous shunt 
Stomal varices 


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Page 57 of 57 
APPENDIX 12. AESI – SEXUAL DYSFUNCTION 
Preferred Term 
Anorgasmia 
Disturbance in sexual arousal 
Dyspareunia 
Ejaculation delayed 
Ejaculation disorder 
Ejaculation dysfunction 
Ejaculation failure 
Erectile dysfunction 
Female orgasmic disorder 
Female sexual arousal disorder 
Female sexual dysfunction 
Inadequate lubrication 
Libido decreased 
Libido disorder 
Loss of libido 
Male orgasmic disorder 
Male sexual arousal disorder 
Male sexual dysfunction 
Orgasm abnormal 
Orgasmic sensation decreased 
Sexual dysfunction 
Vulvovaginal dryness