Conditions: Opioid Use Disorder
Keywords: naltrexone VIVITROL buprenorphine opioid addiction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety, and tolerability of oral naltrexone used in conjunction with buprenorphine in adults with Opioid Use Disorder transitioning from buprenorphine maintenance prior to the first dose of VIVITROL.

Detailed description:

Arms:
arm 1: Placebo naltrexone + buprenorphine arm 2: Naltrexone + buprenorphine

Interventions: intervention 1: Naltrexone intervention 2: Placebo intervention 3: Buprenorphine
Intervention descriptions: intervention 1: daily dosing intervention 2: daily dosing intervention 3: daily dosing

Protocol document:
Prot_000.pdf: 
A Phase 3 Study to Evaluate the Safety, Tolerability, and 
Efficacy of Naltrexone for use in Conjunction with 
Buprenorphine in Adults with Opioid Use Disorder 
Transitioning from Buprenorphine Maintenance Prior to 
First Dose of Vivitrol® 
 
 
Unique Protocol ID: 
ALK6428-A302 
NCT Number: 
NCT02696434 
Date of Protocol:  
14 June 2017 
 


1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK6428-A302 
 
Study Title 
A Phase 3 Study to Evaluate the Safety, Tolerability, and 
Efficacy of Naltrexone for use in Conjunction with 
Buprenorphine in Adults with Opioid Use Disorder 
Transitioning from Buprenorphine Maintenance Prior to First 
Dose of VIVITROL® 
Document Date 
v 4.0 (incorporates Amendment 3.0): 14 Jun 2017 
 
v 3.0 (incorporates Amendment 2.0): 14 Oct 2016 
 
v 2.0 (incorporates Amendment 1.0): 14 Apr 2016 
 
Original Protocol: 15 Dec 2015 
Sponsor 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


 
 
Alkermes, Inc. 
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CONFIDENTIAL 
 
CONTACT INFORMATION 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone 
Alkermes Medical Monitors 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
 
Mobile: 
 
  
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
 
Mobile: 
 
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2. 
SYNOPSIS 
Name of Sponsor/ Company: Alkermes, Inc. 
Name of Investigational Product: Naltrexone 
Name of Active Ingredient: Naltrexone 
Title of Study: A Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of Naltrexone for use 
in Conjunction with Buprenorphine in Adults with Opioid Use Disorder Transitioning from 
Buprenorphine Maintenance Prior to First Dose of VIVITROL® 
Investigator(s): This is a multicenter study in the United States 
Study Period: 
Estimated date of first subject’s consent: Q2 2016 
Estimated date of last subject’s last visit: Q4 2017 
Phase of Development: 3 
Objectives: 
Primary: To evaluate the efficacy of oral naltrexone used in conjunction with buprenorphine in adults 
with Opioid Use Disorder transitioning from buprenorphine maintenance prior to the first dose of 
VIVITROL. 
Secondary: To determine the safety and tolerability of oral naltrexone used in conjunction with 
buprenorphine in adults with Opioid Use Disorder transitioning from buprenorphine maintenance prior 
to the first dose of VIVITROL. 
Methodology: This Phase 3, randomized, double-blind, placebo-controlled, parallel group study will 
evaluate a dosing schedule for active versus placebo oral naltrexone coadministered with buprenorphine 
(BUP) in BUP-dependent individuals prior to first dose of VIVITROL. Eligible subjects will be 
randomized in a 1:1 ratio to one of 2 treatment groups (naltrexone + BUP or placebo naltrexone 
[PBO-N] + BUP) for induction onto VIVITROL, stratified according to low (<8 mg/day) versus high 
(8 mg/day) BUP maintenance dose at the time of initiation of the BUP Lead-in Period. 
This study includes: 
• 
BUP Lead-in Period: 5-day stabilization on 4 mg/day BUP (or less, if entry dose is lower); 
outpatient Days -5 through -3; residential Days -2 and -1 (option for earlier residential 
admission at the study clinician’s discretion) 
• 
Treatment Period: Transitional dosing with oral naltrexone or PBO-N in conjunction with 
BUP taper; residential Days 1/1a to 7 
• 
VIVITROL Induction and Post-VIVITROL Observation Period: 
− 
A naloxone challenge and administration of VIVITROL on Day 8/8a prior to discharge 
− 
Post-VIVITROL outpatient monitoring (Days 9-11) 
The study design is presented in the schematic below. 
Evaluation of withdrawal symptoms will occur throughout the BUP Lead-in Period, the Treatment 
Period, and the VIVITROL Induction and Post-VIVITROL Observation Period (Days -5 through 11). 
Clinical testing sessions to monitor opioid withdrawal effects in response to study drug will occur on 
Days 1/1a through 7. Up to 2 additional study visits may be conducted (Days 1a and 8a), as needed, for 
subjects who do not meet criteria for proceeding with Day 1 or Day 8 procedures. In addition, subjects 
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will receive psychoeducational counseling, starting on Day -5 and throughout the Treatment Period, and 
cognitive assessments will be conducted at screening and on Days -1, 22 and 36. 
Naloxone 
Challenge 
and 
VIVITROL 
Injection
Screening
BUP lead-in 
(4 mg*)
Randomization
on Day 1/1a
Treatment Period
(Days 1/1a-7)
Naltrexone + BUP taper
PBO-N + BUP taper
Post-VIVITROL 
Observation
Follow-up
Days -26 to -6
Days -5 to -1
Day 8/8a
Days 9-11
Discharge 1 hour 
after VIVITROL 
injection
Day 22
Day 36
Residential Period Days -2 to 8/8a
BUP taper 
begins
*Subjects maintained on <4 mg at Day -5 will continue on their current dose until 
the Treatment Period taper calls for further decrease to establish a consistent 
daily dose prior to transitional dosing with naltrexone (see Section 8.2.1).
 
Number of Subjects Planned: Approximately 92 subjects are planned to be randomized; 46 subjects 
per treatment group. 
Main Criteria for Inclusion: To be included in this study, subjects must be between 18 and 60 years of 
age (inclusive) at screening and be willing to provide written informed consent. Subjects must have a 
history of opioid use disorder diagnosis (according to criteria set forth in the Diagnostic and Statistical 
Manual, 5th edition [DSM-5]) for at least the prior 6 consecutive months. Subjects must have a history of 
prescribed BUP (or buprenorphine/naloxone [BUP/Nx]) maintenance for the prior 3 or more consecutive 
months and must be maintained at a dose of ≤8 mg per day for at least 30 days prior to initiating the 
lead-in period (Day -5; to be confirmed at screening by self-report, urine toxicology and prescription 
confirmation).Subjects must be voluntarily seeking treatment for opioid use disorder and be motivated to 
receive antagonist therapy. 
Investigational Product, Dosage, Duration and Mode of Administration: Naltrexone will be 
administered as 2 oral doses, given at least 1 hour apart, on Days 1/1a to 7, as indicated below. 
Study Day 
1st Dose NTX 
2nd Dose NTX 
Day 1/1a 
0.25 mg 
0.25 mg 
Day 2 
0.25 mg 
0.25 mg 
Day 3 
0.5 mg 
0.5 mg 
Day 4 
1.5 mg 
1.5 mg 
Day 5 
3 mg 
3 mg 
Day 6 
7.5 mg 
7.5 mg 
Day 7 
15 mg 
15 mg 
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Reference Therapy, Dosage, Duration and Mode of administration: Placebo naltrexone (PBO-N) 
tablets will match the naltrexone drug product and will be administered as 2 oral doses, given at least 
1 hour apart, on Days 1/1a to 7. 
Sublingual BUP (≤4 mg) will be administered daily to all subjects during the BUP Lead-in Period 
(Days -5 to -1). On Days 1/1a to Day 4, the BUP dose will be tapered down to 0 mg (ie, ≤4 mg on 
Days 1/1a, 2 mg on Days 2-3 and 0 mg on Days 4-8/8a).  
Duration of Study: The study will last approximately 9 weeks; up to 3 weeks for screening (Days -26  
to -6), approximately 2 weeks for BUP Lead-In Period and Treatment Period, 4 to 5 days for VIVITROL 
induction and post-VIVITROL monitoring, and a 4-week follow-up period. 
Criteria for Evaluation: 
Efficacy: 
Efficacy will be assessed via the following: 
• 
Clinical Opiate Withdrawal Scale (COWS) score 
• 
Subjective Opiate Withdrawal Scale (SOWS) score 
• 
Desire for opioids using a Visual Analogue Scale (VAS) 
• 
Patient Global Assessment of Response to Therapy (PGART) 
Exploratory: 
The following exploratory assessments will be conducted: 
• 
Pupil diameter 
• 
Quantitative Substance Use Inventory (QSUI) 
• 
Hamilton Rating Scale for Depression (HAM-D) 
• 
Brief Assessments of Cognition (BAC) Symbol Coding test 
• 
Controlled Oral Word Association (COWA) task 
• 
Wechsler Memory Scale-III Spatial Span (WMS-III SS) test 
• 
Continuous Performance Test (CPT) 
• 
Test of Attentional Performance (TAP) 
Safety: 
Safety and tolerability will be assessed via the following: 
• 
Adverse events (AEs) 
• 
Vital signs and oxygen saturation 
• 
Laboratory test results 
• 
ECG parameters 
• 
C-SSRS score 
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Statistical Methods: 
Efficacy: 
Primary Efficacy Endpoint 
• 
The proportion of subjects who receive and tolerate VIVITROL injection on Day 8/8a as 
demonstrated by mild (COWS ≤12 or SOWS ≤10) opioid withdrawal symptoms following 
VIVITROL administration 
Key Secondary Efficacy Endpoint 
• 
Proportion of days with COWS peak score ≤12 during the Treatment Period prior to the 
VIVITROL injection (Days 1/1a-7) 
Other Secondary Efficacy Endpoints 
• 
Proportion of post-VIVITROL days (Days 9-11) in which subjects in each group 
demonstrate mild (COWS ≤12) opioid withdrawal 
• 
Mean peak COWS scores during the Treatment Period and VIVITROL Induction and Post-
VIVITROL Observation Period (Days 1/1a-11) 
• 
Area under the curve (AUC) for COWS scores during the Treatment Period and VIVITROL 
Induction and Post-VIVITROL Observation Period (Days 1/1a-11) 
• 
Mean score for “desire for opioids” VAS during the Treatment Period and VIVITROL 
Induction and Post-VIVITROL Observation Period (Days 1/1a-11) 
Exploratory Endpoints 
• 
Number and proportion of subjects in PGART response category at the end of the Post-
VIVITROL Observation Period (Day 11) 
• 
Change from baseline in pupil diameter following study drug administration during the 
Treatment Period (Days 1/1a-7) 
• 
Change in frequency of substance use from screening to Day 36 assessed via the QSUI 
• 
AUC for SOWS scores during the Treatment Period and VIVITROL Induction and Post-
VIVITROL Observation Period (Days 1/1a-11) 
• 
Change from baseline in standardized T scores for cognitive assessments 
Efficacy Analysis: The primary efficacy endpoint will be analyzed using logistic regression with 
treatment as a factor. 
Safety: Reported Adverse Events (AE) terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred terms and system organ classes. The incidence of treatment-emergent 
AEs will be summarized by treatment group and overall by system organ class, and preferred terms 
within each system organ class. Serious Adverse Events (SAEs) and AEs resulting in treatment 
discontinuation will also be summarized. AEs occurring during the treatment period preceding the 
naloxone challenge will be analyzed separately from AEs occurring on or after the naloxone challenge 
day. 
The change from baseline in other safety parameters will be summarized by treatment group. 
Concomitant medications will be categorized and presented using the World Health Organization 
(WHO) drug Anatomical Therapeutic Chemical (ATC) classification system. 
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Number and percentage of subjects initiating concomitant medications, including ancillary medications, 
during the induction period will be summarized. 
Sample Size Considerations: The primary efficacy endpoint is the proportion of subjects who receive 
and tolerate VIVITROL injection on Day 8/8a as demonstrated by mild (COWS ≤12 or SOWS ≤10) 
opioid withdrawal symptoms following VIVITROL administration. 
Assuming the proportion of subjects receiving and tolerating VIVITROL administration is 90% in 
Group 1 (naltrexone + BUP) and 60% in Group 2 (PBO-N + BUP), a sample size of approximately 
46 subjects per treatment group will provide at least 90% power to detect a statistically significant 
difference between the two treatment groups at 5% level of significance in a two-sided test. 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................8 
4. 
LIST OF ABBREVIATIONS.....................................................................................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Background .................................................................................................................15 
5.2. 
Study Rationale ...........................................................................................................16 
5.3. 
Rationale for Selection of Dosing Regimen ...............................................................16 
6. 
OBJECTIVES .............................................................................................................18 
6.1. 
Primary Objective .......................................................................................................18 
6.2. 
Secondary Objective ...................................................................................................18 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................19 
7.1. 
Subject Inclusion Criteria ...........................................................................................19 
7.2. 
Subject Exclusion Criteria ..........................................................................................19 
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. 
Buprenorphine Lead-in and Treatment Periods ..........................................................24 
8.2.1. 
Buprenorphine Lead-in Period ...................................................................................24 
8.2.2. 
Treatment Period ........................................................................................................25 
8.2.3. 
Poorly Tolerated Doses ...............................................................................................27 
8.3. 
Day 8/8a Naloxone Challenge and VIVITROL Injection ..........................................28 
8.3.1. 
Naloxone Challenge ....................................................................................................28 
8.3.2. 
VIVITROL Injection ..................................................................................................29 
8.3.3. 
Subjects Who Do Not Transition to VIVITROL ........................................................29 
8.3.3.1. 
Treatment Options for Subjects with a Positive Naloxone Challenge .......................29 
8.3.3.2. 
Treatment Options for Subjects Who Discontinue Prior to Receiving 
VIVITROL .................................................................................................................30 
8.3.4. 
Referrals to Post-Study VIVITROL Provider ............................................................30 
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8.4. 
Withdrawal Assessments Throughout the Residential Period ....................................30 
8.5. 
Follow-up Period ........................................................................................................31 
8.6. 
Minimizing Risks........................................................................................................31 
8.7. 
Schedule of Visits and Assessments ...........................................................................32 
8.8. 
Study Procedures Descriptions ...................................................................................37 
8.8.1. 
Informed Consent .......................................................................................................37 
8.8.2. 
Eligibility Review .......................................................................................................37 
8.8.3. 
Demographics and Medical History ...........................................................................37 
8.8.4. 
Concomitant Medication Review ...............................................................................37 
8.8.5. 
Vital Signs and Oxygen Saturation .............................................................................37 
8.8.6. 
Pupillometry ...............................................................................................................37 
8.8.7. 
Physical Examination .................................................................................................38 
8.8.8. 
Body Height and Weight ............................................................................................38 
8.8.9. 
12-Lead Electrocardiogram ........................................................................................38 
8.8.10. 
Behavioral Therapy: Psychoeducational Counseling .................................................38 
8.8.11. 
Structured Interviews and Questionnaires ..................................................................38 
8.8.11.1. 
Mini-International Neuropsychiatric Interview ..........................................................38 
8.8.11.2. 
Mini-Mental Status Examination ................................................................................38 
8.8.11.3. 
Months of the Year Backward ....................................................................................39 
8.8.11.4. 
Columbia Suicide Severity and Rating Scale .............................................................39 
8.8.11.5. 
Clinical Opiate Withdrawal Scale ..............................................................................39 
8.8.11.6. 
Subjective Opiate Withdrawal Scale ..........................................................................39 
8.8.11.7. 
Desire for Opioids Visual Analogue Scale .................................................................39 
8.8.11.8. 
Short Michigan Alcohol Screening Test .....................................................................40 
8.8.11.9. 
Quantitative Substance Use Inventory ........................................................................40 
8.8.11.10. Patient Global Assessment of Response to Therapy ..................................................40 
8.8.11.11. Hamilton Rating Scale for Depression .......................................................................40 
8.8.11.12. Cognitive Assessments ...............................................................................................40 
8.8.12. 
Laboratory Assessments .............................................................................................41 
8.8.12.1. 
Pregnancy Testing ......................................................................................................41 
8.8.12.2. 
Urine Drug Screen ......................................................................................................42 
8.8.12.3. 
Breath Alcohol Test ....................................................................................................42 
8.8.12.4. 
Clinical Laboratory Assessments ...............................................................................42 
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8.8.13. 
Randomization ............................................................................................................42 
8.8.14. 
Drug Dispensation and Reconciliation .......................................................................43 
8.8.15. 
Adverse Event Monitoring .........................................................................................43 
8.9. 
Study Requirements and Restrictions .........................................................................43 
8.9.1. 
Prohibited Medications and Substances .....................................................................43 
8.9.2. 
Ancillary Medications ................................................................................................43 
8.9.3. 
Concomitant Medications ...........................................................................................44 
8.9.4. 
Contraception and Pregnancy .....................................................................................44 
8.10. 
Residential Period .......................................................................................................45 
9. 
TREATMENT OF SUBJECTS ..................................................................................46 
9.1. 
Investigational Product, Dosage, Duration and Mode of Administration ..................46 
9.2. 
Reference Therapy, Dosage, Duration and Mode of Administration .........................46 
9.3. 
Treatment Adherence ..................................................................................................46 
9.4. 
Randomization/Method of Assigning Subjects to Treatment .....................................46 
9.5. 
Blinding ......................................................................................................................46 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................47 
10.1. 
Study Drug ..................................................................................................................47 
10.2. 
Packaging and Storage ................................................................................................47 
10.3. 
Accountability .............................................................................................................47 
10.4. 
Handling and Disposal ................................................................................................47 
10.5. 
Management of Ancillary Medications ......................................................................48 
11. 
ASSESSMENT OF EFFICACY ................................................................................49 
12. 
ASSESSMENT OF SAFETY .....................................................................................50 
12.1. 
Definition of Adverse Event .......................................................................................50 
12.2. 
Definition of Serious Adverse Event ..........................................................................50 
12.3. 
Relationship to Study Drug ........................................................................................51 
12.4. 
Monitoring and Recording of Adverse Events ...........................................................53 
12.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................53 
13. 
STATISTICS ..............................................................................................................54 
13.1. 
Sample Size Considerations .......................................................................................54 
13.2. 
General Statistical Methodology ................................................................................54 
13.2.1. 
Study Populations .......................................................................................................54 
13.2.1.1. 
Safety Population ........................................................................................................54 
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13.3. 
Demographics and Baseline Data ...............................................................................54 
13.4. 
Efficacy Analyses .......................................................................................................54 
13.4.1. 
Primary Efficacy Endpoint .........................................................................................54 
13.4.2. 
Key Secondary Efficacy Endpoint ..............................................................................55 
13.4.3. 
Other Secondary Endpoints ........................................................................................55 
13.4.4. 
Exploratory Endpoints ................................................................................................55 
13.5. 
Safety and Tolerability Analyses ................................................................................55 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................57 
14.1. 
Study Monitoring ........................................................................................................57 
14.2. 
Audits and Inspections ................................................................................................57 
14.3. 
Institutional Review Board .........................................................................................57 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58 
15.1. 
Case Report Forms .....................................................................................................58 
15.2. 
Confidentiality of Data ...............................................................................................58 
16. 
ETHICAL CONSIDERATIONS................................................................................59 
16.1. 
Ethics Review .............................................................................................................59 
16.2. 
Ethical Conduct of the Study ......................................................................................59 
16.3. 
Written Informed Consent ..........................................................................................59 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................61 
17.1. 
Data Capture ...............................................................................................................61 
17.2. 
Inspection of Records .................................................................................................61 
17.3. 
Retention of Records ..................................................................................................61 
17.4. 
Use of Information and Publication Policy ................................................................62 
18. 
REFERENCES ...........................................................................................................63 
APPENDICES ...............................................................................................................................66 
 
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LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definitions of Terms .........................................................13 
Table 3: 
ALK6428-A302 Dosing Regimen ..............................................................................25 
Table 4: 
Schedule of Visits and Assessments ...........................................................................33 
Table 5: 
Clinical Laboratory Assessments ...............................................................................42 
Table 6: 
Ancillary Medications ................................................................................................44 
Table 7: 
Adverse Event Causality Guidelines ..........................................................................52 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................24 
Figure 2: 
Schematic of Daily Residential Withdrawal Assessments, Days 1/1a to 7 ................27 
 
LIST OF APPENDICES 
Appendix A 
Mini-International Neuropsychiatric Interview 
Appendix B 
Columbia-Suicide Severity Rating Scale 
• 
Baseline/Screening 
• 
Since Last Visit 
Appendix C 
Clinical Opiate Withdrawal Scale 
Appendix D 
Subjective Opiate Withdrawal Scale 
Appendix E 
Desire for Opioids Visual Analogue Scale 
Appendix F 
Short Michigan Alcohol Screening Test 
Appendix G 
Quantitative Substance Use Inventory 
Appendix H 
Patient Global Assessment of Response to Therapy 
Appendix I 
Structured Interview Guide for the Hamilton Rating Scale for Depression 
Appendix J 
Brief Assessments of Cognition Symbol Coding Test 
Appendix K 
Controlled Oral Word Association Task 
Appendix L 
Wechsler Memory Scale-III Spatial Span Test 
Appendix M 
Continuous Performance Test 
Appendix N 
Test of Attentional Performance 
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4. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Table 2: 
List of Abbreviations and Definitions of Terms 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
AUC 
Area under the concentration-time curve 
BAC 
Brief Assessments of Cognition 
BUP 
Buprenorphine 
BUP/Nx 
Buprenorphine/naloxone 
COWA 
Controlled Oral Word Association 
COWS 
Clinical Opiate Withdrawal Scale 
CPT 
Continuous Performance Test 
CRO 
Contract Research Organization 
CSA 
Clinical Study Agreement 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual, 5th edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
EVS 
Electronic vital signs 
GCP 
Good Clinical Practice 
HAM-D 
Hamilton Rating Scale for Depression 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini-International Neuropsychiatric Interview 
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Abbreviation or Term 
Explanation or Definition 
MMSE 
Mini-Mental State Examination 
MOTYB 
Months of the Year Backward 
NIDA 
National Institute on Drug Abuse 
NTX 
Naltrexone 
PBO-N 
Placebo naltrexone 
PGART 
Patient Global Assessment of Response to Therapy 
QSUI 
Quantitative Substance Use Inventory 
SAE 
Serious adverse event 
SMAST 
Short Michigan Alcohol Screening Test 
SOWS 
Subjective Opiate Withdrawal Scale 
TAP 
Test of Attentional Performance 
VAS 
Visual Analogue Scale 
WMS-III SS 
Wechsler Memory Scale-III Spatial Span 
WHO 
World Health Organization 
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5. 
INTRODUCTION 
5.1. 
Background 
Alkermes is developing oral naltrexone to be used in conjunction with buprenorphine (BUP) for 
adults with opioid use disorder prior to the first dose of VIVITROL®. Opioid use disorder is 
among the fastest growing substance abuse issues in the United States, which is primarily 
attributable to the rising rates of prescription drug abuse (Substance Abuse and Mental Health 
Services Administration 2013). The National Institute on Drug Abuse (NIDA) reported that over 
2 million people in the United States suffer from substance use disorder related to opioid pain 
relievers, and in the past year 289,000 people abused heroin (National Institute on Drug Abuse 
2014; Substance Abuse and Mental Health Services Administration 2014). The number of 
individuals with opioid use disorder continues to rise, along with corresponding increases in 
morbidity and mortality (Centers for Disease Control and Prevention 2011). VIVITROL, an 
extended release, injectable form of naltrexone, was FDA approved in 2010 for the prevention of 
relapse to opioid dependence, following opioid detoxification. The partial opioid agonist, BUP, 
has been approved since 2002 in the U.S. for office-based prescribing for the treatment of opiate 
dependence by preventing symptoms of opiate withdrawal. While BUP is effective for many 
patients, there are no studies to support the optimal duration of treatment, and therefore opioid 
agonist treatment is usually considered an open-ended, long-term maintenance approach. Yet 
some individuals, for reasons of either treatment success or treatment failure with BUP, wish to 
transition to become opioid-free. After an initially favorable or unfavorable response, a 
proportion of BUP-maintained patients leave treatment every month. Relapse is a common 
outcome among patients who have discontinued BUP (Ling et al, 2009; Weiss et al, 2011). 
Transition to injection naltrexone represents a mechanism for protecting against relapse, but 
there is currently very little consensus on the best method for opioid detoxification from BUP 
prior to VIVITROL induction. Various opioid agonist/antagonist regimens have been proposed 
to minimize the severity of opioid withdrawal symptoms (Sigmon et al, 2012). A common 
component of many regimens is the use of low doses of naltrexone to shorten the withdrawal 
period. However, there are no clear guidelines or standards on how to successfully manage 
patients during the transition period from BUP to VIVITROL, or on the appropriate length of 
this transition. Establishing a reproducible regimen to transition patients from BUP maintenance 
to VIVITROL treatment represents an important clinical goal. 
Current prescribed treatments for opioid dependence, including VIVITROL, may be 
implemented in an inpatient or outpatient facility. Due to the rising costs of inpatient treatment as 
well as patient preference, an increasing number of providers are initiating treatment in an 
outpatient setting (Day et al, 2005). However, outpatient treatment is not without its challenges; 
rates of completion tend to be low and rates of relapse to opioid use following detoxification are 
high (Day et al, 2005). Kleber et al. reported that approximately 80% of patients relapse during 
outpatient detoxification without transition to medication-assisted treatment (Kleber 2007), 
which can be partly attributed to patients’ strong desire for opioids as well as experiences of 
intolerable withdrawal symptoms including gastrointestinal stress, pain, anxiety and insomnia. 
One recent study comparing rates of outpatient induction onto VIVITROL for opioid-dependent 
patients found that a regimen combining ascending doses of oral naltrexone with a brief 
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decreasing BUP taper demonstrated superiority to a standard BUP-assisted detoxification (56.1% 
versus 32.7%; χ1
2=6.58, p=0.010). These results support the safety, efficacy and tolerability of 
low-dose naltrexone, in conjunction with brief BUP dosing and adjunctive non-opioid 
medications, for initiating adults with opioid dependence onto VIVITROL (Sullivan et al, 2016). 
While agonist maintenance is protective against opioid withdrawal, the question of how long 
patients should be maintained on BUP to provide adequate protection against relapse is of 
considerable clinical relevance. Several studies have found that for heroin or prescription opioid 
users initially transitioned to BUP, rates of relapse are high after stabilization for 4 weeks 
followed by 7- or 28-day taper (Nielsen et al, 2013). Previous trials have noted high relapse rates 
following BUP stabilization periods of up to 3 months. In a multi-site CTN trial, following 
4 weeks of BUP/naloxone maintenance with flexible dosing, only 44% of patients were opioid-
free at its completion. At 1-month follow-up, the percentage of abstinent patients who had 
undergone either taper condition had fallen to 18% (Ling et al, 2009). Another recent study 
examined the efficacy of brief vs. extended BUP/naloxone treatment, with differing counseling 
intensities, for patients dependent on prescription opioids. Weiss et al. (2011) found that more 
than 90% of patients relapsed after an initial 3-week taper; following re-stabilization for 
12 weeks, over 90% of patients again relapsed when tapered off BUP/naloxone, even in patients 
receiving counseling in addition to standard medical management (Weiss et al, 2011). However, 
there has been little research on the outcome of patients tapered off BUP after longer periods of 
stabilization, nor on methods to reduce the risk of relapse after tapering off BUP. 
5.2. 
Study Rationale 
Developing a strategy to assist patients in safely tapering from BUP by induction onto antagonist 
therapy has immediate clinical relevance, as safely transitioning patients off BUP would enable 
more opioid-dependent patients to access treatment. In areas of the country where BUP providers 
have reached maximal federally permissible limits of prescribing for 100 patients, opioid-
dependent individuals seeking treatment may face waiting lists. While some patients who wish to 
discontinue BUP after years of stability are unable to discontinue because of attendant opioid 
withdrawal, others seeking induction cannot be accommodated and bear the risks of ongoing 
opioid abuse, including overdose, risk of contracting hepatitis B or C or HIV, needing to resort to 
crime to support the habit, and so forth. In addition, as of May 2013, 11 states have imposed 
lifetime limits on prescriptions of BUP for the treatment of opioid dependence, ranging from 
12 months to 36 months (Rinaldo et al, 2013). Finally, given the stigma associated with chronic 
maintenance on opioid substitution, development of an effective strategy to assist patients in 
safely transitioning from BUP to injection naltrexone is important and could help attract more 
patients into treatment. 
5.3. 
Rationale for Selection of Dosing Regimen 
Mannelli et al. reported findings from an open-label study evaluating the use of low doses of oral 
naltrexone, in addition to BUP and ancillary medications, to safely transition subjects from 
opioid dependence to VIVITROL treatment (Mannelli et al, 2014). The regimen used in this 
study was based upon prior clinical experience wherein low doses of naltrexone, combined with 
a methadone taper, reduced the severity of withdrawal symptoms during inpatient detoxification 
(Mannelli et al, 2003; Mannelli et al, 2009; Mannelli et al, 2012). Subjects (N=20) were given 
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increasing doses of naltrexone during a 7-day outpatient period, in conjunction with 3 days of 
BUP. Withdrawal discomfort, craving, drug use and adverse events (AEs) were assessed daily 
until the administration of VIVITROL on Day 8. Adverse events were assessed weekly over the 
following month. Fourteen of the 20 subjects received VIVITROL, and 13 subjects completed all 
subsequent safety assessments. Withdrawal discomfort, craving and opioid or other drug use 
were significantly lower during the detoxification/induction period and after VIVITROL 
administration, when compared with the assessments administered at pretreatment baseline. No 
serious AEs (SAEs) occurred. The 7-day outpatient regimen using low doses of naltrexone, in 
combination with BUP, in patients with opioid use disorder prior to induction to VIVITROL was 
reported to be safe and well tolerated. The current study design is based on the regimen 
described in Mannelli’s recent study (Mannelli et al, 2014). 
Recruitment of a clinical population maintained at a BUP dose of ≤8 mg/day at study entry 
supports tolerability of the transition from opioid agonist maintenance, while increasing 
generalizability. Since BUP doses of <8 mg/day yield <80% μ-opioid receptor occupancy 
(Greenwald et al, 2003) and increase risk of relapse (D'amore et al, 2012), these doses require 
clinical management within the protocol (ie, BUP Lead-in phase). In light of difficulty tapering 
to doses below 8 mg BUP (Ling et al, 2009), this study includes 2 days of residential monitoring 
of BUP 4 mg/day to confirm tolerability via Clinical Opiate Withdrawal Scale 
(COWS)/Subjective Opiate Withdrawal Scale (SOWS) prior to randomization. 
Findings from a recent open-label pilot study (Dakwar and Kleber 2015) support the safety and 
tolerability of the proposed regimen for BUP-dependent individuals transitioning to VIVITROL 
during a 7-day inpatient stay. In that investigation, subjects who had tapered to 2 mg daily of 
BUP took their final dose on the day of admission (Day 1). On Day 3, they received 6.25 mg 
naltrexone and then received ascending doses on Days 4 through 6 (12.5, 25, 50 mg). Subjects 
who tolerated the 50 mg dose of oral naltrexone received 380 mg VIVITROL by intramuscular 
injection on Day 6. Adjuvant medications included clonidine, clonazepam, zolpidem, ibuprofen 
and loperamide. Investigators found that 100% (6/6) of subjects were able to transition to 
VIVITROL, and subjects exhibited a significant decrease in SOWS scores (p=0.043) during this 
period. The approach used by Dakwar and Kleber (Dakwar and Kleber 2015) for transitioning 
BUP-dependent adults is largely consistent with that outlined by Sigmon et al. (Sigmon et al, 
2012), who summarized clinical practices for transitioning patients from short-acting opioid 
agonists to naltrexone: namely, the combined use of BUP, oral naltrexone and ancillary 
medications to manage opioid withdrawal symptoms. 
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6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of oral naltrexone used in 
conjunction with buprenorphine in adults with Opioid Use Disorder transitioning from 
buprenorphine maintenance prior to the first dose of VIVITROL. 
6.2. 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of oral naltrexone 
used in conjunction with buprenorphine in adults with Opioid Use Disorder transitioning from 
buprenorphine maintenance prior to the first dose of VIVITROL. 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Each subject must meet all of the inclusion and none of the exclusion criteria to be qualified to 
participate in this study. 
7.1. 
Subject Inclusion Criteria 
1. Is willing and able to provide written informed consent 
2. Is willing and able to provide government issued identification. If government issued 
identification does not contain a photo, a second form of photo identification will be 
required. 
3. Is between 18 and 60 years of age, inclusive, at screening 
4. Has a body mass index (BMI) of 18.0 to 40.0 kg/m2, inclusive, at screening 
5. Has a history of Diagnostic and Statistical Manual, 5th edition (DSM-5) diagnosis of 
opioid use disorder for at least the prior 6 consecutive months 
6. Has a history of prescribed BUP (or buprenorphine/naloxone [BUP/Nx]) maintenance for 
the prior 3 or more consecutive months and is currently BUP-maintained, as confirmed 
by the following: 
• Self-reported daily BUP maintenance 
• Urine toxicology positive for BUP 
• Confirmation of prescription by: 
− Inspection and/or accessing electronic Prescription Monitoring Program registry; 
and/or 
− Direct contact with BUP provider 
7. Has been maintained on a daily BUP dose of ≤8 mg* for at least 30 days prior to Day -5 
(initiation of the BUP Lead-in Period) 
* BUNAVAIL® 4.2 mg or ZUBSOLV® 5.7 mg has bioequivalence to 8 mg of generic 
BUP (Biodelivery Sciences International Inc 2014; Orexo Us Inc 2013-07) 
8. Is voluntarily seeking treatment for opioid use disorder and has a desire or motivation for 
antagonist therapy 
9. Is willing to abide by the contraception requirements for the duration of the study (please 
refer to Section 8.9.4 for additional details regarding contraception) 
10. Is willing to provide written consent to allow the study physician to confer with the BUP 
provider, concerning the subject’s interest in transitioning to VIVITROL 
7.2. 
Subject Exclusion Criteria 
1. Is pregnant (ie, has a positive pregnancy test) or breastfeeding at screening or Day -5 or is 
planning to become pregnant during the study period 
2. Has a positive urine drug screen for methadone at screening or Day -5 


 
 
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3. Has a positive urine drug screen for opiates or oxycodone at screening or Day -5 
4. Has used naltrexone (oral or VIVITROL) within the 90 days prior to Day -5 
5. Has used methadone within the 30 days prior to Day -5 
6. Has a history of seizures (with the exception of febrile seizures), or has received 
anticonvulsant therapy during the past 5 years for treatment of seizures (use of 
anticonvulsant during past detoxification is not exclusionary) 
7. Has a condition, disease state, previous medical history or observed abnormalities 
(including physical examination, electrocardiogram [ECG], laboratory evaluation [eg, 
kidney or liver function test result] or urinalysis finding) at screening that, in the opinion 
of the investigator, would preclude safe participation in the study or interfere with the 
study assessments, including, but not limited to, the following: 
− Uncontrolled hypertension, uncontrolled diabetes, renal disease/impairment, 
stroke or neurological disorder, AIDS indicator disease, cardiovascular (eg, 
endocarditis), neoplastic disease (excluding adequately treated skin cancer or 
carcinoma in situ of the cervix), chronic pain condition requiring ongoing opioid 
analgesia 
− Aspartate aminotransferase or alanine aminotransferase value ≥3 times the upper 
limit of normal 
− Treatment for an active TB infection 
− Oral cavity pathology that would interfere with sublingual absorption 
− Significant hypotension below 90/60 and pulse below 60 bpm 
− Any contraindicated medical condition per the approved labeling for either BUP 
or naltrexone 
8. Has any of the following psychiatric conditions per DSM-5 criteria, as assessed by the 
MINI: 
− Diagnosis of schizoaffective disorder or bipolar disorder; or current, untreated or 
unstable major depressive disorder (subjects with current, but stable depression, 
depressive symptoms or major depressive disorder may be eligible provided 
bipolar disorder and schizoaffective disorder have been ruled out) 
− Diagnosis within the past 12 months of other psychiatric conditions or disorders 
that, in the investigator’s opinion, could interfere with participation in the study 
9. Is currently physiologically dependent on any psychoactive substance (except opioids, 
caffeine or tobacco) requiring medical intervention for detoxification 
− Breathalyzer alcohol test positive at Day -5 will be exclusionary; a positive 
breathalyzer test during screening may be repeated, provided that one negative 
test is obtained by Day -5 
− Benzodiazepine dependence will be confirmed by positive urine drug screen and 
investigator judgment during screening 
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10. Has a history of hypersensitivity or adverse reaction to BUP, naltrexone, VIVITROL or 
naloxone 
11. Has a history of more than 3 unsuccessful inpatient or medically assisted outpatient 
opioid detoxifications during the subject’s lifetime 
12. Has had significant suicidal ideation or behavior within the past year, confirmed by a 
baseline Columbia-Suicide Severity Rating Scale (C-SSRS) response of “Yes” to 
questions 4 or 5 
13. Is currently participating in or has participated in a clinical trial of an investigational 
drug, device or biologic, within 3 months prior to screening 
14. Has a history of accidental drug overdose (defined as an episode of opioid-induced 
unconsciousness or incapacitation) in the past 12 months, whether or not medical 
treatment was sought or received 
15. Is court mandated to receive treatment for opioid use disorder 
16. Is employed by the investigator or study center, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study center, or 
immediate family* member of the employees or the investigator 
17. Is employed by the sponsor or contract research organization (CRO; permanent, 
temporary contract worker or designee responsible for the conduct of the study), or 
immediate family* member of a sponsor or CRO employee 
* Immediate family is defined as a spouse, parent, sibling or child, whether biological 
or legally adopted. 
7.3. 
Subject Withdrawal 
Subjects who initiate screening but are not randomized will be considered screen failures. A 
subject who has previously screen failed may be allowed, at Investigator discretion, to repeat the 
screening process, provided that the circumstance that led to screen failure is no longer present. 
A randomized subject who is eligible to receive the naloxone challenge will be considered a 
treatment completer. Subjects completing all visits during the follow-up period will be 
categorized as completing the study. 
A subject may be discontinued from the study at any time if it is not in the subject’s best interest 
to continue or he/she chooses to withdraw. Reasons for subject withdrawal include: 
• AE 
• Lack of efficacy 
• Withdrawal by subject 
• Lost to follow-up 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
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• Other 
If a subject withdraws or is withdrawn from the study for any reason, any ongoing AEs will be 
followed until resolution, until deemed stable by the investigator or until the subject is deemed 
by the investigator to be lost to follow-up. If, in the opinion of the investigator, it is necessary to 
monitor a subject beyond the last safety follow-up visit, the follow-up period may be extended as 
necessary. In such instances, the sponsor and the investigator will agree to an acceptable follow-
up schedule. 
In the event that a subject chooses to withdraw from the study, the investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. The subject should be encouraged to return to the study center for an early termination 
(ET) visit, as close as possible to the subject’s date of study withdrawal. The ET visit will match 
the procedures at Day 9 (Table 4). If the subject fails or refuses to return to the study center, an 
attempt must be made to contact the subject in order to assess as many safety parameters as 
possible. All data collected remotely must be documented and kept in the subject’s record. 
The investigator must maintain a record of all subjects who fail to complete the study. The 
reason for study discontinuation will be entered on the appropriate electronic case report form 
(eCRF). A subject will be deemed lost to follow-up after 3 attempts at contact have been made. 
The third attempt at contact must be a certified letter accompanied by a survey inquiring the 
reason for study discontinuation. All attempts at contact will be documented. 
7.4. 
Replacement of Subjects 
Randomized subjects who withdraw prior to the completion of the study will not be replaced. 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This Phase 3, randomized, double-blind, placebo-controlled, parallel group study will evaluate a 
dosing schedule for active versus placebo oral naltrexone coadministered with BUP in 
BUP-dependent individuals prior to first dose of VIVITROL. Eligible subjects will be 
randomized in a 1:1 ratio to one of 2 treatment groups (naltrexone + BUP or placebo naltrexone 
[PBO-N] + BUP) for induction onto VIVITROL, stratified according to low (<8 mg/day) versus 
high (8 mg/day) BUP maintenance dose at the time of initiation of the BUP Lead-in Period. 
Approximately 92 subjects are planned to be randomized; 46 subjects per group. 
The study participation for each subject will last approximately 9 weeks; up to 3 weeks for 
screening (Days -26 to -6; during which time subjects will remain under the care of their original 
BUP provider), approximately 2 weeks for the BUP Lead-in Period and the Treatment Period 
(Days -5 to 7), 4 to 5 days for VIVITROL induction and post-VIVITROL monitoring and a 
4-week outpatient follow-up period. 
This study includes: 
• BUP Lead-in Period: Outpatient Days -5 through -3; residential Days -2 and -1 
(option for earlier residential admission at the study clinician’s discretion) 
• Treatment Period: Transitional dosing with oral naltrexone or PBO-N in conjunction 
with BUP taper; residential Days 1* to 7 
* Subjects who do not qualify for randomization on Day 1 will receive Day -1 BUP 
dosing and repeat Day 1 assessments and procedures on the following day, Day 1a. 
• VIVITROL Induction and Post-VIVITROL Observation Period: 
− A naloxone challenge and administration of VIVITROL on Day 8* prior to 
discharge 
* Subjects who do not qualify to receive VIVITROL on Day 8 will receive Day 7 
study drug (naltrexone/PBO-N), and complete Day 7 assessments and 
procedures. Day 8 assessments and procedures will be repeated the following 
day (Day 8a). 
− Post-VIVITROL outpatient monitoring (Days 9-11) 
The design is presented in Figure 1. Each phase is described further below. 
Evaluation of withdrawal symptoms will occur throughout the BUP Lead-in Period, the 
Treatment Period, and the VIVITROL Induction and Post-VIVITROL Observation Period 
(Days -5 through 11). On Days -2 through 8/8a, AM and PM vital signs, COWS/SOWS, and 
visual analogue scale (VAS) will be measured (see Section 8.4 for details regarding the timing of 
these assessments). On the day of discharge (Day 8/8a), PM vital signs, COWS/SOWS and VAS 
will be measured prior to discharge. In addition to the AM and PM assessments described above, 
clinical testing sessions to monitor opioid withdrawal effects in response to study drug will occur 
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on Days 1 through 7. Also, subjects will receive psychoeducational counseling starting on Day -5 
and throughout the Treatment Period. 
Up to 2 additional study visits may be conducted (Days 1a and 8a), as needed, for subjects who 
do not meet criteria for proceeding with procedures on Day 1 or Day 8. 
The combined outpatient and residential design of this trial has been selected to ensure 
tolerability of lower-dose BUP prior to introduction of the treatment regimen, and to afford the 
most accurate measurement possible of opioid withdrawal during the transition from BUP 
maintenance to first dose of VIVITROL. Multiple daily observations of opioid withdrawal will 
be recorded in an environment free from access to nonstudy opioids, thus enabling a more direct 
comparison of the efficacy of a dosing schedule for active versus placebo oral naltrexone 
coadministered with BUP to transition BUP-dependent individuals to first dose of VIVITROL. 
Moreover, this study is the first of its size to examine the transition from opioid agonist to 
antagonist therapy in this subject population, necessitating careful safety monitoring. Conducting 
the Treatment Period in a controlled residential environment will ensure that safety and 
tolerability are carefully monitored. This study will assess the safety, tolerability and efficacy of 
this procedure for use in a residential or outpatient setting for patients seeking to discontinue 
BUP and transition to treatment with VIVITROL. 
See Section 8.4 for more information on withdrawal assessments and clinical testing sessions, 
including a timetable for testing sessions in Figure 2. In addition, the Hamilton Rating Scale for 
Depression (HAM-D) and cognitive assessments will be conducted at screening and on Days -1, 
22 and 36. 
Figure 1: 
Study Design Schematic 
Naloxone 
Challenge 
and 
VIVITROL 
Injection
Screening
BUP lead-in 
(4 mg*)
Randomization
on Day 1/1a
Treatment Period
(Days 1/1a-7)
Naltrexone + BUP taper
PBO-N + BUP taper
Post-VIVITROL 
Observation
Follow-up
Days -26 to -6
Days -5 to -1
Day 8/8a
Days 9-11
Discharge 1 hour 
after VIVITROL 
injection
Day 22
Day 36
Residential Period Days -2 to 8/8a
BUP taper 
begins
*Subjects maintained on <4 mg at Day -5 will continue on their current dose until 
the Treatment Period taper calls for further decrease to establish a consistent 
daily dose prior to transitional dosing with naltrexone (see Section 8.2.1).
 
8.2. 
Buprenorphine Lead-in and Treatment Periods 
8.2.1. 
Buprenorphine Lead-in Period 
Following a screening period of up to 21 days, all subjects meeting eligibility criteria will begin 
a 5-day lead-in period consisting of 3 daily outpatient visits (Days -5 to -3), where subjects will 
report to the research clinic daily to undergo withdrawal assessments and to receive a dose of 
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BUP under supervised conditions, then admission to the residential unit on Day -2 in order to 
ensure tolerability of the BUP maintenance dose in a supervised setting. Subjects may be 
admitted for residential stay earlier if it is the clinical judgment of the investigator that residential 
care is needed for management of opioid withdrawal symptoms. In the event that a subject is 
admitted for the residential stay early (on Days -5, -4, or -3), AM and PM vital signs, 
COWS/SOWS, and VAS will also be measured. Ancillary medications will not be provided 
during the outpatient visits (Days -5 to -3), unless needed for treatment or prophylaxis of a 
documented AE. In the event that a subject is admitted for the residential stay early (on Days -5, 
-4, or -3), the ancillary medication regimen, which begins on Day -2 (see Section 8.9.2), will 
begin as soon as the subject becomes residential. To ensure that all subjects initially stabilize on 
a dose of ≤4 mg BUP daily, and given that such doses are lower than those which afford full μ-
opioid receptor occupancy, up to 4 mg BUP will be administered sublingually once daily for 
5 days to establish a consistent daily dose prior to transitional dosing with naltrexone. Subjects 
entering the BUP Lead-in Period at doses of BUP >4 mg/day will have the option, at the 
discretion of the study physician, to receive an additional take-home dose of BUP 2 mg on Day -
5 only. Subjects maintained on ≤4 mg at Day -5 will continue on their current dose until the 
Treatment Period taper calls for further decrease. Urine toxicology screens will be collected daily 
during this period. Subjects may miss a single day during the 3-day outpatient BUP Lead-in 
Period (Days -5 to -3). 
8.2.2. 
Treatment Period 
Following 5 days of stabilization on ≤4 mg BUP, on the morning of Day 1 of the Treatment 
Period, subjects will undergo an assessment of withdrawal symptoms (the eligibility COWS 
score). Randomization will occur prior to study drug dosing on Day 1. Eligible subjects will 
demonstrate ability to tolerate the lead-in BUP dose based upon exhibiting minimal/mild opioid 
withdrawal symptoms (as confirmed by COWS score ≤12) on Day 1. Subjects who do not 
qualify for randomization on Day 1 will receive Day -1 BUP dosing and complete the remaining 
Day -1 assessments and procedures. These subjects will then repeat Day 1 assessments and 
procedures on the following day, Day 1a. 
The Treatment Period will consist of tapering doses of BUP (on Days 1/1a-3) in conjunction 
with ascending doses of oral naltrexone or PBO-N (Days 1/1a-7); see Table 3. 
Table 3: 
ALK6428-A302 Dosing Regimen 
Study 
Day 
Group 1 
Naltrexone + BUP 
Group 2 
Placebo-NTX + BUP 
1st Dose NTX 
2nd Dose NTXa 
BUPb,c 
1st Dose NTX 
2nd Dose NTXa 
BUPb,c 
Day -5d 
N/A 
N/A 
4 mg 
N/A 
N/A 
4 mg 
Day -4 
N/A 
N/A 
4 mg 
N/A 
N/A 
4 mg 
Day -3 
N/A 
N/A 
4 mg 
N/A 
N/A 
4 mg 
Day -2 
N/A 
N/A 
4 mg 
N/A 
N/A 
4 mg 
Day -1 
N/A 
N/A 
4 mg 
N/A 
N/A 
4 mg 
Day 1 
0.25 mg 
0.25 mg 
4 mg 
PBO-N 
PBO-N 
4 mg 
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Table 3: 
ALK6428-A302 Dosing Regimen (Continued) 
Study 
Day 
Group 1 
Naltrexone + BUP 
Group 2 
Placebo-NTX + BUP 
1st Dose NTX 
2nd Dose NTXa 
BUPb,c 
1st Dose NTX 
2nd Dose NTXa 
BUPb,c 
Day 1a 
0.25 mg 
0.25 mg 
4 mg 
PBO-N 
PBO-N 
4 mg 
Day 2 
0.25 mg 
0.25 mg 
2 mg 
PBO-N 
PBO-N 
2 mg 
Day 3 
0.5 mg 
0.5 mg 
2 mg 
PBO-N 
PBO-N 
2 mg 
Day 4 
1.5 mg 
1.5 mg 
N/A 
PBO-N 
PBO-N 
N/A 
Day 5 
3 mg 
3 mg 
N/A 
PBO-N 
PBO-N 
N/A 
Day 6 
7.5 mg 
7.5 mg 
N/A 
PBO-N 
PBO-N 
N/A 
Day 7 
15 mg 
15 mg 
N/A 
PBO-N 
PBO-N 
N/A 
Day 8 
Naloxone 3.0 mg (1.5 mg + 1.5 mg) 
then VIVITROL 
Naloxone 3.0 mg (1.5 mg + 1.5 mg) 
then VIVITROL 
Day 8ae 
Naloxone 3.0 mg (1.5 mg + 1.5 mg) 
then VIVITROL 
Naloxone 3.0 mg (1.5 mg + 1.5 mg) 
then VIVITROL 
N/A=not applicable; BUP=buprenorphine; NTX=naltrexone; PBO-N=placebo naltrexone 
a The second dose of naltrexone/PBO-N will be administered at least 60 minutes after the first dose of 
naltrexone/PBO-N, following a clinical evaluation of tolerability (based upon withdrawal symptoms). 
b On days when subjects receive both BUP and naltrexone/PBO-N, BUP will be given sublingually immediately 
following the second dose of oral naltrexone/PBO-N. If a subject does not qualify for the second dose of 
naltrexone/PBO-N, the subject will still receive the BUP dose for that day and will be monitored in the clinic for 
60 minutes following the BUP dose. 
c Subjects maintained on <4 mg at study entry will continue on their current dose until the treatment period taper 
calls for further decrease to establish a consistent daily dose prior to transitional dosing with naltrexone. 
d Subjects entering the BUP Lead-in Period at doses of BUP >4 mg/day will have the option, at the discretion of the 
study physician, to receive an additional take-home dose of BUP 2 mg on Day -5 only. 
e If a subject has a positive naloxone challenge on Day 8, he/she will not receive the VIVITROL injection, but will 
receive Day 7 study drug (naltrexone/PBO-N), and complete Day 7 assessments and procedures. He/she will be 
offered the opportunity to remain in the residential unit overnight and may repeat the naloxone challenge the 
following day (Day 8a) to qualify for VIVITROL administration. 
The total daily naltrexone or PBO-N allocation will be split over 2 separate doses administered at 
least 60 minutes apart. Administration of the second naltrexone or PBO-N dose will depend upon 
how well the first was tolerated. 
On Days 1/1a through 7, subjects will undergo a baseline COWS and SOWS assessment prior to 
the first dose of naltrexone or PBO-N (see Figure 2). On Day 1/1a, the eligibility COWS score 
may serve as the predose COWS score, if conducted within 60 minutes prior to dosing. At 
30 and 60 minutes postdose, the COWS and SOWS will be re-administered. If withdrawal 
symptoms are stable (ie, increase of ≤5 points in COWS score from predose COWS) at the 
60-minute assessment, the second dose of oral naltrexone or PBO-N will be administered. For 
these early qualifying subjects, the next COWS/SOWS assessments at 90 and 120 minutes post-
first dose will constitute their post-second dose assessments. 
Subjects who did not qualify for the second dose of naltrexone or PBO-N at 60 minutes will also 
receive the 90- and 120-minute COWS/SOWS assessments (see Figure 2), and if their 
withdrawal symptoms have stabilized sufficiently by 120 minutes post-first dose (ie, increase of 
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≤5 points in COWS score from predose COWS), they will receive the second dose of oral 
naltrexone or PBO-N at this time. These later qualifying subjects will undergo 2 additional 
COWS/SOWS assessments at 150 and 180 minutes post-first dose (30 and 60 minutes post-
second dose) to monitor withdrawal status following the second dose of naltrexone or PBO-N. 
Refer to Section 8.2.3 for instructions on how to proceed should withdrawal symptoms not 
stabilize by 120 minutes. 
Figure 2: 
Schematic of Daily Residential Withdrawal Assessments, Days 1/1a to 7 
Baseline 
Assessmentsa
1st Dose 
NTX/PBO-N
0
30
60
90
120
150
180
Clinical 
Testinga
2nd Doseb 
NTX/PBO-N
Early Qualifiers
2nd Doseb 
NTX/PBO-N
Late Qualifiers
Post-2nd dose 
assessments for 
Early Qualifiers
Post-2nd dose 
assessments for 
Late Qualifiers
aClinical testing sessions will include the following assessments: vital signs (body 
temperature, respiratory rate, heart rate, systolic and diastolic blood pressure), 
oxygen saturation, pupillometry, SOWS, COWS, Opioid Craving VAS. A window of +30 
minutes is allowed for these assessments.
bSubjects whose COWS score is increased ≤5 points above the baseline COWS qualify 
for the second dose of NTX or PBO-N immediately followed by BUP (on BUP dosing 
days). Subjects who do not qualify for the second dose by the 120-minute timepoint 
will not receive a second dose of NTX/PBO-N, but will receive the normal dose of BUP 
(on BUP dosing days). 
Minutes post-1st dose
= All Subjects
= Late Qualifiers Only
Clinical 
Testinga
Clinical 
Testinga
Clinical 
Testinga
Clinical 
Testinga
Clinical 
Testinga
AM Vital Signs, 
COWS/SOWS, VAS
PM Vital Signs, 
COWS/SOWS, VAS
 
Buprenorphine will be administered sublingually immediately following the second oral 
naltrexone or PBO-N dose on Days 1/1a through 3. If a subject does not qualify for the second 
dose of naltrexone or PBO-N, he/she will still receive the BUP dose for that day (see 
Section 8.2.3). Subjects will remain under clinical observation for a minimum of 60 minutes 
after the BUP dose to assess tolerability of withdrawal symptoms. 
8.2.3. 
Poorly Tolerated Doses 
If withdrawal symptoms increase substantially after the initial dose of naltrexone or PBO-N 
(ie, COWS score increased >5 points from the predose COWS) and do not recede during 
subsequent COWS/SOWS testing (up to 120 minutes postdose), the subject will not receive the 
second dose of naltrexone or PBO-N, but may receive the scheduled dose of BUP, as well as 
ancillary medications. Following BUP administration, the subject will be observed for 
60 minutes in the clinical setting. In addition to the standing regimen of ancillary medications 
(see Section 8.9.2), subjects may be administered additional doses of ancillary medications, as 
needed to alleviate any marked withdrawal symptoms (ie, total COWS score >12) not alleviated 
by BUP. The subject will continue all clinical testing sessions and the dosing scheduled for the 
following day. 
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8.3. 
Day 8/8a Naloxone Challenge and VIVITROL Injection 
8.3.1. 
Naloxone Challenge 
Prior to the start of the naloxone challenge, COWS/SOWS assessments will be administered. 
Subjects who are no longer exhibiting significant signs of withdrawal as demonstrated by COWS 
total score ≤12 on Day 8/8a will undergo a 2-part naloxone challenge as follows: 
Part 1: 
• Administer 1.5 mg* of naloxone intramuscularly in the subject’s arm (nondominant 
arm preferred for first injection) 
* Note: Each naloxone injection consists of 1.5 mg. Doses of naloxone sufficient to 
precipitate opioid withdrawal in the presence of short-acting opioids may not suffice 
to displace BUP from the μ-opioid receptor (Gal 1989). 
• Administer COWS and SOWS at 10 and 20 minutes post-naloxone injection. Vital 
signs will be measured and the subject will remain under observation following the 
naloxone injection to monitor for safety 
− At each timepoint (10 and 20 minutes) the COWS score must be no more than 
2 points greater than the pre-naloxone baseline COWS score for subjects to 
qualify for Part 2. 
− If either the 10- or 20-minute COWS score increases by >2 points from the 
pre-naloxone COWS, then the challenge is considered to be positive (see 
Section 8.3.3.1 for instructions on how to proceed following a positive naloxone 
challenge). A positive challenge is indicative of a significant increase in 
withdrawal symptoms and physical dependence on opioids. 
Part 2: 
• Administer second naloxone injection (1.5 mg [see Part 1 above regarding dose] 
naloxone in opposite arm to that used for first injection) 
• Administer COWS and SOWS at 10 and 20 minutes post-naloxone injection. Vital 
signs will be measured and the subject will remain under observation following the 
naloxone injection to monitor for safety 
− At each timepoint (10 and 20 minutes) the COWS score must be no more than 
2 points greater than the immediately previous Part 1 COWS score for subjects to 
qualify for VIVITROL injection 
− If either the 10- or 20-minute COWS score in Part 2 increases by >2 points from 
the immediately previous Part 1 COWS score, then the challenge is considered to 
be positive. See Section 8.3.3.1 for how to proceed following a positive naloxone 
challenge. 
Eligibility for VIVITROL administration on Day 8/8a will consist of the 
following: Part 1 post-naloxone COWS scores increase by ≤2 points from pre-
naloxone scores and Part 2 post-naloxone COWS scores increase by ≤2 points 
from the immediately previous Part 1 score, with a total allowable increase of 
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≤4 points in COWS total score for Parts 1 and 2 of the challenge combined. 
Subjects must have a total COWS score ≤16 following the naloxone challenge to 
qualify for VIVITROL administration. Subjects with a positive naloxone 
challenge on Day 8 will have the opportunity to retry the challenge on the 
following day (Day 8a; see Section 8.3.3.1) 
8.3.2. 
VIVITROL Injection 
If the naloxone challenge is negative, a single intramuscular (gluteal) injection of VIVITROL 
380 mg will be administered following the naloxone challenge on Day 8/8a. Subjects will remain 
on-site for 1 hour for safety observation following VIVITROL administration and then may be 
discharged home, following PM withdrawal assessments. They will be asked to return for 
outpatient visits on the 3 days following VIVITROL injection (Days 9-11). 
8.3.3. 
Subjects Who Do Not Transition to VIVITROL 
Due to loss of opioid tolerance and a heightened risk for overdose in subjects who have 
transitioned from BUP but have not received VIVITROL (due to subject withdrawal of consent 
or a positive naloxone challenge), it is important that subjects be reinstated on BUP/Nx 
maintenance therapy and discharged to their treatment provider to continue BUP maintenance 
and discuss future treatment options. 
8.3.3.1. 
Treatment Options for Subjects with a Positive Naloxone Challenge 
8.3.3.1.1. Day 8 
Subjects with a positive naloxone challenge on Day 8 will not receive the VIVITROL injection 
that day. In such cases, these subjects will receive Day 7 study drug (naltrexone/PBO-N), and 
complete Day 7 assessments and procedures (per Figure 2). Pre- and postdose COWS will be 
assessed for clinical safety purposes only. Day 8 assessments and procedures will be repeated the 
following day (Day 8a). 
For subjects who do not wish to receive a naloxone challenge on Day 8a, the study staff will 
notify the subject’s BUP provider prior to discharge, to inform him/her of the treatment and 
medications the subject has received during the course of the study, and of the need for a follow-
up appointment. Such subjects will be restarted on BUP/Nx while on the residential unit at a 
dose deemed clinically sufficient. Depending upon how many days of blinded treatment 
medication they have received, the investigator may decide that, for safety reasons, the subject 
should remain in the residential unit for up to 48 hours. Upon discharge he/she will be provided 
up to 3 days of BUP maintenance. The subject may choose to discuss other future treatment 
options with his/her BUP provider. 
8.3.3.1.2. Day 8a 
Subjects with a positive naloxone challenge on Day 8a will not receive the VIVITROL injection 
that day. In such cases, the study staff will follow the discharge procedures described in 
Section 8.3.3.1.1 above. 
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8.3.3.2. 
Treatment Options for Subjects Who Discontinue Prior to Receiving 
VIVITROL 
For subjects who discontinue from the study during the course of the residential period, the 
procedures described in Section 8.3.3.1.2 will be followed. 
8.3.4. 
Referrals to Post-Study VIVITROL Provider 
Subjects who have received VIVITROL will return to their previous BUP provider to receive 
subsequent VIVITROL treatment, unless the subject has chosen to transfer to a new treatment 
provider. Study staff will work with subjects to identify local VIVITROL treatment providers, as 
necessary. Subjects will be asked to sign consent for release of clinical record, not to include 
study data, to contact the post-study VIVITROL provider for purposes of follow-up medical 
care. 
8.4. 
Withdrawal Assessments Throughout the Residential Period 
Every morning (AM) and every evening (PM) during the residential period (Days -2 to 8/8a) 
subjects will undergo a basic withdrawal evaluation consisting of COWS, SOWS, VAS, and vital 
signs (Figure 2). The AM assessments should be conducted first thing in the morning and 
≥60 minutes prior to the baseline assessments. On Day 8/8a, the COWS/SOWS conducted as 
part of the AM assessments can serve as the pre-naloxone challenge COWS/SOWS if they are 
administered within an hour (≤60 minutes) prior to the initial administration of naloxone in Part 
1 of the naloxone challenge. The PM assessments should be conducted in the evening. In the 
event that they cannot be conducted in the evening, the earliest they can be completed is at 
60 minutes after the 120-minute post-first NTX/PBO-N dose for early qualifiers, and at 
60 minutes after the 180-minute post-first NTX/PBO-N dose for late qualifiers. The 60-minute 
post-VIVITROL injection assessments on Day 8/8a can serve as the PM assessments for those 
days. 
In the event that a subject is admitted for the residential stay early (on Days -5, -4 or -3), 
standard AM and PM assessments should be conducted. For subjects who remain on the 
residential unit for clinical stabilization on BUP, these study assessments are not required. 
On Days 1/1a to 7, subjects will undergo daily clinical testing to measure opioid withdrawal 
effects in response to study drug dosing. These clinical testing sessions will include the 
following assessments (see Section 8.8 for more details on individual assessments): 
• Vital signs (body temperature, respiration rate, heart rate, systolic and diastolic blood 
pressure) 
• Oxygen saturation 
• Pupillometry 
• COWS 
• SOWS 
• VAS 
A timetable for clinical testing sessions is provided in Figure 2. On Days 1/1a to 7, clinical 
testing sessions will begin approximately 15 minutes prior to the first dose of naltrexone or 
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PBO-N and will last at least 120 minutes following the first dose (60 minutes following the 
second dose). Clinical testing may potentially last 180 minutes for late qualifying subjects who 
receive the second naltrexone or PBO-N dose at the 120-minute timepoint (see Section 8.2.2 for 
more information regarding early and late qualification). A window of +30 minutes is allowed 
for these assessments. 
On Day 8/8a, VAS, COWS/SOWS, vital signs, and pupillometry will be collected pre-
VIVITROL injection, and at 30 and 60 minutes post-VIVITROL injection. The final 
COWS/SOWS assessments of the naloxone challenge will also represent the pre-VIVITROL 
COWS/SOWS scores. Subjects will be discharged following the 60-minute post-VIVITROL 
assessments. 
8.5. 
Follow-up Period 
On Study Days 22 (±3 days) and 36 (±3 days), subjects who have completed the Treatment 
Period and the VIVITROL Induction and Post-VIVITROL Observation Period (Days 1/1a-11) 
will return to the research center for 2 outpatient follow-up visits that will occur 2 and 4 weeks 
after the naloxone challenge/VIVITROL injection. 
8.6. 
Minimizing Risks 
Participants are fully informed by investigators of the potential side effects of the drugs and the 
risks of the procedures. In addition participants are advised about the risk of taking an opioid 
(BUP) in conjunction with benzodiazepines, other CNS depressant medicines or alcohol. 
Participants are monitored for oxygen saturation and vital signs by trained medical staff during 
clinical testing sessions. Emergency medical equipment is available in the testing clinic and the 
clinic is located in either a hospital where a full medical emergency back-up team is constantly 
available; or a medical research facility with appropriate emergency response procedures. 
Additionally, guidelines have been developed for opioid administration such that oxygen 
saturation dictates whether supplemental oxygen will be administered. Naloxone is available 
during all laboratory sessions in the event of serious respiratory depression. It is anticipated, 
however, that careful participant selection, dose selection and participant monitoring will 
eliminate the need for such emergency care. 
Enrolling subjects who are currently under the care of waivered physicians with the ability to 
prescribe BUP ensures that all subjects will have access to an addiction treatment provider at the 
completion of the study, or upon termination of participation in the trial. While it is anticipated 
that many subjects will transition to VIVITROL during the study, those who are not successful at 
induction will be advised to return to BUP maintenance under the care of their prior BUP 
treatment provider, with whom they can discuss additional treatment options. 
See Section 8.3.3.1 for instructions on how to proceed with subjects who are discharged without 
receiving VIVITROL. If not returned to a stable daily dose of BUP/Nx, these subjects will be at 
greater risk for relapsing to illicit or nonmedical use of opioids. Relapse also carries the risk of 
overdose. 
Subjects who have transitioned to VIVITROL and wish to transition to a different treatment 
provider will be offered referrals to local providers who prescribe medication-assisted treatment, 
including VIVITROL and BUP. 
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8.7. 
Schedule of Visits and Assessments 
The schedule of visits and assessments is shown in Table 4. 
For a missed visit, the site should attempt to contact the subject to reschedule. 
Premature discontinuation procedures are provided in Section 7.3. 
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Table 4: 
Schedule of Visits and Assessments 
 
Screening 
Period 
BUP Lead-in Period 
Treatment Period 
Naloxone Challenge, 
VIVITROL, and post-
VIVITROL observation 
Follow-Up 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Day 
-26 to -6 
-5 
-4 
-3 
-2 
-1 
1 
1aa 
2 
3 
4 
5 
6 
7 
8 
8ab 
9/ET 
10 
11 
22 
(±3 days) 
36 
(±3 
days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSEc 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
MOTYBc 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
SMAST 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Testd 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
Physical 
Examinatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry, 
Hematology and 
Urinalysis Samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Breath Alcohol 
Test 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4: 
Schedule of Visits and Assessments (Continued) 
 
Screening 
Period 
BUP Lead-in Period 
Treatment Period 
Naloxone Challenge, 
VIVITROL, and post-
VIVITROL observation 
Follow-Up 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Day 
-26 to -6 
-5 
-4 
-3 
-2 
-1 
1 
1aa 
2 
3 
4 
5 
6 
7 
8 
8ab 
9/ET 
10 
11 
22 
(±3 days) 
36 
(±3 days) 
Drug Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
Residential 
Admission 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Residential 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
Randomizationh 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
NTX/PBO-N 
 
 
 
 
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
Xi 
 
 
 
 
 
 
Administration of 
BUP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Ancillary 
Medicationsj 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
Xk 
Xk 
 
 
Naloxone 
Challenge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
VIVITROL 
Injection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
QSUI 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
COWSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
X 
X 
X 
X 
X 
SOWSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
X 
X 
X 
X 
X 
Desire for 
Opioids VASl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pupillometryn 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
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Table 4: 
Schedule of Visits and Assessments (Continued) 
 
Screening 
Period 
BUP Lead-in Period 
Treatment Period 
Naloxone Challenge, 
VIVITROL, and post-
VIVITROL observation 
Follow-Up 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Day 
-26 to -6 
-5 
-4 
-3 
-2 
-1 
1 
1aa 
2 
3 
4 
5 
6 
7 
8 
8ab 
9/ET 
10 
11 
22 
(±3 days) 
36 
(±3 days) 
PGART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
Xo 
Xp 
 
X 
 
X 
C-SSRSq 
X 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
Psychoeducational 
Counseling  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
HAM-Dr 
Xs 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Cognitive 
Assessmentst 
Xs 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Prior and 
Concomitant 
Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; ET=early termination; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; HAM-D=Hamilton Rating Scale for Depression; MINI=Mini-International Neuropsychiatric Interview; MMSE=Mini-Mental Status 
Examination; MOTYB=Months of the Year Backward; NTX=naltrexone; PBO-N=placebo naltrexone; PGART=Patient Global Assessment of Response to 
Therapy; QSUI=Quantitative Substance Use Inventory; SMAST= Short Michigan Alcohol Screening Test; SOWS=Subjective Opiate Withdrawal Scale; 
VAS=Visual Analogue Scale 
a Subjects who do not qualify for randomization on Day 1 will receive Day -1 BUP dosing and repeat Day 1 assessments and procedures on the following day, 
(Day 1a). 
b Subjects who do not qualify to receive VIVITROL on Day 8 will receive Day 7 study drug (naltrexone/PBO-N), and complete Day 7 assessments and 
procedures. Pre- and postdose COWS will be assessed for clinical safety purposes only. Day 8 assessments and procedures will be repeated the following day 
(Day 8a). 
c Full MMSE will be conducted at screening. The MMSE orientation questions and MOTYB will be performed 60 (-5/+15) minutes following the second dose 
of oral naltrexone/PBO-N or at end of testing session for subjects not receiving second dose. 
d For female subjects only. Urine pregnancy tests will be conducted at all specified timepoints; in addition, serum pregnancy tests will be conducted at Screening 
and Day 1/1a. Urine pregnancy tests to be performed prior to randomization on Day 1/1a and prior to naloxone challenge on Day 8/8a. 
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e Full physical examination at screening and symptom-driven examinations at subsequent timepoints. 
f In addition to the study assessments conducted during the clinical testing sessions, vital signs will be measured each morning and evening throughout the 
residential period (Days -2 to 8/8a and any additional residential days, in the case of earlier admission or later discharge). Vital signs (blood pressure, heart rate, 
respiratory rate and body temperature) will be measured after the subject has been in a seated position for at least 5 minutes. In addition to standard vital sign 
measurements, clinical testing sessions on Days 1/1a to 7 will include oxygen saturation and pupillometry measurements to assess withdrawal effects in 
response to drug dosing. Measurements will be collected pre- and postdose as indicated in Figure 2. Details regarding the timing of these assessments are 
provided in Section 8.4. 
g A urine drug screen will be performed at all specified timepoints. The urine drug screen should be performed in the morning. On Days 1/1a to 7, it should be 
performed prior to the clinical testing sessions. 
h Eligibility will be confirmed prior to randomization and administration of the first dose of NTX/PBO-N. 
i Subjects not qualifying for randomization on Day 1 will receive the Day -1 BUP dose and will not receive NTX/PBO-N. Subjects not qualifying for 
VIVITROL on Day 8 will receive the Day 7 NTX/PBO-N dose, along with the COWS conducted for clinical safety purposes only. 
j Standing ancillary medication regimen begins on Day -2. In the event that a subject is admitted for the residential stay early (on Days -5, -4, or -3), the ancillary 
medication regimen will begin as soon as the subject becomes residential. Also, if needed for AE treatment or prophylaxis, ancillary medications may be 
initiated at the clinician’s discretion on or after Day -5 
k For subjects receiving VIVITROL on Day 8/8a, ancillary medications will be reduced as indicated in Table 6. 
l COWS, SOWS and VAS to be recorded each morning (AM) and evening (PM) throughout the residential period (Days -2 to 8/8a) and any additional 
residential days, in the case of earlier admission or later discharge. On Days 1/1a to 7 the COWS, SOWS and VAS will also be administered as part of clinical 
testing sessions to measure withdrawal effects in response to study drug dosing. Details regarding the timing of these assessments are provided in Section 8.4. 
m On Day 8/8a, additional COWS and SOWS assessments will occur with the naloxone challenge, separate from the clinical testing sessions (pre-naloxone and 
10 and 20 minutes following each naloxone injection; see Section 8.3.1 for details). 
n Pupillometry to be performed during clinical testing sessions to evaluate withdrawal in response to study drug dosing on Days 1/1a to 7, as well as 
pre-VIVITROL injection, and at 30 and 60 minutes post-VIVITROL injection on Day 8/8a. A timetable showing when pupillometry occurs in relation to study 
drug dosing can be found in Figure 2. 
o The PGART will be administered prior to VIVITROL injection on Day 8/8a. 
p For ET visit only. 
q The “Baseline/Screening” version to be used at screening. The “Since Last Visit” version to be used at all subsequent visits. 
r The HAM-D should be administered immediately prior to the cognitive assessments. 
s Initial HAM-D and cognitive assessments should be conducted as early as possible during the screening period. 
t The cognitive assessments that will be conducted are described in detail in Section 8.8.11.12. Cognitive assessments at screening and during the follow-up 
period should be conducted after the completion of all other assessments during the visit. On Day -1, cognitive assessments may be conducted at any time after 
the morning vital sign and withdrawal measurements and prior to the evening vital sign and withdrawal measurements. Caffeine and nicotine use are prohibited 
within 30 minutes prior to the start of cognitive assessments. 
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8.8. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedule of assessments is 
provided in Table 4. 
8.8.1. 
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 16.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential subject. 
8.8.2. 
Eligibility Review 
An eligibility review will be conducted by the investigator at the visits specified in Table 4 using 
the subject inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. 
8.8.3. 
Demographics and Medical History 
Subject’s demographic data and medical history will be reviewed and documented at the 
timepoint specified in Table 4. 
8.8.4. 
Concomitant Medication Review 
All medications (prescription and nonprescription, including vitamins and herbal supplements) 
taken by a given subject within 30 days of screening through follow-up will be recorded. 
At each study visit (see Table 4), the investigator or designee will record the following data on 
all medications used by the subject: name, dose, regimen, route of administration, start and stop 
dates, and the indication for use. 
8.8.5. 
Vital Signs and Oxygen Saturation 
Vital signs (ie, body temperature, respiratory rate, heart rate and blood pressure) will be assessed 
at the timepoints specified in Table 4. Respiratory rate, heart rate and blood pressure will be 
measured after the subject has been resting in a seated position for at least 5 minutes. 
Heart rate, blood pressure (systolic and diastolic) and respiration rate will be measured and 
recorded pre- and postdose according to the timetable provided in Figure 2. In addition to vital 
signs, arterial oxygen saturation will be measured according to the same timetable using a soft 
sensor placed over the fingertip on the nondominant hand. 
8.8.6. 
Pupillometry 
Pupillometry will be conducted in a consistent level of ambient light during clinical testing 
sessions at the timepoints indicated in Table 4 according to the timetable indicated in Figure 2. 
Pupil diameter will be measured before and after drug administration using a digital 
pupillometer. Mean peak (ie, maximum) pupil diameter (which will be noted as “Mean” on the 
printout) will be recorded manually and then entered into the eCRF. Output will be saved with 
the appropriate source documents for each subject. 
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8.8.7. 
Physical Examination 
A physical examination will be performed at the timepoints specified in Table 4, a full physical 
exam at screening and symptom-driven exams at subsequent timepoints. 
8.8.8. 
Body Height and Weight 
Body height and weight will be measured at screening only. 
8.8.9. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be conducted at the timepoints specified in Table 4. 
8.8.10. 
Behavioral Therapy: Psychoeducational Counseling 
Subjects who enter the study will be asked to participate in psychoeducational counseling at the 
timepoints specified in Table 4. Counseling will be conducted by qualified study staff that will 
review common withdrawal symptoms, and instruct subjects on correct medication usage and the 
importance of adherence to study and ancillary medications. 
Subjects who were participating in counseling sessions prior to study entry will be encouraged to 
continue their program upon discharge from the inpatient stay. Subjects will also be provided 
information about local resources for addiction support upon exit from the study. 
8.8.11. 
Structured Interviews and Questionnaires 
8.8.11.1. Mini-International Neuropsychiatric Interview 
The MINI will be administered at screening (Table 4). 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 A. 
8.8.11.2. Mini-Mental Status Examination 
The MMSE is an 11-item, 30-point, clinician-administered questionnaire used to assess global 
cognitive impairment (Faust and Fogel 1989). A score ≤23 is indicative of cognitive impairment 
consistent with possible delirium or dementia. The full MMSE is administered at screening. On 
treatment days (Days 1/1a-7; Table 4), only orientation questions (MMSE items 1-2) will be 
asked. A decrease in score of 2 points total in the orientation questions is indicative of a change 
in mental status and requires a clinical assessment, as described below, prior to continuing 
protocol procedures for that day. 
The study staff may repeat the administration of the MMSE orientation questions if performance 
was deemed to be affected by fatigue or a medication effect. If a decrease of ≥2 points from 
baseline is confirmed on the MMSE, the study physician will conduct a clinical interview with 
the subject to confirm that the subject is alert, oriented, and consents to continuing the study 
procedures. If these conditions are not met, the subject will be observed on site and reassessed 
after 30 minutes. If orientation remains altered, the subject will be referred for medical 
evaluation. If the medical evaluation results in hospitalization, this would constitute an SAE. 
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8.8.11.3. Months of the Year Backward 
The Months of the Year Backward (MOTYB) is a brief assessment of verbal working memory, 
which is also used to screen for delirium (Meagher et al, 2015). Subjects will be instructed to 
recite the months of the year forward, and then backward. Subjects will receive a score of 0 to 2. 
Scores ≤1 indicate the absence of delirium. 
This assessment may be repeated if fatigue or poor effort is deemed to have interfered with the 
subject’s performance. An increase in MOTYB score will warrant assessment by the study 
physician. As noted above (Section 8.8.11.2), a subject found to have altered sensorium will be 
referred for medical evaluation, and if hospitalized, this event would constitute an SAE. 
Subjects will complete the MOTYB on Days 1/1a through 7, as indicated in Table 4. 
8.8.11.4. Columbia Suicide Severity and Rating Scale 
The C-SSRS is a questionnaire administered by a qualified clinician that assesses suicidal 
ideation and behavior (Posner et al, 2011). The “Baseline/Screening” version of the scale will be 
administered at the screening visit. The “Since Last Visit” version will be administered at all 
other timepoints specified in Table 4. Samples of the C-SSRS can be found in Appendix B. 
8.8.11.5. Clinical Opiate Withdrawal Scale 
The COWS is a questionnaire designed to measure 11 common opioid withdrawal signs or 
symptoms (Wesson and Ling 2003). The summed score provides information about the level of 
physical dependence on opioids. The COWS will be administered by research staff at the 
timepoints specified in Table 4. In addition to morning and evening assessments throughout the 
residential period, the COWS will be administered during clinical testing sessions (see 
Section 8.4) according to the timetable provided in Figure 2. A sample of the COWS can be 
found in Appendix C. When possible, the same person should complete the COWS each time. 
8.8.11.6. Subjective Opiate Withdrawal Scale 
The SOWS is a 16-item self-report questionnaire designed to measure the severity of opioid 
withdrawal symptoms. The subject rates the intensity of symptoms using a 5-point scale; with 0 
representing “not at all” and 5 representing “extremely.” The SOWS will be self-administered at 
the timepoints specified in Table 4. In addition to morning and evening assessments throughout 
the residential period, the SOWS will be self-administered during clinical testing sessions (see 
Section 8.4) according to the timetable provided in Figure 2. A sample of the SOWS can be 
found in Appendix D. 
8.8.11.7. Desire for Opioids Visual Analogue Scale 
The desire for opioids will be measured using a 100-mm, horizontal VAS, with 0 anchored on 
the left representing “no desire for opioids” and 100 anchored on the right representing 
“strongest imaginable desire for opioids.” Subjects will place a vertical line on the scale to 
indicate their desire for opioids at that particular time. The VAS will be self-administered at the 
timepoints specified in Table 4. In addition to morning and evening assessments throughout the 
residential period, the VAS will be self-administered during clinical testing sessions (see 
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Section 8.4) according to the timetable provided in Figure 2. A sample can be found in 
Appendix E. 
8.8.11.8. Short Michigan Alcohol Screening Test 
The SMAST is a 13-item self-report instrument designed to measure problems experienced as a 
result of drinking alcohol. The responses are coded as “yes/no.” All “Yes” responses indicate 
problems associated with drinking except for items #1, #4 and #5; for these items, “No” 
responses indicate problems associated with drinking. As a research tool, the SMAST has 
>90 percent sensitivity for identifying alcohol use disorder. The SMAST will be self-
administered at the timepoints specified in Table 4. A sample of the SMAST can be found in 
Appendix F. 
8.8.11.9. Quantitative Substance Use Inventory 
The Quantitative Substance Use Inventory (QSUI) is a 29-item questionnaire designed to 
quantify drug use in a specified period, including classes of drugs, particular substances, as well 
as the route of administration. Subjects will complete the QSUI at the timepoints indicated in 
Table 4. A sample of the QSUI can be found in Appendix G. 
8.8.11.10.  Patient Global Assessment of Response to Therapy 
Treatment satisfaction will be assessed using the Patient Global Assessment of Response to 
Therapy (PGART). The PGART consists of one item: “How would you rate your response to the 
medication that you received during the study?” It is measured on a 5-point Likert scale (0=poor, 
4=excellent). The PGART will be self-administered at the timepoints specified in Table 4. A 
sample of the PGART can be found in Appendix H. 
8.8.11.11. Hamilton Rating Scale for Depression 
The 17-item HAM-D is a clinician-administered depression scale designed to be sensitive to 
treatment effects (Hamilton 1960). The HAM-D will be administered at the timepoints specified 
in Table 4. 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 I. 
8.8.11.12. Cognitive Assessments 
The Brief Assessments of Cognition (BAC) Symbol Coding test, Controlled Oral Word 
Association (COWA) task, Wechsler Memory Scale-III Spatial Span (WMS-III SS) test, 
Continuous Performance Test (CPT) and Test of Attentional Performance (TAP) will be 
administered at the timepoints specified in Table 4. 
8.8.11.12.1. 
Brief Assessments of Cognition Symbol Coding Test 
The BAC Symbol Coding test is used to measure cognitive processing speed (Keefe 1999). 
During this task, subjects are given a list of numbers (numerals 1-9) that are each associated with 
a unique symbol. Subjects decode a list of 110 symbols as quickly as possible in 90 seconds. The 
total number of symbols correctly decoded can range from 0 to 110. Total administration time 
(including instruction and practice items) is 3 minutes. A sample of the BAC Symbol Coding test 
administrator instructions and respondent form can be found in Appendix J. 
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8.8.11.12.2. 
Controlled Oral Word Association Task 
The COWA is a verbal fluency task (Benton et al, 1983). Subjects are asked by a rater to 
spontaneously produce words belonging to a common category or beginning with the same 
designated letter. Total administration time is 5 minutes. A sample of the COWA task 
administrator instructions can be found in Appendix K. 
8.8.11.12.3. 
Wechsler Memory Scale-III Spatial Span Test 
The WMS-III SS test is a measure of working memory (Wechsler 1997). Subjects are presented 
with a board containing blue blocks that are randomly arranged. The clinician begins by tapping 
out a pattern of blocks, beginning with a sequence of 2 blocks and increasing the length of the 
pattern with subject proficiency (up to a sequence of 9 blocks). During the first part of the test, 
the subject is tasked with tapping the same pattern as the clinician. During the second part of the 
test, the subject is tasked with tapping out the reverse pattern of that demonstrated by the 
clinician. The total score ranges from 0 to 32. Total administration time is 8 minutes. A sample 
of the WMS-III SS administrator instructions can be found in Appendix L. 
8.8.11.12.4. 
Continuous Performance Test 
The CPT is a computer-based task that measures attention and vigilance (Cornblatt et al, 1988). 
Subjects are asked to attend to digits flashing on the computer screen and to click the mouse 
when the same string of digits flashes consecutively. There are 3 trials of this subtest; the first 
containing 2-digit sequences, the second containing 3-digit sequences and the third containing 
4-digit sequences. Scoring for this subtest is based on “hits” versus “false alarms” and 
“randoms,” and the total score is represented by a d-prime quotient ranging from -1.00 to 4.24. 
Total administration time is 10 minutes. Screenshots of the CPT instructions can be found in 
Appendix M. 
8.8.11.12.5. 
Test of Attentional Performance 
The TAP is a computer-based divided attention task that involves the simultaneous processing of 
visual and auditory stimuli (Zimmermann and Fimm 2002). For the visual component, a region 
of the screen displays a varying number of crosses simultaneously. When 4 of the crosses form a 
square, the subject is required to press the designated key as quickly as possible. For the auditory 
component, the subject hears a sequence of high and low tones. When the same tone occurs 
twice in a row, the subject is required to press the designated key as quickly as possible. The 
subject is required to pay attention to both the crosses and the tones at the same time. Total 
administration time is 2.5 to 6 minutes. A screenshot of the TAP instructions can be found in 
Appendix N. 
8.8.12. 
Laboratory Assessments 
8.8.12.1. Pregnancy Testing 
A serum pregnancy test will be performed for all women at screening and Day 1/1a. A urine 
pregnancy test will be performed at Day 1/1a, as well as all subsequent timepoints specified in 
Table 4. Results must be negative for initial study eligibility and continued participation. 
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8.8.12.2. Urine Drug Screen 
A urine drug screen will be performed, via urine dipstick, at the timepoints specified in Table 4. 
The urine drug screen will test for opioids, illicit substances and other drugs of abuse (eg, 
opiates, methadone, oxycodone, BUP, cocaine, amphetamine, methamphetamine, 
tetrahydrocannabinol, benzodiazepines, barbiturates, propoxyphene and phencyclidine). 
The urine drug screen may be repeated at the investigator’s discretion. 
8.8.12.3. Breath Alcohol Test 
A breathalyzer test for alcohol will be performed at the timepoints specified in Table 4. Subjects 
must have a negative breath alcohol test prior to admission to the residential unit (Day -2). The 
breath alcohol test may be repeated at the investigator’s discretion. 
8.8.12.4. Clinical Laboratory Assessments 
Blood and urine samples will be collected at the timepoints specified in Table 4 for specific 
hematology, biochemistry and urinalysis assessments listed in Table 5. Samples will be collected 
in accordance with the site’s standard procedures and analyzed by a central laboratory. 
Laboratory assessments may be repeated at the investigator’s discretion. 
Table 5: 
Clinical Laboratory Assessments 
Hematology 
Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell count 
White blood cell count and 
differentiala 
Platelets 
Sodium 
Potassium 
Glucose 
Creatinine 
Total protein 
Blood urea nitrogen (BUN) 
Albumin 
Total bilirubin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Lactic dehydrogenase (LDH) 
Gamma-glutamyl transferase (GGT) 
Alkaline phosphatase (ALK-P) 
Creatine phosphokinase (CPK) 
Thyroid stimulating hormone (TSH)b 
Color 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen 
Occult blood 
Microscopic examination  
only if urinalysis dipstick 
results are abnormal 
a White blood cell differential count (absolute values) will include basophils, eosinophils, lymphocytes, monocytes 
and neutrophils. 
b At screening only. 
8.8.13. 
Randomization 
At the timepoint specified in Table 4, subjects will be randomized as outlined in Section 9.4. 
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8.8.14. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug (naltrexone, 
PBO-N, BUP, naloxone and VIVITROL) will be administered by clinical study staff at the 
timepoints specified in Table 4. The clinical study site is responsible for study drug storage, 
handling and accountability as outlined in Section 10. 
8.8.15. 
Adverse Event Monitoring 
AEs will be monitored continuously from the time a subject signs the informed consent 
document until the completion of the final study visit (see Table 4). AEs and SAEs are defined in 
Section 12.1 and 12.2, respectively. Section 12.4 provides guidance on the monitoring and 
recording requirements for AEs. Section 12.5 provides guidance on the reporting requirements 
for SAEs. 
8.9. 
Study Requirements and Restrictions 
8.9.1. 
Prohibited Medications and Substances 
The medications and substances listed below are prohibited for the specified time periods: 
• Methadone is prohibited at least 30 days prior to Day -5 and for the duration of the 
study 
• All opioid agonists (except BUP when administered during applicable study days), 
including opioid-containing cough medications, are prohibited for the duration of the 
study 
• Naltrexone is prohibited for at least 90 days prior to Day -5 and for the duration of the 
study (except when administered during applicable study visits) 
• On days when cognitive assessments are conducted (see Table 4), caffeine and 
nicotine (oral, inhaled or smoked) are prohibited within 30 minutes prior to the start 
of the assessments. A transdermal nicotine patch may remain in place. Throughout 
the residential period, nicotine replacement therapy is permissible in accordance with 
prevailing clinical policy of the residential unit. 
8.9.2. 
Ancillary Medications 
Subjects will receive ancillary medications on a standing schedule to treat symptoms of 
withdrawal, such as autonomic arousal, sleep disturbance, muscle tension and anxiety. Beginning 
on Day -2, medications listed in Table 6 will be provided to subjects as a standing regimen 
during the residential phase of the study (see Table 4). In the event that a subject is admitted for 
the residential stay early (on Days -5, -4, or -3), the ancillary medication regimen will begin as 
soon as the subject becomes residential. If needed for AE treatment or prophylaxis, ancillary 
medications may be initiated at the clinician’s discretion on or after Day -5. Because mild 
symptoms of withdrawal may be present for several days after the VIVITROL injection, subjects 
will continue using ancillary medications on a modified schedule (see Table 4) through Day 11 
(or, for 3 days after VIVITROL injection). 
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Ancillary medications are commercially available and should be stored according to package 
insert instructions. 
Table 6: 
Ancillary Medications 
Medication 
Dose Regimen 
Days -2 to 7 
Days 8/8a-11a 
Clonidine 
0.1 mg oral tablet, 2 times a day 
0.1 mg oral tablet, 1 time a day 
(only AM dose) 
Clonazepam 
0.5 mg oral tablet, 2 times a day 
0.5 mg oral tablet, 1 time a day 
(only AM dose) 
Trazodone hydrochloride 
100 mg oral tablet, at bedtime  
100 mg oral tablet, at bedtime 
a For subjects receiving VIVITROL on Day 8/8a, ancillary medications will be reduced on Days 9 through 11, as 
indicated. 
Subjects will also be provided with a supply of sports hydration drink, which they will be 
encouraged to drink liberally. 
8.9.3. 
Concomitant Medications 
Prescribed psychoactive medications, including anxiolytics and antidepressants, will be allowed 
for the duration of the study provided the dose is stable at the time of the screening visit. 
8.9.4. 
Contraception and Pregnancy 
All male and female subjects must agree to use an acceptable method of contraception for the 
duration of the study unless they are surgically sterile or postmenopausal (see below). The 
following are considered acceptable methods of contraception: 
• Double-barrier protection (such as a condom with spermicide or a diaphragm with 
spermicide) 
• Intrauterine device (IUD) 
• Hormonal contraceptives (such as birth control pills or patches, a vaginal ring or a 
contraceptive implant); oral contraceptives should be initiated at least 30 days prior to 
Screening 
Subjects who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a hysterectomy, bilateral tubal ligation or bilateral 
salpingo-oophorectomy are considered surgically sterile. Men who have undergone a vasectomy 
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. 
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If a subject becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The early termination and safety follow-up visits will be scheduled and 
the pregnancy will be reported to Alkermes. Additional follow-up may be required. Pregnancies 
in female partners of male subjects should also be reported and will be followed in the same 
manner. 
A Pregnancy Report Form must be submitted to Alkermes (per Section 12.5) immediately, 
within 24 hours of awareness of the pregnancy, irrespective of whether an AE has occurred. The 
pregnancy will be followed until completion or termination. If the outcome of the pregnancy 
meets the criteria for classification as an SAE, it should be reported following the SAE procedure 
(see Section 12.5). 
8.10. 
Residential Period 
Subjects will be confined to a residential unit for 9 to 11 days (Days -2 to 8/8a); the residential period 
may be longer for subjects who are admitted to the residential unit earlier during the BUP Lead-in 
Period, or for subjects who fail the naloxone challenge on Day 8/8a and remain on the residential unit 
per Investigator judgment. 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product, Dosage, Duration and Mode of 
Administration 
Naltrexone will be supplied at the doses specified in Table 3 and provided as tablets for oral 
administration. Naltrexone will be administered as 2 doses, given at least 1 hour apart, on Days 1 
to 7. 
9.2. 
Reference Therapy, Dosage, Duration and Mode of Administration 
Placebo naltrexone (PBO-N) tablets will match the naltrexone drug product and will be 
administered as 2 doses, given at least 1 hour apart, on Days 1/1a to 7. 
Sublingual BUP (up to 4 mg) will be administered daily to all subjects during the BUP Lead-in 
Period (Days -5 to -1). On Days 1/1a to 7, BUP dose will be tapered (see Table 3). 
9.3. 
Treatment Adherence 
Clinical study staff will administer study drug on an inpatient basis and record compliance for 
each subject in the relevant source document(s). 
9.4. 
Randomization/Method of Assigning Subjects to Treatment 
Subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups: naltrexone + BUP or 
PBO-N + BUP, stratified according to low (<8 mg/day) vs. high (8 mg/day) BUP maintenance 
dose at the time of initiation of the BUP Lead-in Period. The naltrexone or PBO-N assignment 
will be blinded while the BUP dose will be open-label. A randomization schedule will be 
prepared by an independent biostatistician and uploaded into an Interactive Web Response 
System (IWRS). The pharmacist or designee will contact the IWRS, which will assign the 
subject to a treatment group according to the next available randomization record. The unblinded 
site pharmacist or designee will dispense naltrexone or placebo for administration to subjects. 
9.5. 
Blinding 
This is a double blind study. All Alkermes staff, clinical staff and subjects will be blinded to 
treatment assignment until database lock. At each study site, study medications will be prepared 
by an unblinded research pharmacist who has no contact with participants in the trial. The 
investigator is responsible for all trial-related medical decisions. If the investigator deems it 
necessary to break the study blind in the interest of a subject’s medical safety, he or she must 
make every effort to contact the sponsor medical monitor before the blind is broken. If the site is 
unable to contact the medical monitor prior to breaking the blind, the medical monitor must be 
contacted within 24 hours following disclosure of study drug assignment. 
Breaking the blind for a single subject will not affect the blind for the remaining subjects. 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Naltrexone for oral administration will be provided as white caplet-shaped IR tablets in the 
following dosages: 0.25, 0.5, 1.5, 3, 7.5 and 15 mg. Daily naltrexone doses are described in 
Table 3 with total daily doses ranging from 0.5 to 30 mg. 
Placebo to match naltrexone drug product (PBO-N) will be provided as white caplet-shaped IR 
tablets. 
Commercially available BUP will be supplied at the doses specified in Table 3 as a rapidly 
disintegrating tablet for sublingual administration. Buprenorphine will be administered in up to 
4 mg daily dose during the lead-in (Days -5 to -1). The dose will then taper down to zero mg 
during the transitional dosing period leading up to the naloxone challenge (Days 1-7). 
Commercially manufactured 1 mg/mL naloxone will be supplied by Alkermes as 2 mL single-
dose prefilled syringes with 21 G × 1½ needles. 
VIVITROL 380 mg will be supplied by Alkermes in single-use kits, each containing a 380 mg 
vial of VIVITROL microspheres and the diluent for suspension. 
10.2. 
Packaging and Storage 
Naltrexone tablets and placebo to match naltrexone tablets (PBO-N) will be supplied in 30-count 
bottles. The primary packaging consists of 60-cc high density polyethylene (HDPE) bottles heat 
sealed with a 1.1 g desiccant and polypropylene cap. The material should be stored at not more 
than 25°C. 
All commercially available products are to be stored according to the manufacturer’s 
recommendations. 
Buprenorphine, a Schedule III narcotic, must be stored in accordance with US restrictions related 
to controlled substances. 
10.3. 
Accountability 
The clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study as well as through IWRS. All unused supplies will be checked against the 
drug movement records during the study and/or at the end of the study. 
Buprenorphine, a Schedule III narcotic, should be accounted for in accordance with the 
requirements of the Controlled Substances Act. 
10.4. 
Handling and Disposal 
Following completion and verification of accountability logs, all unused and used products must 
be destroyed according to applicable local and federal regulations. Alternatively, the sponsor 
may arrange for destruction with a third-party vendor operating in accordance with GCP and/or 
Good Manufacturing Practice (GMP), as applicable. Buprenorphine, as a Schedule III narcotic, 
should be handled and disposed of in accordance with the requirements of the Controlled 
Substances Act. 
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10.5. 
Management of Ancillary Medications 
The ancillary medications are commercially available and should therefore be stored according 
to manufacturer instructions. Clonazepam is a Schedule IV controlled substance and should 
therefore be stored in accordance with US restrictions on controlled substances and should be 
accounted for, handled and disposed of in accordance with the requirements of the Controlled 
Substances Act. 
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11. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed via the following: 
• COWS score 
• SOWS score 
• Desire for opioids using a VAS 
• PGART 
Exploratory Endpoints: 
The following exploratory assessments (described in detail in Section 8.8) will be conducted: 
• Pupil diameter (measured during clinical testing sessions) 
• QSUI 
• HAM-D 
• BAC Symbol Coding test 
• COWA task 
• WMS-III SS test 
• CPT 
• TAP 
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12. 
ASSESSMENT OF SAFETY 
Safety and tolerability will be assessed via the following: 
• AEs 
• Vital signs and arterial oxygen saturation (measured during clinical testing sessions) 
• Laboratory test results 
• ECG parameters (uncorrected QT, QT interval corrected for heart rate using the 
Fridericia formula [QTcF], QT interval corrected for heart rate using the Bazett 
formula [QTcB], HR, RR, and QRS intervals) 
• C-SSRS scores 
12.1. 
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. 
If the severity of a subject’s withdrawal symptoms necessitates administering a nonstudy 
medication, or doses of an ancillary medication that exceed the standing regimen, the condition 
being treated should be noted as an AE. 
Illnesses present prior to the subject signing the informed consent form (ICF) are considered to 
be pre-existing conditions and are documented on the medical history eCRF. Pre-existing 
conditions that worsen during the study are entered on the AE eCRF. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the investigator. Clinically significant values will be considered AEs and recorded 
as such on the eCRFs. 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.9.4, the pregnancy, including a partner’s pregnancy, 
must be reported to Alkermes, and additional follow-up may be required. 
12.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality that meets one or more of 
the following criteria: 
• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
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• Results in persistent or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life threatening or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require intervention to prevent one of the 
other outcomes listed above. 
Admission to a hospital or an inpatient unit for a non-medical reason (ie, social stay admission) 
during the study in the absence of untoward medical occurrence will not be considered as an 
SAE, but will be captured as an AE. 
Hospitalization due to worsening of behavioral health-related issues should be reported as an 
SAE. 
12.3. 
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 7 should 
be used to guide this assessment. Please note that not all criteria must be present to be indicative 
of a particular drug relationship. All study drugs are considered “test drugs” for the purposes of 
the definitions listed in the table. 
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Table 7: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for assessment 
Definitely related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Rechallenge (if feasible) is positive. 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class. 
Probably related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Possibly related 
There is evidence of exposure to the test drug. 
AND 
The temporal sequence of the AE onset relative to administration of the test drug is 
reasonable. 
The AE could have been due to another equally likely cause. 
Dechallenge (if performed) is positive. 
Probably not 
related 
There is evidence of exposure to the test drug. 
AND 
There is another more likely cause of the AE. 
Dechallenge (if performed) is negative or ambiguous. 
Rechallenge (if performed) is negative or ambiguous. 
Definitely not 
related 
The subject did not receive the test drug. 
OR 
Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable. 
OR 
There is another obvious cause of the AE. 
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12.4. 
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 (Visit 10) or 28 days after the final dose of study drug. Any AE or 
SAE having an onset after the safety follow-up visit will not be collected or reported unless the 
investigator feels that the event may be related to the study drug. 
Subjects will be instructed by the investigator or designee to report the occurrence of any AE. 
All volunteered, elicited and observed AEs are to be recorded on the AE eCRFs. 
The investigator will assess all AEs regarding any causal relationship to the study drug (see 
Section 12.3), the intensity (severity) of the event, action taken and subject outcome. 
The following criteria should be used to guide the assessment of intensity (severity): 
• Mild: Causes awareness of sign or symptom, but is easily tolerated; does not interfere 
with usual activities 
• Moderate: Causes discomfort enough to interfere with usual activities 
• Severe: Is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the investigator or until the 
subject is deemed by the investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. 
Withdrawal from the study as a result of an AE and any therapeutic measures that are taken shall 
be at the discretion of the investigator. If a subject withdraws from the study for any reason, any 
ongoing AEs will be followed until resolution, until deemed stable by the investigator or until the 
subject is deemed by the investigator to be lost to follow-up. 
12.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported to Alkermes via 
 
immediately, within 24 hours of discovery, by emailing: 
 or by faxing the report to the following: 
FAX Number: 
 
The written report for SAEs should be submitted on the SAE form provided for this purpose. The 
SAE report must include the Investigator’s opinion as to whether the event is study drug-related. 
If this relationship is determined to be possibly, probably or definitely related to study drug, 
evidence to support this assessment must also be provided. 
The written report for pregnancies in female subjects and in female partners of male subjects 
should be submitted on the Pregnancy Report Form provided for this purpose. 
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13. 
STATISTICS 
13.1. 
Sample Size Considerations 
The primary efficacy endpoint of the study is the proportion of subjects who receive and tolerate 
VIVITROL injection on Day 8/8a as demonstrated by mild (COWS ≤12 or SOWS ≤10) opioid 
withdrawal symptoms following VIVITROL administration. 
Assuming the proportion of subjects receiving and tolerating VIVITROL administration is 90% 
in Group 1 and 60% in Group 2, a sample size of approximately 46 subjects per treatment group 
will provide at least 90% power to detect a statistically significant difference between the two 
treatment groups at 5% level of significance in a 2-sided test. 
13.2. 
General Statistical Methodology 
In general, summary statistics (ie, n, mean, standard deviation, median, minimum and maximum 
for continuous variables, and number [%] of subjects in each category for categorical variables) 
will be provided by treatment group for all variables. 
Baseline values are defined as any nonmissing assessments prior to receiving the first dose of 
naltrexone or PBO-N. 
Source data for the summary tables and statistical analyses will be presented as by-subject data 
listings. 
13.2.1. 
Study Populations 
13.2.1.1. Safety Population 
The safety population is defined as all randomized subjects who receive at least 1 dose of 
naltrexone or PBO-N. 
13.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, weight and baseline will be 
summarized by treatment group for the safety population. 
Medical history will be summarized for the safety population using the number of observations 
and percentage of subjects reporting each category. 
13.4. 
Efficacy Analyses 
Efficacy analyses will be performed using the safety population. 
All statistical tests will be 2-sided with a type I error rate of 5%, unless otherwise specified. 
13.4.1. 
Primary Efficacy Endpoint 
• The proportion of subjects who receive and tolerate VIVITROL injection on Day 8/8a 
as demonstrated by mild (COWS ≤12 or SOWS≤10) opioid withdrawal symptoms 
following VIVITROL administration 
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The analyses will be carried out using logistic regression with treatment as a factor. 
13.4.2. 
Key Secondary Efficacy Endpoint 
• Proportion of days with COWS peak score ≤12 during the Treatment Period prior to 
the VIVITROL injection (Days 1/1a-7) 
The analysis will be carried out using a negative binomial model with treatment as a factor. 
13.4.3. 
Other Secondary Endpoints 
• Proportion of post-VIVITROL days (Days 9-11) in which subjects in each group 
demonstrate mild (COWS ≤12) opioid withdrawal 
The analyses will be carried out using a negative binomial model with treatment as a factor. 
• Mean peak COWS scores during the Treatment Period and VIVITROL Induction and 
Post-VIVITROL Observation Period (Days 1/1a-11) 
• Area under the curve (AUC) for COWS scores during the Treatment Period and 
VIVITROL Induction and Post-VIVITROL Observation Period (Days 1/1a-11) 
• Mean score for “desire for opioids” VAS during the Treatment Period and 
VIVITROL Induction and Post-VIVITROL Observation Period (Days 1/1a-11) 
These endpoints will be analyzed using an analysis of variance (ANOVA), with treatment as a 
factor. 
13.4.4. 
Exploratory Endpoints 
• Number and proportion of subjects in PGART response category at the end of the 
post-VIVITROL observation period (Day 11) 
The analyses will be carried out using a logistic regression model with treatment as a factor. 
• Change from baseline in pupil diameter following study drug administration during 
the Treatment Period (Days 1/1a-7) 
• Change in frequency of substance use from screening to Day 36 assessed via the 
QSUI 
• AUC for SOWS scores during the Treatment Period and VIVITROL Induction and 
Post-VIVITROL Observation Period (Days 1/1a-11) 
• Change from baseline in the standardized T scores for cognitive assessments 
The analyses will be carried out using an analysis of covariance (ANCOVA) with treatment as a 
factor. 
13.5. 
Safety and Tolerability Analyses 
Safety analyses will be performed using the safety population. 
Safety and tolerability will be evaluated based on AEs, vital sign and oxygen saturation 
measurements, laboratory test results, ECG findings and C-SSRS scores. 
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Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
The incidence of treatment-emergent AEs will be summarized by treatment group and overall by 
system organ class, and preferred terms within each system organ class. SAEs and AEs resulting 
in treatment discontinuation will also be summarized. AEs occurring during the treatment period 
preceding the naloxone challenge will be analyzed separately from AEs occurring on or after the 
naloxone challenge day. 
Change from baseline in laboratory tests, vital signs and oxygen saturation, and ECG 
assessments (uncorrected QT, QTcF, QTcB, HR, RR and QRS intervals) will be summarized by 
treatment group and overall at each visit. Number (percentage) of subjects with potentially 
clinically significant (PCS) values at any postbaseline visit will be also summarized by treatment 
group. 
For each ideation/behavior type in C-SSRS, as well as the overall ideation/behavior category, the 
number and percentage of subjects with ‘Yes’ responses at any post baseline visit (including 
unscheduled visit) will be summarized by treatment group. 
Number and percent of subjects initiating concomitant medications, including ancillary 
medications, during the induction period will be summarized. 
Concomitant medications will be categorized and presented using the World Health Organization 
(WHO) drug Anatomical Therapeutic Chemical (ATC) classification system. 
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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. 
14.2. 
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) may visit the site to perform audits or 
inspections, including the drug storage area, study drug stocks, drug accountability records, 
subject charts and source documents, and other records relative to study conduct. The purpose of 
an Alkermes audit or inspection is to systematically and independently examine all study-related 
activities and documents (eg, laboratory reports, x-rays, workbooks, subjects’ medical records) 
to determine whether these activities were conducted, and data recorded, analyzed and accurately 
reported according to the protocol, GCP guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements. 
The investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
14.3. 
Institutional Review Board 
The investigator must obtain IRB approval for the investigation. Initial IRB approval as well as 
all materials approved by the IRB 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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15. 
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 14.2 for details regarding the audit process. 
15.1. 
Case Report Forms 
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data (ie, data directly reported on the eCRF). All eCRFs will be completed by the 
clinic staff prior to review by the Alkermes monitor or designated representative. 
The Alkermes monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF. 
15.2. 
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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16. 
ETHICAL CONSIDERATIONS 
16.1. 
Ethics Review 
The clinical site’s IRB must meet all relevant regulatory requirements. The study protocol and 
ICF will be reviewed by the IRB 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 upon receipt of amendments and annually, as local 
regulatory requirements require. 
The investigator is responsible for submitting all protocol changes and SAE reports to the IRB 
according to local procedures. At a minimum, all SAEs requiring an investigational new drug 
safety report must be immediately reported. 
All relevant correspondence from the IRB will be forwarded by the respective study site to the 
sponsor in a timely fashion. 
16.2. 
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. 
16.3. 
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 study monitor 
may inspect their medical records to verify the accuracy and completeness of the study records 
and results. 
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB, and then signed by all applicable study 
participants. 
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The time that informed consent is obtained must be documented. The investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 
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17. 
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. 
17.1. 
Data Capture 
As stated in Section 15.1, this study will use eCRFs for capturing data. All entries, corrections 
and alterations will be made by the investigator or other authorized study personnel. All data 
entries will be verified for accuracy and correctness by independent monitors. The electronic 
data capture system maintains a full audit trail. 
All electronic source data collected outside the eCRF, such as results from computer- or paper-
based cognitive assessments and the central laboratory, will be transferred directly to Alkermes 
for incorporation into the final data sets. A paper copy of all laboratory reports will remain with 
the source documents at the study site. All out-of-range laboratory values will be deemed as 
clinically significant or not clinically significant by the investigator. Clinically significant values 
will be considered AEs and recorded as such on the eCRFs. 
AEs will be coded using MedDRA. Concomitant medications will be categorized using the 
WHO-ATC classification system. 
17.2. 
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. 
17.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
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17.4. 
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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18. 
REFERENCES 
Benton AL, Hamsher SK, de Sivan AB. Multilingual Aphasia Examination. 2 ed. Iowa City, IA. 
AJA  Associates; 1983. 
Bunavail (buprenorphine and naloxone) buccal film [package insert]. Raleigh, NC: BioDelivery 
Sciences International Inc; Jun 2014. 
Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain 
relievers - United Stats, 1999-2008. MMWR. 2011;60:1487-1492. 
Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-Kimling L. The Continuous 
Performance Test, identical pairs version (CPT-IP): I. New findings about sustained attention in 
normal families. Psychiatry Res. 1988;26(2):223-238. 
D'Amore A, Romano F, Biancolillo V, et al. Evaluation of buprenorphine dosage adequacy in 
opioid receptor agonist substitution therapy for heroin dependence: first use of the 
BUprenorphine-naloxone Dosage Adequacy eVAluation (BUDAVA) questionnaire. Clin Drug 
Investig. 2012;32(7):427-432. doi: 10.2165/11633230-000000000-00000. 
Dakwar E, Kleber HD. Naltrexone-facilitated buprenorphine discontinuation: a feasibility trial. J 
Subst Abuse Treat. 2015;53:60-63. doi: 10.1016/j.jsat.2015.01.004. 
Day E, Ison J, Strang J. Inpatient versus other settings for detoxification for opioid dependence. 
Cochrane Database Syst Rev. 2005(2):CD004580. doi: 10.1002/14651858.CD004580.pub2. 
Faust D, Fogel BS. The development and initial validation of a sensitive bedside cognitive 
screening test. J Nerv Ment Dis. 1989;177(1):25-31. 
Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol 
Ther (St Louis). 1989;45(1):66-71. 
Greenwald MK, Johanson CE, Moody DE, et al. Effects of buprenorphine maintenance dose on 
mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-
dependent volunteers. Neuropsychopharmacology. 2003;28(11):2000-2009. doi: 
10.1038/sj.npp.1300251. 
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62. 
Keefe R. Brief Assessment of Cognition in Schizophrenia (BACS) Manual – A: Version 2.1. 
Durham, NC. Duke University Medical Center; 1999. 
Kleber HD. Pharmacologic treatments for opioid dependence: detoxification and maintenance 
options. Dialogues Clin Neurosci. 2007;9(4):455-470. 
Ling W, Hillhouse M, Domier C, et al. Buprenorphine tapering schedule and illicit opioid use. 
Addiction. 2009;104(2):256-265. 
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Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
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Mannelli P, Gottheil E, Buonanno A, De R, S. Use of very low-dose naltrexone during opiate 
detoxification. J Addict Dis. 2003;22(2):63-70. 
Mannelli P, Patkar AA, Peindl K, Gorelick DA, Wu LT, Gottheil E. Very low dose naltrexone 
addition in opioid detoxification: a randomized, controlled trial. Addict Biol. 2009;14(2):204-
213. doi: 10.1111/j.1369-1600.2008.00119.x. 
Mannelli P, Peindl K, Wu LT, Patkar AA, Gorelick DA. The Combination Very Low-Dose 
Naltrexone-Clonidine in the Management of Opioid Withdrawal. Am J Drug Alcohol Abuse. 
2012(Early online):1-6. 
Mannelli P, Wu LT, Peindl KS, Swartz MS, Woody GE. Extended release naltrexone injection is 
performed in the majority of opioid dependent patients receiving outpatient induction: A very 
low dose naltrexone and buprenorphine open label trial. Drug Alcohol Depend. 2014;138:83-88. 
doi: 10.1016/j.drugalcdep.2014.02.002. 
Meagher J, Leonard M, Donoghue L, et al. Months backward test: A review of its use in clinical 
studies. World journal of psychiatry. 2015;5(3):305-314. doi: 10.5498/wjp.v5.i3.305. 
National Institute on Drug Abuse. Drug Facts: Prescription and Over-the-Counter Medications. 
Rockville, MD: National Institutes of Health , US Department of Health and Human Services; 
2014. 
Nielsen S, Hillhouse M, Thomas C, Hasson A, Ling W. A comparison of buprenorphine taper 
outcomes between prescription opioid and heroin users. J Addict Med. 2013;7(1):33-38. doi: 
10.1097/ADM.0b013e318277e92e. 
Prescribing Information: ZUBSOLV (buprenorphine and naloxone sublingual tablets) [package 
insert]. Orexo US Inc; 2013-07. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704. 
Rinaldo SG, Rialdo DW, The Avisa Group 2013. Availability Without Accessibility? State 
Medicaid Coverage and Authorization Requirements for Opioid Dependence Medications. 2013. 
Sigmon SC, Bisaga A, Nunes EV, O'Connor PG, Kosten T, Woody G. Opioid detoxification and 
naltrexone induction strategies: recommendations for clinical practice. Am J Drug Alcohol 
Abuse. 2012;38(3):187-199. doi: 10.3109/00952990.2011.653426. 
Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 
2011: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: US 
Department of Health and Human Services; 2013. HHS Publication No. (SMA) 13-4760, 
DAWN Series D-39. 
Page 64 of 174


 
 
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Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
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Substance Abuse and Mental Health Services Administration. Substance Use and Mental Health 
Estimates from the 2013 National Survey on Drug Use and Health: Overview of Findings. US 
Department of Health and Human Services; 2014. 
Sullivan MA, Bisaga A, Pavlicova M, et al. Long-acting injectable naltrexone induction: A 
randomized trial of outpatient opioid detoxification with naltrexone vs. buprenorphine. Am J 
Psychiatry. 2016. 
Wechsler D. The Wechsler Memory Scale. 3rd ed. San Antonio, TX. Psychological Corp 
(Harcourt); 1997. 
Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended 
buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized 
controlled trial. Arch Gen Psychiatry. 2011;68(12):1238-1246. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 
2003;35(2):253-259. 
Zimmermann P, Fimm B. A test battery for attentional performance. In: Leclercq M, 
Zimmermann P, eds. Applied Neuropsychology of Attention: Theory, Diagnosis and 
Rehabilitation. London: Psychology Press; 2002:110-151. 
 
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APPENDICES 
Appendix A 
Mini-International Neuropsychiatric Interview 
Appendix B 
Columbia-Suicide Severity Rating Scale 
• 
Baseline/Screening 
• 
Since Last Visit 
Appendix C 
Clinical Opiate Withdrawal Scale 
Appendix D 
Subjective Opiate Withdrawal Scale 
Appendix E 
Desire for Opioids Visual Analogue Scale 
Appendix F 
Short Michigan Alcohol Screening Test 
Appendix G 
Quantitative Substance Use Inventory 
Appendix H 
Patient Global Assessment of Response to Therapy 
Appendix I 
Structured Interview Guide for the Hamilton Rating Scale for Depression 
Appendix J 
Brief Assessments of Cognition Symbol Coding Test 
Appendix K 
Controlled Oral Word Association Task 
Appendix L 
Wechsler Memory Scale-III Spatial Span Test 
Appendix M 
Continuous Performance Test 
Appendix N 
Test of Attentional Performance 
 
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APPENDIX A. MINI-INTERNATIONAL NEUROPSYCHIATRIC 
INTERVIEW 
 
 
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M.I.N.I.	  
	  
	  
	  
	  
MINI	  INTERNATIONAL	  NEUROPSYCHIATRIC	  INTERVIEW	  
	  
	  
English	  Version	  7.0.0	  	  
	  
FOR	  
	  
DSM-­‐5	  
	  
	  
	  
	  
©	  Copyright	  1992-­‐2015	  Sheehan	  DV	  
	  
	  
	  
All	  rights	  reserved.	  	  No	  part	  of	  this	  document	  may	  be	  reproduced	  or	  transmitted	  in	  any	  form,	  or	  by	  any	  means,	  electronic	  
or	  mechanical,	  including	  photocopying,	  or	  by	  any	  information	  storage	  or	  retrieval	  system,	  without	  permission	  in	  writing	  
from	   Dr.	   Sheehan.	   	   Individual	   researchers,	   clinicians	   and	   students	   working	   in	   nonprofit	   or	   publicly	   owned	   settings	  
(including	  universities,	  nonprofit	  hospitals,	  and	  government	  institutions)	  may	  make	  paper	  copies	  of	  a	  M.I.N.I.	  instrument	  
for	  their	  personal	  clinical	  and	  research	  use,	  but	  not	  for	  institutional	  use.	  	  Any	  use	  involving	  financial	  gain	  requires	  a	  license	  
agreement	  from	  the	  copyright	  holder	  and	  payment	  of	  a	  per	  use	  license	  fee.	  
	  
	  
	  
	  
	  
DISCLAIMER	  
	  
Our	  aim	  is	  to	  assist	  in	  the	  assessment	  and	  tracking	  of	  patients	  with	  greater	  efficiency	  and	  accuracy.	  	  Before	  action	  is	  taken	  
on	  any	  data	  collected	  and	  processed	  by	  this	  program,	  it	  should	  be	  reviewed	  and	  interpreted	  by	  a	  licensed	  clinician.	  	  	  
	  
This	  program	  is	  not	  designed	  or	  intended	  to	  be	  used	  in	  the	  place	  of	  a	  full	  medical	  and	  psychiatric	  evaluation	  by	  a	  qualified	  
licensed	   physician	   –	   psychiatrist.	   	   It	   is	   intended	   only	   as	   a	   tool	   to	   facilitate	   accurate	   data	   collection	   and	   processing	   of	  
symptoms	  elicited	  by	  trained	  personnel.	  It	  is	  not	  a	  diagnostic	  test.	  
	  
	  
	  
	  
	  
	  
M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
2 
Patient	  Name:	  
Patient	  Number:	  
	  
Date	  of	  Birth:	  
	  
	   Time	  Interview	  Began:	  
	  
Interviewer’s	  Name:	  
Time	  Interview	  Ended:	  
	  
Date	  of	  Interview:	  
	  
	   Total	  Time:	  
	  
	  
	  
MEETS	  
	  
	  
PRIMARY	  
	  
MODULES	  
TIME	  FRAME	  
CRITERIA	  
DSM-­‐5	  
ICD-­‐10	   	  
DIAGNOSIS	  
 
A	  
MAJOR	  DEPRESSIVE	  EPISODE	  
Current	  (2	  weeks)	  
	  
❐	  
	  
	  
 
	  
	  
	  
Past	  
	  
❐	  
	  
	  
 
 
 
 
Recurrent	  
	  
❐	  
 
 
 
	  
	  
MAJOR	  DEPRESSIVE	  DISORDER	  
Current	  (2	  weeks)	  
	  
❐	  
296.20-­‐296.26	  	  Single	  
F32.x	  
	  
❐	  
	  
	  
Past	  
	  
❐	  
296.20-­‐296.26	  	  Single	  
F32.x	  
	  
❐ 
	  
	  
Recurrent	  
	  
❐	  
296.30-­‐296.36	  	  Recurrent	  
F33.x	  
❐	  
 
 
 
B	  
SUICIDALITY	  
Current	  (Past	  Month)	   	  
❐  
 
 
 
 
❐ 
	  
	  
Lifetime	  attempt	  
	  
❐  
❐	  Low	  	  	  ❐	  Moderate	  	  ❐	  High	  	  
	  
❐	  
	  
SUICIDE	  BEHAVIOR	  DISORDER	  
Current	  	  
	  
❐   
(In	  Past	  Year)	  	   	  
	  
	  
❐ 
 
 
In	  early	  remission	  
	  
❐    
(1	  -­‐	  2	  Years	  Ago)	  	  
	  
	  
❐	  
C	  
MANIC	  EPISODE	  
Current	  
	  
❐	  
	  
	  
	  
 
 
 
 
Past	  
	  
❐	  
 
HYPOMANIC	  EPISODE	  
Current	  
	  
❐	  
	  
	  
	  
 
 
 
 
Past	  
	  
❐	  
❐	  	  	  Not	  Explored	  
 
BIPOLAR	  I	  DISORDER	  
Current	  
	  
❐	  
296.41-­‐296.56	  	  
F31.0-­‐-­‐F31.76 
❐ 
 
 
Past	  
	  
❐	  
296.41-­‐296.56	  	  
F31.0-­‐	  F31.76 
❐ 
 
BIPOLAR	  II	  DISORDER	  
Current	  
	  
❐	  
296.89	  
	  
F31.81	  
❐ 
 
 
Past	  
	  
❐	  
296.89	  
	  
F31.81	  
❐ 
 
BIPOLAR	  DISORDER	  UNSPECIFIED	  
Current	  
	  
❐	  
296.40/296.50	  	  
F31.9	  
❐ 
 
 
Past	  
	  
❐	  
296.40/296.50	  	  
F31.9	  
❐ 
	  
BIPOLAR	  I	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES	   Current	  
	  
❐	  
296.44/296.54	  	  
F31.2/31.5	  
❐ 
 
 
Past	  
	  
❐	  
296.44/296.54	  	  
F31.2/31.5	  
❐ 
 
D	  
PANIC	  DISORDER	  
Current	  (Past	  Month)	   	  
❐	  
300.01	  
	  
F41.0	   	  
❐ 
 
 
Lifetime	  
	  
❐ 
300.01	  
	  
F40.0	   	  
❐	  
E	  
AGORAPHOBIA	  
Current	  
	  
❐	  
300.22	  
	  
F40.00 
❐ 
F	  
SOCIAL	  ANXIETY	  DISORDER	  (Social	  Phobia)	  
Current	  (Past	  Month)	   	  
❐	  
300.23	  
	  
F40.10	   
❐	  
 
G	  
OBSESSIVE-­‐COMPULSIVE	  DISORDER	  
Current	  (Past	  Month)	   	  
❐	  
300.3	  
	  
F42	  
 
❐ 
 
H	  
POSTTRAUMATIC	  STRESS	  DISORDER	  
Current	  (Past	  Month)	   	  
❐	  
309.81	  
	  
F43.10	  	  
❐ 
 
 
I	  
ALCOHOL	  USE	  DISORDER	  
Past	  12	  Months	  
	  
❐	  
303.9	  
	  
F10.10-­‐20 
❐ 
 
J	  
SUBSTANCE	  USE	  DISORDER	  (Non-­‐alcohol)	  
Past	  12	  Months	  
	  
❐	  
304.00-­‐.90/305.20-­‐.90	  
F11.1x-­‐F19.288	  
❐ 
 
K	  
PSYCHOTIC	  DISORDERS	  
Lifetime	  
	  
❐	  
297.3/297.9/	   	  
F20.81-­‐F29 
❐ 
 
 
 
 
 
293.81/298.83/298.89 
 
 
Current	  
	  
❐	  
297.3/297.9/	    
F20.81-­‐F29	  
❐	  
	  
	  
	  
	  
	  
293.81/298.83/298.89	  
MOOD	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES	  
Lifetime 
 
❐ 
296.24/296.34-­‐296.44	  
F31.2/F32.2/F33.3 
❐ 
	  
	  
	  
	  
296.54	  
	  
	  
	  
Current  
 
❐ 
296.24/296.34/296.44/296.54	  F31.2/F32.2/F33.	  3 
❐ 
L	  
ANOREXIA	  NERVOSA	  
Current	  (Past	  3	  Months)	  
❐	  
307.1	  
F50.01-­‐02	  
❐ 
M	  
BULIMIA	  NERVOSA	  
Current	  (Past	  3	  Months)	  
❐	  
307.51	  
	  
F50.2	    
❐ 
MB	   BINGE-­‐EATING	  DISORDER	  
Current	  (Past	  3	  Months)	  
❐	  
307.51	  
	  
F50.8	    
❐ 
 
N	  
GENERALIZED	  ANXIETY	  DISORDER	  
Current	  (Past	  6	  Months)	  
❐	  
300.02	  
	  
F41.1	    
❐ 
 
O 
MEDICAL,	  ORGANIC,	  DRUG	  CAUSE	  RULED	  OUT	  
	  
	  
❐ No      ❐ Yes	  
❐	  	  	  Uncertain	  
	  
 
P	  
ANTISOCIAL	  PERSONALITY	  DISORDER	  
Lifetime	  
	  
❐	  
301.7	  
	  
F60.2	    
❐ 
 
 
 
IDENTIFY	  THE	  PRIMARY	  DIAGNOSIS	  BY	  CHECKING	  THE	  APPROPRIATE	  CHECK	  BOX.	  
	  
(Which	  problem	  troubles	  you	  the	  most	  or	  dominates	  the	  others	  or	  came	  first	  in	  the	  natural	  history?)	  	  	  
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
3 
GENERAL	  INSTRUCTIONS	  
	  
	  
The	  M.I.N.I.	  was	  designed	  as	  a	  brief	  structured	  interview	  for	  the	  major	  Axis	  I	  psychiatric	  disorders	  in	  DSM-­‐5	  and	  ICD-­‐10.	  	  Validation	  
and	   reliability	   studies	   have	   been	   done	   comparing	   the	   M.I.N.I.	   to	   the	   SCID-­‐P	   for	   DSM-­‐III-­‐R	   and	   the	   CIDI	   (a	   structured	   interview	  
developed	  by	  the	  World	  Health	  Organization).	  	  The	  results	  of	  these	  studies	  show	  that	  the	  M.I.N.I.	  has	  similar	  reliability	  and	  validity	  
properties,	  but	  can	  be	  administered	  in	  a	  much	  shorter	  period	  of	  time	  (mean	  18.7	  ±	  11.6	  minutes,	  median	  15	  minutes)	  than	  the	  
above	  referenced	  instruments.	  	  Clinicians	  can	  use	  it,	  after	  a	  brief	  training	  session.	  	  Lay	  interviewers	  require	  more	  extensive	  training.	  
	  
INTERVIEW:	  
	  
In	  order	  to	  keep	  the	  interview	  as	  brief	  as	  possible,	  inform	  the	  patient	  that	  you	  will	  conduct	  a	  clinical	  interview	  that	  is	  more	  
structured	  than	  usual,	  with	  very	  precise	  questions	  about	  psychological	  problems	  which	  require	  a	  yes	  or	  no	  answer.	  
	  
GENERAL	  FORMAT:	  
	  
The	  M.I.N.I.	  is	  divided	  into	  modules	  identified	  by	  letters,	  each	  corresponding	  to	  a	  diagnostic	  category.	  
	  
•At	  the	  beginning	  of	  each	  diagnostic	  module	  (except	  for	  psychotic	  disorders	  module),	  screening	  question(s)	  corresponding	  
to	  the	  main	  criteria	  of	  the	  disorder	  are	  presented	  in	  a	  gray	  box.	  
	  
•At	  the	  end	  of	  each	  module,	  diagnostic	  box(es)	  permit	  the	  clinician	  to	  indicate	  whether	  diagnostic	  criteria	  are	  met.	  
	  
CONVENTIONS:	  
Sentences	   written	   in	   «	  normal	   font	  »	   should	   be	   read	   exactly	   as	   written	   to	   the	   patient	   in	   order	   to	   standardize	   the	  
assessment	  of	  diagnostic	  criteria.	  
	  
Sentences	  written	  in	  «	  CAPITALS	  »	  should	  not	  be	  read	  to	  the	  patient.	  	  They	  are	  instructions	  for	  the	  interviewer	  to	  assist	  in	  the	  
scoring	  of	  the	  diagnostic	  algorithms.	  
	  
Sentences	  written	  in	  «	  bold	  »	  indicate	  the	  time	  frame	  being	  investigated.	  	  The	  interviewer	  should	  read	  them	  as	  often	  as	  
necessary.	  	  Only	  symptoms	  occurring	  during	  the	  time	  frame	  indicated	  should	  be	  considered	  in	  scoring	  the	  responses.	  
	  
Answers	  with	  an	  arrow	  above	  them	  (➨)	  indicate	  that	  one	  of	  the	  criteria	  necessary	  for	  the	  diagnosis	  or	  diagnoses	  is	  not	  
met.	  In	  this	  case,	  the	  interviewer	  should	  go	  to	  the	  end	  of	  the	  module,	  circle	  «	  NO	  »	  in	  all	  the	  diagnostic	  boxes	  and	  move	  to	  
the	  next	  module.	  
	  
When	  terms	  are	  separated	  by	  a	  slash	  (/)	  the	  interviewer	  should	  read	  only	  those	  symptoms	  known	  to	  be	  present	  in	  the	  
patient	  (for	  example,	  questions	  J2b	  or	  K6b).	  
	  
Phrases	  in	  (parentheses)	  are	  clinical	  examples	  of	  the	  symptom.	  	  These	  may	  be	  read	  to	  the	  patient	  to	  clarify	  the	  question.	  
	  
RATING	  INSTRUCTIONS:	  
	  
All	  questions	  must	  be	  rated.	  The	  rating	  is	  done	  at	  the	  right	  of	  each	  question	  by	  circling	  either	  Yes	  or	  No.	  	  Clinical	  judgment	  
by	  the	  rater	  should	  be	  used	  in	  coding	  the	  responses.	  	  Interviewers	  need	  to	  be	  sensitive	  to	  the	  diversity	  of	  cultural	  beliefs	  in	  
their	  administration	  of	  questions	  and	  rating	  of	  responses.	  The	  rater	  should	  ask	  for	  examples	  when	  necessary,	  to	  ensure	  
accurate	  coding.	  	  The	  patient	  should	  be	  encouraged	  to	  ask	  for	  clarification	  on	  any	  question	  that	  is	  not	  absolutely	  clear.	  
The	  clinician	  should	  be	  sure	  that	  each	  dimension	  of	  the	  question	  is	  taken	  into	  account	  by	  the	  patient	  (for	  example,	  time	  
frame,	  frequency,	  severity,	  and/or	  alternatives).	  
Symptoms	  better	  accounted	  for	  by	  an	  organic	  cause	  or	  by	  the	  use	  of	  alcohol	  or	  drugs	  should	  not	  be	  coded	  positive	  in	  the	  
M.I.N.I.	  	  The	  M.I.N.I.	  has	  questions	  that	  investigate	  these	  issues.	  
	  
For	  any	  questions,	  suggestions,	  need	  for	  a	  training	  session	  or	  information	  about	  updates	  of	  the	  M.I.N.I.,	  please	  contact:	  
	  
University	  of	  South	  Florida	  College	  of	  Medicine	  
	  
tel	  :	  
	  
	  
e-­‐mail	  :	  
	  	  
	  
	  
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
4 
A. MAJOR	  DEPRESSIVE	  EPISODE	  	  
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  IN	  THE	  DIAGNOSTIC	  BOX,	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE) 
 
 
A1	  
a	   Were	  you	  ever	  depressed	  or	  down,	  or	  felt	  sad,	  empty	  or	  hopeless	  
	  NO	  	  	  	  	  	  	   YES	  	  	  
	  
	  
most	  of	  the	  day,	  nearly	  every	  day,	  for	  two	  weeks? 
 
 
IF	  NO,	  CODE	  NO	  TO	  A1b:	  	  IF	  YES	  ASK:	  
	  
	  
b	   For	  the	  past	  two	  weeks,	  were	  you	  depressed	  or	  down,	  or	  felt	  sad,	  empty	  or	  hopeless	  
NO	  
YES	  	  	  
	  
	  
most	  of	  the	  day,	  nearly	  every	  day?	  
A2	  
a	   Were	  you	  ever	  much	  less	  interested	  in	  most	  things	  or	  much	  less	  able	  to	  
NO	   	  	  	  	  	  	   YES	  	  	  
	  
	  
enjoy	  the	  things	  you	  used	  to	  enjoy	  most	  of	  the	  time,	  for	  two	  weeks?	  
	  
	  
	  
IF	  NO,	  CODE	  NO	  TO	  A2b:	  	  IF	  YES	  ASK:	  
	  
	  
b	   In	  the	  past	  two	  weeks,	  were	  you	  much	  less	  interested	  in	  most	  things	  or	  
NO	  
YES	  	  	  
	  
	  
much	  less	  able	  to	  enjoy	  the	  things	  you	  used	  to	  enjoy,	  most	  of	  the	  time?	  
 
 
 
➨ 
 
 
IS A1a	  OR	  A2a	  CODED	  YES?	  	  
NO	  
YES	  
 
 
A3	  
	  
IF	  A1b	  OR	  A2b	  =	  YES:	  EXPLORE	  THE	  CURRENT	  AND	  THE	  MOST	  SYMPTOMATIC	  PAST	  EPISODE,	  OTHERWISE	  
	  
	  
IF	  A1b	  AND	  A2b	  =	  NO:	  EXPLORE	  ONLY	  THE	  MOST	  SYMPTOMATIC	  PAST	  EPISODE	  
	  
	  
	  
Over	  that	  two	  week	  period,	  when	  you	  felt	  depressed	  or	  uninterested:	  
	  
	  
	  
Past	  2	  Weeks	  
Past	  Episode	  
	  
	  
a	   Was	  your	  appetite	  decreased	  or	  increased	  nearly	  every	  day?	  	  Did	  your	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
weight	  decrease	  or	  increase	  without	  trying	  intentionally	  (i.e.,	  by	  ±5%	  of	  	  
	  
	  
body	  weight	  or	  ±8	  lb	  or	  ±	  3.5	  kg,	  for	  a	  160	  lb/70	  kg	  person	  in	  a	  month)?	  	  	  
	  
	  
IF	  YES	  TO	  EITHER,	  CODE	  YES.	  
	  
	  
	  
	  
b	   Did	  you	  have	  trouble	  sleeping	  nearly	  every	  night	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
(difficulty	  falling	  asleep,	  waking	  up	  in	  the	  middle	  of	  the	  night,	  	  
	  
	  
early	  morning	  wakening	  or	  sleeping	  excessively)?	  
	  
	  
c	   Did	  you	  talk	  or	  move	  more	  slowly	  than	  normal	  or	  were	  you	  fidgety,	  restless	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
or	  having	  trouble	  sitting	  still	  almost	  every	  day?	  Did	  anyone	  notice	  this?	  
	  
	  
d	   Did	  you	  feel	  tired	  or	  without	  energy	  almost	  every	  day?	  
NO	  
YES	  	  
NO	  
YES	  
	  
	  
	  
	  
e	   Did	  you	  feel	  worthless	  or	  guilty	  almost	  every	  day?	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
IF	  YES,	  ASK	  FOR	  EXAMPLES.	  LOOK	  FOR	  DELUSIONS	  OF	  FAILURE,	  OF	  INADEQUACY,	  OF	  RUIN	  OR	  OF	  GUILT,	  OR	  
	  
	  
OF	  NEEDING	  PUNISHMENT	  OR	  DELUSIONS	  OF	  DISEASE	  OR	  DEATH	  OR	  NIHILISTIC	  OR	  SOMATIC	  DELUSIONS.	  
	  
	  
THE	  EXAMPLES	  ARE	  CONSISTENT	  WITH	  A	  DELUSIONAL	  IDEA. Current	  Episode	   ☐ No  ☐ Yes 
 
 
 
Past	  Episode 
☐ No  ☐ Yes 
 
 
f	  
Did	  you	  have	  difficulty	  concentrating,	  thinking	  or	  making	  decisions	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
almost	  every	  day?	  
	  
	  
g	   Did	  you	  repeatedly	  think	  about	  death	  (FEAR	  OF	  DYING	  DOES	  NOT	  COUNT	  HERE),	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
or	  have	  any	  thoughts	  of	  killing	  yourself,	  or	  have	  any	  intent	  	  
	  
	  
or	  plan	  to	  kill	  yourself?	  Did	  you	  attempt	  suicide?	  IF	  YES	  TO	  EITHER,	  CODE	  YES.	  
	  
	  
	  
	  
	  
	  
A4	  
	  
Did	  these	  symptoms	  cause	  significant	  distress	  or	  problems	  at	  home,	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  YES	  
	  	  	  	  	  	  	  NO	   	  	  	  	  	  	  	  YES	  
	  
	  
at	  work,	  at	  school,	  socially,	  in	  your	  relationships,	  or	  in	  some	  other	  
	  
	  
important	  way,	  and	  are	  they	  a	  change	  from	  your	  previous	  functioning?	  
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
5 
	  
	  
	  
A5	  
	  
In	  between	  2	  episodes	  of	  depression,	  did	  you	  ever	  have	  an	  interval	  of	  at	  least	  2	  
	  
	  
months,	  without	  any	  significant	  depression	  or	  any	  significant	  loss	  of	  interest?	  
N/A	  	  	  	  	  	  	  NO	   	  	  	  	  	  YES	  
	  
 
 
            ARE	  5	  OR	  MORE	  ANSWERS	  (A1-­‐A3)	  CODED	  YES	  AND	  IS	  A4	  CODED	  YES	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  FOR	  THAT	  TIME	  FRAME?	  
	  
AND	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SPECIFY	  IF	  THE	  EPISODE	  IS	  CURRENT	  AND	  /	  OR	  PAST.	  
	  
IF	  A5	  IS	  CODED	  YES,	  CODE	  YES	  FOR	  RECURRENT.	  
 
 
     NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
MAJOR	  DEPRESSIVE	  
EPISODE	  
 
CURRENT                 ☐  
	  	  	  	  	  	  PAST                      ☐ 
	  	  	  	  	  	  RECURRENT             ☐ 
   
	  
	  
A6	  
a	   How	  many	  episodes	  of	  depression	  did	  you	  have	  in	  your	  lifetime?	  	  	  	  _____	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  
Between	  each	  episode	  there	  must	  be	  at	  least	  2	  months	  without	  any	  significant	  depression. 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
6 
B.  SUICIDALITY 
 
 
 
 
                Points	  
 
 
In	  the	  past	  month	  did	  you:	  
	  
B1	  
	  
Have	  any	  accident?	  This	  includes	  taking	  too	  much	  of	  your	  medication	  accidentally.	  
NO	  
YES	  
0	  
	  
	  
IF	  NO	  TO	  B1,	  SKIP	  TO	  B2;	  IF	  YES,	  ASK	  B1a:	  
	  
B1a	   	  
Plan	  or	  intend	  to	  hurt	  yourself	  in	  any	  accident,	  either	  by	  not	  avoiding	  a	  risk	  or	  
NO	  
YES	  
0	  
	  
by	  causing	  the	  accident	  on	  purpose?	  
	  
	  
	  
IF	  NO	  TO	  B1a,	  SKIP	  TO	  B2:	  IF	  YES,	  ASK	  B1b:	  
	  
B1b	   	  
Intend	  to	  die	  as	  a	  result	  of	  any	  accident?	  
NO	  
YES	  
0	  
	  
B2	  
	  
Think	  (even	  momentarily)	  that	  you	  would	  be	  better	  off	  dead	  or	  wish	  you	  were	  dead	  or	  
NO	  
YES	  
1	  
	  
	  
needed	  to	  be	  dead?	  	  	  
	  
B3	  
	  
Think	  (even	  momentarily)	  about	  harming	  or	  of	  hurting	  or	  of	  injuring	  yourself	  
NO	  
YES	  	  
6	  	  	  	  	  	  
-­‐	  with	  at	  least	  some	  intent	  or	  awareness	  that	  you	  might	  die	  as	  a	  result	  	  
	  
	  
-­‐	  or	  think	  about	  suicide	  (i.e.	  about	  killing	  yourself)?	  
	  
	  
	  
	  
	  
IF	  NO	  TO	  B2	  +	  B3,	  SKIP	  TO	  B4.	  	  OTHERWISE	  ASK:	  
	  
Frequency	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Intensity	  
 
Occasionally     ☐   
       Mild             ☐ 
Often      
☐              Moderate     ☐ 
 
  
	  
	  
Very	  often        ☐                  Severe         ☐ 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
                                  
B4	  
	  
Hear	  a	  voice	  or	  voices	  telling	  you	  to	  kill	  yourself	  or	  have	  dreams	  with	  any	  suicidal	  content?	  
NO	  
YES	  
4	  
If	  YES,	  was	  it	  either	  or	  both:	  	  	  ☐ was	  it	  a	  voice	  or	  voices?	  	  	  	  	  	  	  	  	  ☐	  	  was	  it	  a	  dream?	  	   
 
B5	  	   	  
Have	  a	  suicide	  method	  in	  mind	  (i.e.	  how)?	   	  
	  
	  	  	  
	  
	  
	  
NO	  
YES   
8	  
	  
B6	  	   	  
Have	  a	  suicide	  means	  in	  mind	  (i.e.	  with	  what)?	  
	  
	  	  	  
	  
	  
	  
NO	  
YES   
8	  
	  
B7	  	   	  
Have	  any	  place	  in	  mind	  to	  attempt	  suicide	  (i.e.	  where)?	   	   	  
	  
	  
	  
NO	  
YES   
8	  
	  
B8	  	   	  
Have	  any	  date/timeframe	  in	  mind	  to	  attempt	  suicide	  (i.e.	  when)?	  
	  	  
	  
	  
NO	  
YES   
8	  
	  
B9	  	   	  
Think	  about	  any	  task	  you	  would	  like	  to	  complete	  before	  trying	  to	  kill	  yourself?	   	  	  
	  
NO	  
YES   
8	  
 
(e.g.	  writing	  a	  suicide	  note)	  
	  
	  
	  	   	  
	  
	  
	  
B10	   	  
Intend	  to	  act	  on	  thoughts	  of	  killing	  yourself?	  
NO	  
YES	  
8	  
	  
	  
If	  YES,	  mark	  either	  or	  both:	  	  	  	  ☐ did	  you	  intend	  to	  act	  at	  the	  time?	  	  	  	  
	  
	  
	  
☐ did	  you	  intend	  to	  act	  at	  some	  time	  in	  the	  future?	   
	  
B11	   	  
Intend	  to	  die	  as	  a	  result	  of	  a	  suicidal	  act?	  	  
NO	  
YES	  
8	  
	  
	  
If	  YES,	  mark	  either	  or	  both:	  	  	  	  ☐ did	  you	  intend	  to	  die	  by	  suicide	  at	  the	  time?	  	  	  	  
	  
	  
☐ did	  you	  intend	  to	  die	  by	  suicide	  at	  some	  time	  in	  the	  future?	  
 
B12	   	  
Feel	  the	  need	  or	  impulse	  to	  kill	  yourself	  or	  to	  plan	  to	  kill	  yourself	  sooner	  rather	  than	  later?	  
NO	  
YES	  
8	  
	   	   	  	  	  	   If	  YES,	  mark	  either	  or	  both:	  	  	  	  ☐ was	  this	  to	  kill	  yourself?	  	  	  	  	  	  	  	  	  	  	  	  	  ☐ was	  this	  to	  plan	  to	  kill	  yourself?	  	  
	   	   	   If	  YES,	  mark	  either	  or	  both:	  	  	  	  ☐ was	  this	  largely	  unprovoked?	  	  	  	  ☐	  	  	  was	  this	  provoked?	  
	   	   	   	  
	   	   	   IN	  ASSESSING	  WHETHER	  THIS	  WAS	  LARGELY	  UNPROVOKED	  ASK:	  “5	  minutes	  before	  	  
	   	   	   this	  Impulse,	  could	  you	  have	  predicted	  it	  would	  occur	  at	  that	  time?”	  
	   	   	  
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7 
B13  
Have	  difficulty	  resisting	  these	  impulses?	  
	  
	  
	   	  
	  
	  
	  
NO	  
YES	  
8	  
	  
B14	   	  
Take	  any	  active	  steps	  to	  prepare	  for	  a	  suicide	  attempt	  in	  which	  you	  expected	  
	   	  
or	  intended	  to	  die	  (include	  anything	  done	  or	  purposely	  not	  done	  that	  put	  you	  closer	  
	   	  
to	  making	  a	  suicide	  attempt)?	  This	  includes	  times	  when	  you	  were	  going	  to	  kill	  yourself,	  
	  
	  
but	  were	  interrupted	  or	  stopped	  yourself,	  before	  harming	  yourself.	  
NO	  
YES	  	  
	  
	  
	  
IF	  NO	  TO	  B14,	  SKIP	  TO	  B15.	  
	  
B14a	  	  
Take	  active	  steps	  to	  prepare	  to	  kill	  yourself,	  but	  you	  did	  not	  start	  the	  suicide	  attempt?	  
NO	  
YES	  	  
9
	  
	  
	  
B14b	  	  
Take	  active	  steps	  to	  prepare	  to	  kill	  yourself,	  but	  then	  you	  stopped	  yourself	  just	  before	  
NO	  
YES	  	  
10	  
	  
	  
harming	  yourself	  (“aborted”).	  
	  
B14c	  	  
Take	  active	  steps	  to	  prepare	  to	  kill	  yourself,	  but	  then	  someone	  or	  something	  	  
	  
	  
stopped	  you	  just	  before	  harming	  yourself	  (“interrupted”)?	  
NO	  
YES	  	  
11	  
 
B15	   	  
Injure	  yourself	  on	  purpose	  without	  intending	  to	  kill	  yourself?	  
NO	  
YES	  
0	  
	  
B16	   	  
Attempt	  suicide	  (to	  kill	  yourself)?	  	  
	  
NO	  
YES	  
	  
	  
	  
IF	  NO	  TO	  B16,	  SKIP	  TO	  B17.	  
	  
B16a	  	  
Start	  a	  suicide	  attempt	  (to	  kill	  yourself),	  but	  then	  you	  decided	  to	  stop	  
NO	  
YES	  
12	  
	  
	  
and	  did	  not	  finish	  the	  attempt?	  
	  
B16b	  	  
Start	  a	  suicide	  attempt	  (to	  kill	  yourself),	  but	  then	  you	  were	  interrupted	  
NO	  
YES	  
13	  
	  
	  
and	  did	  not	  finish	  the	  attempt?	  
	  
B16c	  	  
Went	  through	  with	  a	  suicide	  attempt	  (to	  kill	  yourself),	  completely	  as	  you	  meant	  to?	  
NO	  
YES	  
14	  
	  
A	  suicide	  attempt	  means	  you	  did	  something	  where	  you	  could	  possibly	  be	  injured,	  
	  
with	  at	  least	  a	  slight	  intent	  to	  die.	  
	  
IF	  NO,	  SKIP	  TO	  B17:	  	  
	  
	  
 
Hope	  to	  be	  rescued	  /	  survive        ☐ 
 
 
Expected	  /	  intended	  to	  die            ☐ 
	  
B17	   	  
TIME	  SPENT	  PER	  DAY	  WITH	  ANY	  SUICIDAL	  IMPULSES,	  THOUGHTS	  OR	  ACTIONS:	  	  
Usual	  time	  spent	  per	  day:	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  ____	  hours	  	  ____	  minutes.	  
Least	  amount	  of	  time	  spent	  per	  day:	  	  ____	  hours	  	  ____	  minutes.	  	  	  	  	  
Most	  amount	  of	  time	  spent	  per	  day:	  	  ____	  hours	  	  ____	  minutes.	  
 
 
 
In	  your	  lifetime:	  
	  
B18	   	  
Did	  you	  ever	  make	  a	  suicide	  attempt	  (try	  to	  kill	  yourself)?	  
NO	  
YES	  
4	  
	  
If	  YES,	  how	  many	  times?	  _____________	  
	  
If	  YES,	  when	  was	  the	  last	  suicide	  attempt?	  	  
	  
Current:	  within	  the	  past	  12	  months         
☐ 
 
 
In	  early	  remission:	  between	  12	  and	  24	  months	  ago            ☐ 
 
In	  remission:	  more	  than	  24	  months	  ago         
 ☐ 
	  
	  
	  
“A	  suicide	  attempt	  is	  any	  self	  injurious	  behavior,	  with	  at	  least	  some	  intent	  (>	  0)	  to	  die	  as	  a	  result	  of	  the	  act.	  Evidence	  that	  
the	  individual	  intended	  to	  kill	  him-­‐or	  herself,	  at	  least	  to	  some	  degree,	  can	  be	  explicit	  or	  inferred	  from	  the	  behavior	  or	  
circumstance.	  For	  example,	  it	  is	  defined	  as	  a	  suicide	  attempt	  if	  it	  is	  clearly	  not	  an	  accident	  or	  if	  the	  individual	  thinks	  	  
	  	  	  
the	  act	  could	  be	  lethal,	  even	  though	  denying	  intent.”	  (FDA	  Guidance	  for	  Industry	  Suicidal	  Ideation	  and	  Behavior	  	  
	  
	  
Document	  2012	  and	  C-­‐CASA	  definition).	  Posner	  K	  et	  al.	  Am	  J	  Psychiatry	  2007;	  164	  (7):	  1035-­‐1043	  &	  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm/	  	  	  
	  
B19	   	  
How	  likely	  are	  you	  to	  try	  to	  kill	  yourself	  within	  the	  next	  3	  months	  on	  a	  scale	  of	  0-­‐100%	  ______%	   	  
	  
	  
ANY	  LIKELIHOOD	  >	  0%	  ON	  B19	  SHOULD	  BE	  CODED	  YES	  	  
NO	  
YES	  
13	  
	  
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8 
 
 
 
   IS	  AT	  LEAST	  1	  OF	  THE	  ABOVE	  	  (EXCEPT	  B1)	  CODED	  YES?	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  IF	  YES,	  ADD	  THE	  TOTAL	  POINTS	  FOR	  THE	  ANSWERS	  (B1-­‐B19)	  CHECKED	  ‘YES’	  AND	  
SPECIFY	  THE	  SUICIDALITY	  SCORE	  CATEGORY	  AS	  INDICATED	  IN	  THE	  DIAGNOSTIC	  BOX:	  	  
	  
INDICATE	  WHETHER	  THE	  SUICIDALITY	  IS	  CURRENT	  (PAST	  MONTH)	  OR	  A	  LIFETIME	  SUICIDE	  ATTEMPT	  OR	  
BOTH	  BY	  MARKING	  THE	  APPROPRIATE	  BOXES	  OR	  BY	  LEAVING	  EITHER	  OR	  BOTH	  OF	  THEM	  UNMARKED.	  	  	  	  	  	  	  	  	  	  	      
CURRENT	  =	  ANY	  POSITIVE	  RESPONSE	  IN	  B1a	  THROUGH	  B16C	  OR	  ANY	  TIME	  SPENT	  IN	  B17.	  	  LIFETIME	  
ATTEMPT	  =	  B18	  CODED	  YES.	  
LIKELY	  IN	  THE	  NEAR	  FUTURE	  	  =	  B19	  CODED	  YES.	  	  
	  
	  	  MAKE	  ANY	  ADDITIONAL	  COMMENTS	  ABOUT	  YOUR	  ASSESSMENT	  OF	  THIS	  PATIENT’S	  CURRENT	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
AND	  NEAR	  FUTURE	  SUICIDALITY	  IN	  THE	  SPACE	  BELOW:	  	  
            
 
	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
SUICIDALITY	  
	  
	  	  	  	  1-­‐8	  points	  	  	  	  	  Low             ☐ 
   9-­‐16	  points	  	  	  Moderate     ☐ 
   >	  17	  points	  	  	  High              ☐ 
   
    CURRENT 	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  ☐  
	  	  	  	  	  	  
	  	  	  	  	  LIFETIME ATTEMPT       ☐ 
 
	  	  	  	  	  LIKELY	  IN	  NEAR	  FUTURE  ☐ 
 
 
	  
	  
 
 
  IS	  B18	  CODED	  YES?	  
	  
AND	  A	  YES	  RESPONSE	  TO	  
	  
Was	  the	  suicidal	  act	  started	  when	  the	  subject	  not	  in	  a	  state	  of	  confusion	  or	  
delirium?	  
	  
AND	  A	  YES	  RESPONSE	  TO	  	  
	  
Was	  the	  suicidal	  act	  done	  without	  a	  political	  or	  religious	  purpose?	  
           IF	  YES,	  SPECIFY	  WHETHER	  THE	  DISORDER	  IS	  CURRENT,	  IN	  EARLY	  REMISSION	  OR	  IN	  REMISSION. 
 
	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
SUICIDAL	  BEHAVIOR	  
DISORDER	  
	  
CURRENT	  
   Current                     ☐ 
   In	  early	  remission     ☐ 
   In	  remission              ☐ 
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9 
C. MANIC	  AND	  HYPOMANIC	  EPISODES 
 
(➨ MEANS:  GO	  TO	  THE	  DIAGNOSTIC	  BOXES,	  CIRCLE	  NO	  IN	  MANIC	  AND	  HYPOMANIC	  DIAGNOSTIC	  BOXES,	  AND	  MOVE	  TO	  NEXT	  MODULE) 
 
Do	  you	  have	  any	  family	  history	  of	  manic-­‐depressive	  illness	  or	  bipolar	  disorder,	  
or	  any	  family	  member	  who	  had	  mood	  swings	  treated	  with	  a	  medication	  like	  lithium,	  
NO	  
	  	  	  	  	  	  	  	  	  	  YES	  
	  
	  	  
	  
sodium	  valproate	  (Depakote)	  or	  lamotrigine	  (Lamictal)?	  	  	  
	  
	  
THIS	  QUESTION	  IS	  NOT	  A	  CRITERION	  FOR	  BIPOLAR	  DISORDER,	  BUT	  IS	  ASKED	  TO	  INCREASE	  	  
	  
	  
THE	  CLINICIAN’S	  VIGILANCE	  ABOUT	  THE	  RISK	  FOR	  BIPOLAR	  DISORDER.	  
IF	  YES,	  PLEASE	  SPECIFY	  WHO:________________________________________	  	  	  	  
	  
	  
C1	  
a	   Have	  you	  ever	  had	  a	  period	  of	  time	  when	  you	  were	  feeling	  'up'	  or	  'high'	  or	  ‘hyper’	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  NO	  	  	  	  	  	  	   YES	  	  	  
	  
	  
and	  so	  active	  or	  full	  of	  energy	  or	  full	  of	  yourself	  that	  you	  got	  into	  trouble,	  -­‐	  or	  that	  
	  
	  
other	  people	  thought	  you	  were	  not	  your	  usual	  self?	  	  (Do	  not	  consider	  
	  
	  
times	  when	  you	  were	  intoxicated	  on	  drugs	  or	  alcohol.)	  
	  
	  
	  
IF	  PATIENT	  IS	  PUZZLED	  OR	  UNCLEAR	  ABOUT	  WHAT	  YOU	  MEAN	  	  
	  
	  
BY	  'UP'	  OR	  'HIGH'	  OR	  ‘HYPER’,	  CLARIFY	  AS	  FOLLOWS:	  	  By	  'up'	  or	  'high'	  or	  ‘hyper’	  	  
	  
	  
I	  mean:	  having	  elated	  mood;	  increased	  energy	  or	  increased	  activity;	  needing	  less	  sleep;	  	  
	  
	  
having	  rapid	  thoughts;	  being	  full	  of	  ideas;	  having	  an	  increase	  in	  productivity,	  motivation,	  
	  
	  
creativity,	  or	  impulsive	  behavior;	  phoning	  or	  working	  excessively	  or	  spending	  more	  money.	  
	  
	  
	  
IF	  NO,	  CODE	  NO	  TO	  C1b:	  	  IF	  YES	  ASK:	  
	  
	  
b	   Are	  you	  currently	  feeling	  ‘up’	  or	  ‘high’	  or	  ‘hyper’	  or	  full	  of	  energy?	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
NO	  
YES	  	  	  
	  
C2	  
a	   Have	  you	  ever	  been	  persistently	  irritable,	  for	  several	  days,	  so	  that	  you	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
NO	   	  	  	  	  	  	   YES	  	  	  
	  
	  
had	  arguments	  or	  verbal	  or	  physical	  fights,	  or	  shouted	  at	  people	  outside	  
	  
	  
your	  family?	  	  Have	  you	  or	  others	  noticed	  that	  you	  have	  been	  more	  irritable	  
	  
	  
or	  over	  reacted,	  compared	  to	  other	  people,	  even	  in	  situations	  that	  you	  felt	  
	  
	  
were	  justified?	  
	  
	  
	  
IF	  NO,	  CODE	  NO	  TO	  C2b:	  	  IF	  YES	  ASK:	  
	  
	  
b	   Are	  you	  currently	  feeling	  persistently	  irritable?	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
NO	  
YES   
 
 
 
➨ 
	  
	  
IS	  C1a	  OR	  C2a	  CODED	  YES?	  	  
NO	  
YES	  
 
 
C3	  
	  
IF	  C1b	  OR	  C2b	  =	  YES:	  EXPLORE	  THE	  CURRENT	  EPISODE	  FIRST	  AND	  THEN	  THE	  MOST	  SYMPTOMATIC	  PAST	  EPISODE,	  OTHERWISE	  
	  
	  
IF	  C1b	  AND	  C2b	  =	  NO:	  EXPLORE	  ONLY	  THE	  MOST	  SYMPTOMATIC	  PAST	  EPISODE	  
	  
	  
WHEN	  EXPLORING	  THE	  CURRENT	  EPISODE,	  PREFACE	  EACH	  QUESTION	  AS	  FOLLOWS:	  
	  
Over	  the	  past	  few	  days	  including	  today,	  when	  you	  felt	  high	  and	  full	  of	  energy	  or	  irritable,	  did	  you:	  
	  
	  
WHEN	  EXPLORING	  THE	  PAST	  EPISODE,	  PREFACE	  EACH	  QUESTION	  AS	  FOLLOWS:	  
	  
Over	  a	  period	  of	  a	  few	  days	  in	  the	  past,	  when	  you	  felt	  most	  high	  and	  most	  full	  of	  energy	  or	  most	  irritable,	  did	  you:	  
	  
	  
	  
	  
Current	  Episode	  
Past	  Episode	  
	  
	  
	  
	  
	  
a	   Feel	  that	  you	  could	  do	  things	  others	  couldn't	  do,	  or	  that	  you	  were	  an	  
NO	  
YES	  
NO	  
YES	  
	  
	  
especially	  important	  person?	  IF	  YES,	  ASK	  FOR	  EXAMPLES.	  
	  
	  
THE	  EXAMPLES	  ARE	  CONSISTENT	  WITH	  A	  DELUSIONAL	  IDEA.	  
Current	  Episode	  ☐ No ☐ Yes	   
 
 
 
Past	  Episode 
☐ No ☐ Yes 
 
 
b	   Need	  less	  sleep	  (for	  example,	  feel	  rested	  after	  only	  a	  few	  hours	  sleep)?	  
NO	  
YES	  
NO	  
YES	  
	  
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Current	  Episode	  
Past	  Episode	  
	  
	  
c	   Talk	  too	  much	  without	  stopping,	  or	  felt	  a	  pressure	  to	  keep	  talking?	  
NO	  
YES	  
NO	  
YES	  
	  
	  
d	   Notice	  your	  thoughts	  going	  very	  fast	  or	  running	  together	  or	  racing	  
NO	  
YES	  	  
NO	  
YES	  
	  
	  
or	  moving	  very	  quickly	  from	  one	  subject	  to	  another?	  
	  
	  
	  
e	   Become	  easily	  distracted	  so	  that	  any	  little	  interruption	  could	  distract	  you?	  
NO	  
YES	  
NO	  
YES	  
	  
	  
f	  
Have	  a	  significant	  increase	  in	  your	  activity	  or	  drive,	  at	  work,	  at	  school,	  
NO	  
YES	  
NO	  
YES	  
	  
	  
socially	  or	  sexually	  or	  did	  you	  become	  physically	  or	  mentally	  restless?	  
	  
This	  increase	  in	  activity	  may	  be	  with	  or	  without	  a	  purpose.	  
	  
	  
g	   Want	  so	  much	  to	  engage	  in	  pleasurable	  activities	  that	  you	  ignored	  the	  risks	  or	   NO	  
YES	  
NO	  
YES	  
	  
	  
consequences	  (for	  example,	  spending	  sprees,	  reckless	  driving,	  or	  sexual	  	  
	  
	  
indiscretions)?	  
 
 
 
 
 
 
C3	  	  SUMMARY:	  	  WHEN	  RATING	  CURRENT	  EPISODE:	  
NO	  
YES	  
NO	  
YES	  
	  
	  
	  
IF	  C1b	  IS	  NO,	  ARE	  4	  OR	  MORE	  C3	  ANSWERS	  INCLUDING	  C3f	  CODED	  YES?	  	  
	  
	  
	  
IF	  C1b	  IS	  YES,	  ARE	  3	  OR	  MORE	  C3	  ANSWERS	  INCLUDING	  C3f	  CODED	  YES?	  
	  
	  
	  
WHEN	  RATING	  PAST	  EPISODE:	  
	  
	  
	  
IF	  C1a	  IS	  NO,	  ARE	  4	  OR	  MORE	  C3	  ANSWERS	  INCLUDING	  C3f	  CODED	  YES?	  	  
	  
	  
	  
IF	  C1a	  IS	  YES,	  ARE	  3	  OR	  MORE	  C3	  ANSWERS	  INCLUDING	  C3f	  CODED	  YES?	  
	  
	  
	  
CODE	  YES	  ONLY	  IF	  THE	  ABOVE	  3	  OR	  4	  SYMPTOMS	  OCCURRED	  DURING	  THE	  SAME	  TIME	  PERIOD.	  	  
	  
	  
	  
	  
	  
RULE:	  	  ELATION/EXPANSIVENESS	  REQUIRES	  ONLY	  THREE	  C3	  SYMPTOMS,	  WHILE	  	  
	  
	  
IRRITABLE	  MOOD	  ALONE	  REQUIRES	  4	  OF	  THE	  C3	  SYMPTOMS.	  
	  
	  
	  
	  
	  
C4	  
	  
What	  is	  the	  longest	  time	  these	  symptoms	  lasted	  (most	  of	  the	  day	  nearly	  every	  day)?	  
ASSESS	  THIS	  DURATION	  FROM	  THE	  VERY	  START	  TO	  THE	  VERY	  END	  OF	  SYMPTOMS,	  NOT	  JUST	  THE	  PEAK.	  
	  
a) 3	  days	  or	  less	  
☐    
☐ 
b) 4	  days	  or	  more	  
☐    
☐ 
c) 7	  days	  or	  more	  
☐    
☐ 
	  
C5	  
	  
Were	  you	  hospitalized	  for	  these	  problems?	  
NO	  
YES	  
NO	  
YES	  
	  
IF	  YES,	  CIRCLE	  YES	  IN	  MANIC	  EPISODE	  FOR	  THAT	  TIME	  FRAME	  AND	  GO	  TO	  C7.	  	  
	  
C6	  
	  
Did	  these	  symptoms	  cause	  significant	  problems	  at	  home,	  at	  work,	  socially,	  	  
NO	  
YES	  
NO	  
YES	  
	  
	  
in	  your	  relationships,	  at	  school	  or	  in	  some	  other	  important	  way?	  
	  
	  
	  
C7	  
	  
Were	  these	  symptoms	  associated	  with	  a	  clear	  change	  in	  the	  way	  that	  you	  	  
NO	  
YES	  
NO	  
YES	  
	  
	  
previously	  functioned	  and	  that	  was	  different	  from	  the	  way	  that	  you	  usually	  are?	  	  	  
	  
 
 
ARE	  C3	  SUMMARY	  AND	  C7	  AND	  (C4C	  OR	  C5	  OR	  C6	  OR	  ANY	  PSYCHOTIC	  FEATURE	  IN	  K1	  THROUGH	  K8)	  
CODED	  YES	  
	  
AND	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  	  
  
SPECIFY	  IF	  THE	  EPISODE	  IS	  CURRENT	  AND	  /	  OR	  PAST. 
 
 
 
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
MANIC	  EPISODE	  
 
CURRENT                 ☐  
PAST                       ☐   
 
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IS	  C3	  SUMMARY	  CODED	  YES	  AND	  ARE	  C5	  AND	  C6	  CODED	  NO	  AND	  C7	  CODED	  YES,	  
AND	  IS	  EITHER	  C4b	  OR	  C4C	  CODED	  YES?	  
AND	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  	  
AND	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  ARE	  ALL	  PSYCHOTIC	  FEATURES	  IN	  K1	  THROUGH	  K8	  CODED	  NO?	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  SPECIFY	  IF	  THE	  EPISODE	  IS	  CURRENT	  AND	  /	  OR	  PAST.	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
IF	  YES	  TO	  CURRENT	  MANIC	  EPISODE,	  THEN	  CODE	  CURRENT	  HYPOMANIC	  EPISODE	  AS	  NO.	  	  
	  
IF	  YES	  TO	  PAST	  MANIC	  EPISODE,	  THEN	  CODE	  PAST	  HYPOMANIC	  EPISODE	  AS	  NOT	  EXPLORED.	  
 
 
HYPOMANIC	  EPISODE	  
	  
 
CURRENT   ☐ 	  NO 
             ☐  YES 	  
	  
PAST        ☐ 	  NO 
             ☐ 	  YES	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  ☐  NOT	  EXPLORED    
 
 
 
          ARE	  C3	  SUMMARY	  AND	  C4a	  CODED	  YES	  AND	  IS	  C5	  CODED	  NO?	  
	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  SPECIFY	  IF	  THE	  EPISODE	  IS	  CURRENT	  AND	  /	  OR	  PAST.	  
	  
IF	  YES	  TO	  CURRENT	  MANIC	  EPISODE	  OR	  HYPOMANIC	  EPISODE,	  	  
THEN	  CODE	  CURRENT	  HYPOMANIC	  SYMPTOMS	  AS	  NO.	  	  
	  
IF	  YES	  TO	  PAST	  MANIC	  EPISODE	  OR	  YES	  TO	  PAST	  HYPOMANIC	  EPISODE,	  	  
THEN	  CODE	  PAST	  HYPOMANIC	  SYMPTOMS	  AS	  NOT	  EXPLORED.	  
 
 
 
	  HYPOMANIC	  SYMPTOMS	  
	  
 
CURRENT    ☐ 	  NO 
              ☐  YES	  
	  
PAST         ☐ 	  NO 
              ☐  YES    
              ☐ NOT	  EXPLORED 	  
 
	  
	  
C8	  
a)	  IF	  MANIC	  EPISODE	  IS	  POSITIVE	  FOR	  EITHER	  CURRENT	  OR	  PAST	  ASK:	  
Did	  you	  have	  2	  or	  more	  of	  these	  (manic)	  episodes	  lasting	  7	  days	  or	  more	  (C4c)	  in	  your	  	  
lifetime	  (including	  the	  current	  episode	  if	  present)?	  	  	  	  	  	  
NO	  	  	  	  	  	  YES	  
	  
	  
	   	  
	  
b)	  IF	  MANIC	  OR	  HYPOMANIC	  EPISODE	  IS	  POSITIVE	  FOR	  EITHER	  CURRENT	  OR	  PAST	  ASK:	  
Did	  you	  have	  2	  or	  more	  of	  these	  (hypomanic)	  episodes	  lasting	  4	  days	  or	  more	  (C4b)	  	  
in	  your	  lifetime	  (including	  the	  current	  episode)?	  	  	  	  	  	  	  	  	  	  	  	  	  	  
NO	  	  	  	  	  	  YES	  
	  
	  
	  
	  
c)	  IF	  THE	  PAST	  “HYPOMANIC	  SYMPTOMS”	  CATEGORY	  IS	  CODED	  POSITIVE	  ASK:	  
	  
Did	  you	  have	  these	  hypomanic	  symptoms	  lasting	  only	  1	  to	  3	  days	  (C4a)	  2	  or	  more	  times	  	  
in	  your	  lifetime,	  (including	  the	  current	  episode	  if	  present)?	  	  	  
NO	  	  	  	  	  YES
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  
	  
	  
	  
	  
	  
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D.  PANIC	  DISORDER 
 
(➨ MEANS:	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
 
 
 
 
➨ 
D1	  
a	   Have	  you,	  on	  more	  than	  one	  occasion,	  had	  spells	  or	  attacks	  when	  you	  suddenly	  
NO	  
YES	  
	  
	  
	  
felt	  anxious,	  very	  frightened,	  uncomfortable	  or	  uneasy,	  even	  in	  situations	  	  
	  
	  
where	  most	  people	  would	  not	  feel	  that	  way?	  	  	  
 
 
 
➨ 
 
b	   Did	  the	  spells	  surge	  to	  a	  peak	  within	  10	  minutes	  of	  starting?	  
NO	  
YES 
 
 
 
 
 
 
 
➨ 
D2	  
	  
At	  any	  time	  in	  the	  past,	  did	  any	  of	  those	  spells	  or	  attacks	  come	  on	  unexpectedly	  
NO	  
YES	  
	  
or	  occur	  in	  an	  unpredictable	  or	  unprovoked	  manner?	  
 
 
 
 
D3	  
Have	  you	  ever	  had	  one	  such	  attack	  followed	  by	  a	  month	  or	  more	  of	  persistent	   	  
	  
NO	  
YES	  
	  
concern	  about	  having	  another	  attack,	  or	  worries	  about	  the	  consequences	  of	  the	  attack	  -­‐	  
or	  did	  you	  make	  any	  significant	  change	  in	  your	  behavior	  because	  of	  the	  attacks	  (e.g.,	  avoiding	  
unfamiliar	  situations,	  or	  avoiding	  leaving	  your	  house	  or	  shopping	  alone,	  or	  doing	  things	  	  
to	  avoid	  having	  a	  panic	  attack	  or	  visiting	  your	  doctor	  or	  the	  emergency	  room	  more	  frequently)?	  	  	  
	  
	  	  
D4	  
	  
During	  the	  worst	  attack	  that	  you	  can	  remember:	  
	  
	  
	  
	  
a	   Did	  you	  have	  skipping,	  racing	  or	  pounding	  of	  your	  heart?	  
NO	  
YES	  
	  
	  
	  
	  
	  
b	   Did	  you	  have	  sweating	  or	  clammy	  hands?	  
NO	  
YES	  
	  
	  
	  
	  
	  
c	   Were	  you	  trembling	  or	  shaking?	  
NO	  
YES	  
	  
	  
	  
d	   Did	  you	  have	  shortness	  of	  breath	  or	  difficulty	  breathing	  or	  a	  smothering	  sensation?	  
NO	  
YES	  
	  
	  
	  
	  
	  
e	   Did	  you	  have	  a	  choking	  sensation	  or	  a	  lump	  in	  your	  throat?	  
NO	  
YES	  
	  
	  
	  
	  
	  
f	  
Did	  you	  have	  chest	  pain,	  pressure	  or	  discomfort?	  
NO	  
YES	  
	  
	  
	  
	  
	  
g	   Did	  you	  have	  nausea,	  stomach	  problems	  or	  sudden	  diarrhea?	  
NO	  
YES	  
	  
	  
	  
	  
	  
h	   Did	  you	  feel	  dizzy,	  unsteady,	  lightheaded	  or	  feel	  faint?	  
NO	  
YES	  
	  
	  
	  
	  
	  
i	  
Did	  you	  have	  hot	  flushes	  or	  chills?	  
NO	  
YES	  
	  
	  
	  
	  
j	  
Did	  you	  have	  tingling	  or	  numbness	  in	  parts	  of	  your	  body?	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
k	   Did	  things	  around	  you	  feel	  strange,	  unreal,	  detached	  or	  unfamiliar,	  or	  did	  
NO	  
YES	  
	  
	  you	  feel	  outside	  of	  or	  detached	  from	  part	  or	  all	  of	  your	  body?	  
	  
	  
	  
l	  
Did	  you	  fear	  that	  you	  were	  losing	  control	  or	  going	  crazy?	  
NO	  
YES	  
	  
	  
	  
	  
	  
m	   Did	  you	  fear	  that	  you	  were	  dying?	  
NO	  
YES	  
	  
	  
➨	  
	  
D5	  
	  
ARE	  BOTH	  D3,	  AND	  4	  OR	  MORE	  D4	  ANSWERS,	  CODED	  YES?	  
NO	  
YES	  
	  
	  
PANIC	  DISORDER	  
LIFETIME	  
	  
D6	  
	  
In	  the	  past	  month	  did	  you	  have	  persistent	  concern	  about	  having	  another	  attack,	  
NO	  
YES	  
	  
or	  worry	  about	  the	  consequences	  of	  the	  attacks,	  
	  
PANIC	  DISORDER	  
	  	  
or	  did	  you	  change	  your	  behavior	  in	  any	  way	  because	  of	  the	  attacks?	  
	  
CURRENT	  
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
13 
	  
 
	  
	  
	  
	  
IS	  EITHER	  D5	  OR	  D6	  	  CODED	  YES,	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
AND	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  	  
	  
SPECIFY	  IF	  THE	  EPISODE	  IS	  CURRENT	  AND	  /	  OR	  LIFETIME. 
	  
	  
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
PANIC	  DISORDER	  
	  
LIFETIME         ☐  
CURRENT         ☐   
	  
	  
E.  AGORAPHOBIA	  
(➨ MEANS:	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
	  
 
E1	  
	  
Do	  you	  feel	  anxious	  or	  uneasy	  in	  places	  or	  situations	  where	  help	  might	  not	  be	  available	  	  
	  
	  
or	  escape	  might	  be	  difficult	  if	  you	  had	  a	  panic	  attack	  or	  panic-­‐like	  or	  embarrassing	  symptoms,	  like:	  
	  
being	  in	  a	  crowd,	  or	  standing	  in	  a	  line	  (queue),	  
	  
being	  in	  an	  open	  space	  or	  when	  crossing	  a	  bridge,	  
	  
being	  in	  an	  enclosed	  space,	  	  
	  
when	  you	  are	  alone	  away	  from	  home,	  or	  alone	  at	  home,  
➨	  
	  
or	  traveling	  in	  a	  bus,	  train	  or	  car	  or	  using	  public	  transportation?	  	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
➨	  
	  
	  
ARE	  2	  OR	  MORE	  E1	  SITUATIONS	  CODED	  YES?	  	  
NO	  
YES	  
	  
 
 
 
 
➨	  
E2	  
	  
Do	  these	  situations	  almost	  always	  bring	  on	  fear	  or	  anxiety?	  
	  
NO	  
YES	  
	  
	  
	  
	  
➨	  
E3	  
	  
Do	  you	  fear	  these	  situations	  so	  much	  that	  you	  avoid	  them,	  or	  suffer	  
NO	  
YES	  
	  
	  
	  
through	  them,	  or	  need	  a	  companion	  to	  face	  them?	  
 
 
 
 
➨	  
E4	  
	  
Is	  this	  fear	  or	  anxiety	  excessive	  or	  out	  of	  proportion	  to	  the	  real	  danger	  in	  the	  situation?	  
	  
NO	  
YES	  
	  
	  	  
 
 
 
➨	  
E5	  
	  
Did	  this	  avoidance,	  fear	  or	  anxiety	  persist	  for	  at	  least	  6	  months?	  
NO	  
YES	  
	  
 
 
 
➨	  
E6	  
	  
Did	  these	  symptoms	  cause	  significant	  distress	  or	  problems	  at	  home,	  
	  	  	  	  	  	  NO	   	  	  	  	  	  	  	  YES	  
	  
	  
at	  work,	  socially,	  at	  school	  or	  in	  some	  other	  important	  way?	  	  
	  
	  
	  
	  
	  
IS	  E6	  CODED	  YES?	  
	  	  
	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
AGORAPHOBIA	  
CURRENT	  
	  
SAMPLE
Page 80 of 174


M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
14 
F.  SOCIAL	  ANXIETY	  DISORDER	  (Social	  Phobia)	  
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
 
 
 
 
➨ 
F1	  
	  
In	  the	  past	  month,	  did	  you	  have	  persistent	  fear	  and	  significant	  anxiety	  at	  being	  watched,	  
NO	  
YES	  
	  
	  
	  
being	  the	  focus	  of	  attention,	  or	  of	  being	  humiliated	  or	  embarrassed	  or	  rejected?	  	  
	  
	  
This	  includes	  things	  like	  speaking	  in	  public,	  eating	  in	  public	  or	  with	  others,	  writing	  	  
	  
	  
while	  someone	  watches,	  performing	  in	  front	  of	  others	  or	  being	  in	  social	  situations.	  
 
	  
EXAMPLES	  OF	  SUCH	  SOCIAL	  SITUATIONS	  TYPICALLY	  INCLUDE	  	  
• 
INITIATING	  OR	  MAINTAINING	  A	  CONVERSATION,	  	  
• 
PARTICIPATING	  IN	  SMALL	  GROUPS,	  	  
• 
DATING,	  	  
• 
SPEAKING	  TO	  AUTHORITY	  FIGURES,	  	  
• 
ATTENDING	  PARTIES,	  	  
• 
PUBLIC	  SPEAKING,	  	  
• 
EATING	  IN	  FRONT	  OF	  OTHERS,	  
• 
PERFORMING	  IN	  FRONT	  OF	  OTHERS,	  	  
• 
URINATING	  IN	  A	  PUBLIC	  WASHROOM,	  ETC.	  
 
 
 
 
➨	  
F2	  
	  
Do	  these	  social	  situations	  almost	  always	  bring	  on	  fear	  or	  anxiety?	  
	  
NO	  
YES	  
	  
	  
	  
	  
➨	  
F3	  
	  
Do	  you	  fear	  these	  social	  situations	  so	  much	  that	  you	  avoid	  them,	  or	  suffer	  
NO	  
YES	  
	  
	  
	  
through	  them,	  or	  need	  a	  companion	  to	  face	  them?	  
 
 
 
 
➨	  
F4	  
	  
Is	  this	  social	  fear	  or	  anxiety	  excessive	  or	  unreasonable	  in	  these	  social	  situations?	  
	  
NO	  
YES	  
	  
	  	  
 
 
 
➨	  
F5	  
	  
Did	  this	  social	  avoidance,	  fear	  or	  anxiety	  persist	  for	  at	  least	  6	  months?	  
NO	  
YES	  
	  
 
 
 
➨	  
F6	  
	  
Did	  these	  social	  fears	  cause	  significant	  distress	  or	  interfere	  with	  your	  ability	  
	  	  	  	  	  	  NO	   	  	  	  	  	  	  	  YES	  
	  
	  
to	  function	  at	  work,	  at	  school	  or	  socially	  or	  in	  your	  relationships	  or	  	  
in	  some	  other	  important	  way? 
 
 
	  
	  
IS	  F6	  CODED	  YES	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  
	  	  
	  
NOTE	  TO	  INTERVIEWER:	  PLEASE	  SPECIFY	  IF	  THE	  SUBJECT’S	  FEARS	  ARE	  RESTRICTED	  TO	  SPEAKING	  OR	  
PERFORMING	  IN	  PUBLIC. 
                                           
     NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
SOCIAL	  ANXIETY	  
DISORDER	  	  
(Social	  Phobia)	  
CURRENT 
 
 
RESTRICTED	  TO	  PERFORMANCE	  
SAD	  ONLY       ☐ 
 
 
	  
	  
 
 
 
 
	  
SAMPLE
Page 81 of 174


M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
15 
G.  OBSESSIVE-­‐COMPULSIVE	  DISORDER 
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
 
 
 
 
 
G1a	   	  
In	  the	  past	  month,	  have	  you	  been	  bothered	  by	  recurrent	  thoughts,	  impulses,	  or	  
NO	  
YES	  
	  
 
 
images	  that	  were	  unwanted,	  distasteful,	  inappropriate,	  intrusive,	  or	  distressing?	  -­‐ 
↓  
 
 
 
(For	  example,	  the	  idea	  that	  you	  were	  dirty,	  contaminated	  or	  had	  germs,	  or	  fear	  of	  	  
SKIP	  TO	  G3a	  
	  
	  
contaminating	  others,	  or	  fear	  of	  harming	  someone	  even	  though	  it	  disturbs	  or	  distresses	  	  
	  
	  
you,	  or	  fear	  you	  would	  act	  on	  some	  impulse,	  or	  fear	  or	  superstitions	  that	  you	  would	  	  
	  
	  
be	  responsible	  for	  things	  going	  wrong,	  or	  obsessions	  with	  sexual	  thoughts,	  images	  
	  
	  
or	  impulses,	  or	  religious	  obsessions.)	  
	  
G1b	   	  
In	  the	  past	  month,	  did	  you	  try	  to	  suppress	  these	  thoughts,	  impulses,	  or	  
NO	  
YES	  
 
 
images	  or	  to	  neutralize	  or	  to	  reduce	  them	  with	  some	  other	  thought	  or	  action?	  -­‐ 
↓  
 
 
 
	  
SKIP	  TO	  G3a	  
	  
	  
	  
(DO	  NOT	  INCLUDE	  SIMPLY	  EXCESSIVE	  WORRIES	  ABOUT	  REAL	  LIFE	  PROBLEMS.	  	  DO	  NOT	  	  
	  
	  
INCLUDE	  OBSESSIONS	  DIRECTLY	  RELATED	  TO	  HOARDING,	  HAIR	  PULLING,	  SKIN	  PICKING,	  	  
	  
	  
BODY	  DYSMORPHIC	  DISORDER,	  EATING	  DISORDERS,	  SEXUAL	  DEVIATIONS,	  	  
	  
	  
PATHOLOGICAL	  GAMBLING,	  OR	  ALCOHOL	  OR	  DRUG	  ABUSE	  BECAUSE	  THE	  PATIENT	  MAY	  	  
	  
	  
DERIVE	  PLEASURE	  FROM	  THE	  ACTIVITY	  AND	  MAY	  WANT	  TO	  RESIST	  IT	  ONLY	  BECAUSE	  OF	  	  
	  
	  
ITS	  NEGATIVE	  CONSEQUENCES.)	  
	  
 
G2	  
	  
Did	  they	  keep	  coming	  back	  into	  your	  mind	  even	  when	  you	  tried	  to	  ignore	  or	  	  
NO	  
YES	  
	  
	  
	  
get	  rid	  of	  them? 
	  
obsessions 	  	  	   
 
 
G3a	   	  
In	  the	  past	  month,	  did	  you	  feel	  driven	  to	  do	  something	  repeatedly	  in	  response	  to	  an	  
NO	  
YES	  
	  
	  
obsession	  or	  in	  response	  to	  a	  rigid	  rule,	  like	  washing	  or	  cleaning	  excessively,	  counting	  or	  
	  
	  
	  
checking	  things	  over	  and	  over,	  or	  repeating	  or	  arranging	  things,	  
	  
	  
	  
	  
or	  other	  superstitious	  rituals?	  
	  
G3b	   	  
Are	  these	  rituals	  done	  to	  prevent	  or	  reduce	  anxiety	  or	  distress	  or	  to	  prevent	  something	  	  
NO	  
YES	  
	  
	  
bad	  from	  happening	  and	  are	  they	  excessive	  or	  unreasonable?	  
	  
	  
	  
	  
compulsions 	  	  	  	  
 
 
 
 
➨ 
 
 
ARE	  (G1a	  AND	  G1b	  AND	  G2)	  OR	  (G3a	  AND	  G3b)	  CODED	  YES? 
NO	  
YES	  
	  
	  
	  
	  
G4	  	  	  	  	  	  	  	  	  In	  the	  past	  month,	  did	  these	  obsessive	  thoughts	  and/or	  compulsive	  behaviors	  	  
cause	  significant	  distress,	  or	  interfere	  with	  your	  ability	  to	  function	  at	  home,	  at	  work,	  at	  
school	  or	  socially	  or	  in	  your	  relationships	  or	  in	  some	  other	  important	  way	  or	  did	  they	  
take	  more	  than	  one	  hour	  a	  day?	  
	  
and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  
(CHECK	  FOR	  ANY	  OC	  SYMPTOMS	  STARTING	  WITHIN	  3	  WEEKS	  OF	  AN	  INFECTION)	  
	  
SPECIFY	  THE	  LEVEL	  OF	  INSIGHT	  AND	  IF	  THE	  EPISODE	  IS	  TIC-­‐RELATED. 
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
O.C.D.	  
CURRENT	  
	  
	  	  	  	  INSIGHT:	  
GOOD	  OR	  FAIR     ☐  
POOR                ☐   
	  	  	  	  	  	  	  	  	  	  ABSENT            ☐ 
	  	  	  	  	  	  	  	  	  	  DELUSIONAL       ☐  
 
TIC-­‐RELATED         ☐   
	  
SAMPLE
Page 82 of 174


M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
16 
H.  POSTTRAUMATIC	  STRESS	  DISORDER 
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO,	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE) 
 
 
 
 
 
 
➨ 
H1	  
	  
Have	  you	  ever	  experienced	  or	  witnessed	  or	  had	  to	  deal	  with	  an	  extremely	  traumatic	  
NO	  
YES	  
	  
	  
	  
event	  that	  included	  actual	  or	  threatened	  death	  or	  serious	  injury	  or	  sexual	  violence	  	  
	  
	  
to	  you	  or	  someone	  else?	  
	  
	  
	  
EXAMPLES	  OF	  TRAUMATIC	  EVENTS	  INCLUDE:	  SERIOUS	  ACCIDENTS,	  SEXUAL	  OR	  PHYSICAL	  	  
	  
	  
ASSAULT,	  A	  TERRORIST	  ATTACK,	  BEING	  HELD	  HOSTAGE,	  KIDNAPPING,	  FIRE,	  DISCOVERING	  	  
	  
	  
A	  BODY,	  WAR,	  OR	  NATURAL	  DISASTER,	  WITNESSING	  THE	  VIOLENT	  OR	  SUDDEN	  DEATH	  OF	  	  
	  
	  
SOMEONE	  CLOSE	  TO	  YOU,	  OR	  A	  LIFE	  THREATENING	  ILLNESS.	  
 
 
 
➨ 
H2	  
	  
Starting	  after	  the	  traumatic	  event,	  did	  you	  repeatedly	  re-­‐experience	  the	  event	  
NO	  
YES	  
	  
	  
	  
in	  an	  unwanted	  mentally	  distressing	  way,	  (such	  as	  in	  recurrent	  dreams	  related	  to	  the	  event,	  	  
	  
	  
intense	  recollections	  or	  memories,	  or	  flashbacks	  or	  as	  if	  the	  event	  was	  recurring)	  or	  did	  you	  
	  	  
	  
have	  intense	  physical	  or	  psychological	  reactions	  when	  you	  were	  reminded	  about	  the	  	  
	  
	  
event	  or	  exposed	  to	  a	  similar	  event?	  
	  
 
H3	  
	  
In	  the	  past	  month:	  
	  
	  
a	   Did	  you	  persistently	  try	  to	  avoid	  thinking	  about	  or	  remembering	  distressing	  details	  
NO	  
YES	  
	  
	  
	  
or	  feelings	  related	  to	  the	  event	  ?	  
	  
	  
b	   Did	  you	  persistently	  try	  to	  avoid	  people,	  conversations,	  places,	  situations,	  
NO	  
YES	  
	  
	  
	  
activities	  or	  things	  that	  bring	  back	  distressing	  recollections	  of	  the	  event?	  
 
 
 
➨	  
	  
	  
ARE	  1	  OR	  MORE	  H3	  ANSWERS	  CODED	  YES?	  	  
NO	  
YES	  
	  
H4	  
	  
In	  the	  past	  month:	  
	  	  
	  
	  
	  
	  
a	   Did	  you	  have	  trouble	  recalling	  some	  important	  part	  of	  the	  trauma?	  
NO	  
YES	  
	  
	  
	  
(but	  not	  because	  of	  or	  related	  to	  head	  trauma,	  alcohol	  or	  drugs).	  
	  
	  
b	   Were	  you	  constantly	  and	  unreasonably	  negative	  about	  yourself	  or	  others	  or	  the	  world?	  
NO	  
YES	  
	  
	  
	  
c	   Did	  you	  constantly	  blame	  yourself	  or	  others	  in	  unreasonable	  ways	  for	  the	  trauma?	  
NO	  
YES	  
	  
	  
	  
d	   Were	  your	  feelings	  always	  negative	  (such	  as	  fear,	  horror,	  anger,	  guilt	  or	  shame)?	  
NO	  
YES	  
	  
	  
	  
e	   Have	  you	  become	  much	  less	  interested	  in	  participating	  in	  activities	  that	  
NO	  
YES	  
	  
	  
were	  meaningful	  to	  you	  before?	  
	  
	  
f	  
Did	  you	  feel	  detached	  or	  estranged	  from	  others?	  
NO	  
YES	  
	  
	  
g	   Were	  you	  unable	  to	  experience	  any	  good	  feelings	  (such	  as	  happiness,	  satisfaction	  
NO	  
YES	  
	  
	  
or	  loving	  feelings)?	  
 
 
 
➨ 
 
 
ARE	  2	  OR	  MORE	  H4	  ANSWERS	  CODED	  YES?	  
NO	  
YES	  
	  
H5	  
	  
In	  the	  past	  month:	  
	  
	  
a	   Were	  you	  especially	  irritable	  or	  did	  you	  have	  outbursts	  of	  anger	  with	  little	  or	  no	  provocation?	  
NO	  
YES	  
	  
	  
b	   Were	  you	  more	  reckless	  or	  more	  self	  destructive?	  
NO	  
YES	  
	  
	  
	  
c	   Were	  you	  more	  nervous	  or	  constantly	  on	  your	  guard?	  
NO	  
YES	  
	  
	  
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17 
	  
d	   Were	  you	  more	  easily	  startled?	  
NO	  
YES	  
	  
	  
	  
e	   Did	  you	  have	  more	  difficulty	  concentrating?	  
NO	  
YES	  
	  
	  
	  
f	  
Did	  you	  have	  more	  difficulty	  sleeping?	  
NO	  
YES	  
	  
	  
 
 
 
➨ 
 
 
ARE	  2	  OR	  MORE	  H5	  ANSWERS	  CODED	  YES?	  
NO	  
YES	  
	  
 
 
 
➨	  
H6	  
	  
Did	  all	  these	  problems	  start	  after	  the	  traumatic	  event	  and	  last	  for	  more	  than	  one	  month?	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
H7	  
	  	  	  	  	  	  During	  the	  past	  month,	  did	  these	  problems	  cause	  significant	  distress,	  	  
	  
	  	  	  	  	  	  or	  interfere	  with	  your	  ability	  to	  function	  at	  home,	  at	  work,	  at	  
school	  or	  socially	  or	  in	  your	  relationships	  or	  in	  some	  other	  important	  way?	  
	  
	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  
	  
	  
SPECIFY	  IF	  THE	  CONDITION	  IS	  ASSOCIATED	  WITH	  DEPERSONALIZATION,	  DEREALIZATION	  OR	   
WITH	  DELAYED	  EXPRESSION.	  	  	  
	  	  	  	  	  	  
	  	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
POSTTRAUMATIC	  
	  STRESS	  DISORDER	  
CURRENT	  
	  
WITH	  
DEPERSONALIZATION   ☐  
	  	  	  	  	  DEREALIZATION          ☐   
	  	  	  	  	  DELAYED	  EXPRESSION	  	  	  ☐	   
	  	  
SAMPLE
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
18 
I.  ALCOHOL	  USE	  DISORDER	  	  
 
(➨ MEANS:	  	  GO	  TO	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE) 
 
 
 
 
 
➨  
 
 
I1	  
	  
In	  the	  past	  12	  months,	  have	  you	  had	  3	  or	  more	  alcoholic	  drinks,	  -­‐	  within	  a	  
NO	  
YES	  
	  
	  
	  
3	  hour	  period,	  -­‐	  on	  3	  or	  more	  occasions?	  
 
 
I2	  
	  
In	  the	  past	  12	  months:	  
	  
	  
a.	   During	  the	  times	  when	  you	  drank	  alcohol,	  did	  you	  end	  up	  drinking	  more	  than	  
NO	  
YES	  
	  
	  
you	  planned	  when	  you	  started?	  
	  
	  
b.	   Did	  you	  repeatedly	  want	  to	  reduce	  or	  control	  your	  alcohol	  use?	  
NO	  
YES	  
	  
	  
	  
Did	  you	  try	  to	  cut	  down	  or	  control	  your	  alcohol	  use,	  but	  failed?	  
	  
	  
IF	  YES	  TO	  EITHER,	  CODE	  YES.	  
	  
	  
c.	   On	  the	  days	  that	  you	  drank,	  did	  you	  spend	  substantial	  time	  obtaining	  
NO	  
YES	  
	  
	  
alcohol,	  drinking,	  or	  recovering	  from	  the	  effects	  of	  alcohol?	  
	  
d.	   	  Did	  you	  crave	  or	  have	  a	  strong	  desire	  or	  urge	  to	  use	  alcohol?	  
NO	  
YES	  
	  
	  
	  
e.	   Did	  you	  spend	  less	  time	  meeting	  your	  responsibilities	  at	  work,	  at	  school,	  
NO	  
YES	  
	  
	  
	  
or	  at	  home,	  because	  of	  your	  repeated	  drinking?	  
	  
f.	   	  If	  your	  drinking	  caused	  problems	  with	  your	  family	  or	  other	  people,	  
NO	  
YES	  
	  
	  
	  
did	  you	  still	  keep	  on	  drinking?	  
	  
g.	   Were	  you	  intoxicated	  more	  than	  once	  in	  any	  situation	  where	  you	  or	  others	  were	  physically	  
NO	  
YES	  
	  
	  
	  
at	  risk,	  for	  example,	  driving	  a	  car,	  riding	  a	  motorbike,	  using	  machinery,	  boating,	  etc.?	  
	  
h.	   Did	  you	  continue	  to	  use	  alcohol,	  even	  though	  it	  was	  clear	  that	  the	  alcohol	  	  
NO	  
YES	  
	  
	  
	  
had	  caused	  or	  worsened	  psychological	  or	  physical	  problems?	  
	  
i.	   Did	  you	  reduce	  or	  give	  up	  important	  work,	  social	  or	  recreational	  activities	  
NO	  
YES	  
	  
	  
	  
because	  of	  your	  drinking?	  
	  
	  
j.	   Did	  you	  need	  to	  drink	  a	  lot	  more	  in	  order	  to	  get	  the	  same	  effect	  that	  you	  got	  when	  you	  first	  
NO	  
YES	  
	  
	  
	  
started	  drinking	  or	  did	  you	  get	  much	  less	  effect	  with	  continued	  use	  of	  the	  same	  amount?	  
	  
	  
k1.	  When	  you	  cut	  down	  on	  heavy	  or	  prolonged	  drinking	  did	  you	  have	  any	  of	  the	  following:	  
NO	  
YES	  
	  
	  
	  
	  
1.	  increased	  sweating	  or	  increased	  heart	  rate,	  	  
☐	  
	  
	  
2.	  hand	  tremor	  or	  “the	  shakes”	  	  
☐	  
	  
	  
3.	  trouble	  sleeping	  	  	  
☐	  
	  
	  
4.	  nausea	  or	  vomiting	  	  
	  
☐	  
	  
	  
5.	  hearing	  or	  seeing	  things	  other	  people	  could	  not	  see	  or	  hear	  	  	  
	  
	  
	  
	   or	  having	  sensations	  in	  your	  skin	  for	  no	  apparent	  reason	  	  	  
☐	  
	  
	  
6.	  agitation	  	  
☐	  
	  
	  
7.	  anxiety	  	  
☐	  
	  
	  
8.	  seizures	  	  	  
☐	  
	  
	  
	  
	  
	  
IF	  YES	  TO	  2	  OR	  MORE	  OF	  THE	  ABOVE	  8,	  CODE	  k1	  AS	  YES.	  
	  
	  
k2.	  Did	  you	  drink	  alcohol	  to	  reduce	  or	  avoid	  withdrawal	  symptoms	  or	  to	  avoid	  being	  hung-­‐over?	  	  	  
NO	  
YES	  
	  
	  
	  
	  	  
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19 
	  	  
K	  SUMMARY:	  IF	  YES	  TO	  k1	  OR	  k2,	  CODE	  YES	  	  
NO	  
YES	  
	  
	  
 
 
           ARE	  2	  OR	  MORE	  I2	  ANSWERS	  FROM	  I2a	  THROUGH	  12J	  AND	  12K	  SUSUMMARY	  CODED	  YES?	  
 
  
                                       
        NO                      YES 
	  
ALCOHOL	  USE	  DISORDER	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  PAST	  12	  MONTHS  
	  
	  
	  
	  
SPECIFIERS	  FOR	  ALCOHOL	  USE	  DISORDER:	  
	  
	  
MILD	  =	  2-­‐3	  OF	  THE	  I2	  SYMPTOMS	  	  
MODERATE	  =	  4-­‐5	  OF	  THE	  I2	  SYMPTOMS	  
SEVERE	  =	  6	  OR	  MORE	  OF	  THE	  I2	  SYMPTOMS	  
	  
IN	  EARLY	  REMISSION	  =	  CRITERIA	  NOT	  MET	  FOR	  BETWEEN	  3	  &	  12	  MONTHS	  
IN	  SUSTAINED	  REMISSION	  =	  CRITERIA	  NOT	  MET	  FOR	  12	  MONTHS	  OR	  MORE	  
(BOTH	  WITH	  THE	  EXCEPTION	  OF	  CRITERION	  d.	  –	  (CRAVING)	  ABOVE).	  
	  
IN	  A	  CONTROLLED	  ENVIRONMENT	  	  =	  WHERE	  ALCOHOL	  ACCESS	  IS	  RESTRICTED	  
	  
	  
	  	  	  	  	  	  
SPECIFY	  IF:	  
	  
	  
	  	  	  	  	  	  	  	  MILD            ☐  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  MODERATE          ☐   
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SEVERE	              ☐ 
 
	  	  	  	  IN	  EARLY	  REMISSION       ☐  
	  	  	  	  IN	  SUSTAINED	  REMISSION	  	  ☐  
	  
IN	  A	  CONTROLLED	  ENVIRONMENT	  	  ☐  
	  	  
 
	  
SAMPLE
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20 
J. 	  SUBSTANCE	  USE	  DISORDER	  (NON-­‐ALCOHOL) 
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE) 
 
 
 
 
 
 
Now	  I	  am	  going	  to	  show	  you	  /	  read	  to	  you	  a	  list	  of	  street	  drugs	  or	  medicines.	  
	  
 
 
 
 
➨  
 
 
J1	  
a	   In	  the	  past	  12	  months,	  did	  you	  take	  any	  of	  these	  drugs	  more	  than	  once,	  	  
NO	  
YES	  
	  
	  
to	  get	  high,	  to	  feel	  elated,	  to	  get	  “a	  buzz”	  or	  to	  change	  your	  mood?	  
 
 
 
 
 
CIRCLE	  EACH	  DRUG	  TAKEN:	  
	  
	  
Stimulants:	  	  amphetamines,	  "speed",	  crystal	  meth,	  “crank”,	  Dexedrine,	  Ritalin,	  diet	  pills.	  
	  
	  
Cocaine:	  	  snorting,	  IV,	  freebase,	  crack,	  "speedball".	  	  	  
	  
	  
Opiates:	  	  heroin,	  morphine,	  Dilaudid,	  opium,	  Demerol,	  methadone,	  Darvon,	  codeine,	  Percodan,	  Vicodin,	  OxyContin.	  	  	  
	  
	  
Hallucinogens:	  	  LSD	  ("acid"),	  mescaline,	  peyote,	  psilocybin,	  STP,	  "mushrooms",	  “ecstasy”,	  MDA,	  MDMA.	  
	  
	  
Dissociative	  Drugs:	  	  PCP	  (Phencyclidine	  ,"Angel	  Dust",	  "Peace	  Pill",	  “Hog”),	  or	  ketamine	  (“Special	  K”).	  
	  
	  
Inhalants:	  	  "glue",	  ethyl	  chloride,	  “rush”,	  nitrous	  oxide	  ("laughing	  gas"),	  amyl	  or	  butyl	  nitrate	  ("poppers").	  
	  
	  
Cannabis:	  	  marijuana,	  hashish	  ("hash"),	  THC,	  "pot",	  "grass",	  "weed",	  "reefer".	  	  	  
	  
	  
Tranquilizers:	  	  Quaalude,	  Seconal	  ("reds"),	  Valium,	  Xanax,	  Librium,	  Ativan,	  Dalmane,	  Halcion,	  barbiturates,	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  
Miltown,	  GHB,	  Roofinol,	  “Roofies”.	  	  	  
	  
	  
Miscellaneous:	  	  steroids,	  nonprescription	  sleep	  or	  diet	  pills.	  	  Cough	  Medicine?	  Any	  others?	  	  
	  
	  
SPECIFY	  THE	  MOST	  USED	  DRUG(S):	  	  	  
	  
WHICH	  DRUG(S)	  CAUSE	  THE	  BIGGEST	  PROBLEMS?	  	  	  
	  
FIRST	  EXPLORE	  THE	  CRITERIA	  BELOW	  FOR	  THE	  DRUG	  CLASS	  CAUSING	  THE	  BIGGEST	  PROBLEMS	  AND	  THE	  ONE	  MOST	  LIKELY	  TO	  MEET	  CRITERIA	  
FOR	  SUBSTANCE	  USE	  DISORDER.	  IF	  SEVERAL	  DRUG	  CLASSES	  HAVE	  BEEN	  MISUSED,	  EXPLORE	  AS	  MANY	  OR	  AS	  FEW	  AS	  REQUIRED	  BY	  THE	  PROTOCOL.	  
	  
	  
	  
	  
	  
J2	  
	  
Considering	  your	  use	  of	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED),	  in	  the	  past	  12	  months:	  
 
	  
a.	   During	  the	  times	  when	  you	  used	  the	  drug,	  did	  you	  end	  up	  using	  more	  
NO	  
YES	  
	  
	  
(NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  than	  you	  planned	  when	  you	  started?	  
	  
	  
b.	   Did	  you	  repeatedly	  want	  to	  reduce	  or	  control	  your	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  use?	  
NO	  
YES	  
	  
	  
	  
Did	  you	  try	  to	  cut	  down	  or	  control	  your	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  use,	  but	  failed?	  
	  
	  
IF	  YES	  TO	  EITHER,	  CODE	  YES.	  
	  
	  
c.	   On	  the	  days	  that	  you	  used	  more	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED),	  did	  you	  spend	  substantial	  
NO	  
YES	  
	  
	  
time	  obtaining	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED),	  using	  it,	  or	  recovering	  from	  the	  its	  effects?	  
	  
	  
	  
d.	   	  Did	  you	  crave	  or	  have	  a	  strong	  desire	  or	  urge	  to	  use	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)?	  
NO	  
YES	  
	  
	  
	  
e.	   Did	  you	  spend	  less	  time	  meeting	  your	  responsibilities	  at	  work,	  at	  school,	  or	  at	  home,	  
NO	  
YES	  
	  
	  
	  
because	  of	  your	  repeated	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  use?	  
	  
f.	   	  If	  your	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  use	  caused	  problems	  with	  your	  family	  or	  
NO	  
YES	  
	  
	  
	  
other	  people,	  did	  you	  still	  keep	  on	  using	  it?	  
	  
g.	   Did	  you	  use	  the	  drug	  more	  than	  once	  in	  any	  situation	  where	  you	  or	  others	  were	  physically	  
NO	  
YES	  
	  
	  
	  
at	  risk,	  for	  example,	  driving	  a	  car,	  riding	  a	  motorbike,	  using	  machinery,	  boating,	  etc.?	  
	  
h.	   Did	  you	  continue	  to	  use	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED),	  even	  though	  it	  was	  clear	  
NO	  
YES	  
	  
	  
	  
that	  the	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  had	  caused	  or	  worsened	  psychological	  
	  
	  
or	  physical	  problems?	  
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i.	   Did	  you	  reduce	  or	  give	  up	  important	  work,	  social	  or	  recreational	  activities	  
NO	  
YES	  
	  
	  
	  
because	  of	  your	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  use?	  
	  
	  
j.	   Did	  you	  need	  to	  use	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  a	  lot	  more	  in	  order	  to	  get	  the	  
NO	  
YES	  
	  
	  
same	  effect	  that	  you	  got	  when	  you	  first	  started	  using	  it	  or	  did	  you	  get	  much	  less	  effect	  	  
	  
	  
with	  continued	  use	  of	  the	  same	  amount?	  
	  
	  
THIS	  CRITERION	  IS	  CODED	  NO	  IF	  THE	  MEDICATION	  IS	  PRESCRIBED	  AND	  USED	  UNDER	  MEDICAL	  SUPERVISION.	  
	  
	  
	  
	  
k1.	  When	  you	  cut	  down	  on	  heavy	  or	  prolonged	  use	  of	  the	  drug	  did	  you	  have	  any	  of	  the	  
NO	  
YES	  
	  
	  
	  
following	  withdrawal	  symptoms:	  
	  
	  
IF	  YES	  TO	  THE	  REQUIRED	  NUMBER	  OF	  WITHDRAWAL	  SYMPTOMS	  FOR	  EACH	  CLASS,	  CODE	  J2k1	  AS	  YES.	  
	  
	  
THIS	  CRITERION	  IS	  CODED	  NO	  IF	  THE	  MEDICATION	  IS	  PRESCRIBED	  AND	  USED	  UNDER	  MEDICAL	  SUPERVISION.	  
	  
Sedative,	  Hypnotic	  or	  Anxiolytic	  (2	  or	  more)	  
	  
	  
1.	  increased	  sweating	  or	  increased	  heart	  rate	  	  
☐	  
	  
	  
2.	  hand	  tremor	  or	  “the	  shakes”	  	  
☐	  
	  
	  
3.	  trouble	  sleeping	  	  	  
☐	  
	  
	  
4.	  nausea	  or	  vomiting	  	  
	  
☐	  
	  
	  
5.	  hearing	  or	  seeing	  things	  other	  people	  could	  not	  see	  or	  hear	  	  	  
	  
	  
	  
	   or	  having	  sensations	  in	  your	  skin	  for	  no	  apparent	  reason	  	  	  
☐	  
	  
	  
6.	  agitation	  	  
☐	  
	  
	  
7.	  anxiety	  	  
☐	  
	  
	  
8.	  seizures	  	  	  
☐ 
 
Opiates	  (3	  or	  more)	  
	  
	  
1.	  feeling	  depressed	  
☐	  
	  
	  
2.	  nausea	  or	  vomiting	  
☐	  
	  
	  
3.	  muscle	  aches	  	  	  
☐ 
	  
	  
4.	  runny	  nose	  or	  teary	  eyes	  	  	  
☐	  
	  
	  
5.	  dilated	  pupils,	  goose	  bumps	  or	  hair	  standing	  on	  end	  
	  
	  
or	  sweating	  	  
	  
☐	  	  
	  
	  
6.	  diarrhea	  	  
☐	  
	  
	  
7.	  yawning	  	  
☐	  
	  
	  
8.	  hot	  flashes	  	  
☐	  
	  
	  
9.	  trouble	  sleeping	  	  	  	  	  
☐	  
	  
Stimulants	  (2	  or	  more)	  
	  
	  
1.	  fatigue	  	  
☐	  
	  
	  
2.	  vivid	  or	  unpleasant	  dreams	  	  
☐	  
	  
	  
3.	  difficulty	  sleeping	  or	  sleeping	  too	  much	  	  
☐	  
	  
	  
4.	  increased	  appetite	  	  
	  
☐	  
	  
	  
5.	  feeling	  or	  looking	  physically	  or	  mentally	  slowed	  down	  
☐	  
 
 
 
Cannabis	  (3	  or	  more)	  
	  
	  
1.	  irritability,	  anger	  or	  aggression	  	  
☐	  
	  
	  
2.	  nervousness	  or	  anxiety	  	  
☐	  
	  
	  
3.	  trouble	  sleeping	  	  	  
☐	  
	  
	  
4.	  appetite	  or	  weight	  loss	  	  
	  
☐	  
	  
	  
5.	  restlessness	  	  	  
	  
☐	  
	  
	  
6.	  feeling	  depressed	  	  
☐ 
	  
	  
7.	  significant	  discomfort	  from	  one	  of	  the	  following:	  
	  
	  
	   “stomach	  pain”,	  tremors	  or	  “shakes”,	  sweating,	  hot	  flashes,	  	  
	  
	  
	  
	   chills,	  headaches.	  
☐	  
	  
	  
	  
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k2.	  Did	  you	  use	  (NAME	  OF	  DRUG	  /	  DRUG	  CLASS	  SELECTED)	  to	  reduce	  or	  avoid	  withdrawal	  symptoms?	  
NO	  
YES	  
	  
	  	  
	  
	  
J2k	  SUMMARY:	  IF	  YES	  TO	  J2k1	  OR	  J2k2,	  CODE	  YES	  	  
NO	  
YES	  
	  
 
 
            ARE	  2	  OR	  MORE	  J2	  ANSWERS	  FROM	  J2a	  THROUGH	  J2k	  SUMMARY	  CODED	  YES?	  
(J2k1	  AND	  J2k2	  TOGETHER	  COUNT	  AS	  ONE	  AMONG	  THESE	  CHOICES) 
  
                                 
          NO                      YES 
	  
SUBSTANCE	  	  
(Drug	  or	  Drug	  Class	  Name)	  
USE	  DISORDER	  
	  
PAST	  12	  MONTHS	  
	  
	  
	  
	  
SPECIFIERS	  FOR	  SUBSTANCE	  USE	  DISORDER:	  
	  
	  
MILD	  =	  2-­‐3	  OF	  THE	  J2	  SYMPTOMS	  	  
MODERATE	  =	  4-­‐5	  OF	  THE	  J2	  SYMPTOMS	  
SEVERE	  =	  6	  OR	  MORE	  OF	  THE	  J2	  SYMPTOMS	  
	  
IN	  EARLY	  REMISSION	  =	  CRITERIA	  NOT	  MET	  FOR	  BETWEEN	  3	  &	  12	  MONTHS	  
IN	  SUSTAINED	  REMISSION	  =	  CRITERIA	  NOT	  MET	  FOR	  12	  MONTHS	  OR	  MORE	  
(BOTH	  WITH	  THE	  EXCEPTION	  OF	  CRITERION	  d.	  –	  (CRAVING)	  ABOVE).	  
	  
IN	  A	  CONTROLLED	  ENVIRONMENT	  	  =	  WHERE	  SUBSTANCE	  /	  DRUG	  ACCESS	  IS	  
RESTRICTED	  
	  
	  	  	  	  	  	  
SPECIFY	  IF:	  
	  
	  	  	  	  	  	  	  	  MILD            ☐  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  MODERATE          ☐   
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SEVERE	              ☐ 
 
	  	  	  	  IN	  EARLY	  REMISSION       ☐  
	  	  	  	  IN	  SUSTAINED	  REMISSION	  	  ☐  
	  
IN	  A	  CONTROLLED	  ENVIRONMENT	  	  ☐  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
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	   K. PSYCHOTIC	  DISORDERS	  AND	  MOOD	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES 
 
ASK	  FOR	  AN	  EXAMPLE	  OF	  EACH	  QUESTION	  ANSWERED	  POSITIVELY.	  	  CODE	  YES	  ONLY	  IF	  THE	  EXAMPLES	  CLEARLY	  SHOW	  A	  DISTORTION	  OF	  THOUGHT	  OR	  OF	  PERCEPTION	  OR	  IF	  	  
THEY	  ARE	  NOT	  CULTURALLY	  APPROPRIATE.	  	  THE	  PURPOSE	  OF	  THIS	  MODULE	  IS	  TO	  EXCLUDE	  PATIENTS	  WITH	  PSYCHOTIC	  DISORDERS.	  THIS	  MODULE	  NEEDS	  EXPERIENCE.	  
	  
	  
	  
Now	  I	  am	  going	  to	  ask	  you	  about	  unusual	  experiences	  that	  some	  people	  have.	  
	  
	  
	  
	  
	  
	  
	  
K1	  
a	   Have	  you	  ever	  believed	  that	  people	  were	  spying	  on	  you,	  or	  that	  someone	  
NO	  
YES	  
	  
	  
	  
	  
was	  plotting	  against	  you,	  or	  trying	  to	  hurt	  you?	  
	  
	  
	  
	  
	  
NOTE:	  	  ASK	  FOR	  EXAMPLES	  TO	  RULE	  OUT	  ACTUAL	  STALKING.	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
b	  
IF	  YES:	  do	  you	  currently	  believe	  these	  things?	  
NO	  
YES	  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K2	  
a	   Have	  you	  ever	  believed	  that	  someone	  was	  reading	  your	  mind	  or	  could	  hear	  
NO	  
YES	  
	  
	  
	  
	  
your	  thoughts,	  or	  that	  you	  could	  actually	  read	  someone’s	  mind	  or	  hear	  what	  	  
	  
	  
	  
	  
	  
another	  person	  was	  thinking?	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
b	  
IF	  YES:	  do	  you	  currently	  believe	  these	  things?	  
NO	  
YES	  
 
 
 
 
 
 
 
 
	  
	  
	  
	  
	  
	  
K3	  
a	   Have	  you	  ever	  believed	  that	  someone	  or	  some	  force	  outside	  of	  yourself	  	  
NO	  
YES	  
	  
	  
	  
	  
put	  thoughts	  in	  your	  mind	  that	  were	  not	  your	  own,	  or	  made	  you	  act	  in	  a	  
	  
	  
	  
	  
	  
way	  that	  was	  not	  your	  usual	  self?	  	  Have	  you	  ever	  felt	  that	  you	  were	  
	  
	  
	  
	  
possessed?	  
	  
	  
	  
	  
	  
CLINICIAN:	  	  ASK	  FOR	  EXAMPLES	  AND	  DISCOUNT	  ANY	  THAT	  ARE	  NOT	  PSYCHOTIC.	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
b	  
IF	  YES:	  do	  you	  currently	  believe	  these	  things?	  
NO	  
YES	  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K4	  
a	   Have	  you	  ever	  believed	  that	  you	  were	  being	  sent	  special	  messages	  through	  
NO	  
YES	  
	  
	  
	  
	  
the	  TV,	  radio,	  internet,	  newspapers,	  books,	  or	  magazines	  or	  that	  a	  person	  
	  
	  
	  
	  
	  
you	  did	  not	  personally	  know	  was	  particularly	  interested	  in	  you?	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
b	  
IF	  YES:	  do	  you	  currently	  believe	  these	  things?	  
NO	  
YES	  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K5	  
a	   Have	  your	  relatives	  or	  friends	  ever	  considered	  any	  of	  your	  beliefs	  odd	  
NO	  
YES	  
	  
	  
	  
	  
or	  unusual?	  
	  
	  
	  
	  
	  
INTERVIEWER:	  ASK	  FOR	  EXAMPLES.	  ONLY	  CODE	  YES	  IF	  THE	  EXAMPLES	  ARE	  CLEARLY	  
	  
	  
	  
	  
	  
DELUSIONAL	  IDEAS	  NOT	  EXPLORED	  IN	  QUESTIONS	  K1	  TO	  K4,	  FOR	  EXAMPLE,	  RELIGIOUS,	  DEATH,	  
	  
	  
	  
	  
	  
DISEASE	  OR	  SOMATIC	  DELUSIONS,	  DELUSIONS	  OF	  GRANDIOSITY,	  JEALOUSY	  OR	  GUILT,	  OR	  OF	  
	  
	  
	  
	  
	  
FAILURE,	  INADEQUACY,	  RUIN,	  OR	  DESTITUTION,	  OR	  NIHILISTIC	  DELUSIONS.	  
	  
	  
	  
	  
	  
b	  
IF	  YES:	  do	  they	  currently	  consider	  your	  beliefs	  strange	  or	  unusual?	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
	  
	  
K6	  
a	   Have	  you	  ever	  heard	  things	  other	  people	  couldn't	  hear,	  such	  as	  voices?	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
IF	  YES	  TO	  VOICE	  HALLUCINATION:	  Was	  the	  voice	  commenting	  on	  your	  thoughts	  
NO	  	  	  	  	   YES	  	  	  	  
	  
	  
	  
or	  behavior	  or	  did	  you	  hear	  two	  or	  more	  voices	  talking	  to	  each	  other?	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
b	  
IF	  YES	  TO	  K6a:	  have	  you	  heard	  sounds	  /	  voices	  in	  the	  past	  month?	  	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
	  
IF	  YES	  TO	  VOICE	  HALLUCINATION:	  Was	  the	  voice	  commenting	  on	  your	  thoughts	  
NO	  	  	  	  	  	  YES	  	  	  	  	  
	  
or	  behavior	  or	  did	  you	  hear	  two	  or	  more	  voices	  talking	  to	  each	  other?	  
	  
	  
 
	  
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K7	  
a	   Have	  you	  ever	  had	  visions	  when	  you	  were	  awake	  or	  have	  you	  ever	  seen	  things	  	  
NO	  
YES	  
	  
	  
	  
other	  people	  couldn't	  see?	  	  
	  
	  
CLINICIAN:	  CHECK	  TO	  SEE	  IF	  THESE	  ARE	  CULTURALLY	  INAPPROPRIATE.	  
	  
	  
b	  
IF	  YES:	  	  have	  you	  seen	  these	  things	  in	  the	  past	  month?	  
NO	  
YES	  
	  
	  
	  
	  
CLINICIAN'S	  JUDGMENT	  
	  
K8	  
a	   DID	  THE	  PATIENT	  EVER	  IN	  THE	  PAST	  EXHIBIT	  DISORGANIZED,	  INCOHERENT	  OR	  DERAILED	  
NO	  
YES	  
	  
	  
	  
SPEECH,	  OR	  MARKED	  LOOSENING	  OF	  ASSOCIATIONS?	  
	  
K8	  
b	  
IS	  THE	  PATIENT	  CURRENTLY	  EXHIBITING	  INCOHERENCE,	  DISORGANIZED	  OR	  DERAILED	  
NO	  
YES	  
	  
	  
	  
SPEECH,	  OR	  MARKED	  LOOSENING	  OF	  ASSOCIATIONS?	  
	  
K9	  
a	   DID	  THE	  PATIENT	  EVER	  IN	  THE	  PAST	  EXHIBIT	  DISORGANIZED	  OR	  CATATONIC	  	  
NO	  
YES	  
	  
	  
	  
BEHAVIOR?	  
	  
K9	  
b	  
IS	  THE	  PATIENT	  CURRENTLY	  EXHIBITING	  DISORGANIZED	  OR	  CATATONIC	  	  
NO	  
YES	  
	  
	  
	  
BEHAVIOR?	  
	  
K10	   a	   DID	  THE	  PATIENT	  EVER	  IN	  THE	  PAST	  HAVE	  NEGATIVE	  SYMPTOMS,	  E.G.	  SIGNIFICANT	  REDUCTION	  OF	  
NO	  
YES	  
	  
	  
	  
EMOTIONAL	  EXPRESSION	  OR	  AFFECTIVE	  FLATTENING,	  POVERTY	  OF	  SPEECH	  (ALOGIA)	  OR	  	  
	  
	  
AN	  INABILITY	  TO	  INITIATE	  OR	  PERSIST	  IN	  GOAL-­‐DIRECTED	  ACTIVITIES	  (AVOLITION)?	  	  
	  
K10	   b	  
ARE	  NEGATIVE	  SYMPTOMS	  OF	  SCHIZOPHRENIA,	  E.G.	  SIGNIFICANT	  REDUCTION	  OF	  EMOTIONAL	  
NO	  
YES	  
	  
	  
	  
EXPRESSION	  OR	  AFFECTIVE	  FLATTENING,	  POVERTY	  OF	  SPEECH	  (ALOGIA)	  OR	  AN	  INABILITY	  
	  
	  
TO	  INITIATE	  OR	  PERSIST	  IN	  GOAL-­‐DIRECTED	  ACTIVITIES	  (AVOLITION),	  PROMINENT	  DURING	  	  
	  
	  
THE	  INTERVIEW?	  
	  
K11	   a	  
	  ARE	  1	  OR	  MORE	  «	  a	  »	  QUESTIONS	  FROM	  K1a	  TO	  K7a,	  CODED	  YES?	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  
ARE	  	  AND	  IS	  EITHER:	  	  
	  
	  
	  
	   	   MAJOR	  DEPRESSIVE	  EPISODE,	  (CURRENT,	  RECURRENT	  OR	  PAST)	  
	  
	   	   OR	  
	  
	  
	  
	  	  MANIC	  OR	  HYPOMANIC	  EPISODE,	  (CURRENT	  OR	  PAST)	  CODED	  YES?	  
NO	  
YES	  
 
 
 
9	  	  K13 
	  
	  
HOW	  LONG	  HAS	  THE	  MOOD	  EPISODE	  LASTED?	  _________	  
	  
	  
HOW	  LONG	  HAS	  THE	  PSYCHOTIC	  EPISODE	  LASTED?	  _________ 
	  
	  
IF	  SUCH	  A	  MOOD	  EPISODE	  IS	  PRESENT,	  IT	  MUST	  BE	  PRESENT	  FOR	  THE	  MAJORITY	  OF	  THE	  TOTAL	  DURATION	  	  
	  
	  
OF	  THE	  ACTIVE	  AND	  RESIDUAL	  PERIODS	  OF	  THE	  PSYCHOTIC	  SYMPTOMS.	  OTHERWISE	  CODE	  NO	  TO	  K11a.	  	  
	  
	  
	  
IF	  NO	  TO	  K11a,	  CIRCLE	  NO	  IN	  BOTH	  ‘MOOD	  DISORDER	  WITH	  PSYCHOTIC	  	  
	  
	  
FEATURES’	  DIAGNOSTIC	  BOXES	  AND	  MOVE	  TO	  K13.	  
 
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	  	  	  	  	  	  	  	  b	  	  	  You	  told	  me	  earlier	  that	  you	  had	  period(s)	  when	  you	  felt	  (depressed/high/persistently	  	  
	  	  	  	  	  	  	  	  	  	  	  	  irritable).	  
	  
Were	  the	  beliefs	  and	  experiences	  you	  just	  described	  (SYMPTOMS	  CODED	  YES	  FROM	  K1a	  TO	  K7a)	  
restricted	  exclusively	  to	  times	  when	  you	  were	  feeling	  depressed/high/irritable?	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
	  	  	  	  	  	  	  	  	  	  	  	  	  	  IF	  THE	  PATIENT	  EVER	  HAD	  A	  PERIOD	  OF	  AT	  LEAST	  2	  WEEKS	  OF	  HAVING	  THESE	  BELIEFS	  OR	  EXPERIENCES	  
(PSYCHOTIC	  SYMPTOMS)	  WHEN	  THEY	  WERE	  NOT	  DEPRESSED/HIGH/IRRITABLE,	  CODE	  NO	  TO	  THIS	  DISORDER.	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  IF	  THE	  ANSWER	  IS	  NO	  TO	  THIS	  DISORDER	  GROUPING,	  ALSO	  CIRCLE	  NO	  TO	  K12	  AND	  MOVE	  TO	  K13	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
	  
MOOD	  DISORDER	  WITH	  
	  	  	  	  PSYCHOTIC	  FEATURES	  
	  
LIFETIME	  
	  
	  
	  
K12	   a	  
ARE	  1	  OR	  MORE	  «	  b	  »	  QUESTIONS	  FROM	  K1b	  TO	  K7b	  CODED	  YES	  AND	  IS	  EITHER:	  
	  
	  
	  
	  
	  
MAJOR	  DEPRESSIVE	  EPISODE	  (CURRENT)	  
	  
	  
	  
OR	  
	  
	  
	  	  
MANIC	  OR	  HYPOMANIC	  EPISODE	  (CURRENT)	  CODED	  YES?	  
	  
	  	  	  IF	  THE	  ANSWER	  IS	  YES	  TO	  THIS	  DISORDER	  (LIFETIME	  OR	  CURRENT),	  CIRCLE	  NO	  TO	  K13	  AND	  K14	  AND	  	  	  
MOVE	  TO	  THE	  NEXT	  MODULE.	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
	  
MOOD	  DISORDER	  WITH	  
	  	  	  	  PSYCHOTIC	  FEATURES	  
	  
CURRENT	  
 
	  
	  
K13	   	  	  	  	  ARE	  1	  OR	  MORE	  «	  b	  »	  QUESTIONS	  FROM	  K1b	  TO	  K8b,	  CODED	  YES?	  
	  
	  	  	  AND	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  ARE	  2	  OR	  MORE	  «	  b	  »	  QUESTIONS	  FROM	  K1b	  TO	  K10b,	  CODED	  YES?	  
	  
	  
	  
	  	  AND	  DID	  AT	  LEAST	  TWO	  OF	  THE	  PSYCHOTIC	  SYMPTOMS	  OCCUR	  DURING	  THE	  SAME	  1-­‐MONTH	  PERIOD?	  
	  
AND	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	        
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
PSYCHOTIC	  DISORDER	  
CURRENT	  
	  
	  
	  
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K14	   	  	  	  	  IS	  K13	  CODED	  YES	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  OR	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  (ARE	  1	  OR	  MORE	  «	  a	  »	  QUESTIONS	  FROM	  K1a	  TO	  K8a,	  CODED	  YES?	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  AND	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  ARE	  2	  OR	  MORE	  «	  a	  »	  QUESTIONS	  FROM	  K1a	  TO	  K10a,	  CODED	  YES	  
	  
	  
	            
	  	  	  	  	  	  	  	  	  	  	  	  	  	  AND	  DID	  AT	  LEAST	  TWO	  OF	  THE	  PSYCHOTIC	  SYMPTOMS	  OCCUR	  DURING	  THE	  SAME	  1-­‐MONTH	  PERIOD?)	  
	  
	  AND	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	    
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
	  
	  
PSYCHOTIC	  DISORDER	  
LIFETIME	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
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L.  ANOREXIA	  NERVOSA  
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO,	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE) 
 
L1	  
a	   How	  tall	  are	  you? 
☐ft ☐☐in. 
 
 
 
☐ ☐ ☐cm          
 
b.	  	  What	  was	  your	  lowest	  weight	  in	  the	  past	  3	  months? 
☐ ☐ ☐lb 
   
☐ ☐ ☐kg 
 
 
 
 
➨ 
 
 
 
c	  
IS	  PATIENT’S	  WEIGHT	  EQUAL	  TO	  OR	  BELOW	  THE	  THRESHOLD	  CORRESPONDING	  TO	  
NO	  
YES	  
	  
	  
	  
	  
HIS	  /	  HER	  HEIGHT?	  	  (SEE	  TABLE	  BELOW) 
 
 
 
 
 
 
 
 
In	  the	  past	  3	  months:	  
	  
	  
	  
➨ 
L2	  
	  
In	  spite	  of	  this	  low	  weight,	  have	  you	  tried	  not	  to	  gain	  weight	  or	  to	  restrict	  your	  food	  intake?	  
NO	  
YES	  
	  
 
 
 
➨ 
L3	  
	  
Have	  you	  intensely	  feared	  gaining	  weight	  or	  becoming	  fat,	  even	  though	  you	  were	  underweight?	   NO	  
YES	  
	  
 
L4	  
a	   Have	  you	  considered	  yourself	  too	  big	  /	  fat	  or	  that	  part	  of	  your	  body	  was	  too	  big	  /	  fat?	  
NO	  
YES	  
	  
	  
	  
b	   Has	  your	  body	  weight	  or	  shape	  greatly	  influenced	  how	  you	  felt	  about	  yourself?	  
NO	  
YES	  
	  
	  
	  
c	   Have	  you	  thought	  that	  your	  current	  low	  body	  weight	  was	  normal	  or	  excessive?	  
NO	  
YES	  
	  
 
 
 
➨ 
L5	  
	  
ARE	  1	  OR	  MORE	  ITEMS	  FROM	  L4	  CODED	  YES?	  
NO	  
YES	  
 
 
 
 
	  
	  
	  	  	  	  	  	  	  	   IS	  L5	  CODED	  YES?	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
ANOREXIA	  NERVOSA	  
CURRENT	  
	  
HEIGHT	  /	  WEIGHT	  TABLE	  CORRESPONDING	  TO	  A	  BMI	  THRESHOLD	  OF	  17.0	  KG/M2	  	  
	  
Height/Weight	  
ft/in	  
4'9	  
4'10	  
4'11	  
5'0	  
5'1	  
5'2	  
5'3	  
5'4	  
5'5	  
5'6	  
5'7	  
5'8	  
5'9	  
5'10	  
lb	  
79	  
82	  
84	  
87	  
90	  
93	  
96	  
99	  
102	  
106	  
109	  
112	  
115	  
119	  
cm	  
145	  
147	  
150	  
152	  
155	  
158	  
160	  
163	  
165	  
168	  
170	  
173	  
175	  
178	  
kg	  
36	  
37	  
38.5	  
39.5	  
41	  
42.5	  
43.5	  
45.5	  
46.5	  
48	  
49	  
51	  
52	  
54	  
	  
	  
	  
	  
	  
Height/Weight	  
	  
ft/in	  
5'11	  
6'0	  
6'1	  
6'2	  
6'3	  
lb	  
122	  
125	  
129	  
133	  
136	  
	  
cm	  
180	  
183	  
185	  
188	  
191	  
	  
kg	  
55	  
57	  
58.5	  
60	  
62	  
The	  weight	  thresholds	  above	  are	  calculated	  using	  a	  body	  mass	  index	  (BMI)	  equal	  to	  or	  below	  17.0	  kg/m2	  for	  the	  patient's	  height	  using	  the	  Center	  
of	  Disease	  Control	  &	  Prevention	  BMI	  Calculator.	  	  This	  is	  the	  threshold	  guideline	  below	  which	  a	  person	  is	  deemed	  underweight	  by	  the	  DSM-­‐5	  for	  
Anorexia	  Nervosa.	  
SAMPLE
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
28 
M.	  	  BULIMIA	  NERVOSA	  
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOXES,	  CIRCLE	  NO	  IN	  ALL	  DIAGNOSTIC	  BOXES,	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
 
 
 
 
 
M1	   	  
In	  the	  past	  three	  months,	  did	  you	  have	  eating	  binges	  or	  times	  when	  you	  ate	  	  
NO	  
YES	  
 
 
a	  very	  large	  amount	  of	  food	  within	  a	  2-­‐hour	  period?	  
  9	  	  M3	  
 
 
 
 
 
M2	   	  
During	  these	  binges,	  did	  you	  feel	  that	  your	  eating	  was	  out	  of	  control?	  
NO	  
YES	  
 
 
 
 
 
 
 
 
➨ 
M3	   	  
Did	  you	  do	  anything	  to	  compensate	  for,	  or	  to	  prevent	  a	  weight	  gain,	  
NO	  
YES	  
	  
	  
	  
like	  vomiting,	  fasting,	  exercising	  or	  taking	  laxatives,	  enemas,	  diuretics	  	  
	  
	  
(fluid	  pills),	  or	  other	  medications?	  Did	  you	  do	  this	  as	  often	  as	  once	  a	  week?	  
	  
	  
	  
CODE	  YES	  TO	  M3	  ONLY	  IF	  THE	  ANSWER	  TO	  BOTH	  THESE	  M3	  QUESTIONS	  IS	  YES.	  
	  
M3a	  
Number	  of	  Episodes	  of	  Inappropriate	  Compensatory	  Behaviors	  per	  Week?	  ______	  
	  
Number	  of	  Days	  of	  Inappropriate	  Compensatory	  Behaviors	  per	  Week?	  	  	  	  	  	  	  	  ______	  
	  
 
 
 
➨ 
M4	   	  
In	  the	  last	  3	  months,	  did	  you	  have	  eating	  binges	  as	  often	  as	  once	  a	  week?	  
NO	  
YES	  
	  
 
 
 
	  
	  
	  
 
 
 
➨ 
M5	   	  
Does	  your	  body	  weight	  or	  shape	  greatly	  influence	  how	  you	  feel	  about	  yourself?	  
NO	  
YES	  
	  
 
M6	   	  
DO	  THE	  PATIENT’S	  SYMPTOMS	  MEET	  CRITERIA	  FOR	  ANOREXIA	  NERVOSA?	  
NO	  
YES	  
	  
 
 
 
↓ 
 
 
 
Skip	  to	  M8	  
	  
	  
M7	   	  
Do	  these	  binges	  occur	  only	  when	  you	  are	  under	  (______lb/kg)?	  
NO	  
YES	  
	  
	  
	  
INTERVIEWER:	  WRITE	  IN	  THE	  ABOVE	  PARENTHESIS	  THE	  THRESHOLD	  WEIGHT	  FOR	  THIS	  PATIENT’S	  	  
	  
	  
HEIGHT	  FROM	  THE	  HEIGHT	  /	  WEIGHT	  TABLE	  IN	  THE	  ANOREXIA	  NERVOSA	  MODULE.	  	  
	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  M8	  	  	  	  	  	  	  IS	  M5	  CODED	  YES	  AND	  IS	  EITHER	  M6	  OR	  M7	  CODED	  NO?	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
BULIMIA	  NERVOSA	  
CURRENT	  
	  
	  
	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  IS	  M7	  CODED	  YES?	  
	  
	  	  	  	  	  	  	  	  
	  
	  
	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
ANOREXIA	  NERVOSA	  
Binge	  Eating/Purging	  Type	  
CURRENT	  
	  
	  
SAMPLE
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29 
	  
	  
DO	  THE	  PATIENT’S	  SYMPTOMS	  MEET	  CRITERIA	  FOR	  ANOREXIA	  NERVOSA?	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  AND	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  ARE	  M2	  AND	  M3	  CODED	  NO?	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
ANOREXIA	  NERVOSA	  
Restricting	  Type	  
CURRENT	  
	  
	  
	  
	  
	  	  	  	  	  SPECIFIERS	  OF	  EATING	  DISORDER:	  
	  
	  
MILD	  =	  1-­‐3	  EPISODES	  OF	  INAPPROPRIATE	  COMPENSATORY	  BEHAVIORS	  	  
MODERATE	  =	  4-­‐7	  EPISODES	  OF	  INAPPROPRIATE	  COMPENSATORY	  BEHAVIORS	  
SEVERE	  =	  8-­‐13	  EPISODES	  OF	  INAPPROPRIATE	  COMPENSATORY	  BEHAVIORS	  
EXTREME	  =	  14	  OR	  MORE	  EPISODES	  OF	  INAPPROPRIATE	  COMPENSATORY	  BEHAVIORS	  
	  
	  	  	  	  	  	  
	  	  SPECIFY	  IF:	  
	  
	  	  	  	  	  	  	  	  MILD           ☐  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  MODERATE      ☐   
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SEVERE	          ☐ 
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  EXTREME	        ☐ 
 
	  
MB.	  	  BINGE	  EATING	  DISORDER	  
	  
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO	  IN	  THE	  DIAGNOSTIC	  BOX,	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
 
 
 
 
 
 
 
 
 
➨	  
MB1	  	  
DO	  THE	  PATIENT’S	  SYMPTOMS	  MEET	  CRITERIA	  FOR	  ANOREXIA	  NERVOSA?	  
NO	  
YES	  
	  
 
 
 
 
➨	  
MB2	  	  
DO	  THE	  PATIENT’S	  SYMPTOMS	  MEET	  CRITERIA	  FOR	  BULIMIA	  NERVOSA?	  
NO	  
YES	  
	  
 
 
 
➨	  
MB3	  	  
M2	  IS	  CODED	  YES	  
NO	  
YES	  
 
 
 
 
 
 
 
 
 
➨ 
MB4	  	  
M3	  IS	  CODED	  YES	  
NO	  
YES	  
	  
	  
 
 
 
➨ 
MB5	  	  
M4	  IS	  CODED	  YES	  
NO	  
YES	  
	  
	  
 
 
In	  the	  last	  3	  months	  during	  the	  binging	  did	  you: 
 
 
 
 
 
MB6a	  
Eat	  more	  rapidly	  than	  normal?	  
NO	  
YES	  
	  
MB6b	  
Eat	  until	  you	  felt	  uncomfortably	  full?	  
NO	  
YES	  
	  
MB6c	  
Eat	  large	  amounts	  of	  food	  when	  you	  were	  not	  hungry?	  
NO	  
YES	  
	  
MB6d	  
Eat	  alone	  because	  you	  felt	  embarrassed	  about	  how	  much	  you	  were	  eating?	  
NO	  
YES	  
	  
MB6e	  
Feel	  guilty,	  depressed	  or	  disgusted	  with	  yourself	  after	  binging?	  
NO	  
YES	  
	  
	  
	  
	  
➨	  
ARE	  3	  OR	  MORE	  MB6	  QUESTIONS	  CODED	  YES?	  	  
NO	  
YES	  
	  
 
 
SAMPLE
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
30 
 
➨	  
MB7	  	  
Does	  your	  binging	  distress	  you	  a	  lot?	  
NO	  
YES 
 
	  
	  	  
MB8	  
Number	  of	  Binge	  Eating	  Episodes	  per	  Week?	  ______	  
	  
Number	  of	  Binge	  Eating	  Days	  per	  Week?	  	  	  	  	  	  	  	  ______	  
	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  
	  IS	  MB7	  CODED	  YES?	  	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
BINGE-­‐EATING	  DISORDER	  
	  
CURRENT	  
	  
	  
	  
	  
	  
	  	  	  	  	  SPECIFIERS	  OF	  EATING	  DISORDER:	  
	  
	  
MILD	  =	  1-­‐3	  EPISODES	  OF	  BINGE	  EATING	  PER	  WEEK	  	  
MODERATE	  =	  4-­‐7	  EPISODES	  OF	  BINGE	  EATING	  PER	  WEEK	  
SEVERE	  =	  8-­‐13	  EPISODES	  OF	  BINGE	  EATING	  PER	  WEEK	  
EXTREME	  =	  14	  OR	  MORE	  EPISODES	  OF	  BINGE	  EATING	  PER	  WEEK	  
	  
	  	  	  	  	  	  
	  	  SPECIFY	  IF:	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  MILD          ☐  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  MODERATE      ☐   
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  SEVERE	          ☐ 
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  EXTREME	        ☐ 
	  
SAMPLE
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
31 
N.	  	  GENERALIZED	  ANXIETY	  DISORDER	  
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX,	  CIRCLE	  NO,	  AND	  MOVE	  TO	  THE	  NEXT	  MODULE)	  
	  
 
 
 
➨ 
N1	  
a	   	  
Were	  you	  excessively	  anxious	  or	  worried	  about	  several	  routine	  things,	  
NO	  
YES	  
	  
	  
	  
	  
over	  the	  past	  6	  months?	  	  
	  
	  
	  
IN	  ENGLISH,	  IF	  THE	  PATIENT	  IS	  UNCLEAR	  ABOUT	  WHAT	  YOU	  MEAN,	  PROBE	  BY	  ASKING	  
	  
	  
	  
	  (Do	  others	  think	  that	  you	  are	  a	  worrier	  or	  a	  “worry	  wart”?)	  AND	  GET	  EXAMPLES. 
 
 
 
 
 
➨ 
	  
b	   	  
Are	  these	  anxieties	  and	  worries	  present	  most	  days?	  
NO	  
YES	  
 
 
 
 
 
 
➨ 
 
 
 
ARE	  THE	  PATIENT’S	  ANXIETY	  AND	  WORRIES	  RESTRICTED	  EXCLUSIVELY	  	  
NO	  
YES	  
	  
	  
	  
	  
TO,	  OR	  BETTER	  EXPLAINED	  BY,	  ANY	  DISORDER	  PRIOR	  TO	  THIS	  POINT?	  
	  
 
 
 
 
➨ 
N2	  
	  
	  
Do	  you	  find	  it	  difficult	  to	  control	  the	  worries?	  
NO	  
YES	  
	  
 
 
 
N3	  
	  
	  
FOR	  THE	  FOLLOWING,	  CODE	  NO	  IF	  THE	  SYMPTOMS	  ARE	  CONFINED	  TO	  	  
	  
	  
	  
FEATURES	  OF	  ANY	  DISORDER	  EXPLORED	  PRIOR	  TO	  THIS	  POINT.	  
	  
	  
	  
	  
	  
	  
	  
When	  you	  were	  anxious	  over	  the	  past	  6	  months,	  did	  you,	  most	  of	  the	  time:	  	  	  
	  
	  
	  
a	   Feel	  restless,	  keyed	  up	  or	  on	  edge?	  
NO	  
YES	  
	  
	  
	  
	  
b	   Have	  muscle	  tension?	  
NO	  
YES	  
	  
	  
	  
	  
c	   Feel	  tired,	  weak	  or	  exhausted	  easily?	  
NO	  
YES	  
	  
	  
	  
	  
d	   Have	  difficulty	  concentrating	  or	  find	  your	  mind	  going	  blank?	  
NO	  
YES	  
	  
	  
	  
	  
e	   Feel	  irritable?	  
NO	  
YES	  
	  
	  
	  
	  
f	   Have	  difficulty	  sleeping	  (difficulty	  falling	  asleep,	  waking	  up	  in	  the	  middle	  
NO	  
YES	  
	  
	  
	  
	  
of	  the	  night,	  early	  morning	  wakening	  or	  sleeping	  excessively)?	  
 
 
 
 
➨ 
	  
	  
	  
ARE	  3	  OR	  MORE	  N3	  ANSWERS	  CODED	  YES?	  
NO	  
YES	  
	  
 
 
N4	  	   	  
Do	  these	  anxieties	  and	  worries	  significantly	  disrupt	  your	  ability	  to	  work,	  	  
	  
	  
to	  function	  socially	  or	  in	  your	  relationships	  or	  in	  other	  important	  areas	  of 
           your	  life	  or	  cause	  you	  significant	  distress?	  
	  
AND	  IS	  “RULE	  OUT	  ORGANIC	  CAUSE	  (O2	  SUMMARY)”	  CODED	  YES?	  	  
 
                                           
	  	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
GENERALIZED	  ANXIETY	  
DISORDER	  
CURRENT 
	  
O.	  	  RULE	  OUT	  MEDICAL,	  ORGANIC	  OR	  DRUG	  CAUSES	  FOR	  ALL	  DISORDERS	  
	  
	  
IF	  THE	  PATIENT	  CODES	  POSITIVE	  FOR	  ANY	  CURRENT	  DISORDER	  ASK:	  
	  
Just	  before	  these	  symptoms	  began:	  
	  
	  
O1a	  
Were	  you	  taking	  any	  drugs	  or	  medicines	  or	  in	  withdrawal	  from	  any	  of	  these? 
❐ No      ❐ Yes	  
❐ Uncertain 
 
 
 
 
 
O1b	  
Did	  you	  have	  any	  medical	  illness? 
❐ No      ❐ Yes	  
❐ Uncertain 
 
 
 
 
 
O2 
IF	  O1a	  OR	  O1b	  IS	  CODED	  YES,	  IN	  THE	  CLINICIAN’S	  JUDGMENT	  IS	  EITHER	  LIKELY	  TO	  BE	  A	  DIRECT	  	  
	  
	  
CAUSE	  OF	  THE	  PATIENT'S	  DISORDER?	  	  IF	  NECESSARY,	  ASK	  ADDITIONAL	  OPEN-­‐ENDED	  QUESTIONS.	  
❐ No      ❐ Yes	  
❐ Uncertain	  
	  
	  
	  
O2	  SUMMARY:	  AN	  “ORGANIC”	  /	  MEDICAL	  /	  DRUG	  RELATED	  CAUSE	  BEEN	  RULED	  OUT 
 
❐ No      ❐ Yes      ❐ Uncertain	  
	  
IF	  O2	  IS	  YES,	  THEN	  O2	  SUMMARY	  IS	  NO.	  IF	  O2	  IS	  NO,	  THEN	  O2	  SUMMARY	  IS	  YES.	  OHTERWISE	  IT	  IS	  UNCERTAIN.	  	  
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P.	  ANTISOCIAL	  PERSONALITY	  DISORDER	  	  
 
(➨ MEANS:	  	  GO	  TO	  THE	  DIAGNOSTIC	  BOX	  AND	  CIRCLE	  NO) 
 
P1	  
	  
Before	  you	  were	  15	  years	  old,	  did	  you:	  
	  
	  
a	   	  repeatedly	  skip	  school	  or	  run	  away	  from	  home	  overnight	  or	  stayed	  out	  
NO	  
YES	  
	  
	  
	  
at	  night	  against	  your	  parent’s	  rules?	  
	  
	  
b	   	  repeatedly	  lie,	  cheat,	  "con"	  others,	  or	  steal	  or	  break	  into	  someone’s	  house	  or	  car?	  
NO	  
YES	  
	  
	  
	  
c	   	  start	  fights	  or	  bully,	  threaten,	  or	  intimidate	  others?	  
NO	  
YES	  
	  
	  
	  
d	   	  deliberately	  destroy	  things	  or	  start	  fires?	  
NO	  
YES	  
	  
	  
	  
e	   	  deliberately	  hurt	  animals	  or	  people?	  
NO	  
YES	  
	  
	  
	  
f	  
	  force	  someone	  into	  sexual	  activity?	  
NO	  
YES	  
	  
 
 
 
➨ 
 
 
ARE	  2	  OR	  MORE	  P1	  ANSWERS	  CODED	  YES?	  	  
NO	  
YES	  
	  
	  
	  
	  
DO	  NOT	  CODE	  YES	  TO	  THE	  BEHAVIORS	  BELOW	  IF	  THEY	  ARE	  EXCLUSIVELY	  POLITICALLY	  OR	  RELIGIOUSLY	  MOTIVATED.	  
	  
	  
	  
P2	  
	  
Since	  you	  were	  15	  years	  old,	  have	  you:	  
	  
	  
a	   done	  things	  that	  are	  illegal	  or	  would	  be	  grounds	  to	  get	  arrested,	  even	  if	  you	  didn't	  
NO	  
YES	  
	  
	  
	  
get	  caught	  (for	  example	  destroying	  property,	  shoplifting,	  stealing,	  selling	  drugs,	  	  
	  
	  
or	  committing	  a	  felony)?	  
	  
	  
b	   often	  lied	  or	  "conned"	  other	  people	  to	  get	  money	  or	  pleasure,	  or	  lied	  just	  	  
NO	  
YES	  
	  
	  
	  
for	  fun?	  
	  
	  
c	   been	  impulsive	  and	  didn’t	  care	  about	  planning	  ahead?	  
NO	  
YES	  
	  
	  
d	   been	  in	  physical	  fights	  repeatedly	  or	  assaulted	  others	  (including	  physical	  fights	  
NO	  
YES	  
	  
	  
	  
with	  your	  spouse	  or	  children)?	  
	  
	  
e	   exposed	  others	  or	  yourself	  to	  danger	  without	  caring?	  
NO	  
YES	  
	  
	  
f	  
repeatedly	  behaved	  in	  a	  way	  that	  others	  would	  consider	  irresponsible,	  like	  
NO	  
YES	  
	  
	  
	  
failing	  to	  pay	  for	  things	  you	  owed,	  deliberately	  being	  impulsive	  or	  deliberately	  
	  
	  
not	  working	  to	  support	  yourself?	  	  	  
	  
	  
g	   felt	  no	  guilt	  after	  hurting,	  mistreating,	  lying	  to,	  or	  stealing	  from	  others,	  or	  
NO	  
YES	  
	  
	  
	  
after	  damaging	  property?	  
	  
	  
	  
	  
	  
	  
ARE	  3	  OR	  MORE	  P2	  QUESTIONS	  CODED	  YES?	  
	  
	  
	  	  	  	  	  	  	  	  
	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	        
	  	  	  	  NO	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  YES	  
	  
ANTISOCIAL	  PERSONALITY	  
DISORDER	  
LIFETIME	  
	  
 
THIS	  CONCLUDES	  THE	  INTERVIEW  
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MOOD	  DISORDERS:	  DIAGNOSTIC	  ALGORITHM	  
	  
	  
Consult	  Modules:	  
A	  
Major	  Depressive	  Episode	  
	  
	  
C	  
(Hypo)manic	  Episode	  
	  
	  
K	  
Psychotic	  Disorders	  
	  
	  
	  
MODULE	  K:	  
	  
	  
1a	   	   IS	  K11b	  CODED	  YES?	  
NO	  
YES	  
	  
	  
1b	  
IS	  K12a	  CODED	  YES?	  
NO	  
YES	  
	  
	  
	  
	  
	  
	  
	  
MODULES	  A	  and	  C:	  
Current	  
Past	  
	  
2	  
a	   CIRCLE	  YES	  IF	  A	  DELUSIONAL	  IDEA	  IS	  IDENTIFIED	  IN	  A3e 
YES 
YES 
 
OR	  ANY	  PSYCHOTIC	  FEATURE	  IN	  K1	  THROUGH	  K7	  
 
	  	  	  	  	  	  	  	  	  b	  	  	  	  CIRCLE	  YES	  IF	  A	  DELUSIONAL	  IDEA	  IS	  IDENTIFIED	  IN	  C3a 
YES 
YES 
 
OR	  ANY	  PSYCHOTIC	  FEATURE	  IN	  K1	  THROUGH	  K7 
 
	  
	  	  	  	  	  	  
c	  	  	  	  Is	  Major	  Depressive	  Episode	  coded	  YES	  (current	  or	  past)?	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  is	  Manic	  Episode	  coded	  NO	  (current	  and	  past)?	  
and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  is	  Hypomanic	  Episode	  coded	  NO	  (current	  and	  past)?	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  is	  “Rule	  out	  Organic	  Cause	  (O2	  Summary)”	  coded	  YES?	  
	  
Specify:	  	  
• If	  the	  depressive	  episode	  is	  current	  or	  past	  or	  both	  
	  	  
• With	  Psychotic	  Features	  Current:	  If	  1b	  or	  2a	  (current)	  =	  YES	  	  
With	  Psychotic	  Features	  Past:	  If	  1a	  or	  2a	  (past)	  =	  YES	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
                   
	  
MAJOR	  DEPRESSIVE	  
DISORDER	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  current	  	  	  	  past	  
MDD 
❏        ❏ 
	  
With	  Psychotic	  Features	  
Current 
 ❏ 
Past  
 ❏ 
 
 
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d	  	  	  	  Is	  a	  Manic	  Episode	  coded	  YES	  (current	  or	  past)?	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
	  	  	  Specify:	  
	  
• If	  the	  Bipolar	  I	  Disorder	  is	  current	  or	  past	  or	  both	  
	  
• With	  Single	  Manic	  Episode:	  If	  Manic	  episode	  (current	  or	  past)	  	  =	  YES	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  MDE	  (current	  and	  past)	  =	  NO	  
	  
• With	  Psychotic	  Features	  Current:	  If	  1b	  or	  2a	  (current)	  or	  2b	  (current)	  =	  YES	  	  
With	  Psychotic	  Features	  Past:	  If	  1a	  or	  2a	  (past)	  or	  2b	  (past)	  =	  YES	  	  
	  
• If	  the	  most	  recent	  episode	  is	  manic,	  depressed,	  	  
	  or	  hypomanic	  or	  unspecified	  (all	  mutually	  exclusive)	  
	  
• Most	  Recent	  Episode	  Unspecified	  if	  the	  Past	  Manic	  Episode	  is	  coded	  YES	  	  
	  
AND	  
	  	  
(If	  any	  current	  C3	  symptoms	  are	  coded	  YES	  and	  current	  C3	  Summary	  is	  coded	  NO)	  
	  
OR	  
	  
(If	  current	  C3	  Summary	  is	  coded	  YES	  
AND	  
If	  current	  Manic	  Episode	  diagnostic	  box	  is	  coded	  NO	  current)	  
	  
BIPOLAR	  I	  
DISORDER	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  current	  	  	  past	  
Bipolar	  I	  Disorder 
❏     ❏ 
Single	  Manic	  Episode ❏     ❏ 
	  
With	  Psychotic	  Features	  
Current 
 ❏ 
Past  
 ❏ 
 
Most	  Recent	  Episode	  
Manic 
 ❏ 
Depressed   
 ❏ 
Hypomanic 
 ❏ 
Unspecified 
 ❏ 
 
Most	  Recent	  Episode	  
Mild 
 ❏ 
Moderate   
 ❏ 
Severe 
 ❏ 
 
 
	  	  	  	  	  	  	  	  	  	  e	  	  	  	  	  	  Is	  Major	  Depressive	  Episode	  coded	  YES	  (current	  or	  past)	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  
	  	  	  Is	  Hypomanic	  Episode	  coded	  YES	  (current	  or	  past)	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Is	  Manic	  Episode	  coded	  NO	  (current	  and	  past)?	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Specify:	  
	  
• If	  the	  Bipolar	  Disorder	  is	  current	  or	  past	  or	  both	  
	  	  
• If	  the	  most	  recent	  mood	  episode	  is	  hypomanic	  or	  depressed	  (mutually	  exclusive)	  
	  
• Most	  Recent	  Episode	  Unspecified	  if	  the	  Past	  Manic	  /	  Hypomanic	  Episode	  is	  	  
coded	  YES	  	  
AND	  
	  	  
(If	  any	  current	  C3	  symptoms	  are	  coded	  YES	  and	  current	  C3	  Summary	  is	  coded	  NO)	  
	  
OR	  
	  
(If	  current	  C3	  Summary	  is	  coded	  YES	  
AND	  
If	  current	  Hypomanic	  Episode	  diagnostic	  box	  is	  coded	  NO	  current)	  
	  
 
 
BIPOLAR	  II	  
DISORDER	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  current	  	  	  past	  
Bipolar	  II	  Disorder 
❏     ❏ 
 
Most	  Recent	  Episode	  
 
Hypomanic 
❏ 
Depressed	    
❏ 
Hypomanic 
 ❏ 
Unspecified 
 ❏ 
 
Most	  Recent	  Episode	  
Mild 
 ❏ 
Moderate   
 ❏ 
Severe 
 ❏ 
 
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f	  	  	  	  	  	  	  Is	  MDE	  coded	  NO	  (current	  and	  past)	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  
	  	  Is	  Manic	  Episode	  coded	  NO	  (current	  and	  past)	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Is	  C4b	  coded	  YES	  for	  the	  appropriate	  time	  frame	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  	  
Is	  C8b	  coded	  YES?	  
___________________________________________________	  	  	  	  	  	  
	  
or	  
___________________________________________________	  
	  
Is	  Manic	  Episode	  coded	  NO	  (current	  and	  past)	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  
	  	  Is	  Hypomanic	  Episode	  coded	  NO	  (current	  and	  past)	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Is	  C4a	  coded	  YES	  for	  the	  appropriate	  time	  frame	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  and	  	  
Is	  C8c	  coded	  YES?	  
	  
Specify	  if	  the	  Bipolar	  Disorder	  Unspecified	  is	  current	  or	  past	  or	  both.   
	  
BIPOLAR	  	  
DISORDER	  UNSPECIFIED	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  current	  	  	  	  past	  
	  
Bipolar	  Disorder 
❏      ❏ 
Unspecified	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
SAMPLE
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OPTIONAL	  ASSESSMENT	  MEASURES	  TO	  TRACK	  CHANGES	  OVER	  TIME	  
	  
	  
A:	  CROSS	  CUTTING	  MEASURES	  
	  
 
	  
SEVERITY	  OF	  SYMPTOM	  
 
Use	  this	  scale	  to	  rate	  the	  severity	  of	  your	  symptom	  in	  the	  score	  column	  in	  the	  table	  below:	  
	  
	  
	  
	  
	  
	  
 
 
Assessment	  of	  Symptoms	  That	  Cut	  Across	  Disorders	  	  
 
 
	  	  
Symptom	  Name	  
Score	  
1	  
Depression	  
	  	  
2	  
Anger	  
	  	  
3	  
Mania	  (feeling	  up	  or	  high	  or	  hyper	  or	  full	  of	  energy	  with	  racing	  thoughts)	  	  
	  	  
4	  
Anxiety	  
	  	  
5	  
Physical	  (somatic)	  symptoms	  
	  	  
6	  
Suicidal	  thoughts	  (having	  ANY	  thoughts	  of	  killing	  yourself)	  
	  	  
7	  
Hearing	  sounds	  or	  voices	  others	  can’t	  hear	  or	  fearing	  someone	  can	  hear	  or	  read	  
your	  thoughts	  or	  believing	  things	  others	  don’t	  accept	  as	  true	  e.g.	  that	  people	  
are	  spying	  on	  you	  or	  plotting	  against	  you	  or	  talking	  about	  you	  (Psychosis)	  
	  	  
8	  
Sleep	  problems	  
	  	  
9	  
Memory	  problems	  
	  	  
10	  
Repetitive	  thoughts	  or	  behaviors	  
	  	  
11	  
Feeling	  things	  around	  you	  are	  strange,	  unreal,	  detached	  or	  unfamiliar,	  or	  
feeling	  outside	  or	  detached	  from	  part	  or	  all	  of	  your	  body	  (Dissociation)	  
	  	  
12	  
Ability	  to	  function	  at	  work,	  at	  home,	  in	  your	  life,	  or	  in	  your	  relationships	  
(Personality	  functioning)	  
	  	  
13	  
Overusing	  alcohol	  or	  drugs	  
	  	  
 
 
 
 
 
 
 
 
Severe 
Moderate 
Extreme 
Mild 
Not present 
0
1
2
3
4
5
6
7
8
9
10
y
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B:	  DISABILITY	  /	  FUNCTIONAL	  IMPAIRMENT	  
 
 
	  
SEVERITY	  OF	  DISABILITY	  /	  IMPAIRMENT	  	  
 
Use	  this	  scale	  to	  rate	  in	  the	  score	  column	  of	  the	  table	  below,	  how	  much	  your	  symptoms	  	  
have	  disrupted	  your	  ability	  to	  function	  in	  the	  following	  areas	  of	  your	  life:	  
	  
	  
	  
	  
	  
	  
	  
	  
Assessment	  of	  Impairment	  of	  Functioning	  /Disability	  
 
	  	  
Domain	  Name	  
Score	  
1	  
Work	  or	  school	  work	  	  
	  	  
2	  
Social	  life	  or	  leisure	  activities	  (like	  hobbies	  or	  things	  you	  do	  for	  enjoyment)	  
	  	  
3	  
Family	  life	  and	  /	  or	  home	  responsibilities	  	  
	  	  
4	  
Ability	  to	  get	  along	  with	  people	  
	  	  
5	  
Personal	  and	  social	  relationships	  
	  
6	  
Ability	  to	  understand	  and	  to	  communicate	  with	  others	  
	  
7	  
Ability	  to	  take	  care	  of	  yourself	  (washing,	  showering,	  bathing,	  dressing	  properly,	  
brushing	  teeth,	  laundry,	  combing	  /	  brushing	  hair,	  eating	  regularly)	  
	  	  
8	  
Made	  you	  disruptive	  or	  aggressive	  towards	  others	  
	  	  
9	  
Financially	  (ability	  to	  manage	  your	  money)	  
	  	  
10	  
Ability	  to	  get	  around	  physically	  
	  
11	  
Spiritual	  or	  religious	  life	  
	  	  
12	  
How	  much	  did	  your	  condition	  have	  an	  impact	  on	  other	  people	  in	  your	  family?	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
Severe 
Moderate 
Extreme 
Mild 
Not present 
0
1
2
3
4
5
6
7
8
9
10
y
SAMPLE
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REFERENCES	  
	  
1.	   Sheehan	   DV,	   Lecrubier	   Y,	   Harnett-­‐Sheehan	   K,	   Amorim	   P,	   Janavs	   J,	   Weiller	   E,	   Hergueta	   T,	   Baker	   R,	   Dunbar	   G:	   The	   Mini	  
International	   Neuropsychiatric	   Interview	   (M.I.N.I.):	   The	   Development	   and	   Validation	   of	   a	   Structured	   Diagnostic	   Psychiatric	  
Interview.	  J.	  Clin	  Psychiatry,	  1998;59(suppl	  20):	  22-­‐33.	  
	  
2.	  Sheehan	  DV,	  Lecrubier	  Y,	  Harnett-­‐Sheehan	  K,	  Janavs	  J,	  Weiller	  E,	  Bonara	  LI,	  Keskiner	  A,	  Schinka	  J,	  Knapp	  E,	  Sheehan	  MF,	  Dunbar	  
GC.	   	   Reliability	   and	   Validity	   of	   the	   MINI	   International	   Neuropsychiatric	   Interview	   (M.I.N.I.):	   According	   to	   the	   SCID-­‐P.	   	   European	  
Psychiatry.	  1997;	  12:232-­‐241.	  	  
	  
3.	  Lecrubier	  Y,	  Sheehan	  D,	  Weiller	  E,	  Amorim	  P,	  Bonora	  I,	  Sheehan	  K,	  Janavs	  J,	  Dunbar	  G.	  	  The	  MINI	  International	  Neuropsychiatric	  
Interview	   (M.I.N.I.)	   A	   Short	   Diagnostic	   Structured	   Interview:	   Reliability	   and	   Validity	   According	   to	   the	   CIDI.	   European	   Psychiatry.	  	  
1997;	  12:	  224-­‐231.	  
	  
4.	   Amorim	   P,	   Lecrubier	   Y,	   Weiller	   E,	   Hergueta	   T,	   Sheehan	   D:	   DSM-­‐III-­‐R	   Psychotic	   Disorders:	   procedural	   validity	   of	   the	   Mini	  
International	  Neuropsychiatric	  Interview	  (M.I.N.I.).	  	  Concordance	  and	  causes	  for	  discordance	  with	  the	  CIDI.	  	  European	  Psychiatry.	  	  
1998;	  13:26-­‐34.	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
ACKNOWLEDGEMENTS	  
	  
	  
The	  author	  wishes	  to	  acknowledge	  the	  valuable	  contributions	  made	  to	  the	  earlier	  versions	  of	  the	  MINI	  for	  DSM	  III-­‐R	  and	  DSM	  IV	  by:	  	  
1.	  Yves	  Lecrubier,	  my	  close	  collaborator	  (now	  deceased)	  on	  the	  initial	  development	  of	  the	  MINI	  for	  DSM	  III-­‐R,	  the	  DSM	  IV	  and	  ICD-­‐
10.	  
2.	  Juris	  Janavs,	  Emanuelle	  Weiller,	  Christer	  Allgulander,	  Kathy	  Harnett-­‐Sheehan,	  Roxy	  Baker,	  Michael	  Sheehan,	  Chris	  Gray,	  Thierry	  
Hergueta,	  N.	  Kadri,	  David	  Baldwin,	  Christian	  Even,	  Rosario	  Hidalgo,	  Marelli	  Soto-­‐Colon,	  Ossama	  Osman.	  
3.	  Patricia	  Amorim	  for	  her	  extensive	  work	  on	  the	  development	  of	  the	  expanded	  version	  of	  the	  Psychotic	  Disorders	  Module	  and	  
algorithms	  for	  DSM	  III-­‐R.	  	  We	  have	  evolved	  her	  model	  further	  in	  the	  MINI	  for	  Psychotic	  Disorders	  7	  and	  in	  the	  MINI	  Plus	  7	  for	  
DSM-­‐5.	  
4.	  Executive	  Scientific	  committee	  for	  the	  MINI	  6.0.0:	  
Christer	  Allgulander,	  Stockholm,	  Sweden	  
A.	  Carlo	  Altamura,	  Milano,	  Italy	  
Cyril	  Hoschl,	  Praha,	  Czech	  Republic	  
George	  Papadimitriou,	  Athens,	  Greece	  
Hans	  Ågren,	  Göteborg,	  Sweden	  
Hans-­‐Jürgen	  Möller,	  München,	  Germany	  
Hans-­‐Ulrich	  Wittchen,	  Dresden,	  Germany	  
István	  Bitter,	  Budapest,	  Hungary	  
Jean-­‐Pierre	  Lépine,	  Paris,	  France	  
Jules	  Angst,	  Zurich,	  Switzerland	  
Julio	  Bobes,	  Oviedo,	  Spain	  
Luciano	  Conti,	  Pisa,	  Italy	  
Marelli	  Colon-­‐Soto	  MD,	  Puerto	  Rico,	  United	  States	  
Michael	  Van	  Ameringen	  MD,	  Toronto,	  Canada	  
Rosario	  Hidalgo	  MD,	  Tampa,	  United	  States	  
Siegfried	  Kasper,	  Vienna,	  Austria	  
Thomas	  Schlaepfer,	  Bonn,	  Germany	  
5.	  Mapi	  and	  the	  many	  academic	  translation	  teams	  internationally	  who	  collaborated	  in	  ensuring	  that	  quality	  translations	  became	  
available	  in	  over	  70	  languages	  or	  language	  variants.	  Mapi	  (http://www.mapigroup.com)	  is	  now	  the	  official	  translation	  and	  
linguistic	  validation	  service	  for	  all	  variants	  of	  the	  MINI.	  
6.	  Individual	  clinicians	  and	  patients	  who	  over	  the	  years	  made	  countless	  suggestions	  to	  help	  improve	  the	  accuracy	  and	  clinical	  value	  
to	  the	  MINI:	  JM	  Giddens	  for	  her	  advice	  on	  the	  MINI	  	  7	  version	  of	  the	  Suicidality	  Module,	  Dr.	  Michael	  Van	  Ameringen	  for	  
assistance	  with	  the	  ADHD	  module,	  and	  Dr	  P	  Powers	  for	  her	  advice	  on	  the	  modules	  on	  Anorexia	  Nervosa	  and	  Bulimia.	  	  	  
7.	   A	   validation	   study	   of	   this	   instrument	   was	   made	   possible,	   in	   part,	   by	   grants	   from	   SmithKlineBeecham	   and	   the	   European	  
Commission.	  
	  
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39 
	  
M.I.N.I.	  PLUS	  
	  
The	  shaded	  modules	  below	  are	  additional	  modules	  available	  in	  the	  MINI	  PLUS	  beyond	  what	  is	  available	  in	  the	  standard	  MINI.	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	      
The	  un-­‐shaded	  modules	  below	  are	  in	  the	  standard	  MINI.	  	  
	  
These	  MINI	  PLUS	  modules	  can	  be	  inserted	  into	  or	  used	  in	  place	  of	  the	  standard	  MINI	  modules,	  as	  dictated	  by	  the	  
specific	  needs	  of	  any	  study.	  
	  
	  
	  
	  
MODULES	  
TIME	  FRAME	  
	  
 
A	  
MAJOR	  DEPRESSIVE	  EPISODE	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
	  
Past	  
	  
	  
 
 
 
Recurrent	  
	  
	  
	  
	  
	  
MAJOR	  DEPRESSIVE	  DISORDER	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
Past	  
	  
	  
	  
	  
	  
Recurrent	  
	  
	  
	  
	  
	  
	  
MDE	  WITH	  MELANCHOLIC	  FEATURES	  	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
MDE	  WITH	  CATATONIC	  FEATURES	  	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
MDE	  WITH	  ATYPICAL	  FEATURES	  	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
	  
MAJOR	  DEPRESSIVE	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES	  	  
Current	  
	  
	  
	  
	  
	  
Past	  
	  
	  
	  
 
	  
MINOR	  DEPRESSIVE	  DISORDER	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
(DEPRESSIVE	  DISORDER	  UNSPECIFIED)	  
Past	  
	  
	  
 
 
 
Recurrent	  
	  
	  
 
	  
 
 
MOOD	  DISORDER	  DUE	  TO	  A	  GENERAL	  MEDICAL	  CONDITION	  	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
	  
Past	  
	  
	  
	  
	  
	  
SUBSTANCE	  INDUCED	  MOOD	  DISORDER	  	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
	  
Past	  
	  
	  
	  
AY	  
DYSTHYMIA	  
Current	  
	  
	  
	  
 
B	  
SUICIDALITY	  
Current	  (Past	  Month)	   	  
❐  
 
	  
	  
Lifetime	  attempt	  
	  
❐  
❐	  Low	  	  	  ❐	  Moderate	  	  ❐	  High	  
	  
SUICIDE	  BEHAVIOR	  DISORDER	  
Current	  	  
	  
❐   
(In	  Past	  Year) 
 
 
In	  early	  remission	  
	  
❐    
(1	  -­‐	  2	  Years	  Ago)	  
 
C	  
MANIC	  EPISODE	  
Current	  
	  
	  
	  
	  
	  
 
 
 
 
Past	  
	  
	  
 
HYPOMANIC	  EPISODE	  
Current	  
	  
	  
	  
	  
	  
 
 
 
 
Past	  
	  
	  
 
 
 
BIPOLAR	  I	  DISORDER	  
Current	  
	  
 
 
 
Past	  
	  
 
 
 
 
BIPOLAR	  II	  DISORDER	  
Current	  
	  
 
 
 
Past	  
	  
 
 
 
 
BIPOLAR	  DISORDER	  UNSPECIFIED	  
Current	  
	  
 
 
 
Past	  
	  
	  
	  
	  
	  
BIPOLAR	  I	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES	  
Current	  
	  
	  
	  
	  
Past	  
	  
	  
 
 
 
MANIC	  EPISODE	  DUE	  TO	  A	  GENERAL	  MEDICAL	  CONDITION	  	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
Past	  
	  
	  
 
 
 
HYPOMANIC	  EPISODE	  DUE	  TO	  A	  GENERAL	  MEDICAL	  CONDITION	  	   Current	  (2	  weeks)	  
	  
	  
	  
	  
Past	  
	  
	  
 
 
 
SUBSTANCE	  INDUCED	  MANIC	  EPISODE	  
Current	  (2	  weeks)	  
	  
	  
SAMPLE
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40 
	  
	  
Past	  
	  
	  
 
 
	  
SUBSTANCE	  INDUCED	  HYPOMANIC	  EPISODE	  
Current	  (2	  weeks)	  
	  
	  
	  
	  
Past	  
	  
	  
	  
	  
	  
MOOD	  DISORDER	  UNSPECIFIED	  
Lifetime	  	  
	  
	  
	  
D	  
PANIC	  DISORDER	  
Current	  (Past	  Month)	   	  
 
 
 
Lifetime	  
	  
	  
 
	  
	  
ANXIETY	  DISORDER	  WITH	  PANIC	  ATTACKS	  DUE	  TO	  
	  
	  
A	  GENERAL	  MEDICAL	  CONDITION	  
Current	  
	  
	  
	  
	  
	  
SUBSTANCE	  INDUCED	  ANXIETY	  DISORDER	  WITH	  PANIC	  ATTACKS	   Current	  
	  
	  
 
E	  
AGORAPHOBIA	  
Current	  
	  
 
	  
F	  
SOCIAL	  ANXIETY	  DISORDER	  (Social	  Phobia)	  
Current	  (Past	  Month)	  
	  
	  
Generalized	  
	  
 
 
 
Non-­‐Generalized	  
	  
 
 
FA	   SPECIFIC	  PHOBIA	  
Current	  
	  
 
	  
G	  
OBSESSIVE-­‐COMPULSIVE	  DISORDER	  (OCD)	  
Current	  (Past	  Month)	   	  
	  
	  
	  
OCD	  DUE	  TO	  A	  GENERAL	  MEDICAL	  CONDITION	  	  
Current	  	  
	  
	  
	  
	  
	  
	  
SUBSTANCE	  INDUCED	  OCD	  
Current	  
	  
	  
	  
	  
	  
H	  
POSTTRAUMATIC	  STRESS	  DISORDER	  
Current	  (Past	  Month)	   	  
	  
HL	   POSTTRAUMATIC	  STRESS	  DISORDER	  
Lifetime	  
	  
	  
 
 
I	  
ALCOHOL	  USE	  DISORDER	  
Past	  12	  Months	  
	  
	  
	  
IL	  
ALCOHOL	  USE	  DISORDER	  
Lifetime	  	  
	  
	  
 
J	  
SUBSTANCE	  DEPENDENCE	  (Non-­‐alcohol)	  
Past	  12	  Months	  
	  
	  
	  
SUBSTANCE	  ABUSE	  (Non-­‐alcohol)	  
Past	  12	  Months	  
	  
	  
 
JL 
SUBSTANCE	  USE	  DISORDER	  (Non-­‐alcohol)	  
Lifetime	  
	  
	  
	  
K	  
PSYCHOTIC	  DISORDERS	  
Lifetime	  	  
	  
	  
	  
	  
Current	  
	  
	  
 
 
 
 
	  
 
MOOD	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES	  
Lifetime 
 
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
MOOD	  DISORDER	  WITH	  PSYCHOTIC	  FEATURES	  
Current 
 
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
SCHIZOPHRENIA	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
SCHIZOAFFECTIVE	  DISORDER	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
SCHIZOPHRENIFORM	  DISORDER	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
BRIEF	  PSYCHOTIC	  DISORDER	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
DELUSIONAL	  DISORDER	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
PSYCHOTIC	  DISORDER	  DUE	  TO	  A	  GENERAL	  MEDICAL	  CONDITION	  	   Current	  
	  
	  
	  
	  
Lifetime	  
	  
	  
	  
	  
SUBSTANCE	  INDUCED	  PSYCHOTIC	  DISORDER	  
Current	  
	  
	  
	  
	  
Lifetime	  
	  
	  
SAMPLE
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
41 
	  
	  
PSYCHOTIC	  DISORDER	  UNSPECIFIED	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
L	  
ANOREXIA	  NERVOSA	  
Current	  (Past	  3	  Months)	  
	  
ANOREXIA	  NERVOSA,	  BINGE	  EATING/PURGING	  TYPE	  
Current	  
	  
	  
	  
 
ANOREXIA	  NERVOSA,	  RESTRICTING	  TYPE	  
Current	  
	  
	  
M	  
BULIMIA	  NERVOSA	  
Current	  (Past	  3	  Months)	  
	  
	  
BULMIA	  NERVOSA,	  PURGING	  TYPE	  
Current	  
	  
	  
	  
	  
BULMIA	  NERVOSA,	  NON-­‐PURGING	  TYPE	  
Current	  
	  
 
 
 
	  
MB	   BINGE-­‐EATING	  DISORDER	  
Current	  (Past	  3	  Months)	  
	  
	  
	  
	  
N	  
GENERALIZED	  ANXIETY	  DISORDER	  (GAD)	  
Current	  (Past	  6	  Months)	  
	  
	  
 
GAD	  DUE	  TO	  A	  GENERAL	  MEDICAL	  CONDITION	  	  
Current	  
	  
	  
	  
SUBSTANCE	  INDUCED	  GAD	  
Current	  
	  
	  
	  
O	  
SOMATIZATION	  DISORDER	  
Current	  
	  
	  
	  
	  
Lifetime	  	  
	  
	  
	  
	  
	  
P	  
HYPOCHONDRIASIS	  
Current	  
	  
	  
	  
Q	  
BODY	  DYSMORPHIC	  DISORDER	  
Current	  
	  
	  
	  
R	  
PAIN	  DISORDER	  
Current	  
	  
	  
	  
S	  
CONDUCT	  DISORDER	  
Current	  (past	  12	  months)	   	  
	  
T	  
ATTENTION	  DEFICIT/	  HYPERACTIVITY	  DISORDER	  
Current	  (Past	  6	  months)	  (Children	  /Adolescents)	  
	  
	  
	  
ADHD	  COMBINED   
 
 
 
 
 
 
ADHD	  INATTENTIVE   
 
 
 
 
 
 
ADHD	  HYPERACTIVE	  /	  IMPULSIVE   
 
 
 
 
TA	   ATTENTION	  DEFICIT/	  HYPERACTIVITY	  DISORDER	  
Current	  (Past	  6	  months)	  (Adults)	  
 
 
 
ADHD	  COMBINED   
 
 
 
 
 
 
ADHD	  INATTENTIVE   
 
 
 
 
 
 
ADHD	  HYPERACTIVE	  /	  IMPULSIVE   
 
 
 
	  
U	  
PREMENSTRUAL	  DYSPHORIC	  DISORDER	  
Current	  
	  
	  
 
V	  
MIXED	  ANXIETY	  DEPRESSIVE	  DISORDER	  
Current	  
	  
	  
 
W	  	   ADJUSTMENT	  DISORDERS	  
Current	  
	  
 
 
X 
MEDICAL,	  ORGANIC,	  DRUG	  CAUSE	  RULED	  OUT	  
	  
	  
	  
	  
 
Y	  
ANTISOCIAL	  PERSONALITY	  DISORDER	  
Lifetime	  
	  
 
 
For	  Schizophrenia	  and	  psychotic	  disorder	  studies	  and	  for	  psychotic	  disorder	  subtyping	  in	  clinical	  settings,	  use	  the	  
MINI	  for	  Psychotic	  Disorders	  instead	  of	  the	  standard	  MINI.	  	  For	  many	  clinical	  settings	  this	  level	  of	  psychotic	  disorder	  
subtyping	  detail	  is	  not	  necessary.	  	  
For	  children	  and	  adolescents,	  use	  the	  MINI	  Kid	  or	  the	  MINI	  Kid	  Parent	  of	  the	  MIN	  Kid	  for	  Psychotic	  Disorders.	  	  
A	  computerized	  version	  of	  the	  MINI	  is	  available	  from	  Medical	  Outcomes	  Systems	  https://www.medical-­‐
outcomes.com	  
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M.I.N.I.	  7.0.0	  (January	  5,	  2015)	  (1/5/15)	  
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Page 109 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
4 
 
APPENDIX B. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
 
− Baseline/Screening 
− Since Last Visit 
Page 110 of 174


 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening 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 for use by trained clinicians. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidality depends on clinical judgment. 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
  
 
SAMPLE
Page 111 of 174
PPD
PPD


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 __ 
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 
□   □ 
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 ). For prior to study entry, ask about time he/she was feeling the most 
suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X 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 definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others.       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.                     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                         living with the pain or  how you were feeling). 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
 
 
____ 
 
Version 1/14/09 
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Page 112 of 174


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
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 
□   □ 
Yes     No 
□   □ 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
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 
 
______ 
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 
□   □ 
 
 
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). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
SAMPLE
Page 113 of 174


 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidality depends on clinical judgment. 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact 
  
SAMPLE
Page 114 of 174
PPD
PPD


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes,” 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it”.  
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the least severe 
and 5 being the most severe ).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others.       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.                     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                         living with the pain or  how you were feeling). 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
Version 1/14/09 
SAMPLE
Page 115 of 174


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Completed Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g. surface scratches). 
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes intact; third-degree burns less 
than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
SAMPLE
Page 116 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX C. CLINICAL OPIATE WITHDRAWAL SCALE 
Page 117 of 174


 
 
 
Clinical Opiate Withdrawal Scale (COWS)
Daily Assessments Days -5 to 11/Follow-up (Morning and Evening during Residential Days -2 to 7, Morning Only Day 8/8a)
For each item, write in the number that best describes the patient’s signs or symptoms. 
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 increased pulse 
rate would not add to the score. 
Subject ID: 
Date: 
Time: (eg,15:00) 
24-hour clock 
Resting Pulse Rate: (record beats per 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 
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 
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 
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 
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 
SAMPLE
Page 118 of 174


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 
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 
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 
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 
Anxiety or Irritability
0 none 
1 patient reports increasing irritability or anxiousness 
2 patient obviously irritable or anxious 
4 patient so irritable or anxious that participation in the 
assessment is difficult 
Gooseflesh skin
0 skin is smooth 
3 piloerection of skin can be felt or hairs standing up on arms 
5 prominent piloerection 
Total score :
The total score is the sum of all 11 items 
Rater Initials: 
Score:
5-12 = mild;
13-24 = moderate;
25-36 = moderately severe;
More than 36 = severe withdrawal
SAMPLE
Page 119 of 174


Clinical Opiate Withdrawal Scale (COWS) 
Clinical Testing Sessions (Days 1/1a-7) 
Note: Day 14 session is paired with VIVITROL injection and only extends 60 min postdose. 
For each item, write in the number that best describes the patient’s signs or symptoms. 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 increased pulse rate would not add 
to the score. 
Subject ID: 
Date: 
Predose 
30 Min 
Postdose 
60 Min 
Postdose 
90 Min 
Postdose 
120 Min 
Postdose 
150 Min 
Postdose 
180 Min 
Postdose 
Time: (eg,15:00) 
24-hour clock 
Resting Pulse Rate: (record beats per 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 
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 
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 
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 
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 
SAMPLE
Page 120 of 174


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 
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 
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 
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 
Anxiety or Irritability
0 none 
1 patient reports increasing irritability or anxiousness 
2 patient obviously irritable or anxious 
4 patient so irritable or anxious that participation in the 
assessment is difficult 
Gooseflesh skin
0 skin is smooth 
3 piloerection of skin can be felt or hairs standing up on arms 
5 prominent piloerection 
Total scores
The total score is the sum of all 11 items 
Rater Initials
Score:
5-12 = mild;
13-24 = moderate;
25-36 = moderately severe;
More than 36 = severe withdrawal
SAMPLE
Page 121 of 174


Clinical Opiate Withdrawal Scale (COWS) 
Day 8/8a – Naloxone Challenge/VIVITROL Injection
For each item, write in the number that best describes the patient’s signs or symptoms. 
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 increased pulse 
rate would not add to the score. 
Subject ID: 
Date: 
Challenge, 
Part 1 
Challenge, 
Part 2 
Predose 
10 Min 
Postdose 
Part 1 
20 Min 
Postdose 
Part 1 
10 Min 
Postdose 
Part 2 
20 Min 
Postdose 
Part 2 
1 Hour 
Postdose 
VIVITROL 
Times: (eg, 15:00) 
24-hour clock 
Resting Pulse Rate: (record beats per 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 
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 
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 
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 
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 
SAMPLE
Page 122 of 174


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 
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 
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 
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 
Anxiety or Irritability
0 none 
1 patient reports increasing irritability or anxiousness 
2 patient obviously irritable or anxious 
4 patient so irritable or anxious that participation in the 
assessment is difficult 
Gooseflesh skin
0 skin is smooth 
3 piloerection of skin can be felt or hairs standing up on 
arms 
5 prominent piloerection 
Total scores
The total score is the sum of all 11 items 
Rater Initials
Same rater as previous? (Y/N)
N/A 
Score:
5-12 = mild;
13-24 = moderate;
25-36 = moderately severe;
More than 36 = severe withdrawal
SAMPLE
Page 123 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
APPENDIX D. SUBJECTIVE OPIATE WITHDRAWAL SCALE 
Page 124 of 174


 
ALKERMES ALK6428-A302 
Subject Initials: 
Site No. / Subject ID No. 
Date of Assessment 
(DD/MMM/YYYY) 
Time Performed 
(24 hours) 
  
/  
/  
 
  
:   
 
 
 
SOWS 
 
Instructions:  Please complete a survey each evening. 
Answer the following s t a t e m e n t s as accurately a s  you can, circling the answer that b e s t fits 
the way you feel now. 
 
0 = not at  all 
1 = a little 
2 = moderately 
3 = quite  a bit 
4 = extremely 
 
 
Not at A 
Quite a 
1 
feel 
2 
feel like 
3 
I’m 
4 
My eyes are 
5 
My nose is 
6 
have goose 
7 
am 
8 
have hot 
9 
have cold 
10 My bones and muscles 
11 
feel 
12 
feel 
13 
feel like 
14 My muscles 
15 
have cramps in my 
16 
feel like 
up 
 
Page 125 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX E. DESIRE FOR OPIOIDS VISUAL ANALOGUE SCALE 
Page 126 of 174


Desire for Opioids VAS 
Instructions: Below is a question regarding your desire for opioids. We would like to know how 
strong your desire for opioids has been over the past 24 hours. Please place a vertical line ( l ) 
somewhere on the line between 0 and 100 to indicate how strong your desire for opioids has been over 
the past 24 hours.  
 
Correct:  
 
 
 
 
 
 
Incorrect: 
 
 
 
 
 
If you make a mistake, cross out your answer, initial and date it, and place a new vertical mark on the 
line. 
 
Please indicate how strong your desire for opioids has been over the past 24 hours below:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Your own 
desire for 
opioids 
0 
No Desire 
for Opioids 
100 
Strongest 
Imaginable 
Desire for 
Opioids 
             0 
   No desire for opioids 
 
             100  
     Worst imaginable  
     desire for opioids 
 X 
             0 
   No desire for opioids 
 
             100  
     Worst imaginable  
     desire for opioids 
SAMPLE
Page 127 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
APPENDIX F. SHORT MICHIGAN ALCOHOL SCREENING TEST 
Page 128 of 174


 
SHORT MICHIGAN ALCOHOL SCREENING TEST 
(SMAST) 
 
 
NAME: ______________________________ Date:___________________ 
 
 
The following questions concern information about your involvement with alcohol during 
the past 12 months. Carefully read each statement and decide if your answer is “YES” or 
“NO”. Then, circle the appropriate answer beside the question.  
 
Please answer every question. If you have difficulty with a statement, then choose the 
response that is mostly right. 
 
These questions refer to the past 12 months only. 
Please circle the appropriate answer. 
  
  
  
1.    Do you feel you are a normal drinker? (by normal we mean do you drink less 
       than or as much as most other people.) 
Yes No 
2.    Do your wife, husband, a parent or other near relative ever worry or   
       complain about your drinking? 
Yes No 
3.    Do you ever feel guilty about your drinking? 
Yes No 
4.    Do friends or relatives think you are a normal drinker? 
Yes No 
5.    Are you always able to stop drinking when you want to? 
Yes No 
6.    Have you ever attended a meeting of Alcoholics Anonymous (AA)? 
Yes No 
7.    Has drinking ever created problems between you and your wife, husband, a  
       parent or other near relative? 
Yes No 
8.    Have you ever gotten into trouble at work because of drinking? 
Yes No 
9.    Have you ever neglected your obligations, your family, or your work for 2 or  
       more days in a row because you were drinking? 
Yes No 
10.  Have you ever gone to anyone for help about your drinking? 
Yes No 
11.  Have you ever been in the hospital because of drinking? 
Yes No 
12.  Have you ever been arrested for drunken driving, driving while intoxicated,  
       or driving under the influence of alcoholic beverages? 
Yes No 
13.  Have you ever been arrested, even for a few hours, because of other drunken  
       behaviors?  
Yes No 
 
* SMAST Score___________ 
* See scoring instructions for correct scoring procedures 
 
  
SAMPLE
Page 129 of 174


 
SHORT MICHIGAN ALCOHOL SCREENING TEST 
(SMAST) 
Administration & Interpretation 
Instructions 
From: A Self-Administered Short Michigan Alcohol Screening Test (SMAST) 
M.L. Seltzer, A. Vinokur, and L.J. Van Rooijen. Studies on Alcohol 36:117-126, 1975 
 
The Short Michigan Alcohol Screening Test (SMAST) is a 13-item questionnaire that 
requires a 7th grade reading level, and only a few minutes to complete. It was developed 
from the Michigan Alcoholism Screening Test. Evaluation data indicate that it is an 
effective diagnostic instrument, and does not have a tendency for false positives, as does 
the Michigan Alcoholism Screening Test. It is strongly recommended that the DAST-10 
be used along with the SMAST unless there is a clear indication that the client uses 
alcohol but does not use any other drug at all.  
 
The SMAST is self-administered. All questions are to be answered with “YES” or “NO” 
answers only. A "No" answer to questions 1,4, and 5, and each "Yes" response to the 
other questions earn one point.  
 
Interpretations: A score of 1 or 2 indicates that there is no alcohol problem and no 
further action is needed at this time. A score of 3 indicates a borderline alcohol problem 
and further investigation is necessary.  
 
 
 
 
 
SMAST 
 Score 
Degree of Problem 
Alcohol  Involvement         
               Suggested 
Action 
0-2 
No problems reported 
None at this time. 
 
3 
 
Borderline alcohol 
problem reported 
 
Further investigation 
is required. 
 
4 or more 
 
Potential Alcohol Abuse 
reported 
 
A full assessment 
is required. 
 
 
 
 
 
 
SAMPLE
Page 130 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX G. QUANTITATIVE SUBSTANCE USE INVENTORY 
Page 131 of 174


 IRB #6374 – 
-Principal Investigator 
Pt. Study ID:  ______________ 
 
 
 
 
Date: ____________ 
Rater Initials: ______________ 
 
 
 
 
Study Week #:___________ 
Title (circle):  
Participant     Physician     Nurse 
 
 
Study Visit #:____________ 
 
 
Psychiatrist    Therapist      RA     IR 
V081005 
QUANTITATIVE SUBSTANCE USE INVENTORY 
(Page 1 of 2) 
Day Start: 
____________ 
Day End: 
____________ 
 
1. Number of Days Assessed 
 
 
 
 
 
 
1.  _______ 
2. Opiate Use 
    a. # days on which opiates used 
 
 
 
 
 
2a. _______ 
    b. Average $ value of opiates used per day of opiate use 
 
 
2b. _______ 
    c. Maximum $ value opiates used per day of opiate use 
 
 
2c. _______ 
    d. Principal route of opiate use 
 
 
 
 
 
2d. _______ 
        (0=NA; 1=PO; 2-IN; 3=SC; 4=IV) 
    e. # days on which urge, desire, or craving for opiates occurred 
 
2e. _______ 
    f. Opiate craving 
 
 
 
 
 
 
 
2f. _______ 
        ‘In the past week did you crave heroin (opiates) or have 
         the urge to use it?  How strong was the urge?  How hard 
         was it to resist?’ 
        0=none 
        1=mild urges, easily resisted 
        2=moderate urges, requiring effort to resist 
        3=strong urges to use, difficult to resist 
        4=severe, usually impossible to resist urges to use 
3. Cocaine use 
    a. # days on which cocaine used 
 
 
 
 
 
3a. _______ 
    b. Average $ value of cocaine used per day of cocaine use 
 
 
3b. _______ 
    c. Maximum $ value cocaine used per day of cocaine use 
 
 
3c. _______ 
    d. Principal route of cocaine use 
 
 
 
 
 
3d. _______ 
        (0=NA; 2=IN; 3=FB/crack; 4=IV)  
    e. Number of days on which urge, desire, or craving   
 
 
3e. _______ 
        for cocaine occurred 
    f. Cocaine craving 
 
 
 
 
 
 
 
3f. _______ 
        ‘In the past  week did you crave cocaine or have the 
         urge to use it?  How strong was the urge?  How hard  
         was it to resist?’ 
        0=none 
        1=mild urges, easily resisted 
        2=moderate urges, requiring effort to resist 
        3=strong urges to use, difficult to resist 
        4=severe, usually impossible to resist urges to use 
SAMPLE
Page 132 of 174
PPD


IRB 6374 Study – 
-Principal Investigator 
Pt. Study ID:  ______________ 
 
 
 
 
Date: ____________ 
 
QUANTITATIVE SUBSTANCE USE INVENTORY—CLINICIAN RATED 
(Page 2 of 2) 
 
4. Other drug or alcohol use number of days of use of each of the following: 
    a. alcohol 
 
 
 
 
 
 
 
 
4a. _______ 
          # drinks/drinking day 
 
 
 
 
 
 
      _______ 
    b. cannabis (marijuana, hashish, etc)  
 
 
 
 
4b. _______ 
    c. benzodiazepines 
 
 
 
 
 
 
 
4c. _______ 
    d. other sedatives/hypnotics  
 
 
 
 
 
4d. _______ 
    e. stimulants  
 
 
 
 
 
 
 
4e. _______ 
    f. PCP (angel dust) 
 
 
 
 
 
 
 
4f. _______ 
    g. hallucinogens 
 
 
 
 
 
 
 
4g. _______ 
    h. other   
 
 
 
 
 
 
 
 
4h. _______ 
 i. # days which urge, desire, or craving for 
 
 
 
 
4i. _______ 
   other drug or alcohol 
 j. Other drug or alcohol craving  
 
 
 
 
 
4j. _______ 
    ‘In the past week did you crave (other drug/alcohol) or have  
     the urge to use it?  How strong was the urge?  How hard was 
     it to resist?’ 
    0=none 
        1=mild urges, easily resisted 
        2=moderate urges, requiring effort to resist 
        3=strong urges to use, difficult to resist 
        4=severe, usually impossible to resist urges to use 
 
5. Summary Drug Use 
    a. # days using any illicit drugs 
 
 
 
 
 
5a. _______ 
    b. # days using heroin, cocaine, or both 
 
 
 
 
5b. _______ 
    c. # days using any IV or SC  
 
 
 
 
 
5c. _______ 
    d. # days with urge, desire, or craving for any drug 
 
 
 
5d. _______ 
    e. Overall drug craving 
 
 
 
 
 
 
5e. _______ 
        ‘In the past week did you crave drugs in general or have 
         the urge to use them?  How strong was the urge?  How hard 
         was it to resist?’ 
        0=none 
        1=mild urges, easily resisted 
        2=moderate urges, requiring effort to resist 
        3=strong urges to use, difficult to resist 
        4=severe, usually impossible to resist urges to use 
 
SAMPLE
Page 133 of 174
PPD


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX H. PATIENT GLOBAL ASSESSMENT OF RESPONSE TO 
THERAPY 
 
Page 134 of 174


 
PATIENT GLOBAL ASSESSMENT OF RESPONSE TO THERAPY 
(PGART)  
 
How would you rate your response to the medication that you received during the study? Please 
check one of the following: 
□ Poor  
□ Fair  
□ Good  
□ Very Good  
□ Excellent 
SAMPLE
Page 135 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX I. STRUCTURED INTERVIEW GUIDE FOR THE 
HAMILTON RATING SCALE FOR DEPRESSION 
Page 136 of 174


 
 
 
©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, 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. 
 
 
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 both the Hamilton Depression Scale (Hamilton, Max:  A rating scale for depression.  J 
Neurol Neurosurg Psychiat 23:56-61, 1960).  The anchor point descriptions for both scales, 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
Page 137 of 174
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: 
 
 
 
 
SAMPLE DO NOT USE
Page 138 of 174


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 to 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 activities; (Clear 
reduction in interest, pleasure or functioning) 
3 -  decrease in actual time spent in activities or 
decrease in productivity.  In hosp., pt. spends 
less than 3 hrs./day in activities (hospital job or 
hobbies) exclusive of ward chores (Profound 
reduction in interest, pleasure, or functioning)  
4 -  stopped working bec. 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) 
 
SAMPLE DO NOT USE
Page 139 of 174


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) 
 
 
 
 
 
SAMPLE - DO NOT USE
Page 140 of 174


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 TO 3 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 
3 -  not assessed 
 
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 
3 -  not assessed 
 
NOTE: AVOID CODING “3” IF POSSIBLE 
 
 
 
 
SAMPLE - DO NOT USE
Page 141 of 174


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 
SAMPLE - DO NOT USE
Page 142 of 174


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 of 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) 
SAMPLE - DO NOT USE
Page 143 of 174


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 
GI - dry mouth, gas, indigestion, diarrhea, stomach 
cramps, belching 
CV - heart palpitations, headaches 
Resp - 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
Page 144 of 174


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
Page 145 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
APPENDIX J. BRIEF ASSESSMENTS OF COGNITION SYMBOL 
CODING TEST 
Page 146 of 174


Sample
Page 147 of 174


Sample
Page 148 of 174


Sample
Page 149 of 174


 
 
Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX K. 
CONTROLLED ORAL WORD ASSOCIATION TASK 
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1 
Alkermes ALK6428-A302 
Controlled Oral Word Association Test (COWAT) 
 
(Allow 60 seconds per trial) 
 
 
INSTRUCTIONS:  Say to the patient: 
 
I will say a letter of the alphabet.  Then I want you to give me as many 
words that begin with the letter as quickly as you can.  For instance, if I say 
'B', you might give me 'bad', 'battle', 'bed'... I do not want you to use words 
that are proper names or things that would start with a capital letter, such 
as 'Boston', 'Bob', or 'Buick'.  Also, do not use the same word again with a 
different ending such as 'eat' and 'eating'.  Any questions?  (pause)  Begin 
when I say the letter.  The first letter is 'F'.  You have one minute.  Go 
ahead. 
 
Begin timing immediately.  Allow one minute.  If patients discontinue before the end of 
the minute, encourage them to try to think of more words.  If there is a silence of 15 
seconds, repeat the basic instructions:  
 
 
Remember, you are to tell me as many words as you can that begin with 
the letter ‘F’.   
 
For scoring purposes, write down the actual words in the order in which they are 
produced.  A score sheet for recording individual patient responses has been included 
on the following page.  If shorthand is used, be sure to make each word legible for 
review.   Write all words, even if they are repetitions or incorrect.  If repetitions occur 
that may be accepted if an alternate meaning was intended by the patient, (“four” and 
“for”, “son” and “sun”), then ask what was meant by this word at the END of the 1-
minute period. 
 
The first (letter-F) trial is followed by the following instruction: 
 
Now tell me as many words beginning with the letter ‘A’ as you can.  You 
have one minute. Ready, go.  
 
 
 
 
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2 
Alkermes ALK6428-A302 
 Last, the patient is instructed: 
 
Now tell me as many words beginning with the letter ‘S’ as you can. You 
have one minute.  Ready, go. 
 
 
SCORING:   
 
Repetitions of words are not corrected but are not included in scoring.  The total 
number of correct words generated for each letter, F, A, and S, (excluding intrusions, 
repeated roots or repetitions of the same word) are counted and entered on the 
response sheet.  For example, if a patient generated 18 F-words, 12 A-words, and 20 
S-words, the totals would be entered on the response sheet. 
 
Scoring Rules 
 
Acceptable words begin with the given letter (F, A, or S).  Slang words and foreign 
words that are part of standard English (e.g. “amigo”) are acceptable.  
 
UNACCEPTABLE WORDS include the following:   
 Words that are proper names, as indicated in the instructions.  Generally, 
these proper names are capitalized.  The following proper names would all 
be unacceptable:  France, Fred, February, Friday, and Fritos. 
 
 Words that sound like they belong but the actual spelling dictates that the 
word choice was incorrect.  For example, “phone” is not acceptable as an 
“F” word. 
   
 
 Words that are repetitions.   For example, if the patient says, “feel” as the 
first word, then repeats it later; the patient will receive credit only for the first 
time the word is given.  Homonyms, however, are acceptable if the patient 
indicates that the word has a different meaning from the first time it was 
given.  For example, a patient may say “ant” and then later say “aunt”.  You 
may need to ask the patient what word was intended.  Credit for both words 
would be given. 
 
 
 Words that have the same root and basically refer to the same thing.  This 
is sometimes difficult to judge.  Words that are clearly variations of the root 
word are not given credit.  For example, if  “fast, faster, fastest” were given, 
credit would go only to “fast.” If “flexible, flexibility” were given, credit would 
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3 
Alkermes ALK6428-A302 
go only to “flexible.” In addition, the repetition of a word as a compound 
word is unacceptable.  For example, if  “air, air mattress” were given, credit 
would go only to “air”.   
 
 
However, words that have the same root, yet refer to clearly different things, 
should be given credit.  For example, if “fool, foolhardy” or “fireman, fireplug” were 
given, credit would go to both words.  (These are also one word responses, not two 
words with the same first word.)  The best rule of thumb for determining whether a 
word is a repetition or not is to refer to the phrase in the instructions that asks the 
patients not to “use the same word again with a different ending.” 
 
 
Numbers pose a problem because some patients attempt to give a series of 
numbers.  In keeping with the rules above, “five, fifty, and fifteen” would all receive 
credit, yet “fifty-one, fifty-two” or “five, five thousand” would receive only one point.  
 
 
 
 
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Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
APPENDIX L. WECHSLER MEMORY SCALE-III SPATIAL SPAN TEST 
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Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
 
APPENDIX M. 
CONTINUOUS PERFORMANCE TEST 
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Alkermes, Inc. 
Protocol ALK6428-A302 v 4.0 (Amendment 3.0) 
CONFIDENTIAL 
 
 
APPENDIX N. TEST OF ATTENTIONAL PERFORMANCE 
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Sample
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SAP_001.pdf: 
A P h ase 3 St u d y t o E v al u ate t he S afet y, T oler a bilit y, a n d 
Effic ac y of N altre x o ne f or use i n C o nj u ncti o n wit h 
B u pre n or p hi ne i n A d ults wit h O pi oi d Use Dis or der 
Tr a nsiti o ni n g fr o m B u pre n or p hi ne M ai nte n a nce Pri or t o 
First D ose of Vi vitr ol ®  
 
 
U ni q ue Pr ot oc ol I D:   
A L K 6 4 2 8 -A 3 0 2  
N C T N u m ber:  
N C T 0 2 6 9 6 4 3 4  
D ate of St atistic al A n al ysis 
Pl a n :  
2 9 N o ve m ber 2 0 1 7  
 


 
S  T  A  TI S  TI  C  A  L   A  N  A  L  Y SI S  P  L  A  N  
A  L  K  6 4 2 8-  A 3 0 2 
 
St u d y  T itl e:   
A  P h as e  3  St u d y t o  E v al u at e t h e  S af et y,  T ol er a bilit y,  a n d  Effi c a c y  of 
N altr e x o n e f or  us e i n   C o nj u n cti o n   wit h   B u pr e n or p hi n e i n   A d ults   wit h 
O pi oi d   Us e   Dis or d er  Tr a nsiti o ni n g fr o  m   B u pr e n or p hi n e   M ai nt e n a n c e 
Pri or t o  First   D os e  of   VI  VI T  R  O L ®  
D o c u  m e nt  S  t at us:   
Fi n al  V ersi o n  ,  1. 0  
D o c u  m e nt   D  at e:    
2 9   N o v e  m b er  2 0 1 7 
B as e d  o n: 
Pr ot o c ol   A  m e n d  m e nt  3,  d at e d  1 4 J u n e  2 0 1 7 
S p o ns or: 
Al k er  m es,   I n c. 
8 5 2   Wi nt er  Str e et 
W alt h a  m,   M  A   0 2 4 5 1 
U S  A   
T his st u d y is  b ei n g  c o n d u ct e d i n  c o  m pli a n c e   wit h  g o o d  cli ni c al  pr a cti c e,  
i n cl u di n g t h e  ar c hi vi n g  of  ess e nti al  d o c u  m e nts. 
 
 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 
 
 
 
 
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
LI S T   O F  A  B  B  R E  VI  A TI  O  N S   .......................................................................................................... 4 
1.  
I  N T  R  O  D  U  C TI  O  N ........................................................................................................ 6 
1. 1.  
St u d y   O bj e cti v e(s)  ........................................................................................................ 6 
1. 1. 1.  
Pri  m ar y   O bj e cti v e  ......................................................................................................... 6 
1. 1. 2.  
S e c o n d ar y   O bj e cti v e  ..................................................................................................... 6 
1. 2.  
S u  m  m ar y  of  St u d y   D esi g n  ............................................................................................ 6 
1. 3.  
Crit eri a f or  E v al u ati o n   .................................................................................................. 8 
2.  
S  A  M P L E  SI Z E   C  O  N SI  D E  R  A TI  O  N S  ......................................................................... 9 
3.  
D  A T  A   A  N  A L  Y S E S   ................................................................................................... 1 0 
3. 1.  
G e n er al   St atisti c al   M et h o d ol o g y  ................................................................................ 1 0 
3. 2.  
St u d y  P o p ul ati o ns  ....................................................................................................... 1 0 
3. 2. 1.  
S af et y  P o p ul ati o n  ........................................................................................................ 1 0 
3. 2. 2.  
Dis p ositi o n  of  S u bj e cts   ............................................................................................... 1 0 
3. 2. 3.  
Pr ot o c ol   D e vi ati o ns  .................................................................................................... 1 1 
3. 3.  
D e  m o gr a p hi c  a n d   B as eli n e   C h ar a ct eristi cs   ................................................................ 1 2 
3. 4.  
Pri or,   C o n c o  mit a nt  a n d   A n cill ar y   M e di c ati o ns  .......................................................... 1 2 
3. 5.  
Tr e at  m e nt   A d h er e n c e   R at e  a n d  E xt e nt  of  E x p os ur e  ................................................... 1 3 
3. 5. 1.  
Tr e at  m e nt   A d h er e n c e   R at e  ......................................................................................... 1 3 
3. 5. 2.  
E xt e nt  of  E x p os ur e  ..................................................................................................... 1 3 
3. 6.  
Effi c a c y   A n al ys es  ....................................................................................................... 1 3 
3. 6. 1.  
G e n er al   C o nsi d er ati o ns   ............................................................................................... 1 3 
3. 6. 2.  
Pri  m ar y  Effi c a c y  E n d p oi nt  ......................................................................................... 1 3 
3. 6. 3.  
S e c o n d ar y  Effi c a c y  E n d p oi nts  .................................................................................... 1 4 
3. 6. 4.  
E x pl or at or y  Effi c a c y  E n d p oi nts  ................................................................................. 1 6 
3. 7.  
S af et y   A n al ys es  .......................................................................................................... 1 8 
3. 7. 1.  
A d v ers e  E v e nts   ........................................................................................................... 1 8 
3. 7. 2.  
Cli ni c al  L a b or at or y  P ar a  m et ers   .................................................................................. 1 9 
3. 7. 3.  
Vit al  Si g ns  a n d   O x y g e n  S at ur ati o n   ............................................................................. 2 1 
3. 7. 4.  
1 2- L e a d  El e ctr o c ar di o gr a  m ( E  C  G)  ............................................................................. 2 1 
3. 7. 5.  
C ol u  m bi a-  S ui ci d e  S e v erit y   R ati n g  S c al e  .................................................................... 2 2 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
3 
 
 
 
3. 7. 6.  
Ot h er   Q u esti o n n air es   .................................................................................................. 2 3 
3. 8.  
P h ar  m a c o ki n eti c/  P h ar  m a c o d y n a  mi cs   D at a   A n al ysis  ................................................ 2 3 
4.  
I  N T E  RI  M   A  N  A L  Y SI S ............................................................................................... 2 3 
5.  
C  H  A  N  G E S I  N   C  O  N  D  U  C T   O  R  P L  A  N  N E  D   A  N  A L  Y S E S  F  R  O  M 
P  R  O T  O  C  O L  ............................................................................................................... 2 3 
6.  
D E FI  NI TI  O  N S   A  N  D   C  O  N  V E  N TI  O  N S  F  O  R   H  A  N  D LI  N  G   O F   D  A T  A   ................... 2 4 
6. 1.  
A n al ysis   Visit   Wi n d o  ws   ............................................................................................. 2 4 
6. 2.  
H a n dli n g  of  P arti al   D at es  of   C o n c o  mit a nt   M e di c ati o n   .............................................. 2 4 
6. 3.  
S af et y   D at a   H a n dli n g  .................................................................................................. 2 4 
7.  
G E  N E  R  A L  S T  A TI S TI  C  A L   M E T  H  O  D  O L  O  G  Y   ....................................................... 2 5 
7. 1.  
R e p orti n g  Pr e cisi o n   .................................................................................................... 2 5 
8.  
R  E F E  R E  N  C E  ............................................................................................................. 2 6 
 
 
 
 
LI S  T   O F   T  A  B  L  E S   
T a bl e   1: 
P  C S   Crit eri a f or  L a b or at or y  P ar a  m et ers  ..................................................................... 2 0 
T a bl e   2: 
P  C S   Crit eri a f or   Vit al  Si g n  a n d   O x y g e n  S at ur ati o n  P ar a  m et ers  ................................ 2 1 
T a bl e   3: 
P  C S   Crit eri a f or   Q T c  B  a n d   Q T c F  .............................................................................. 2 2 
T a bl e   4: 
C-  S S  R S   C at e g ori es f or   A n al ysis  ................................................................................ 2 2 
T a bl e   5: 
D e gr e e  of  Pr e cisi o n   ..................................................................................................... 2 5 
 
LI S  T   O F  FI  G  U  R  E S   
Fi g ur e   1: 
St u d y   D esi g n  S c h e  m ati c  ............................................................................................... 7 
 
 
 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
4 
 
 
 
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N  S 
T h e f oll o  wi n g  a b br e vi ati o ns  ar e  us e d i n t h e st atisti c al  a n al ysis  pl a n . 
A b b r e vi ati o n  o r   T e r  m     
E x pl a n ati o n  o r   D efi niti o n   
A E   
A d v ers e  e v e nt   
A  N  O  V  A   
A  n al ysis  of  v ari a n c e  
A T  C   
A n at o  mi c al  T h er a p e uti c   C h e  mi c al [ cl assifi c ati o n s yst e  m]   
B  U P   
B u pr e n or p hi n e 
B  MI   
B o d y   m ass i n d e x 
C  O  W S   
Cli ni c al   O pi at e   Wit h dr a  w al  S c al e    
CI   
C  o nfi d e n c e i nt er v al  
C- S S  R S  
C ol u  m bi a-  S ui ci d e  S e v erit y   R ati n g  S c al e  
E  C  G  
El e ctr o c ar di o gr a  m  
E  O T  
E n d  of t r e at  m e nt 
E T  
E arl y  t er  mi n ati o n 
H  A  M  -  D 
H a  milt o n   R ati n g  S c al e f or   D e pr essi o n   
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es   
MI  NI   
M  i ni-I nt er n ati o n al   Ne ur o ps y c hi atri c  Int er vi e  w  
M  M S E   
M  i ni-  Me nt al  S t at e E x a  mi n ati o n 
M  O T  Y  B   
M o nt hs  of t h e   Y  e ar  B  a c k  w ar d  
N T  X   
N altr e x o n e 
P  B  O  
Pl a c e b o  
P  B  O -  N 
Pl a c e b o f or  n altr e x o n e 
P  C S  
P ot e nti all y  cli ni c all y si g nifi c a nt  
P  G  A  R T  
P ati e nt   Gl o b al   Ass ess  m e nt  a n d   R es p o ns e t o  T h er a p y  
Q S  UI   
Q u a ntit ati v e  S u bst a n c e   Us e I n v e nt or y 
Q T c  B   
Q T i nt er v al  c orr e ct e d  usi n g   B a z ett  ’s f or  m ul a 
Q T c F   
Q T i nt er v al  c orr e ct e d  usi n g  Fri d eri ci a  ’s f or  m ul a 
S  A E  
S eri o us  a d v ers e  e v e nt  
S  A P  
St atisti c al  a n al ysis  pl a n  
S  M  A S T  
S h ort   Mi c hi g a n   Al c o h ol  S cr e e ni n g  T est  
S  O  W S  
S u bj e cti v e   O pi at e   Wit h dr a  w al  S c al e  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
5 
 
 
 
A b b r e vi ati o n  o r   T e r  m     
E x pl a n ati o n  o r   D efi niti o n   
S  D  
St a n d ar d  d e vi ati o n  
T E  A E  
Tr e at  m e nt -e  m er g e nt  a d v ers e  e v e nt  
U L  N   
U p p er   li  mit  of  n or  m al 
V  A S   
Vis u al   A n al o g u e  S c al e 
W  H  O   
W orl d   H e alt h   Or g a ni z ati o n 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
6 
 
 
 
1.    
I  N  T  R  O  D  U  C  TI  O  N 
T his st atisti c al  a n al ysis  pl a n ( S  A P)  d es cri b es t h e st atisti c al   m et h o ds t o  b e  us e d f or  a n al ys es    a n d 
d at a  pr es e nt ati o n f or r e p orti n g  effi c a c y  a n d s af et y r es ults f or st u d y   A L  K 6 4 2 8- A 3 0  2.   T his 
d o c u  m e nt  h as  b e e n  pr e p ar e d  b as e d  o n   Al k er  m es  A L  K  6 4 2 8- A 3 0  2   St u d y  Pr ot o c ol   A  m e n d  m e nt  3 
(d at e d   1 4 J u n e,  2 0 1 7) [1 ]. 
1. 1.    
St u d y   O bj e cti v e(s)  
1. 1. 1.    
P ri  m a r y   O bj e cti v e  
•    T o  e v al u at e t h e  effi c a c y  of  or al  n altr e x o n e  us e d i n  c o nj u n cti o n   wit h  b u pr e n or p hi n e 
(  B  U P) i n  a d ults   wit h   O pi oi d   Us e   Dis or d er tr a nsiti o ni n g fr o  m B  U P   m ai nt  e n a n c e  pri or  
t o t h e first  d os e  of   VI  VI T  R  O L®  
1. 1. 2.    
S e c o n d a r y   O bj e cti v e  
•    T o  d et er  mi n e t h e s af et y  a n d t ol er a bilit y  of  or al  n altr e x o n e  us e d i n  c o nj u n cti o n   wit h 
B  U P   i n  a d ults   wit h   O pi oi d   Us e   Dis or d er tr a nsiti o ni n g fr o  m B  U P   m ai nt e n a n c e  pri or   t o 
t h e first  d os e  of   VI  VI T  RO L    ® 
1. 2.    
S u  m  m a r y  o f  St u d y   D esi g n 
T his  P h as e  3, r a n d o  mi z e d,  d o u bl e- bli n d,  pl a c e b o- c o ntr oll e d,  p ar all el  gr o u p st u d y   will  e v al u at e  a 
d osi n g s c h e d ul e f or  a cti v e  vs  pl a c e b o  or al  n altr e x o n e  c o -a d  mi nist er e d   wit h   B  U P i n 
B  U P  - d e p e n d e nt i n di vi d u als  pri or t o first  d os e  of   VI  VI T  R  O L.  Eli gi bl e s u bj e cts   will  b e 
r a n d o  mi z e d i n  a  1: 1 r ati o t o  o n e  of t  w o tr e at  m e nt  gr o u ps ( n altr e x o n e +   B  U P  or  pl a c e b o 
n altr e x o n e [ P  B  O -  N]  +   B  U P) f or i n d u cti o n  o nt o   VI  VI T  R  O L, str atifi e d  a c c or di n g t o l o  w 
( < 8 m g  / d a y)  vs  hi g h ( 8  m g/ d a y)   B  U P   m ai nt e n a n c e  d os e  at t h e ti  m e  of i niti ati o n  of t h e   B  U P 
L e a d -i n  P eri o d.   A p pr o xi  m at el y  9 2 s u bj e cts  ar e  pl a n n e d t o  b e r a n d o  mi z e d;  4 6 s u bj e cts  p er  gr o u p. 
T h e st u d y  p arti ci p ati o n f or  e a c h s u bj e ct   will l ast  a p pr o xi  m at el y  9   w e e ks;  u p t  o  3   w e e ks f or 
s cr e e ni n g (  D a ys  - 2 6 t o -6;  d uri n g   w hi c h ti  m e s u bj e cts   will r e  m ai n  u n d er t h e  c ar e  of t h eir  ori gi n al  
B  U P  pr o vi d er),  a p pr o xi  m at el y  2   w e e ks f or t h e   B  U P  L e a d-i n  P eri o d  a n d t h e  Tr e at  m e nt  P eri o d 
(  D a ys - 5 t o  7),  4 t o  5  d a ys f or   VI  VI T  R  O L i n d u cti o n  a n d  p ost-VI  VI T  R  O L   m o nit ori n g  ,  a n d  a 
4-  w e e k  o ut p ati e nt f oll o  w- u p  p eri o d. 
T his st u d y i n cl u d es: 
•    B  U P  L e a d  -i n  P eri o d:   O ut p ati e nt   D a ys - 5 t hr o u g h - 3; resi d e nti al   D a ys  -2  a n d  - 1 
( o pti o n f or  e arli er r esi d e nti al  a d  missi o n  at t h e st u d y  cli ni ci a n’s  dis cr eti o n)  
•    Tr e at  m e nt   P eri o d:  Tr a nsiti o n al  d osi n g   wit h  or al  n altr e x o n e  or  P  B  O-  N i n  c o nj u n cti o n 
wit h   B  U P t a p er; r esi d e nti al   D a ys    11 t o  7 
 
                                                 
1 S u bj e cts   w h o  d o  n ot  q u alif y f or  r a n d o  mi z ati o n  o n   D a y  1   will r e c ei v e   D a y -1   B  U P  d osi n g  a n d r e p e at   D a y  1 
ass ess  m e nts  a n d  pr o c e d ur es  o n t h e f oll o  wi n g  d a y,   D a y  1 a.  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
7 
 
 
 
•    VI  VI T  R  O L I n d u cti o n   a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d  
−    A  n al o x o n e  c h all e n g e  a n d  a d  mi nistr ati o n  of   VI  VI T  R  O L  o n   D a y  8 2  pri or t o 
dis c h ar g e  
−    P ost-  VI  VI T  R  O L  o ut p ati e nt   m o nit ori n g (  D a ys  9- 1 1) 
A s c h e  m ati c  of t h e st u d y  d esi g n is  pr o vi d e d i n   Fi g ur e  1 . Pl e as e r ef er t o t h e fi n al st u d y  pr ot o c ol 
f or th e s c h e d ul e  of  pr o c e d ur es/ ass ess  m e nts  a n d  a d diti o n al  d et ails  o n st u d y  c o n d u ct. 
 
Fi g u r e   1:   
St u d y   D esi g n  S c h e  m ati c  
N al o x o n e 
C h all e n g e 
a n d 
VI VI T R  O L 
I nj e cti o n
S cr e e ni n g
B U P l e a d-i n 
( 4   m g *)
R a n d o  miz ati o n
o n  D a y  1/ 1 a
Tr e at  m e nt  P eri o d
( D a ys  1/ 1 a- 7)
N altr e x o n e  +  B U P t a p er
P B  O- N  +  B U P t a p er
P ost- VI VI T R  O L 
O bs er v ati o n
F oll o  w- u p
D a ys - 2 6 t o - 6    D a ys - 5 t o - 1
D a y  8/ 8 a
D a ys  9- 1 1
Dis c h ar g e  1  h o ur 
aft er  VI VI T R  O L 
i nj e cti o n
D a y  2 2    D a y  3 6
R esi d e nti al  P eri o d  D a ys - 2 t o  8/ 8 a
B U P t a p er 
b e gi ns
* S u bj e cts   m ai nt ai n e d  o n  < 4   m g  at  D a y - 5   will  c o nti n u e  o n t h eir  c urr e nt  d os e  u ntil 
t h e  Tr e at  m e nt  P eri o d t a p er  c alls f or f urt h er  d e cr e as e t o  est a blis h  a  c o nsist e nt 
d ail y  d os e  pri or t o tr a nsiti o n al  d osi n g   wit h  n altr e x o n e (s e e  Pr ot o c ol  S e cti o n  8. 2. 1).
 
 
E v al u ati o n  of   wit h dr a  w al s y  m pt o  ms   will  o c c ur t hr o u g h o ut t h e   B  U P  L e a d-i n  P eri o d, t h e 
Tr e at  m e nt  P eri o d,  a n d t h e   VI  VI T  R  O L I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d   (  D a ys 
- 5 t hr o u g h  1 1).   O n   D a ys - 2 t hr o u g h  8/ 8 a,   A  M  a n d  P  M  vit al si g ns, Cli ni c al   O pi at e   Wit h dr a  w al 
S c al e ( C  O  W S  )/ S u bj e cti v e   O pi at e   Wit h dr a  w al  S c al e ( S  O  W S ), a n d    Vis ual  A  n al o g u e  S c al e (  V  A S) 
will  b e   m e as ur e d.   O n   D a y  8/ 8 a,  P  M  vit al si g ns,   C  O  W S/ S  O  W S  a n d   V  A S   will  b e   m e as ur e d  pri or 
t o  dis c h ar g e. I n  a d diti o n t o t h e   A  M  a n d P  M  ass ess  m e nts  d es cri b e d  a b o v e,  cli ni c al t esti n g 
s essi o ns t o   m o nit or  o pi oi d   wit h dr a  w al  eff e cts i n r es p o ns e t o st u d y  dr u g   will  o c c ur  o n   D a ys  1 
t hr o u g h  7.   Als o, s u bj e cts   will r e c ei v e  ps y c h o e d u c ati o n al  c o u ns eli n g st arti n g  o n   D a y - 5  a n d 
t hr o u g h o ut t h e  Tr e at  m e nt  P eri o d. 
U p t o   t  w o a d diti o n al i n p ati e nt  visits   m a y  b e  c o n d u ct e d (  D a ys  1 a  a n d  8 a),  as  n e e d e d, f or s u bj e cts 
w h o  d o  n ot   m e et  crit eri a   f or  pr o c e e di n g   wit h  pr o c e d ur es  o n   D a y  1  a n d   D a y  8.  
 
                                                 
2 S u bj e cts   w h o  d o  n ot  q u alif y t o r e c ei v e   VI  VI T  R  O L  o n   D a y  8   will r e c ei v e   D a y  7  st u d y  dr u g ( n altr e x o n e/ P  B  O -N). 
Pr e - a n d  p ost d os e   C O  W S   will  b e  ass ess e d f or   cli ni c al s af et y  p ur p os es  o nl y.   D a y  8  ass ess  m e nts  a n d  pr o c e d ur es 
will  b e   r e p e at e d t h e f oll o  wi n g  d a y (  D a y  8 a). 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
8 
 
 
 
1. 3.    
C rit e ri a f o r   E v al u ati o n   
Effi c a c y:   
Effi c a c y   will  b e  ass ess e d  vi a t h e  f oll o  wi n g:  
•    A d  mi nistr ati o n  of   VI  VI T  R  O L   
•    O pi oi d   wit h dr a  w al  usi n g t h e   C  O  W S   s cor e  
•    O pi oi d   wit h dr a  w al  usi n g t h e  S  O  W S   s c or e 
•    D esir e f or  o pi oi ds  usi n g  a   V  A S 
•    P ati e nt   Gl o b al   Ass ess  m e nt  of   R es p o ns e t o  T h er a p y ( P  G  A  R T) 
E x pl or at or y  E n d p oi nts:  
T h e f oll o  wi n g  e x pl or at or y  ass ess  m e nts   will  b e  e v al u at e d :  
•    P u pil  di a  m et er (  m e as ur e d  d uri n g  cli ni c al s e ssi o ns) 
•    Q u a ntit ati v e  S u bst a n c e   Us e I n v e nt or y (  Q S  UI  ) 
•    H a  milt o n   R ati n g  S c al e f or   D e pr essi o n   (H  A  M  -  D) 
•    Bri ef   Ass ess  m e nts  of   C o g niti o n   (B  A  C  )  S y  m b ol   C o di n g  T est 
•    W e c hsl er   M e  m or y  S c al e  -III  S p ati al  S p a n (W  M S  -III  S S) T est  
•    C o nti n u o us  P erf or  m a n c e  T est (  C P T) 
•    T est  of   Att e nti o n al  P erf or  m a n c e ( T  A P)   
S af et y  a n d   T ol e r a bilit y: 
S af et y  a n d t ol er a bilit y  will  b e   ass ess e d  vi a t h e f oll o  wi n g: 
•    A d v ers e  e v e nts (  A Es  ) 
•    Vit al si g ns  a n d  art eri al  o x y g e n s at ur ati o n (  m e as ur e d  d uri n g  cli ni c al t esti n g s essi o ns)   
•    L a b or at or y t est r es ults  
•    El e ctr o c ar di o gr a  m  (E  C  G ) p ar a  m et ers ( u n c orr e ct e d   Q T,   Q T i nt er v al  c orr e ct e d f or 
h e art r at e  usi n g t h e  Fri d eri ci a f or  m ul a [  Q T c F],   Q T i nt er v al  c orr e ct e d f or  h e art r at e 
usi n g t h e   B a z ett f or  m ul a [  Q T c  B],   H  R,   R  R,  a n d   Q  R S i nt er v als) 
•    C ol u  m bi a-  S ui ci d e  S e v erit y   R ati n g  S c al e ( C-  S S  R S ) s c or es  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
9 
 
 
 
2.    
S  A  M P  L  E  SI  Z E   C  O  N SI  D  E  R A  TI  O  N S   
T h e  pri  m ar y  effi c a c y  e n d p oi nt  of t h e st u d y is t h e  pr o p orti o n  of s u bj e cts   w h o r e c ei v e d  a n d 
t ol er at ed   VI  VI T  R  O L i nj e cti o n  o n   D a y  8/ 8 a  as  d e  m o nstr at e d  b y   mil d  o pi oi d   wit h dr a  w al 
s y  m pt o  ms (  C  O  W S  ≤ 1 2  or  S  O  W S  ≤ 1 0) f oll o  wi n g VI  VI T  R  O L  a d  mi nistr ati o n.   
Ass u  mi n g t h e  pr o p orti o n  of s u bj e cts r e c ei vi n g  a n d t ol er ati n g   VI  VI T  R  O L  a d  mi nistr ati o n is  9 0  % 
i n   Gr o u p  1  a n d  6 0  % i n   Gr o u p  2,  a s a  m pl e si z e  of  a p pr o xi  m at el y  4 6 s u bj e cts  p er tr e at  m e nt  gr o u p 
will  pr o vi d e  at l e ast  9 0  %  p o  w er t o  d et e ct  a   st atisti c all y si g nifi c a nt  diff er e n c e  b et  w e e n t h e t  w o  
tr e at  m e nt  gr o u ps  at  5  % l e v el  of si g nifi c a n c e i n  a  2-si d e d t est. 
 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
1 0  
 
 
 
3.    
D  A  T  A   A  N  A  L  Y S  E S   
3. 1.    
G e n e r al  St atisti c al   M et h o d ol o g y   
T h e s af et y  a n d  effi c a c y  e n d p oi nts   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all  as 
d es cr i b e d  b el o  w. I n  g e n er al, s u  m  m ar y st atisti cs ( n,   m e a n, st a n d ar d  d e vi ati o n [ S  D],   m e di a n, 
mi ni  m u  m  ,  a n d   m a xi  m u  m f or  c o nti n u o us  v ari a bl es,  a n d  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts i n 
e a c h  c at e g or y f or  c at e g ori c al  v ari a bl es)   will  b e  pr o vi d e d  b y tr e at  m e nt  gr o u p.  All s u  m  m ar y t a bl es 
will  b e  b as e d  o n  o bs er v e d  d at a,  a n d   missi n g  v al u es   will  n ot  b e i  m p ut e d  u nl ess  ot h er  wis e 
i n di c at e d.   M e as ur e  m e nts  c oll e ct e d fr o  m  u ns c h e d ul e d  visits  or r e p e at e d  ass ess  m e nts   will  n ot  b e 
i n cl u d e d i n t h e  b y- visit s u  m  m ar y t a bl es  or fi g ur es,  b ut   will  b e i n cl u d e d i n t h e  d eri v ati o n  of t h e 
l ast  p ost-b as eli n e  v al u e  d uri n g tr e at  m e nt, t h e  a n al ys es f or t h e  P  C S  p ost - b as eli n e  v al u es,  a n d 
s u bj e ct listi n gs.  S o ur c e  d at a f or t h e s u  m  m ar y t a bl es  a n d st atisti c al  a n al ys es   will  b e  pr es e nt e d  as 
b y -s u bj e ct  d at a listi n gs . 
B as eli n e  v al u e is  d efi n e d  as t h e l ast  n o n  -  missi n g  ass ess  m e nt  pri or t o t h e first  d os e  of st u d y  dr u g. 
All st atisti c al t ests  a n d  c o nfi d e n c e i nt er v als (  CIs),  u nl ess st at e d  ot h er  wis e,   will  b e  2  -si d e d  a n d 
will  b e s et  at  a n  al p h a l e v el  of  0. 0 5. 
All t h e  effi c a c y   a n al ys es   will  b e s u  m  m ari z e d  b y t h e  pl a n n e d tr e at  m e nt  assi g n  m e nt,  a n d  all t h e 
s af et y  a n al ys es   will  b e s u  m  m ari z e d  b y  a ct u al tr e at  m e nt.  
T h e  d at a   will  b e s u  m  m ari z e d f or t h e f oll o  wi n g t  w o st u d y  p eri o ds  as  a p pr o pri at e. 
•    Tr e at  m e nt  P eri o d , w hi c h   is  d efi n e d  as t h e first  d os e st art  d at e t o t h e  d at e  of  e n d  of 
tr e at  m e nt ( E  O T).  F or t h e  effi c a c y  a n al ysis,  E  O T is  d efi n e d  as st u d y   D a y  7  or t h e  d a y  of 
e arl y t er  mi n ati o n ( E T ), if  a s u bj e ct  dis c o nti n u es  b ef or e   D a y  7.  F or t h e s af et y  a n al ysis, 
E  O T is  d efi n e d  as   D a y  8/ 8 a  or t h e  d a y  of  E T , if  a s u bj e ct  dis c o nti n u es  b ef or e   D a y  8/ 8 a.  
•    F oll o  w- u p  P eri o d,   w hi c h  is  d efi n e d  as t h e p eri o d  b et  w e e n t h e  d at e  of t h e  E  O T  visit  pl us  1 
d a y  a n d t h e l ast st u d y  visit. 
 
3. 2.    
St u d y  P o p ul ati o ns   
3. 2. 1.    
S af et y  P o p ul ati o n 
T h e  S af et y  P o p ul ati o n   will i n cl u d e  all r a n d o  mi z e d s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of 
n altr e x o n e  or  P  B  O -  N.  T h e S af et y  P o p ul ati o n  will  b e   us e d f or  b ot h  t h e s af et y a n d  effi c a c y 
a n al ys es . 
3. 2. 2.    
Dis p ositi o n  of  S u bj e cts   
S u bj e cts   w h o i niti at e s cr e e ni n g  b ut  ar e  n ot r a n d o  mi z e d   will  b e  c o nsi d er e d s cr e e n f ail ur es.   A 
r a n d o  mi z e d s u bj e ct   w h o is  eli gi bl e t o r e c ei v e t h e  n al o x o n e  c h all e n g e   will  b e  c o nsi d er e d  a 
tr e at  m e nt  c o  m pl et er.  S u bj e cts  c o  m pl eti n g  all  visits  d uri n g t h e F oll o  w- u p  P eri o d   will  b e 
c at e g ori z e d  as  c o  m pl eti n g t h e st u d y.  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
1 1  
 
 
 
S u bj e ct  dis p ositi o n  will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all   f or all r a n d o  mi z e d 
s u bj e cts,  a n d i n cl u d es t h e f oll o  wi n g: 
•    S u bj e cts   w h o   w er e r a n d o  mi z e d  
•    S u bj e cts i n t h e  S af et y  P o p ul ati o n   
•    S u bj e cts   w h o  w er e tr e at  m e nt  c o  m pl et er  s (s u bj e cts  eli gi bl e t o r e c ei v e t h e  n al o x o n e 
c h all e n g e)   
•    S u bj e cts   w h o r e c ei v e d t h e  n al o x o n e  c h all e n g e  o n   D a y  8/ 8 a  
•    S u bj e cts   w h o r e c ei v e d t h e   VI  VI T  R  O L i nj e cti o n  
•    S u bj e cts   w h o  c o  m pl et e d t h e tr e at  m e nt  (s u bj e ct st at us i n  dis p ositi o n   C  R F  p a g e) 
•    S u bj e cts   w h o  c o  m pl et e d t h e st u d y 
•    S u bj e cts   w h o  dis c o nti n u e d t h e st u d y  d uri n g t h e  T r e at  m e nt P eri o d  
•    S u bj e cts   w h o  dis c o nti n u e d t h e st u d y  d uri n g t h e  F oll o  w - u p  P eri o d  
•    R e as o ns f or  dis c o nti n u ati o n 
P er c e nt a g es  of  dis p ositi o n  ar e  b as e d  o n t h e s u bj e cts i n t h e  S af et y  P o p ul ati o n . A listi n g  of 
dis p ositi o n   will  b e  pr o vi d e d f or  all s u bj e cts.  
3. 2. 3.    
P r ot o c ol   D e vi ati o ns 
S u bj e cts   wit h   m aj or  pr ot o c ol  d e vi ati o ns   will  b e s u  m  m ari z e d  b y  tr e at  m e nt  gr o u p  a n d  o v er all, 
al o n g   wit h s u p p orti v e listi n gs,  f or  e a c h of t h e f oll o  wi n g  c at e g or i es: 
•    Di d  n ot   m e et t h e i n cl usi o n/ e x cl usi o n  crit eri a    
•    R e c ei v e d  pr o hi bit e d   m e di c ati o ns  
•    F ail e d t o  a d h er e t o t h e  pr ot o c ol: 
−    F ail ur e  t o r e  m ai n i n s e c ur e i n p ati e nt r esi d e nti al  ar e as f or t h e  d ur ati o n  of t h e 
r esi d e nti al  p eri o d. 
−    Miss e  d   m or e t h a n  a si n gl e  d a y  of st u d y   m e di c ati o n  d uri n g t h e l e a d-i n  p eri o d, 
D a ys   - 5 t o - 3 
−    Miss e  d   m or e t h a n  a si n gl e  d a y  of st u d y   m e di c ati o n  d uri n g t h e r esi d e nti al 
tr e at  m e nt  p eri o d  
−    F ail ur e t o  p erf or  m  pr e- VI  VI T  R  O L  n al o x o n e  c h all e n g e  as i n di c at e d  a n d s u bj e ct 
re c ei v es   VI  VI T  R  O L.  
−    F ail ur e t o  c o  m pl y   wit h st u d y  pr ot o c ol r e g ar di n g s u bj e cts   w h o  d o  n ot tr a nsiti o n t o 
VI  VI T  R  O L (s e e s e cti o n  8. 3. 3 f or  d et ail e d i nstr u cti o ns r e g ar di n g r ei nst at e  m e nt  of 
B  U P/  N x tr e at  m e nt  a n d  n otifi c ati o n  of/r ef err al  b a c k t o   B  U P  pr o vi d er).  T his 
i n cl u d es ( 1) f ail ur e t o r ef er t h os e s u bj e cts   w h o  h a v e tr a nsiti o n e d fr o  m   B  U P  b ut 
h a v e  n ot r e c ei v e d   VI  VI T  R  O L t o  a   B  U P  pr o vi d er;  a n d ( 2) f ail ur e t o r ei niti at e   B  U P 
i n t h es e s u bj e cts  pri or t o  dis c h ar g e. 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
1 2  
 
 
 
•    R a n d o  mi z ati o n  or  d osi n g  err or 
•    Ot h er   m aj or  d e vi ati o ns (s u c h   as  d u pli c at e s u bj e ct,  or f ail ur e t o  dis c o nti n u e  d osi n g if 
g ati n g   C  O  W S  is n ot  d o n e  or is  o ut  of r a n g e) 
D u pli c at e s u bj e cts i n cl u d e s u bj e cts   w h o  ar e  e nr oll e d   m ulti pl e ti  m es i n t h e s a  m e st u d y.   D uri n g 
t h e  c o n d u ct  of t his st u d y,  d at a (  C  R F  a n d s o ur c e) will  b e   r e vi e  w e d t o i d e ntif y  d u pli c at e s u bj e cts 
a n d sit es  will  b e    c o nt a ct e d t o i n v esti g at e  a n d  c o nfir  m.   U p o n  c o nfir  m ati o n,  d u pli c at e s u bj e cts will 
b e  pr o hi bit e d fr o  m f urt h er  p arti ci p ati o n i n t h e tri al  a n d   w ill  b e  dis c o nti n u e d fr o  m t h e st u d y. 
B y  e nr olli n g i n t h e s  t u d y  a s e c o n d ti  m e, t h es e s u bj e cts  g o  a g ai nst t h e s pirit  of t h e  pr ot o c ol   w hi c h 
is t o  ass ess t h e  effi c a c y, s af et y  a n d t ol er a bilit y  of t h e   A L  K S  6 4 2 8 r e gi  m e n i n  a  p ati e nt  p o p ul ati o n 
t h at is  pr es u  m a bl y  n aï v e t o t h e r e gi  m e n.  T h e  d at a  c oll e ct e d  o n t h es e s u bj e cts  d uri n g t h eir s e c o n d 
e nr oll  m e nt  ar e t h er ef or e  u nr eli a bl e , as t h eir  e x p eri e n c e  d uri n g t h eir first  e nr oll  m e nt   m a y  h a v e 
i  m p a ct e d t h eir  o ut c o  m e i n t h e s e c o n d  e nr oll  m e nt.   B e c a us e  d at a fr o  m t h e s e c o n d  e nr oll  m e nt 
c o ul d  p ot e nti all y   misi nf or  m  a n d  a d v ers el y i nfl u e n c e t h e i nt er pr et ati o n  of t h e st u d y,  t h es e  d at a 
will  b e   i n cl u d e d i n t h e s af et y  a n al ys es  b ut e x cl u d e d fr o  m t h e  effi c a c y  a n al ys es.  
3. 3.    
D e  m o g r a p hi c  a n d   B as eli n e   C h a r a ct e risti cs   
D e  m o gr a p hi cs  a n d  b as eli n e  c h ar a ct eristi cs s u c h   as  g e n d er,  a g e,  r a c e,  et h ni cit y,   w ei g ht, h ei g ht 
a n d  b o d y   m ass i n d e x ( B  MI  ), will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e   S af et y 
P o p ul ati o n.  Ot h er  b as eli n e  c h ar a ct eristi cs s u c h  as   B  U P   m ai nt e n a n c e  d os e ( < 8   m g/ d a y  vs  8 
m g/ d a y)  ,  al c o h ol  br e at h test  r es ults,   Mi ni-M e nt al  St at e  E x a  mi n ati o n (  M  M S E  ) s c or e,   V  A S/ 
C  O  W S  /S  O  W S s c or es ,  p u pil  di a  m et er,   H  A  M-D t ot al s c or e,   S h ort   Mi c hi g a n   Al c o h ol  S cr e e ni n g 
T es et ( S  M  A S T ) s c or e,   B  A  C  S y  m b ol   C o di n g t est s c or e,   C  O  W  A t as k s c or e,   W  M S-III  S S t est 
s c or e,   C P T s c or e,  a n d  T  A P  s c or e will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e 
S af et y  P o p ul ati o n. 
M e di c al    hist or y will    b e  s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e S af et y  P o p ul ati o n. 
D e  m o gr a p hi c,  b as eli n e  c h ar a ct eristi cs  a n d   m e di c al  hist or y listi n gs   will  b e  pr o vi d e d f or  all 
s u bj e cts. 
3. 4.    
P ri o r,  C o n c o  mit a nt  a n d   A n cill a r y   M e di c ati o ns   
Pri or   m e di c ati o ns  ar e  d efi n e d  as   m e di c ati o ns t a k e n  pri or t o t h e first  d os e  of st u d y  dr u g. 
C o n c o  mit a nt   m e di c ati o ns  ar e  d efi n e d  as   m e di c ati o ns t a k e n  o n  or  aft er t h e first  d os e   of  st u d y 
dr u g.   All   m e di c ati o ns  as  d o c u  m e nt e d  b y t h e I n v esti g at or   will  b e  c o d e d  usi n g t h e   W orl d   H e alt h 
Or g a ni z ati o n   A n at o  mi c al  T h er a p e uti c   C h e  mi c al (  W  H  O  -  A T  C)  dr u g  di cti o n ar y  E n h a n c e d  v ersi o n 
M ar c h  2 0 1 6.  S  u bj e cts  als o r e c ei v e  st a n di n g  d os es  of  t h e  a n cill ar y   m e di c ati o ns ( d efi n e d i n 
Pr ot o c ol  S e cti o n  8. 9. 2)  t o tr e at s y  m pt o  ms  of   wit h dr a  w al. 
Pri or  a n d  c o n c o  mit a nt   m e di c ati o ns , i n cl u di n g  a n cill ar y   m e di c ati o ns, will  b e s u  m  m ari z e d  b y 
tr e at  m e nt  gr o u p  a n d  o v er all f or t h e S af et y  P o p ul ati o n .  F or t h e s u  m  m ar y t a bl es, if  a s u bj e ct  h as 
t a k e n  a m e di c ati o n   m or e t h a n  o n c e, t h e s u bj e ct   will  b e  c o u nt e d  o nl y  o n c e f or t h e   m e di c ati o n. 
All  pri or    a n d  c o n c o  mit a nt m e di c ati o n  s, i n cl u di n g  a n cill ar y   m e di c ati o ns will  b e list e d  . 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
1 3  
 
 
 
3. 5.    
T r e at  m e nt   A d h e r e n c e   R at e  a n d   E xt e  nt  of   E x p os u r e  
3. 5. 1.    
T r e at  m e nt   A d h e r e n c e   R at e   
St u d y  dr u g  a d  mi nistr ati o n   will  b e  eit h er  dir e ctl y  o bs er v e d ( or al  n altr e x o n e/ B  U P    a n d 
P  B  O -N/  B  U P  )  or  a d  mi nist er e d (  VI  VI T  R  O L i nj e cti o ns)  b y  cli ni c al st u d y st aff. T h er ef or e, t h e 
tr e at  m e nt  a d h er e n c e r at e   will  b e  d eri v e d  dir e ctl y  usi n g t h e f oll o  wi n g f or  m ul a: 
A d h er e n c e r at e  =  n u  m b er  o  f  d a ys   wit h st u d y  dr u g t a k e n ÷  n u  m b er  of  d a ys i n  att e n d e d i n 
T r e at  m e nt P eri o d  × 1 0 0.  
A n y  d e vi ati o ns  or tr e at  m e nt  n o n- a d h er e n c e iss u es   will  b e r e c or d e d  b y t h e  p ers o n  o bs er vi n g   or 
a d  mi nist eri n g t h e tr e at  m e nt.  Tr e at  m e nt  a d h er e n c e r at e   will  b e s u  m  m ari z e d f or  t h e  S af et y 
P o p ul ati o n  b y tr e at  m e nt  gr o u p  a n d  o v er all f or  t h e T r e at  m e nt P eri o d  (  D a ys  1  – 7). I n  a d diti o n, t h e 
n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   w h o  c o  m pl et e d  o n e  d a y, t  w o  d a ys  a n d  u p t o s e v e n  d a ys  of 
tr e at  m e nt   will  b e s u  m  m ari z e d  a n d t a b ul at e d. 
3. 5. 2.    
E xt e nt  of   E x p os u r e 
E x p os ur e  ( d a ys) t o st u d y  dr u g is  d efi n e d  as t h e  n u  m b er  of  d a ys fr o  m t h e  d at e t h e first  d os e  of 
st u d y  dr u g w as   t a k e n t o t h e  d at e t h e l ast  d os e   w as t a k e n, i n cl usi v e (i e, l ast  d os e  d at e –  first  d os e 
d at e  +  1)  d uri n g t h e  Tr e at  m e nt  P eri o d  (  D a ys  1  – 7).  E x p os ur e t o st u d y  dr u g   will  b e s u  m  m ari z e d 
b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n  usi n g  d es cri pti v e st atisti cs ( n u  m b er  of 
s u bj e cts,   m e a n,  S  D,   mi ni  m u  m,   m e di a n,  a n d  m a xi  m u  m).   
3. 6.    
Effi c a c y   A n al ys es   
3. 6. 1.    
G e n e r al   C o nsi d e r ati o ns   
 
Effi c a c y  a n al ys es   will  b e  p erf or  m e d  usi n g t h e  S af et y  P o p ul ati o n. 
All  st atisti c al t ests   will  b e  2  -si d e d   wit h  a t y p e I  err or r at e  of  5  %,  u nl ess  ot h er  wis e  s p e cifi e d.   All 
c o nfi d e n c e i nt er v als   will  b e  2-si d e d  9 5  %  c o nfi d e n c e i nt er v als. 
3. 6. 2.    
P ri  m a r y   Effi c a c y  E n d p oi nt   
T h e  pri  m ar y  effi c a c y  e n d p oi nt is t h e  pr o p orti o n  of s u bj e cts   w h o r e c ei v e d  a n d t ol er at e d 
VI  VI T  R  O L i nj e cti o n  o n   D a y  8/ 8 a  as  d e  m o nstr at e d  b y   mil d  o pi oi d   wit h dr a  w al s y  m pt o  ms 
(  C  O  W S  ≤ 1 2  or  S  O  W S ≤ 1 0) f oll o  wi n g   VI  VI T  R  O L  a d  mi nistr ati o n. 
A t  w o  - p art  n al o x o n e  c h all e n g e   will  b e  a d  mi nist er e d  o n   D a y  8.  S u bj e cts   wit h  a  n e g ati v e  n al o x o n e 
c h all e n g e (i e,  n ot  p h ysi c all y  d e p e n d e nt  o n  o pi oi ds)   will t h e n r e c ei v e  a   VI  VI T  R  O L i nj e cti o n. 
S u bj e cts   w h o  h a v e  a  p ositi v e  n al o x o n e  c h all e n g e  o n   D a y  8 (i e, still  p h ysi c all y  d e p e n d e nt  o n 
o pi oi ds)   will r e p e at   D a y  7   d osi n g  a n d  ass ess  m e nts a n d t h e n t a k e t h e  c h all e n g e  a g ai n t h e  n e xt  d a y  
(  D a y  8 a). 
S u bj e cts  i n t h e  S af et y P o p ul ati o n,  w h o   m e et   t h e f oll o  wi n g t  w o  crit eri a,   will  b e i n cl u d e d i n 
c al c ul ati n g  t h e  pr o p orti o n  of s u bj e cts   w h o r e c ei v e d  a n d t ol er at e d  a   VI  VI T  R  O L i nj e cti o n: 
1.     S u bj e ct r e c ei v es  a   VI  VI T  R  O L i nj e cti o n  o n   D a y  8/ 8 a . 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
1 4  
 
 
 
2.    Aft er t h e   VI  VI T  R  O L i nj e cti o n  o n   D a y  8/ 8 a, t h e s u bj e ct’s  o pi oi d   wit h dr a  w al s y  m pt o  ms 
ar e  mil d (  C  O  W S ≤ 1 2  or  S  O  W S  ≤ 1 0).  T h e  1- h o ur  p ost-  d os e   VI  VI T  R  O L   C  O  W S/ S  O  W S 
ass ess  m e nt  o n   D a y  8/ 8 a   will  b e  us e d f or t his  e v al u ati o n.  
T h e  n u  m er at or is t h e  n u  m b er  of s u bj e cts i n t h e  S af et y  P o p ul ati o n   w h o   m e et t h e t  w o  crit eri a 
a b o v e,  a n d t h e  d e n o  mi n at or is t h e  n u  m b er  of s u bj e cts i n  t h e S af et y  P o p ul ati o n.  T h e  pri  m ar y 
effi c a c y  e n d p oi nt   will  b e  a n al y z e d  usi n g  a l o gisti c r e gr essi o n   m o d el  wit h tr e at  m e nt  a n d 
r a n d o  mi z ati o n str atifi c ati o n f a ct or  of B  U P   m ai nt e n a n c e  d os e ( < 8   m g/ d a y  v ers us  8   m g/ d a y)   as 
f a ct ors.  
T h e  pr o p orti o ns,  diff er e n c e i n  pr o p orti o ns  (  N T  X/  B  U P  vs P  B  O -N/  B  U P)  ,  P- v al u e  a n d o d ds r ati o  
wit h  9 5  %   CI   will  b e s u  m  m ari z e d.   
I n  a d diti o n, t h e   C  O  W S  a n d  S  O  W S s c or es  1  h our  p ost-  VI  VI T  R  O L  o n   D a y  8/ 8 a   will  b e 
s u  m  m ari z e d (n,   m e a n, st a n d ar d  d e vi ati o n,   m e di a n,   mi ni  m u  m,  m a xi  m u  m  ,   C  O  W S  c at e g or y [ ≤ 1 2 
or  > 1 2] ,  a n d  S  O  W S  c at e gor y  [ ≤ 1 0  or  > 1 0])  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e S af et y 
P o p ul ati o n.  T h e  n u  m b er  of s u bj e cts   w h o r e c ei v e  a  VI  VI T  R  O L i nj e cti o n   will  als o  b e 
s u  m  m ari z e d. 
3. 6. 3.    
S e c o n d a r y   Effi c a c y   E n d p oi nts 
T h e s e c o n d ar y  effi c a c y  e n d p oi nts  ar e  d efi n e d  as f oll o  ws: 
•    M e a n s c or e  s f or  “ d esir e f or  o pi oi ds ”   V  A S  d uri n g t h e  Tr e at  m e nt  P eri o d (  D a ys  1/ 1 a- 7);   
VI  VI T  R  O L I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys  8/ 8 a- 1 1);  a n d t h e 
e ntir e st u d y (  D a ys  1/ 1 a- E n d  of  St u d y) 
•    N u  m b er  of  d a ys   wit h   C  O  W S  p e a k s c or e  ≤ 1 2  d uri n g  Tr e at  m e nt  P eri o d  pri or t o t h e 
VI  VI T  R  O L i nj e cti o n (  D a ys  1/ 1 a-  7)  
•    N u  m b er  of  p ost-  VI  VI T  R  O L  d a ys (  D a ys  9  - 1 1) i n   w hi c h s u bj e cts i n  e a c h  gr o u p 
d e  m o nstr at e   mil d (  C  O  W S  ≤ 1 2)  o pi oi d   wit h dr a  w al 
•    M e a n  p e a k   C  O  W S s c or es  d uri n g t h e  Tr e at  m e nt  P eri o d   (  D a ys  1/ 1 a- 7);  an d   VI  VI T  R  O L 
I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys  8/ 8 a- 1 1) 
•    Ar e a  u n d er t h e  c ur v e (  A  U  C) f or   C  O  W S s c or es  d uri n g t h e  Tr e at  m e nt  P eri o d   (  D a ys  1/ 1 a-
7);  a n d   VI  VI T  R  O L  I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys  8/ 8 a- 1 1) 
T h e   m e a n   V  A S s c or e  d uri n g t h e  Tr e at  m e nt  P eri o d  (  D a ys  1/ 1 a-7)  f or  e a c h s u bj e ct i n t h e  S af et y 
P o p ul ati o n  will  b e   d eri v e d  as:  
M e a n   V A S  S c o r e  =
 ∑    V A S  S c o r e   
#  of  V A S  a s s e s s  m e nt s  d u ri n g  D a y s    1 /1 a  t h r o u g h  7 
T h e   m e a n   V  A S s c or e  d uri n g  VI  VI T  R  O L I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d 
(  D a ys 8/ 8 a- 1 1),  a n d t h e  e ntir e st u d y (  D a ys  1/ 1 a- E n d  of  St u d y)   will  b e  d eri v e d  usi n g t h e   m et h o d 
si  mil ar  as t h e   m e a n   V  A S s c or e  d uri n g t h e  Tr e at  m e nt  P eri o d  (  D a ys  1/ 1 a-7).   
T h e   V  A S s c or e  a n d  c h a n g e fr o  m  b as eli n e  d uri n g t h e  Tr e at  m e nt  P eri o d,  d uri n g t h e   VI  VI T  R  O L 
I n d u cti o n  P eri o d,  a n d  d uri n g t h e  P ost-VI  VI T  R  O L   O bs er v ati o n  P eri o ds (  D a ys  1/ 1 a-  1 1)   will  b e 
s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n,   w h er e  b as eli n e   V  A S s c or e 
is  d efi n e d  as th e   m ost r e c e nt  visit  pri or t o   D a y  1. 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
1 5  
 
 
 
T h e   C  O  W S   will  b e  a d  mi nist er e d  4 -6 ti  m es  p er  d a y  d uri n g t h e  Tr e at  m e nt  P eri o d (  D a y  1/ 1 a  –  D a y 
7).   T h e   C  O  W S s c or e is t h e t ot al s c or e f or  all t h e it e  m s c or es.   O n  e a c h  d a y  d uri n g t h e  Tr e at  m e nt 
P eri o d, t h e  hi g h est   C  O  W S s c or e  a  m o n g t h e  4- 6   C  O  W S  a d  mi nist er e d   will  b e i d e ntifi e d  as t h e 
d ail y  p e a k   C  O  W S s c or e.  T h e  n u  m b er  of  d a ys  d uri n g t h e  Tr e at  m e nt  P eri o d   will  b e  c o u nt e d   w h er e 
t h e  d ail y  p e a k   C  O  W S s c or e is  ≤ 1 2.   A  n e g ati v e  bi n o  mi al   m o d el   will  b e  us e d f or t h e  a n al ysis  of 
t h e s e c o n d ar y  e n d p oi nt,  n u  m b er  of  d a ys   wit h   C  O  W S p e a k s c or e  ≤ 1 2  d uri n g  Tr e at  m e nt  P eri o d 
pri or t o t h e   VI  VI T  R  O L i nj e cti o n (  D a ys  1/ 1 a- 7) . T h e   m o d el   will i n cl u d e  t h e  n u  m b er  of  d a ys   wit h 
C  O  W S  p e a k s c or e   ≤ 1 2  as t h e r es p o ns e  v ari a bl e,  t h e tr e at  m e nt  gr o u p  a n d r a n d o  mi z ati o n 
str atifi c ati o n f a ct or  of  B  U P   m ai nt e n a n c  e  d os e ( < 8   m g/ d a y  vs  8   m g/ d a y)  as  pr e di ct ors i n t h e 
a n al ysis.  T h e  o d ds r ati o, st a n d ar d  err or,  9 5  %   CI f or t h e  o d ds  r ati o,  a n d  P-v al u e   will  b e 
s u  m  m ari z e d.  
N u  m b er  of  d a ys   wit h   C  O  W S  p e a k s c or e  ≤ 1 2  d uri n g t h e  T  r e at  m e nt P eri o d   will  b e s u  m  m ari z e d ( n, 
m e a n, st a n d ar d  d e vi ati o n,   m e di a n,   mi ni  m u  m  a n d   m a xi  m u  m)  b y tr e at  m e nt  gr o u p  a n d  o v er all f or 
t h e  S af et y  P o p ul ati o n.  
T h e  n u  m b er  of  p ost- VI  VI T  R  O L  d a ys (  D a ys  9  - 1 1)   wit h   C  O  W S  p e a k s c or e  ≤ 1 2 will  b e   a n al y z e d . 
A   n e g ati v e  bi n o  mi al   m o d el   will  b e  us e d,   wit h t h e  n u  m b er  of  p ost- VI  VI T  R  O L  d a ys (  D a ys  9  - 1 1) 
wit h   C  O  W S  p e a k s c or e  ≤ 1 2   as t h e r es p o ns e  v ari a bl e.  T h e   m o d el   will i n cl u d e t h e tr e at  m e nt  gr o u p 
a n d  r a n d o  mi z ati o n str atifi c ati o n f a ct or  of B  U P   m ai nt e n a n c e  d os e ( < 8   m g/ d a y  vs  8   m g/ d a y)   as 
pr e di c t ors i n t h e  a n al ysis.  T h e o d ds r ati o, st a n d ar d  err or,  9 5  %   CI f or t h e  o d ds  r ati o,  a n d  P-v al u e 
will  b e s u  m  m ari z e d  . 
T h e  d ail y  p e a k   C  O  W S s c or e f or  e a c h s u bj e ct  is  d eri v e d  b as e d  o n t h e  al g orit h  m  d es cri b e d  a b o v e 
f or  e a c h tr e at  m e nt  d a y. T h e   m e a n  p e a k  C  O  W S s c or e   d uri n g t h e  Tr e at  m e nt  P eri o d  (  D a ys  1/ 1 a- 7) 
f or  e a c h s u bj e ct is  d eri v e d  as: 
M e a n   P e a k  C O  W S  S c o r e  =
 ∑   D ail y   P e a k  C O  W S  S c o r e  
N u  m b e r   of  D a y s   wit h   d ail y  P e a k  C O  W S  s c o r e  
T h e  d ail y  p e a k   C  O  W S s c or e  d uri n g  VI  VI T  R  O L I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n 
P eri o d (  D a y s 8/ 8 a- 1 1),  a n d t h e  e ntir e st u d y (  D a ys  1/ 1 a- E n d  of  St u d y)   will  b e  d eri v e d  usi n g t h e 
m et h o d   si  mil ar  as  d ail y  p e a k   C  O  W S s c or e  d uri n g t h e  Tr e at  m e nt  P eri o d  (  D a ys  1/ 1 a-7).   
T h e t ot al   A  U  C   C  O  W S s c or e f or  e a c h s u bj e ct  is  d eri v e d  b as e d  o n t h e  a ct u al ti  m e (i n   mi n ut es) t h e 
C  O  W S   is a d  mi nist er e d  o n  e a c h  d a y  d uri n g  t h e  Tr e at  m e nt  P eri o d (  D a ys  1/ 1 a- 7)  b y  usi n g t h e 
li n e ar tr a p e z oi d al r ul e. T h e t ot al   A  U  C   C  O  W S s c or e  d uri n g t h e tr e at  m e nt  p eri o d  (  D a ys  1/ 1 a- 7) is 
t h e s u  m  m ati o n  of  d ail y   A  U  C   C  O  W S s c or es  d uri n g   D a y  1/ 1 a t hr o u g h D a y   7 . T h e n , t h e 
n or  m ali z e d  A  U  C     C  O  W S s c or e f or  e a c h s u bj e ct  d uri n g   D a y  1/ 1 a t hr o u g h D a y   7  is  d eri v e d  as:  
N o r  m ali z e d   A U C  C O  W S  S c o r e     =
 ∑   D ail y   A U C  C O  W S  S c o r e  
N u  m b e r   of  D a y s   wit h   d ail y  A U C  C O  W S  s c o r e  
T h e  n or  m ali z e d  A  U  C     C  O  W S s c or e  d uri n g   VI  VI T  R  O L I n d u cti o n  a n d  P ost-VI  VI T  R  O L 
O bs er v ati o n  P eri o d (  D a ys  8/ 8 a- 1 1),  a n d t h e  e ntir e st u d y (  D a ys  1/ 1 a- E n d  of  St u d y)   will  b e 
d eri v e d  usi n g t h e   m et h o d  si  mil ar  as t h e  n or  m ali z e d  A  U  C   C  O  W S s c or e  d uri n g t h e  Tr e at  m e nt 
P eri o d (  D a ys  1/ 1 a- 7).   
T h e   m e a n  p e a k   C  O  W S s c or e,  n or  m ali z e d  A  U  C   C  O  W S s c or e  a n d   m e a n   V  A S s c or e   e n d p oi nts 
will  b e  a n al y z e d  usi n g  a n  a n al ysis  of  c o v ari a n c e (  A  N  C  O  V  A)   m o d el.  T h e   m o d el   will i n cl u d e 


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tr e at  m e nt  a n d r a n d o  mi z ati o n str atifi c ati o n f a ct or  of B  U P   m ai nt e n a n c e  d  os e ( < 8   m g/ d a y  vs  8 
m g/ d a y)   as f a ct ors ,  a n d c orr es p o n di n g  b as eli n e  v al u e  as  a  c o v ari at e . T h e l e ast s q u ar es ( L S)   m e a n, 
st a n d ar d  err or ( S E),  a n d  L S   m e a n  diff er e n c e  b et  w e e n  (  N T  X/  B  U P  vs.  P  B  O-N/  B  U P  ) al o n g   wit h 
t h e  9 5  %   CI,   will  b e s u  m  m ari z e d. 
T h e   m e a n  p e a k   C  O  W S s c or e,  n or  m ali z e d  A  U  C   C  O  W S s c or e   a n d   m e a n   V  A S s c or e  d uri n g t h e 
T r e at  m e nt P eri o d  pri or t o t h e   VI  V T  R  O L i nj e cti o n ,  d uri n g t h e   VI  VI T  R  O L I n d u cti o n  P eri o d,  a n d 
d uri n g t h e  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys  1/ 1 a- 1 1)  will  b e s u  m  m ari z e d  b y tr e at  m e nt 
gr o u p  a n d  o v er all f or  t h e S af et y  P o p ul ati o n.  A  d at a listi n g f or   m e a n  p e a k   C  O  W S s c or es, 
n or  m ali z e d  A  U  C   C  O  W S s c or es,  a n d   m e a n   V  A S s c or es   will  b e  pr o vi d e d.  
I n  a d diti o n,  d ail y  p e a k   C  O  W S s c or e,  d ail y  a v er a g e   C  O  W S s c or e,  d ail y  a v er a g e  S  O  W S s c or e  a n d 
d ail y  a v er a g e   V  A S s c or e  d uri n g t h e  Tr e at  m e nt  P eri o d  pri or t o t h e   VI  VI T  R  O L i nj e cti o n,  d uri n g 
t h e   VI  VI T  R  O L I n d u cti o n  P eri o d,  a n d  d uri n g t h e  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys 
1/ 1 a- 1 1)  will  b e s u  m  m ari z e d (  n,   m e a n, st a n d ar d  d e vi ati o n,   m e di a n,   mi ni  m u  m  a n d  m a xi  m u  m  )  b y 
tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n. D at a listi n gs f or   C  O  W S  a n d  S  O  W S s c or es 
at  e a c h st u d y  visit  ass ess  m e nt, i n cl u di n g t h e it e  m s c or es,   will  als o  b e  pr o vi d e d.  
3. 6. 4.    
E x pl o r at o r y   Effi c a c y   E n d p oi nts 
T h e  e x pl or at or y  e n d p oi nts  ar e  d efi n e d  as f oll o  ws :  
•    N u  m b er  a n d  pr o p orti o n  of s u bj e cts i n  P  G  A  R T r es p o ns e  c at e g or y  at t h e  e n d  of t h e  P ost-
VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a y  1 1) 
•    C h a n g e fr o  m  b as eli n e i n  p u pil  di a  m et er f oll o  wi n g st u d y  dr u g  a d  mi nistr ati o n  d uri n g t h e 
Tr e at  m e nt  P eri o d (  D a ys  1/ 1 a- 7) 
•    C h a n g e i n fr e q u e n c y  of s u bst a n c e  us e fr o  m s cr e e ni n g t o   D a y  3 6  ass ess e d  vi  a t h e   Q S  UI  
•    A  U  C f or  S  O  W S s c or es  d uri n g t h e  Tr e at  m e nt  P eri o d  a n d   VI  VI T  R  O L I n d u cti o n  a n d  P ost-
VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys  1/ 1 a- 1 1) 
•    C h a n g e fr o  m  b as eli n e i n st a n d ar di z e d  T s c or es f or  c o g niti v e  ass ess  m e nts 
o    T h e  B  A  C    S y  m b ol   C o di n g t est,  
o    C  O  W  A   t as k,  
o    W  M S  -III S S t est  
o    C P T   
o    T  A P  
T h e  P  G  A  R T   will  b e  us e d t o  ass ess t r e at  m e nt s atisf a cti o n.  T h e  P  G  A  R T  c o nsists  of  o n e it e  m: 
“  H o  w   w o ul d  y o u r at e  y o ur r es p o ns e t o t h e   m e di c ati o n t h at  y o u r e c ei v e d  d uri n g t h e st u d y ? ” It is 
m e as ur e d  o n  a  5  -p oi nt  Li k ert s c al e ( 0  =  P o or,  1  =  F air,  2  =   G o o d,  3  =   V er y   G o o d,  4  =  E x c ell e nt).   
T h e  P  G  A  R T r es p o ns e   will  b e  c at e g ori z e d  as  a  bi n ar y  v ari a bl e ( <  2  a n d  ≥  2).  T h e  c at e g ori z e d 
P  G  A  R T r es p o ns e f or   D a y  1 1   will  b e  a n al y z e d  usi n g t h e l o gisti c r e gr essi o n   m o d el  wit h tr e at  m e nt 
a n d r a n d o  mi z ati o n str atifi c at i o n f a ct or  of B  U P   m ai nt e n a n c e  d os e ( < 8   m g/ d a y  vs  8   m g/ d a y)   as 
f a ct ors. 
T h e  d es cri pti v e st atisti cs f or t h e  P  G  A  R T r es p o ns e  at  e a c h  ass ess  m e nt  visit   will  als o  b e 
s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n.   A  d at a listi n g f or  P  G  A  R T 
at  e a c h st u d y  visit  ass ess  m e nt   will  als o  b e  pr o vi d e d. 


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T h e   m e a n  c h a n g e fr o  m  b as eli n e i n  p u pil  di a  m et er  f or  e a c h  d a y  d uri n g t h e tr e at  m e nt  p eri o d (D a y  s 
1/ 1 a t o  7)  will  b e   a n al y z e d  usi n g  a n   A  N  C O  V  A   m o d el.  T h e   m o d el   will i n cl u d e tr e at  m e nt  a n d 
r a n d o  mi z ati o n str atifi c ati o n f a ct or  of B  U P   m ai nt e n a n c e  d o  s e ( < 8   m g/ d a y  v ers us  8   m g/ d a y)  as 
f a ct ors,  a n d c orr es p o n di n g  b as eli n e  v al u e  as  a  c o v ari at e . T h e l e ast s q u ar es ( L S)   m e a n, st a n d ar d 
err or ( S E),  a n d  L S   m e a n  diff er e n c e  b et  w e e n (  N T  X/  B  U P  vs  P  B  O -N/  B  U P)  al o n g   wit h t h e  9 5  %   CI, 
will  b e s u  m  m ari z e d.   I n  a d diti o n, t h e  p u pil  di a  m et er   will  b e d es cri pti v el y s u  m  m ari z e d  b y 
tr e at  m e nt  gr o u p  a n d  o v er all  at  e a c h  ass ess  m e nt  visit f or t h e S af et y  P o p ul ati o n .   A  d at a listi n g  at 
e a c h  st u d y  visit  ass ess  m e nt   will  b e  pr o vi d e d . 
T h e  c h a n g e i n fr e q u e n c y  of s u bst a n c e  us e fr o  m s cr e e ni n g t o   D a y  3 6   will  b e  ass ess e d  usi n g t h e 
Q u a ntit ati v e  S u bst a n c e   Us e I n v e nt or y (  Q S  UI  ) Q u esti o n  5 a (t h e  n u  m b er  of  d a ys  usi n g  a n y illi cit 
dr u gs).  T h e  b as eli n e  v al u e  of   Q u esti o n  5 a   will  b e s u btr a ct e d fr o  m t h e   D a y  3 6  v al u e  of   Q u esti o n 
5 a.  T his  c h a n g e i n  n u  m b er  of  d a ys  usi n g  a n y illi cit  dr u gs (  Q u esti o n  5 a)  at  D a y   3 6   will  b e 
a n al y z e d  usi n g  a n   A  N C  O  V  A   m o d el   wit h tr e at  m e nt  a n d r a n d o  mi z ati o n str atifi c ati o n f a ct or  of 
B  U P   m ai nt  e n a n c e  d o s e ( < 8   m g/ d a y  vs  8   m g/ d a y)  as f a ct ors ,  a n d c orr es p o n di n g  b as eli n e  v al u e  as 
a  c o v ari at e . T h e l e ast s q u ar es ( L S)   m e a n, st a n d ar d  err or ( S E),  a n d  L S   m e a n  diff er e n c e  b et  w e e n 
(  N T  X/  B  U P  vs.  P  B  O-  N/  B  U P)  al o n g   wit h t h e  9 5  %   CI,   will  b e s u  m  m ari z e d. I n  a d diti o n,  ea c h 
q u esti o n  of t h e   Q S  UI s c al e   will  b e  d es cri pti v el y s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all  at 
e a c h  ass ess  m e nt  visit f or t h e  S af et y  P o p ul ati o n .   A  d at a listi n g  at  e a c h st u d y  visit  ass ess  m e nt   will 
b e  pr o vi d e d. 
T h e  A  U  C f or  S  O  W S s c or es  d uri n g t h e  Tr e at  m e nt  P eri o d  a n d   VI  VI T  R  O L I n d u cti o n  a n d  P ost-
VI  VI T  R  O L   O bs er v ati o n  P eri o d (  D a ys  1/ 1 a- 1 1)   will  b e  d eri v e d  a n d  a n al y z e d  usi n g t h e   A  N  O  V  A 
m o d el si  mil ar t o t h e   m et h o d  us e d f or t h e t ot al   A  U  C   f or C  O  W S s c or es.   
St a n d ar di z e d  T s c or es   will  b e  c al c ul at e d f or  e a c h  o f t h e  c o g niti v e  p ar a  m et ers  at  e a c h  visit 
ass ess  m e nt .  T h e  c h a n g e i n st a n d ar di z e d  T s c or e fr o  m  b as eli n e t o   D a y  2 2  a n d   D a y  3 6   will  b e 
a n al y z e d  usi n g  a n   A  N C  O  V  A   m o d el   r es p e cti v el y, wit h tr e at  m e nt   a n d  r a n d o  mi z ati o n str atifi c ati o n 
f a ct or  of B  U P   m ai nt e n a n c e  d os e (  < 8   m g/ d a y  vs  8   m g/ d a y)  as f a ct ors ,  a n d  c orr es p o n di n g  b as eli n e 
v al u e  as  a  c o v ari at e . I n  a d diti o n,  e a c h  p ar a  m et er   will  b e d es cri pti v el y  s u  m  m ari z e d  at  e a c h  visit 
ass ess  m e nt  b y tr e at  m e nt  gr o u p  a n d  o v er all  f or t h e S af et y  P o p ul ati o n.  A  d at a listi n g  at  e a c h st u d y   
visit  ass ess  m e nt   will  b e  pr o vi d e d.  
T h e f oll o  wi n g  gr a p hi c al  dis pl a ys   will  b e  pr es e nt e d  b y tr e at  m e nt  gr o u p: 
•    Pl ot  of    M e a n   ( S E)  D ail y  P e a k   C  O  W S  S c or e  d uri n g   t h e  Tr e at  m e nt  P eri o d  pri or  t o  t h e 
VI  VI T  R  O L  i nj e cti o n,   d uri n g   t h e    VI  VI T  R  O L  I n d u cti o n   P eri o d,  a n d  d uri n g   t h e   P ost-
VI  VI T  R  O L   O bs er v ati o n  P eri o d.  
•    Pl ot  of   M e a n  ( S E) D ail y   A v er a g e   C  O  W S  S c or e   d uri n g  t h e Tr e at  m e nt  P eri o d  pri or t o t h e 
VI  VI T  R  O L  i nj e cti o n,   d uri n g   t h e    VI  VI T  R  O L  I n d u cti o n   P eri o d,  a n d  d uri n g   t h e   P ost-
VI  VI T  R  O L   O bs er v ati o n  P eri o d. 
•    Pl ot  of   M e a n  ( S E) D ail y   A v er a g e  S  O  W S  S c or e   d uri n g  t h e Tr e at  m e nt  P eri o d  pri or t o t h e 
VI  VI T  R  O L  i nj e cti o n,   d uri n g   t h e    VI  VI T  R  O L  I n d u cti o n   P eri o d,  a n d  d uri n g   t h e   P ost-
VI  VI T  R  O L   O bs er v ati o n  P eri o d. 
•    Pl ot  of    M e a n   ( S E)  D ail y    A v er a g e    V  A S  s c or e   d uri n g    Tr e at  m e nt   P eri o d  pri or  t o  t h e 
VI  VI  T  R  O L  i nj e cti o n,   d uri n g   t h e    VI  VI T  R  O L  I n d u cti o n   P eri o d,  a n d  d uri n g   t h e   P ost-


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VI  VI T  R  O L   O bs er v ati o n  P eri o d. 
3. 7.    
S af et y   A n al ys es  
T h e s af et y  a n al ysis   will  b e  c arri e d  o ut  usi n g t h e  S af et y  P o p ul ati o n.  S af et y  ass ess  m e nts   will  b e 
s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs  al o n g   wit h s u p p orti v e listi n gs  b as e d  o n  o bs er v e d  v al u es. 
Listi n gs   will  b e  pr o vi d e d f or  all s af et y  p ar a  m et ers.   
3. 7. 1.    
A d v e rs e   E v e nts   
A d v ers e  e v e nts   will  b e  c o d e d  b y  S yst e  m   Or g a n   Cl ass  a n d  Pr ef err e d  T er  m  usi n g t h e   M e di c al 
Di cti o n ar y f or   R e g ul at or y   A cti viti es (  M e d  D  R  A ® )   V ersi o n  1 9. 1.  T h e  v er b ati  m t er  m   will  b e 
i n cl u d e d i n t h e   A E listi n gs. 
A n   A E   will  b e  c o nsi d er e d  as tr e at  m e nt   e  m er g e nt   A E ( T E  A E) if t h e  e v e nt  st arts  or   w ors e ns  o n  or 
aft er t h e  d at e  of first  d os e  of st u d y  dr u g .  F or t h e  d et er  mi n ati o n  of t h e  T E  A Es  d uri n g t h e 
T r e at  m e nt P eri o d,   A Es   wit h t h e  gr e at est s e v erit y  b ef or e t h e  b as eli n e   will  b e  us e d  as t h e 
b e n c h  m ar k f or  c o  m p aris o n   wit h t h e   A Es  o c c urri n g  d uri n g t h e  T r e at  m e nt P eri o d.  T h e  T r e at  m e nt 
P eri o d is  d efi n e d  as t h e  first  d os e st art  d at e t o  d at e  of E  O T , i n cl usi v e. T h e  T E  A E   will  b e 
s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or  S af et y  P o p ul ati o n. 
N e  wl y  -e  m er g e nt   A Es (  N E  A Es),  d efi n e d  as   A Es t h at st art e d  or   w ors e n e d  aft er t h e  d at e  of t h e 
E  O T  visit,   will  als o  b e s u  m  m ari z e d.  T h e   A Es   wit h t h e  gr e at est s e v erit y  o n  or  b ef or e t h e  d at e  of 
t h e  E  O T  visit   will  b e  us e d  as t h e  b e n c h  m ar k f or t h e  c o  m p aris o n  of t h e   A Es  o c c urri n g  d uri n g t h e 
F oll o  w- u p  P eri o d.  T h e  F oll o  w- u p  P eri o d is  d efi n e d  as t h e  p eri o d  b et  w e e n t h e  d at e  of  t h e E  O T 
visit  pl us  1  d a y  a n d t h e l ast st u d y  visit, i n cl usi v e. 
All     A Es   will  b e list e d  b y s u bj e ct  b ut  o nl y  T E  A Es, s eri o us   A Es (S  A Es ),   A Es l e a di n g t o st u d y 
dis c o nti n u ati o n,  a n d   N E  A Es   will  b e i n cl u d e d i n t h e s u  m  m ar y t a bl es.  S u  m  m ar y t a bl es   will  b e 
pr o vi d e d f or t h e  T r e at  m e nt P eri o d  a n d  F oll o  w- u p  P eri o d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e 
S af et y  P o p ul ati o n.  T h e    A E l e a di n g t o st u d y  dis c o nti n u ati o n  a n d  S  A Es l e a di n g t o  d e at h,   will  b e 
s u  m  m ari z e d i n t h e  p eri o d   w h e n t h e  dis c o nti n u ati o n  or  d e at h  o c c urr e d. 
A n  o v er vi e  w t a bl e, i n cl u di n g  n u  m b er  of s u bj e cts   wit h  T E  A Es,   A Es l e a di n g t o   st u d y 
dis c o nti n u ati o n,  S  A Es  a n d st u d y  dr u g r el at e d  T E  A Es   will  b e  pr o vi d e d.  
T h e  f oll o  wi n g s u  m  m ar y t a bl es   will  b e  pr o d u c e d f or t h e  Tr e at  m e nt P eri o d f or t h e  S af et y 
P o p ul ati o n: 
•    T E  A Es  b y  S yst e  m   Or g a n   Cl ass  a n d  Pr ef err e d  Ter  m  
•    T E  A Es  e x p eri e n c e d  b y  ≥ 5  %  of s u bj e ct s  
•    T E  A Es  b y  S yst e  m   Or g a n   Cl ass,  Pr ef err e d  Ter  m,  a n d  S e v erit y  
•    Dr u g  -R el at e d  T E  A Es  b y  S yst e  m   Or g a n  Cl ass,   a n d  Pr ef err e d  Ter  m  


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I n  a d diti o n, t h e   A E  o v er vi e  w t a bl e  a n d   A Es  b y  S yst e  m   Or g a n   Cl ass  a n d  Pr ef err e d  T er  m f or 
N E  A Es  d uri n g t h e  F  oll o  w - u p  P eri o d   will  b e  pr o vi d e d. 
A  ll   A E t a bl es   will  b e s ort e d  b y  S yst e  m   Or g a n   Cl ass  a n d t h e n  Pr ef err e d  T er  m i n  d e cr e asi n g 
fr e q u e n c y  b as e d  o n t h e “ all  s u bj e cts”  c ol u  m n. 
A s u bj e ct  h a vi n g t h e s a  m e   A E ( as  d et er  mi n e d  b y t h e  c o d e d   M e d  D  R  A   pr ef err e d t er  m)   m or e t h a n 
o n c e   will  b e  c o u nt e d  o nl y  o n c e i n t h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts'  c al c ul ati o n f or t h at   A E. 
Si  mil arl y, if  a s u bj e ct  h a d   m or e t h a n  o n e   A E i n  a  S yst e  m   Or g a n   Cl ass, t h e s u bj e ct   will  b e 
c o u nt e d  o nl y  o n c e i n t h e t ot al  n u  m b er  of s u bj e cts   wit h  a n   A E f or t h at  S yst e  m   Or g a n   Cl ass. If  a 
s u bj e ct  h a d t h e s a  m e   A E  o n   m ulti pl e  o c c asi o ns, t h e  hi g h est s e v erit y (s e v er e  >   m o d er at e  >   mil d) 
r e c or d e d f or t h e  e v e nt   will  b e  pr es e nt e d i n t h e   A E  b y s e v erit y s u  m  m ar y.  Si  mil arl y, if  a s u bj e ct 
h a d  t h e s a  me   A E  o n   m ulti pl e  o c c asi o ns, t h e  cl os est r el ati o ns hi p (r el at e d  >  n ot r el at e d,   w h er e 
r el at e d i n cl u d es  d efi nit el y r el at e d,  pr o b a bl y r el at e d,  a n d  p ossi bl y r el at e d;  a n d  n ot r el at e d i n cl u d es 
pr o b a bl y  n ot r el at e d  a n d  d efi nit el y  n ot r el at e d) r e c or d e d f or t h e  e v e nt  will  b e  pr es e nt e d i n t h e   A E 
b y r el ati o ns hi p s u  m  m ar y.   
All   A Es   will  b e i n cl u d e d i n t h e listi n gs.  T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  at l e ast  o n e 
S  A E   will  b e s u  m  m ari z e d  b y  S yst e  m   Or g a n   Cl ass  a n d  Pr ef err e d  T er  m f or t h e  S af et y  P o p ul ati o n. 
A  d v ers e  e v e nt s l e a di n g t o  dis c o nti n u ati o n   will  b e s u  m  m ari z e d si  mil arl y.  S u p p orti n g listi n gs  of 
S  A Es  a n d   A Es l e a di n g t o st u d y  dis c o nti n u ati o n   will  b e  pr o vi d e d.  S u bj e cts   w h o  di e d  d uri n g t h e 
st u d y   will  als o  b e list e d . 
3. 7. 2.    
Cli ni c al   L a b o r at o r y  P a r a  m et e rs   
L a b or at or y  p ar a  m et ers   will  b e  pr es e nt e d i n  c o n v e nti o n al  u nits.   O nl y s c h e d ul e d l a b or at or y 
p ar a  m et ers   will  b e i n cl u d e d i n t h e s u  m  m ari es.   All l a b or at or y  d at a, i n cl u di n g t h os e  c oll e ct e d  at 
u ns c h e d ul e d  visits,   will  b e i n cl u d e d i n t h e listi n gs.  L a b or at or y r es ults ( b as eli n e  a n d  c h a n g e fr o  m 
b as eli n e) f or  c h e  mistr y  a n d  h e  m at ol o g y  p ar a  m et ers  f or  e a c h  visit  d uri n g t h e  e ntir e st u d y will  b e 
s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n. 
F or  uri n al ysis, t h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts  e x p eri e n ci n g  a b n or  m aliti es  at  a n y  p ost -
b as eli n e  visit   will  b e s u  m  m ari z e d. I n  a d diti o n, t h e   n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  v al u es 
c o nsi d er e d  p ot e nti all y  cli ni c all y si g nifi c a nt ( P  C S)  o c c urri n g  at  a n y  p ost- b as eli n e  visit f or 
s el e ct e d  p ar a  m et ers   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all  f or t h e S af et y 
P o p ul ati o n. 
Cli ni c al l a b or at or y t est  v al u es, s c h e d ul e d  or  u ns c h e d ul e d,   will  b e  c o nsi d er e d  P  C S if t h e y   m e et 
t h e crit eri a list e d i n  T a bl e   1. T h e  p er c e nt a g e   will  b e  c al c ul at e d   w h er e t h e  n u  m er at or is t h e 
n u  m b er  of s u bj e cts i n t h e  S af et y  P o p ul ati o n  wit h   n o n- P  C S  v al u es  at  b as eli n e  a n d  P  C S  v al u es  at 
a n y  p ost b as eli n e  ass ess  m e nt;  a n d t h e  d e n o  mi n at or is t h e  n u  m b er  of s u bj e cts i n t h e  S af et y 
P o p ul ati o n   wit h  n o n- P  C S  v al u es  at  b as eli n e  a n d  at l e ast  o n e  p ost -b as eli n e  ass ess  m e nt . A 
s u p p orti v e listi n g   will  pr es e nt  all  v al u es  of  a  p ar a  m et er f or s u bj e cts   wit h  at l e ast  o n e  P  C S  v al u e 
f or t h at  p ar a  m et er. 
T h e f oll o  wi n g  gr a p hi c al  dis pl a ys   will  b e  pr es e nt e d  b y tr e at  m e nt  gr o u p: 
•    M e a n   ( S E) c h a n g e fr o  m  b as eli n e  o v er ti  m e  f or s el e ct e d c h e  mistr y  a n d  h e  m at ol o g y 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 0  
 
 
 
l a b or at or y  p ar a  m et ers.   
Pr e g n a n c y  a n d  dr u g t est  d at a   will  b e list e d . 
P ositi v e  o pi oi d  uri n e  dr u g s cr e e n r es ults   will  b e s u  m  m ari z e d f or  e a c h  visit  d uri n g t h e  e ntir e st u d y 
b y tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n.   O pi oi d  uri n e  dr u g s cr e e n t ests i n cl u d e 
M et h a d o n e,   O pi at e  ,   B u pr e n or p hi n e  a n d   O x y c o d o n e.   A n y  p ositi v e t esti n g r es ults i n t h es e 
c at e g ori es   will  b e  c o u nt e d  as  “ P ositi v e ”.   B as eli n e  f or t h e  o pi oi d  uri n e  dr u g s cr e e n is  d efi n e d  as 
l ast  n o n-  missi n g r e c or d  b ef or e  d os e st art  d at e/ti  m e,   w hi c h i n cl u d es  uri n e  dr u g s cr e e n t ests fr o  m 
eit h er  t h e s cr e e ni n g  visit,   B  U P  L e a d -i n   Visit  or   V 5   D a y  1   Visit. 
T a bl e  1:   
P  C S   C rit e ri a f o r   L a b o r at o r y  P a r a  m et e rs   
C at e g o r y   
P a r a  m et e r  
C rit e ri a   
H e  m at ol o g y      
E osi n o p hils  
> 1. 0 × 1 0 3/ u L 
H e  m at o crit    
≤ 3 2  % ( F e  m al e)  
≤ 3 7  % (  M al e)  
H e  m o gl o bi n    
≤ 9. 5  g/ d L ( F e  m al e)  
≤ 1 1. 5  g/ d L (  M al e)  
L e u k o c yt es  
≤ 2. 8 × 1 0 3/ u L 
≥ 1 6 × 1 0 3/ u L 
L y  m p h o c yt e s  
< 1. 0 × 1 0 3/ u L 
N e utr o p hils,   A bs ol ut e   
< 1. 5 × 1 0 3/ u L 
Pl at el ets   
< 7 5. 1 × 1 0 3/ u L 
≥ 7 0 0 × 1 0 3/ u L 
C h e  mistr y   
 
Al a ni n e   A  mi n otr a nsf er as e   (  U/ L)   
≥ 3  ×  U L  N   
Al b u  mi n   
< 2. 5  g/ d L  
Al k ali n e  P h os p h at a s e   (  U/ L)   
≥ 3  ×  U L  N   
As p art at e   A  mi n otr a nsf er a s e   (  U/ L)   
≥ 3  ×  U L  N   
Bl o o d   Ur e a   Nitr o g e n   (  B  U  N)   
> 3 0   m g/ dl  
Cr e ati n e   Ki n a s e (  U/ L)   
≥ 3  ×  U L  N   
Cr e ati ni n e   
≥ 2   m g/ d L  
G a  m  m a   Gl ut a  m yltr a nsf er as e     
≥ 3  ×  U L  N   
Gl u c os e   
< 5 0   m g/ d L   
> 2 0 0   m g/ d L  
L a ct at e   D e h y dr o g e n as e  (  U/ L)   
> 3  ×  U L  N   
C hl ori d e   
≤ 9 0   m  m ol/ L  
≥ 1 1 8  m  m ol/ L   
P ot assi u  m  
< 3   m  m ol/ L  
> 5. 5   m  m ol/ L  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 1  
 
 
 
C at e g o r y   
P a r a  m et e r  
C rit e ri a   
S o di u  m  
< 1 3 0   m  m ol/ L  
> 1 5 0   m  m ol/ L  
T h yr oi d sti  m ul ati n g  h or  m o n e ( T S  H)    
> 5. 5  uI  U/  m L  
T ot al   Bilir u bi n  
≥ 2. 0   m g/ d L  
Uri n al ysis   
Gl u c os e   
at l e ast  2 +  
Pr ot ei n  
at l e ast  2 +  
 
3. 7. 3.    
Vit al  Si g ns    a n d   O x y g e n  S at u r ati o n 
Vit al si g ns   a n d  o x y g e n s at ur ati o n f or  e a c h  visit  d uri n g t h e  e ntir e st u d y   will  b e s u  m  m ari z e d  b y 
tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n. All  vit al si g ns    a n d  o x y g e n s at ur ati o n d at a 
will  b e  pr es e nt e d i n t h e s u bj e ct  d at a listi n gs  . 
N u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  vit al si g n  v al u es  c o nsi d er e d  P  C S 
(s e e T a bl e   2) o c c urri n g  at  a n y  p ost- b as eli n e  visit   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d 
o v er all f or  t h e S af et y  P o p ul ati o n.  T h e  n u  m er at or is t h e  n u  m b er  of s u bj e cts i n t h e  S af et y 
P o p ul ati o n  wit h   n o n- P  C S  v al u es  at  b as eli n e  a n d  P  C S  v al u es  at  a n y  p ost -b as eli n e  ass ess  m e nt;  a n d 
t h e  d e n o  mi n at or is t h e  n u  m b er  of s u bj e cts i n t h e  S af et y  P o p ul ati o n   wit h  n o n-P  C S  v al u es  at 
b as eli n e  a n d  at l e ast  o n e  p ost- b as eli n e  a ss ess  m e nt. A s u p p orti v e listi n g   will  pr es e nt  all  v al u es   of  
a  p ar a  m et er f or s u bj e cts   wit h  at l e ast  o n e  P  C S  v al u e f or t h at  p ar a  m et er . 
I n  a d diti o n,   m e a n  c h a n g e fr o  m  b as eli n e  al o n g   wit h t h e  c orr es p o n di n g  S E   will  b e s u  m  m ari z e d  b y 
visit  a n d tr e at  m e nt  gr o u p f or s yst oli c  bl o o d  pr ess ur e,  di ast oli c  bl o o d  pr ess ur e,  a n d  h e art r at e. 
T h e f oll o  wi n g  gr a p hi c al  dis pl a ys   will  b e  pr es e nt e d  b y tr e at  m e nt  gr o u p: 
•    M e a n   v al u e  a n d   m e a n   c h a n g e fr o  m  b as eli n e  al o n g   wit h t h e  c orr es p o n di n g  S E f or vit al 
si g n  a n d  o x y g e n s at ur ati o n p ar a  m et e rs 
T a bl e  2:   
P  C S  C rit e ri a   f o r Vit al  Si g n   a n d   O x y g e n  S at u r ati o n  P a r a  m et e rs   
P a r a  m et e r  
P  C S   C rit e ri a 
S yst oli c  bl o o d  pr ess ur e 
L o  w:  ≤  9 0  m  m   H g  a n d  d e cr e as e  ≥  2 0   m  m   H g  
Hi g h:   ≥ 1 8 0   m  m   H g  a n d i n cr e as e  ≥  2 0   m  m   H g 
Di ast oli c   bl o o d  pr ess ur e  
L o  w:  ≤  5 0  m  m   H g  a n d  d e cr e as e  ≥  1 5   m  m   H g  
Hi g h:   ≥ 1 0 5   m  m   H g  a n d i n cr e as e  ≥  1 5   m  m   H g 
H e art   R at e   
L o  w:  ≤  5 0  b p  m  a n d  d e cr e as e  ≥  1 5  b p  m 
Hi g h:   ≥ 1 2 0  b p  m  a n d i n cr e as e  ≥  1 5  b p  m 
O x y g e n  S at ur ati o n 
<  9 3  % 
3. 7. 4.    
1 2- L e a d   El e ct r o c a r di o g r a  m (  E  C  G)   
E l e ctr o c ar di o gr a  m p ar a  m et ers ( h e art r at e,   R  R i nt er v al,  P  R i nt er v al,   Q  R S i nt er v al,   Q T i nt er v al, 
Q T c  B [  Q T i nt er v al  c orr e ct e d  usi n g   B a z ett’s   m et h o d],   Q T c F [  Q T i nt er v al  c orr e ct e d  usi n g 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 2  
 
 
 
Fri d eri ci a's   m et h o d])   will  b e s u  m  m ari z e d f or  e a c h  visit  d uri n g t h e  e ntir e st u d y  b y tr e at  m e nt 
gr o u p  a n d  o v er all f or  t h e S af et y  P o p ul ati o n.  
N u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h   Q T c  B  or   Q T c F  p ar a  m et er  v al u es  c o nsi d er e d  P  C S 
o c c urri n g  at  a n y  p ost -b as eli n e  visit   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or  t h e 
S af et y  P o p ul at i o n.   Crit eri a f or  P  C S v al u es  ar e  liste d  i n T a bl e   3 a n d   will  b e  pr es e nt e d f or  e a c h 
p ar a  m et er .   A s u bj e ct   will  b e  c o u nt e d  o nl y  o n c e i n t h e  hi g h est  c at e g or y f or  a  gi v e n  p ar a  m et er 
b as e d  o n t h e l ar g est  p ost- b as eli n e  v al u e.  T h e  p er c e nt a g es   will  b e  c al c ul at e d r el ati v e t o t h e 
n u  m b er  of  s u bj e cts i n t h e  S af et y  P o p ul ati o n wit h  b as eli n e  v al u e  s  ≤ 4 5 0   ms e c  a n d  at l e ast  o n e 
p ost- b as eli n e  ass ess  m e nt.   
A s u p p orti v e listi n g   will  pr es e nt  all  v al u es   of  a  p ar a  m et er f or s u bj e cts   wit h  at l e ast  o n e  P  C S 
v al u e f or t h at  p ar a  m et er . 
T a bl e  3:   
P  C S  C rit e ri a f o r   Q  T c  B  a n d   Q  T c F   
E  C  G  P a r a  m et e r   
P  C S   C rit e ri a  
Q T c  B,   Q T c F   
> 5 0 0   ms e c,  
> 4 8 0 -  ≤ 5 0 0   ms e c  
> 4 5 0 -  ≤ 4 8 0   ms e c 
Q T c  B,   Q T c F   
C h a n g e fr o  m  b as eli n e  of  >  6 0   ms e c   
C h a n g e   fr o  m  b as eli n e  >3 0  t o   ≤ 6 0 ms e c   
3. 7. 5.    
C ol u  m bi a  -S ui ci d e  S e v e rit y   R ati n g  S c al e  
T h e   C -S S  R S is  a  q u esti o n n air e  us e d t o   m e as ur e t h e  pr es e n c e  a n d i nt e nsit y  of  s ui ci d al   b e h a vi or 
a n d  i d e ati o n. 
S ui ci d al  b e h a vi or  a n d s ui ci d al i d e ati o n   will  b e s u  m  m ari z e d  b y tr e at  m e nt  gr o u p  a n d  o v er all f or 
t h e S af et y  P o p ul ati o n.  T h e  pr o p orti o n  of s u bj e cts   w h o   m e et t h e  crit eri o n f or  e a c h  of t h es e 
c at e g ori es   will  b e s u  m  m ari z e d , as  d es cri b e d i n  T a bl e  4 . A listi n g  of r es ults  at  all  visit 
ass ess  m e nts   will  b e  pr o vi d e d. 
 
T a bl e  4:     
C- S S  R S   C at e g o ri es f o r   A n al ysis  
C at e g o r y   
C-  S S  R S It e  m  r es p o ns e is  “ Y  E S  ” 
S ui ci d al  b e h a vi or 
•    Pr e p ar at or y  a cts  or  b e h a vi or  
•    A b ort e d  att e  m pt 
•    I nt err u pt e d  att e  m pt 
•    A ct u al  att e  m pt   
•    C o  m pl et e s ui ci d e   


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 3  
 
 
 
S ui ci d al i d e ati o n  
•    Wis h t o  b e  d e a d 
•    N o n  -s p e cifi c  a cti v e s ui ci d al t h o u g hts  
•    A cti v e s ui ci d al i d e ati o n   wit h  a n y   m et h o ds ( n ot   pl a n)   wit h o ut i nt e nt 
t o  a ct 
•    A cti v e s ui ci d al i d e ati o n   wit h s o  m e i nt e nt t o  a ct,   wit h o ut s p e cifi c 
pl a n  
•    A cti v e s ui ci d al i d e ati o n   wit h s p e cifi c  pl a n  a n d i nt e nt 
 
3. 7. 6.    
Ot h e r   Q u esti o n n ai r es   
Q u esti o n n air e  d at a  c oll e ct e d  d uri n g t h e st u d y (  i e,   M  M S E,   M o nt hs  of t h e   Y e ar B a c k  w ar d 
(  M  O T  Y  B),  S  M  A S T,   H  A  M-  D will  b e  d es cri pti v el y s u  m  m  ari z e d  at  e a c h  ass ess  m e nt  visit  b y 
tr e at  m e nt  gr o u p  a n d  o v er all f or t h e  S af et y  P o p ul ati o n.   A s u p p orti v e listi n g f or  e a c h  q u esti o n n air e 
will   b e  pr o vi d e d. 
3. 8.    
P h a r  m a c o ki n eti c/  P h a r  m a c o d y n a  mi cs  D at a   A n al ysis   
N o  p h ar  m a c o ki n eti c/ p h ar  m a c o d y n a  mi cs  d at a  a n al ysis is  pl a n n e d f or t his st u d y. 
4.    
I  N  T  E  RI  M   A  N  A  L  Y SI S 
N o i nt eri  m  a n al ysis is    pl a n n e d f or t his st u d y. 
5.    
C  H  A  N  G  E S I  N   C  O  N  D  U  C  T   O  R  P  L  A  N  N  E  D   A  N  A  L  Y S  E S  F  R  O  M 
P  R  O  T  O  C  O  L 
T h e  k e y s e c o n d ar y  effi c a c y  e n d p oi nt  w a  s c h a n g e d t o  o n e  of t h e s e c o n d ar y  effi c a c y  e n d p oi nts 
a n d  w as r e d efi n e d  as   “ n u  m b er  of  d a ys   wit h   C  O  W S  p e a k s c or e  ≤ 1 2  d uri n g t h e  T r e at  m e nt P eri o d 
pri or t o t h e   VI  VI T  R  O L i nj e cti o n ”.  A   n e g ati v e  bi n o  mi al r e gr essi o n   m o d el   will  b e  us e d t o  a n al y z e 
t his s e c o n d ar y  e n d p oi nt.  
T h e first s e c o n d ar y  effi c a c y  e n d p oi nt   w as  c h a n g e d t o   M e a n s c or e f or  “ d esir e f or  o pi oi ds ”   V  A S 
d uri n g t h e  Tr e at  m e nt  P eri o d  a n d   VI  VI T  R  O L I n d u cti o n  a n d  P ost-  VI  VI T  R  O L   O bs er v ati o n  P eri o d 
(  D a ys  1/ 1 a- 1 1). 
A n ot h er s e c o n d ar y  effi c a c y  e n d p oi nt   w a  s  c h a n g e d t o  “ n u  m b er  of  p ost- VI  VI T  R  O L  d a ys (  D a ys  9  -
1 1) i n   w hi c h s u bj e cts i n  e a c h  gr o u p  d e  m o nstr at e   mil d  o pi oi d   wit h dr a  w al (  C  O  W S  ≤ 1 2) ”.  A 
n e g ati v e  bi n o  mi al r e gr essi o n   m o d el   will  b e  us e d t o  a n al y z e  t his s e c o n d ar y  e n d p oi nt.  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 4  
 
 
 
6.    
D  E FI  NI  TI  O  N S   A  N  D   C  O  N  V  E  N  TI  O  N S  F  O  R   H  A  N  D  LI  N  G   O F   D  A  T  A   
6. 1.    
A n al ysis   Visit   Wi n d o  ws   
D at as et s p e cifi c ati o ns   will  b e  pr o vi d e d i n  a s e p ar at e  d o c u  m e nt. 
6. 2.    
H a n dli n g   of  P a rti al   D at es  of   C o n c o  mit a nt   M e di c ati o n  
P arti al   st art  d at es   of  pri or  a n d   c o n c o  mit a nt  m e di c ati o ns    will    b e  ass u  m e d   t o  b e  t h e  e arli est 
p ossi bl e  d at e  c o nsist e nt   wit h t h e  p arti al  d at e.  P arti al st o p  d at es  of  pri or  a n d  c o n c o  mit a nt 
m e di c ati o ns   will    b e ass u  m e d  t o  b e t h e l at est  p ossi bl e d at e   c o nsist e nt wit h   t h e p arti al  d at e.  I n 
t h e  c as e  of  a c o  m pl et el y   missi n g st o p  d at e,   m e di c ati o n   will  b e  ass u  m e d t o  b e   o n g oi n g. 
6. 3.    
S af et y  D  at a  H a n dli n g   
All  eff orts  s h o ul d  b e   m a d e t o  o bt ai n t h e   missi n g i nf or  m ati o n fr o  m t h e   In v esti g at or.  F or   C -S S  R S, 
vit al  si g ns,  l a b or at or y  t esti n g  ( c h e  mistr y,   h e  m at ol o g y,   uri n al ysis),   a n d   1 2 -l e a d    E  C  Gs,   o nl y 
o bs er v e d  d at a   will  b e  us e d f or  a n al ys es,  a n d   missi n g  d at a   will  n ot  b e i  m p ut e d.  


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 5  
 
 
 
7.    
G  E  N  E  R  A  L  S  T  A  TI S  TI  C  A  L   M  E  T  H  O  D  O  L  O  G  Y   
7. 1.    
R e p o rti n g  P r e cisi o n   
S u  m  m ar y st atisti cs   will  b e  pr es e nt e d t o t h e f oll o  wi n g  d e gr e e  of  pr e cisi o n,  u nl ess  ot h er  wis e 
s p e cifi e d:  
T a bl e  5:   
D e g r e e  of  P r e cisi o n   
St atisti cs  
D e g r e e  of  P r e cisi o n   
 
M e a n,   M e di a n,   C o nfi d e n c e li  mit  b o u n d ari es   
O n e   m or e t h a n t h e r a  w  d at a,  u p t o   t hr e e d e ci  m al  pl a c es  
St a n d ar d  d e vi ati o n,  St a n d ar d  err or 
O n e   m or e t h a n t h e   m e a n,  u p t o   t hr e e d e ci  m al  pl a c es  
Mi ni  m u  m,   M a xi  m u  m   
T h e s a  m e  as t h e r a  w  d at a,  u p t o  t  w o d e ci  m al  pl a c es  
P- v al u e  
R o u n d e d t o   t hr e e d e ci  m al  pl a c es  a n d t h er ef or e  pr es e nt e d 
as  0. x x x;  P- v al u es s  m all er t h a n  0. 0 0 1  as  “ < 0. 0 0 1 ” ; P-
v al u es  gr e at er t h a n  0. 9 9 9  as  “ > 0. 9 9 9 ” 
P er c e nt a g e  
O n e  d e ci  m al  pl a c e.   A  p er c e nt a g e  of   1 0 0  %   will  b e r e p ort e d 
as  1 0 0. 0 %.  P er c e nt a g es  of  z er o   will  b e r e p ort e d  as  0   
Fr a cti o n al  n u  m eri c  v al u es   will  b e  pr es e nt e d   wit h  a  z er o t o t h e l eft  of t h e  d e ci  m al  p oi nt (f or 
e x a  m pl e,  0. 1 2  –  0. 3 0). 
F or   w ei g ht,  h ei g ht,  a n d   B  MI,  o n e  d e ci  m al  pl a c e   will  b e  us e d f or  s u  m  m ar y st atisti cs. 


Al k er  m es, I n c   
 
St atisti c al   A n al ysis  Pl a n  
A L  K 6 4 2 8-  A 3 0 2 
 
C o nfi d e nti al 
 
 
2 6  
 
 
 
8.    
R  E F  E  R  E  N  C  E   
1.    Al k er  m es   A L  K  6 4 2 8-  A 3 0 2  St u d y  Pr ot o c ol  A  m e n d  m e nt   3  (d at e d  1 4 J u n e  2 0 1 7 ).