Conditions: Opioid Use Disorders
Keywords: Opioid Use Incarceration Vivitrol Patient Navigator Drug Education
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 151
Healthy volunteers: no

Brief summary:
The aim of this trial is to assess the clinical utility, effectiveness, and cost implications of treatment for incarcerated offenders with opioid use disorders who are randomly assigned to one of three treatment conditions to include a depot formulation of naltrexone (XR-NTX, as Vivitrol®) only (XR-NTX), Vivitrol provided with sessions with a patient navigator (PN) XR-NTX+PN, and a drug education procedure (ETAU) before being released to the community. This trial will investigate whether effective medication therapy used in non-incarcerated populations will also be effective in incarcerated individuals. Empirical evidence demonstrates that starting treatment before release greatly increases the probability of successful outcome including reduced alcohol and drug use, increased employment rates, and reduced recidivism rates.

Detailed description:
This randomized, open-label trial will examine the feasibility, efficacy, and net economic benefits of XR-NTX for opioid addiction delivered with and without a platform of PN provided for six months compared against an education (ETAU) condition. Before release from jail, participants in the XR\_NTX and XR-NTX+PN conditions will receive their first Vivitrol injection (and those in the XR-NTX+PN condition will meet with a Patient Navigator) and will then be scheduled for medication management sessions twice monthly for months 1-3, with monthly injections in months 4-6. Participants in the XR-NTX+PN condition will meet with a PN who will provide behavioral assistance to overcome possible barriers to community outpatient treatment and will be provided with referrals for community treatment programs. Participants in the ETAU condition will receive education designed to reduce the likelihood of overdose on the same schedule as the XR-NTX and XR-NTX+PN groups.

Participants will be individuals who meet DSM-5 (Diagnostic and Statistical Manual-5) (via CIDI-2 (composite international diagnostic interview

)) criteria for opioid use disorders, are 18 years and older, who have been detoxified from opioids in the Metropolitan Detention Center in Albuquerque, New Mexico. This study will include only those participants for whom the study physician determines that possible treatment with the study drug is in the best interest, and informed consent will be obtained.

All participants will be scheduled for twice-monthly medical management and assessment appointments for the first three months of the 24-week post-release intervention phase, with monthly appointments for months 4-6. Eligible participants will be randomly assigned to treatment condition (XR-NTX, XR-NTX+PN, ETAU) in equal numbers. XR-NTX and XR-NTX+PN participants will undergo a naloxone challenge to ensure opioid abstinence at the time of Vivitrol induction. Those in the XR-NTX+PN condition will be provided with a PN (patient navigator) who will facilitate attendance at outpatient treatment programs as well as assist with other needs. The ETAU group will not receive any medication but will be scheduled for assessments and education on drugs of abuse, maintaining abstinence, and methods for avoiding overdoses on the same schedule as the other two groups. All groups will also be provided with referrals to community-based substance abuse treatment programs.

Arms:
arm 1: 50 participants will be randomized to the long-acting naltrexone condition (XR-NTX) which will include monthly injections of study drug. arm 2: 50 participants will be randomized to receive long-acting naltrexone (XR-NTX) and will be assigned to a patient navigator (PN). arm 3: 50 participants will be randomized to the drug-education/treatment-as-usual group.

Interventions: intervention 1: XR-NTX intervention 2: XR-NTX+PN intervention 3: ETAU
Intervention descriptions: intervention 1: Monthly injections of XR-NTX will be administered to participants assigned to either the XR-NTX or XR-NTX+PN groups. intervention 2: In addition to long-acting naltrexone (XR-NTX), participants assigned to the XR-NTX+PN condition will meet regularly with a patient navigator to assist in accessing psychosocial services when released from jail. intervention 3: Participants assigned to the ETAU group will receive drug education.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
Injectable Pharmacotherapy for 
Opioid Use Disorders (IPOD) 
 
NCT02110264 
 
Version 1.0 
 
December 2, 2013 
 


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CONTACT INFORMATION 
Principal Investigator: 
David Farabee, PhD 
 
 
 
 
 
Department of Psychiatry & Biobehavioral Sciences 
UCLA Integrated Substance Abuse Programs 
 
University of California, Los Angeles 
 
11075 Santa Monica Blvd., Suite 100 
 
Los Angeles, CA 90025 
 
Phone: (310) 267-5535 
 
Fax: (310) 312-0552 
 
dfarabee@ucla.edu 
Principal Investigator:  
 
Walter Ling, MD 
 
 
 
 
 
UCLA Integrated Substance Abuse Programs 
 
 
 
 
 
University of California, Los Angeles 
 
 
 
 
 
1640 Sepulveda Blvd., Suite 120 
 
 
 
 
 
Los Angeles, CA 90025 
 
 
 
 
 
Phone: (310) 267-5888 
 
 
 
 
 
Fax: (310) 312-0552 
 
 
 
 
 
lwalter@ucla.edu 
 
Investigator: 
 
 
 
Maureen Hillhouse, PhD 
 
 
 
 
 
UCLA Integrated Substance Abuse Programs 
 
 
 
 
 
University of California, Los Angeles 
 
 
 
 
 
1640 Sepulveda Blvd., Suite 120 
 
 
 
 
 
Los Angeles, CA 90025 
 
 
 
 
 
Phone: (310) 267-5308 
 
 
 
 
 
Fax: (310) 312-0552 
 
 
 
 
 
hillhous@ucla.ed 
 
Site Principal Investigator: 
 
Timothy P. Condon, PhD 
 
 
 
 
 
Center on Alcoholism, Substance Abuse and Addictions 
 
 
 
 
 
The University of New Mexico 
 
 
 
 
 
2650 Yale Blvd, Southeast 
 
 
 
 
 
Albuquerque, NM  87106 
 
 
 
 
 
Phone: (505) 925-2319 
 
 
 
 
 
Fax: (505) 925-2301 
 
 
 
 
 
tcondon@unm.edu 
 
Site Investigator: 
 
 
Barbara McCrady, PhD 
 
 
 
 
 
Center on Alcoholism, Substance Abuse and Addictions 
 
 
 
 
 
The University of New Mexico 
 
 
 
 
 
2650 Yale Blvd, Southeast 
 
 
 
 
 
Albuquerque, NM  87106 
 
 
 
 
 
Phone: (505) 925-2388 
 
 
 
 
 
Fax: (505) 925-2301 
 
 
 
 
 
bmccrady@unm.ed


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TABLE OF CONTENTS 
 
1.0 
LIST OF ABBREVIATIONS ............................................................................................ 6 
2.0 
ABSTRACT..................................................................................................................... 7 
2.1 
Study Objective ........................................................................................................... 7 
2.2 
Study Design ............................................................................................................... 7 
2.3    
Study Participants ....................................................................................................... 7 
2.4   
Interventions ............................................................................................................... 7 
2.3 
Assessments ............................................................................................................... 8 
2.4 
Analyses ..................................................................................................................... 8 
3.0 
STUDY SCHEMA ............................................................................................................ 9 
4.0 
INTRODUCTION ........................................................................................................... 10 
4.1 
Background and Rationale ........................................................................................ 10 
4.1.1 
Issues of MAT in Correctional Settings .............................................................. 11 
4.1.2 
Preventing relapse to opioid addiction and reducing HIV transmission ............... 12 
4.2 
Significance of the Project to the Field ...................................................................... 12 
4.3 
Objectives ................................................................................................................. 13 
4.3.1 
Primary Objectives ............................................................................................. 13 
4.3.2 
Secondary Objectives ........................................................................................ 13 
5.0 
STUDY DESIGN ........................................................................................................... 14 
5.1 
Overview of Study Design ......................................................................................... 14 
5.2 
Duration of Study and Clinic Visit Schedule............................................................... 14 
5.3 
Study Population ....................................................................................................... 14 
5.3.1 
Inclusion Criteria ................................................................................................ 14 
5.3.2 
Exclusion Criteria ............................................................................................... 15 
5.4 
Participant Recruitment ............................................................................................. 15 
5.5 
Study Sites ................................................................................................................ 16 
6.0 
OUTCOME MEASURES ............................................................................................... 18 
6.1 
Primary Outcome Measure ....................................................................................... 18 
6.2 
Secondary Outcome Measures ................................................................................. 18 
7.0 
STUDY PROCEDURES ................................................................................................ 19 
7.1 
The Consent Process ................................................................................................ 19 
7.2 
Screening and Baseline ............................................................................................ 19 
7.3 
Random Assignment ................................................................................................. 19 
7.4 
Medication Pre-Induction ........................................................................................... 20 
7.4.1 
Vivitrol Pre-Induction .......................................................................................... 20 
7.5 
Pharmacotherapy ...................................................................................................... 21 
7.5.1 
Extended-release Naltrexone (VI) ...................................................................... 21 
7.6 
Behavioral Treatment ................................................................................................ 21 
7.6.1 
Drug Education (DE) .......................................................................................... 21 
7.6.2 
Patient Navigators (PN) ..................................................................................... 21 


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7.7 
Study Team Training ................................................................................................. 22 
7.8 
Medical Management ................................................................................................ 22 
7.9 
"Rescue" Protocol ..................................................................................................... 22 
7.10 
Discharge, Early Termination, Taper, and Post-study Procedures. ........................... 22 
7.11 
Ancillary Medications ................................................................................................ 22 
7.12 
Concomitant Medications .......................................................................................... 23 
7.12.1 
Study Medication Storage .................................................................................. 23 
7.12.2 
Unused Medication ............................................................................................ 23 
7.12.3 
Dispensing of Study Medications ....................................................................... 23 
7.12.4 
Drug Packaging ................................................................................................. 23 
7.13 
Participant Withdrawal .............................................................................................. 23 
7.14 
Blinding ..................................................................................................................... 24 
7.15 
Participant Reimbursement ....................................................................................... 24 
8.0 
STUDY ASSESSMENTS .............................................................................................. 25 
8.1 
Safety and Medical Measures ................................................................................... 25 
8.1.1 
Medical and Psychiatric History ......................................................................... 25 
8.1.2 
Physical Examination ......................................................................................... 26 
8.1.3 
Injection Site Examination .................................................................................. 26 
8.1.4 
Electrocardiogram (ECG) ................................................................................... 26 
8.1.5 
Clinical Laboratory Tests .................................................................................... 26 
8.1.7 
Pregnancy and Birth Control Assessment .......................................................... 26 
8.1.8 
Vital Signs .......................................................................................................... 26 
8.1.6 
Prior and Concomitant Medications ................................................................... 26 
8.1.7 
Adverse Events (AEs) and Serious Adverse Events (SAEs) .............................. 26 
8.2 
Drug Use Measures and Psychological Measures .................................................... 27 
8.2.1 
Substance Use Report: Timeline Follow-Back (TLFB) ....................................... 27 
8.2.2 
Urine Drug Screen (UDS) .................................................................................. 27 
8.2.3 
Visual Analog Craving Scale (VAS) ................................................................... 27 
8.2.4 
DSM-5 Checklist ................................................................................................ 27 
8.2.5 
Risk Assessment Battery (RAB) ............................ Error! Bookmark not defined. 
8.3 
Crime and Recidivism ............................................................................................... 27 
8.3.1 
Arrest Records ................................................................................................... 27 
8.3.2 
CJ-DATS Crime Grid ......................................................................................... 27 
8.4 
Data Collection and Management ............................................................................. 28 
8.5 
Data Sharing ............................................................................................................. 28 
9.0 
TRAINING ..................................................................................................................... 29 
10.0 
STATISTICAL ANALYSES ........................................................................................... 30 
10.1 
Primary Outcome ...................................................................................................... 30 
11.0 
REGULATORY COMPLIANCE AND SAFETY MONITORING ..................................... 35 
11.1 
Regulatory Compliance ............................................................................................. 35 
11.2 
Institutional Review Board Approval .......................................................................... 35 


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11.3 
Informed Consent...................................................................................................... 35 
11.4 
Drug Accountability ................................................................................................... 35 
11.5 
Quality Assurance and Safety Monitoring .................................................................. 36 
11.6 
Data and Safety Monitoring Board (DSMB) ............................................................... 36 
11.7 
Medical Monitor ......................................................................................................... 36 
11.8 
Quality Assurance Monitor ........................................................................................ 36 
11.9 
Statement of Compliance .......................................................................................... 36 
11.10 Confidentiality ........................................................................................................... 37 
11.11 Health Insurance Portability Accountability Act (HIPAA) ............................................ 37 
11.12 Investigator Assurances ............................................................................................ 37 
11.13 Financial Disclosure .................................................................................................. 37 
11.14 Inclusion of Women and Minorities ............................................................................ 37 
11.15 Description of Plans to Conduct Valid Analyses of Study Results by Gender and 
Race/Ethnicity ........................................................................................................... 38 
11.16 Regulatory Files ........................................................................................................ 38 
11.17 Records Retention and Requirements ....................................................................... 38 
11.18 Audits ........................................................................................................................ 38 
11.19 Reporting to Sponsor ................................................................................................ 38 
11.20 Study Documentation ................................................................................................ 38 
11.21 Protocol Deviations, Violations, and Reporting and Management ............................. 39 
11.22 Safety Monitoring ...................................................................................................... 39 
11.22.1 
Adverse Events (AEs) ........................................................................................ 39 
11.22.2 
Definitions of Adverse Events and Serious Adverse Events ............................... 40 
11.22.3 
Reportable Adverse Events and Serious Adverse Events .................................. 40 
11.23 Possible Risks of Study Medications ......................................................................... 40 
12.0 
DATA MANAGEMENT AND PROCEDURES ............................................................... 41 
12.1 
Operations Manual .................................................................................................... 41 
12.2 
Data and Statistics Center Responsibilities ............................................................... 41 
12.3 
Data Collection and Entry .......................................................................................... 41 
12.3.1 
Data Monitoring, Cleaning, and Editing .............................................................. 41 
12.4 
Study Documentation and Records Retention ........................................................... 41 
12.5 
Data Transfer and Lock ............................................................................................. 42 
12.6 
Confidentiality ........................................................................................................... 42 
12.6.1 
Confidentiality of Data ........................................................................................ 42 
13.0 
SIGNATURES ............................................................................................................... 43 
14.0 
REFERENCES .............................................................................................................. 44 
15.0 
APPENDICES ............................................................................................................... 51 
 


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1.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ASI-Lite 
Addiction Severity Index-Lite 
CAP 
College of American Pathologists 
CJ-DATS 
Criminal Justice Drug Abuse Treatment Studies  
CLIA 
Clinical Laboratory Improvement Amendment of 1988 
CNS 
Central Nervous System 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Form 
DATCAP 
Drug Abuse Treatment Cost Analysis Program 
DE 
Drug Education 
DEA 
Drug Enforcement Agency 
DL 
Dose Logs 
DMC 
Data Management Center 
DSMB 
Data and Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders Fourth Edition 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IND 
Investigational New Drug 
LFT 
Liver Function Test 
Mg 
Milligrams 
NDA 
New Drug Application 
NTX 
Naltrexone 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
PN 
Patient Navigator 
PNV 
Patient Navigator and Vivitrol Condition 
PI 
Principal Investigator 
RAB 
Risk Assessment Battery 
SAE 
Serious Adverse Event 
SOWS 
Subjective Opiate Withdrawal Scale 
SSI-M 
Modified Scale for Suicide Ideation 
UDS 
Urine Drug Screen 
TEA 
Treatment Effects Assessment 
TES 
Treatment Effectiveness Score 
TLFB 
Time Line Follow Back 
VAS 
Visual Analog Scale 
VI 
Extended-Release Naltrexone (as Vivitrol®) 
 
 


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2.0 
ABSTRACT 
2.1 
Study Objective 
The aim of this trial is to assess the clinical utility, effectiveness, and cost implications of treatment 
for incarcerated offenders with opioid use disorders who are randomly assigned to one of three 
treatment conditions to include a depot formulation of naltrexone (Vivitrol®) only (VI), a patient 
navigation (PN) procedure plus Vivitrol (PNV), and a drug education procedure (DE) before being 
released to the community. This trial will investigate whether effective medication therapy used in 
non-incarcerated populations will also be effective in incarcerated individuals. Empirical evidence 
demonstrates that starting treatment before release greatly increases the probability of successful 
outcome including reduced alcohol and drug use, increased employment rates, and reduced 
recidivism rates. 
2.2 
Study Design 
This four-year randomized, open-label trial will examine the feasibility, efficacy, and net economic 
benefits of VI for opioid addiction delivered with and without a platform of PN provided for six 
months compared against a DE condition. Before release from jail, participants in the VI and PNV 
conditions will receive their first Vivitrol injection (and those in the PNV condition will meet with a 
Patient Navigator) and will then be scheduled for medication management sessions twice monthly 
for months 1-3, with monthly injections in months 4-6. Participants in the PNV condition will meet 
with a PN who will provide behavioral assistance to overcome possible barriers to community 
outpatient treatment and will be provided with a schedule of possible community treatment 
programs. Participants in the DE condition will receive education designed to reduce the likelihood 
of overdose on the same schedule as the VI and PNV groups. All participants will receive weekly 
study phone calls to assess well being and possible adverse events.   
    2.3   Study Participants 
Participants will be 150 individuals, who meet DSM-5 criteria for opioid use disorders, are 18 
years and older, who have been detoxified from opioids in the Metropolitan Detention Center in 
Albuquerque, New Mexico. This study will include only those participants for whom the study 
physician determines that possible treatment with the study drug is in the best interest, and 
informed consent will be obtained. 
2.4   Interventions 
All participants will be scheduled for twice-monthly medical management and assessment 
appointments for the first three months of the 24-week post-release intervention phase, with 
monthly appointments for months 4-6. Eligible participants will be randomly assigned to treatment 
condition (VI, PNV, DE) in equal numbers. VI and PNV participants will undergo a naloxone 
challenge to ensure opioid abstinence at the time of Vivitrol induction. Those in the PNV condition 
will be provided with a PN who will facilitate attendance at outpatient treatment programs as well 
as assist with other needs. The DE group will not receive any medication but will be scheduled 
for assessments and education on drugs of abuse, maintaining abstinence, and methods for 
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provided with naloxone kits to be used in the event of overdose. All groups will also be provided 
with referrals to community-based substance abuse treatment programs.   
2.3 
Assessments  
Screening/baseline assessments will include a medical and psychiatric history, physical 
examination, clinical lab tests (blood chemistry, hematology, urinalysis and hepatitis screening), 
12-lead electrocardiograph, vital signs, pregnancy test (for females), and urine toxicology screen. 
Assessments completed at months 1, 3, 6, 7, and 12 include drug use, dosing and protocol 
compliance, pregnancy tests for females of child-bearing potential, and other measures of status 
and functioning. Safety of study participants and intervention tolerability will be assessed 
throughout the study by collection of adverse events, suicidality, and measures of drug use. 
Participants who experience an adverse event deemed as compromising their safety will be 
discontinued from participation and provided referrals for medical care.  
2.4 
Analyses 
The primary outcomes include opioid use and DSM-5 diagnosis of opioid use disorder via 
modified CIDI-2 Substance Abuse Module at 6-months post-intervention. Opioid use will be 
computed from the Timeline Follow-Back (TLFB) as the number of days of self-reported opioid 
use in the past 30 days at the 6-month assessment. The cost analysis will measure and value 
resources associated with VI, including medical personnel (physician/nurses), labs, and 
medications. To ascertain cost-effectiveness ratios of VI and PNV, cost data will be compared to 
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3.0 
STUDY SCHEMA 
 
Recruitment 
Jail staff identifies possible study 
candidate who has been detoxified and 
may be released < 4 weeks   
Pre-Screening 
 Opioid Use Disorder (DSM-5) 
 Mental/physical Status 
 No allergy/sensitivity to buprenorphine, 
naloxone, naltrexone 
 Willingness to participate for 6 months and 
possibly receive drug 
Consent/Screening 
Randomization to Condition 
Vivitrol +PN (PNV) (n=50)  
o Naloxone Challenge 
o Vivitrol Injection 
Vivitrol  (VI) (n=50) 
o Naloxone Challenge 
o Vivitrol Injection 
 
Drug Education (DE) (n=50) 
 
o Injection site monitoring 
o 
Injection site monitoring 
o Matched contact with study 
team 
o Outpatient Behavioral 
Treatment Schedule 
o Study Visit Schedule 
o Drug Education Meeting 
o Outpatient Behavioral 
Treatment Schedule 
o Study Visit Schedule 
o PN Meeting 
o Outpatient Behavioral 
Treatment Schedule 
o Study Visit Schedule 
 
o Medical Management and  
     Assessments 
o Monthly Injections 
o PN Appointments for 3 
months 
o Assessments at Months 
1, 3, 6, 7, 12 
o Medical Management and 
Assessments 
o Assessments at Months 
1, 3, 6, 7, 12 
 
o Medical Management and 
Assessments 
o Assessments at Months 
1, 3, 6, 7,12 
 
 
Post-Release 
Pre-Release 
In-Jail Follow-Up 


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4.0 
INTRODUCTION 
4.1 
Background and Rationale 
Although prison and jail can be effective at reducing levels of crime and drug use during the period 
of incarceration, resumption of these behaviors upon release is the norm. Nearly 7 in 10 released 
offenders are re-arrested within three years (Bureau of Justice Statistics, 2002; Pew Center on 
the States, 2011). Data regarding drug use are even more disquieting, indicating that in many 
cases offenders are re-addicted within one month of release from incarceration (Bird & 
Hutchinson, 2003; Kinlock et al., 2011) and their drug use and/or crime levels following prison can 
even exceed use levels prior to incarceration (Hough, 2002).  
 
Not surprisingly, such persistent patterns of drug use and crime are associated with comorbid 
health problems and even premature death. In a given year, a quarter of all people in the United 
States who have HIV, a third who have HCV infection, and more than 40% who have tuberculosis 
disease will pass through a correctional facility that same year (Bergier et al., 2010; Hammett et 
al., 2002). Likewise, the risk of death among parolees during the first two weeks following release 
from prison is nearly 13 times greater than those of similar demographic background—with drug 
overdose being the leading cause (Binswanger et al., 2007). As dire as this finding is, it may be 
an underestimate of the problem. A study of newly released prisoners in England and Wales 
found that mortality rates among males were 29 times higher than the general population during 
the first two weeks of release. Female offenders’ mortality rates were 69 times higher (Farrell & 
Marsden, 2007). These studies are included in a recent meta-analysis of drug-related deaths 
following prison release that revealed a three- to eight-fold increase in the risk of drug-related 
deaths during the first two weeks following release (relative to the subsequent 10 weeks), with 
relatively high risk of death remaining throughout the first month of reentry (Merrall et al., 2010). 
These authors concluded that “further research is urgently needed on mortality after release from 
prison, as well as interventions to reduce the risk of drug-related deaths during the transition from 
prison to the community” (pp. 1552-1553). 
 
A substantial body of research now exists supporting the safety and efficacy of naltrexone and 
buprenorphine, in both their oral, daily-dose forms and in depot long-acting formulations (e.g., 
Chiang et al. 2003; Krupitsky et al., 2011; Ling & Wesson, 2003; Ling et al., 2010; Lobmaier et 
al., 2010; Mattick et al., 2008; Mello & Mendelson, 1980). Nonetheless, MAT, particularly 
pharmacotherapies other than methadone, has not been readily adopted in correctional settings. 
A survey of correctional agencies (conducted as part of NIDA’s CJ-DATS collaborative) revealed 
that two-thirds of the jails surveyed provided methadone (primarily for detoxification), but none 
offered naltrexone to opiate-dependent inmates (Friedmann et al., 2012). Although the use of 
MAT is more common in jails than in prisons (used primarily to manage opiate withdrawal), it is 
important to note that MAT remains unavailable in most jails for purposes beyond detoxification 
(Oser et al., 2009).  
 
The efficacy of naltrexone has been well established. Naltrexone, an opioid receptor antagonist, 
blocks the euphoric effects of heroin and other opioids. This characteristic has fostered growing 
acceptance of naltrexone by correctional authorities who wish to avoid the perception that they 
are merely replacing one drug with another (Farabee, 2006).  However, it must be taken orally on 
a daily basis, making adherence a problem among all but the most committed patients. Cornish 
et al. (1997) randomly assigned federal probationers to a 6-month program of probation plus 
naltrexone and brief drug counseling or to probation plus counseling alone and found that opioid 
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tests among the naltrexone subjects at 8%, versus 30% for control subjects (p < .05). Likewise 
56% of the controls and 26% of the naltrexone group (p <. 05) had their probation status revoked 
within the 6-month study period and were returned to prison. But treatment compliance was a 
problem, with only 52% of subjects in the naltrexone group continuing for the 6-months duration 
of the study.  
 
Still, the effectiveness of oral naltrexone is mitigated by poor compliance hampering clinical utility 
in real-world settings. In one study of a prison-based naltrexone program, only 7% of the enrolled 
patients remained in treatment for six months (Shearer, Wodak, & Dolan, 2007). To address this 
issue, Vivitrol® (~380mg naltrexone delivered intramuscularly every four weeks; Alkermes, Inc.) 
was developed to provide long-acting pharmacotherapy for one month per dose. The purpose of 
this proposed study is to assess the relative effects and net economic benefits of this 
pharmacotherapy in comparison with a patient navigator (PN) and drug education (DE) conditions 
for criminal-justice-involved offenders.  
4.1.1 
Issues of MAT in Correctional Settings 
 
Although many have called for expanding the use of medication-assisted treatment in prison 
(Cropsey et al., 2005; Kinlock et al., 2011), there are several features of jails that make the latter 
more promising settings for MAT. Perhaps the most critical difference is that detoxification 
typically occurs in jails, not prisons. Virtually all prison inmates spend time in local jails while 
awaiting trial or sentencing. Therefore, whether an offender is serving a brief jail sentence or is 
awaiting transfer to prison, detoxification typically falls under the purview of the jails. The second 
reason for focusing on jails relates to the time period of incarceration. Jails tend to house offenders 
for a few days to several months, whereas prisons are reserved for those serving sentences for 
a year or more—on average 29 months (Kuziemko, 2007). As a result, the costs of maintaining 
prison inmates on naltrexone, buprenorphine, or methadone for the entire duration of their 
sentence would likely be prohibitive. The third consideration is that more offenders pass through 
jails than prisons. This is an important point that is often missed: Although prisons house more 
inmates than jails at any one time (1,512,576 in prison versus 780,581 in jail at year-end 2007 
[BJS, 2008a]), the number of entrants to these two systems tells a very different story, with 
751,593 admissions to prison during 2007 versus approximately 13 million admissions to jails 
during that same period (BJS, 2008a,b). The increased flow between jails and the community 
likely accounts for reports that the availability of drugs in jails exceeds that in prisons.    
 
A recent survey of criminal justice agencies affiliated with NIDA’s Criminal Justice Drug Abuse 
Treatment Studies (CJ-DATS) collaborative found that MAT is underutilized in the treatment of 
substance use disorders (Friedmann et al., 2012). Offenders most likely to receive MAT were 
pregnant women and those experiencing withdrawal. Offenders least likely to receive MAT were 
those re-entering the community after serving a prison or jail term. Among the primary factors 
influencing the use of MAT in these correctional settings were preferences for drug-free treatment 
and limited knowledge of the benefits of MAT. Addressing these philosophical- and knowledge-
related barriers requires relevant research, specifically, data collected in real-world settings 
testing practical MAT administration models on offender populations. It is also important to note 
that even if philosophical barriers shift in favor of MAT, tight local and state budgets may require 
a higher threshold of evidence—particularly related to costs—before allowing a wider adoption of 
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4.1.2 
Preventing relapse to opioid addiction and reducing HIV transmission 
 
Research has shown that substitution or maintenance medication is an effective way of managing 
opioid dependence, preventing relapse to drug use, and concomitantly resulting in reduced 
HIV/AIDS infection by curtailing drug-related behaviors that promote transmission of HIV 
(Metzger, Woody, & O’Brien, 2010; Morris, Levine, & Weaver, 2004; WHO, 2004).  This aspect is 
especially pertinent among the criminal justice population, where the prevalence of confirmed 
AIDS is more than double that of the general U.S. population (Maruschack, 2009). Effective MAT 
also provides an opportunity to educate about unsafe sexual activities and to reduce HIV-risky 
sexual activities such as having concurrent/multiple sexual partners, especially in overlapping 
networks that greatly increase HIV infection liability (Copenhaver et al., 2006; Morris, 1997; Morris 
& Kretzschmar, 1997). Research has documented significant reductions in HIV risk behavior and 
overdose deaths and improved outcomes from antiretroviral treatment in HIV-infected opioid 
users when treated with buprenorphine (Johnson et al., 2000). 
 
Naltrexone offers an approach to combat the spread of HIV predicated on its opioid antagonist 
mechanism of action, in contrast to the full or partial agonists (methadone or buprenorphine). 
Vivitrol may be especially useful where cultural and regulatory conditions inhibit use of opioid 
agonists with reinforcing aspects, because of perceived “coddling” of addicts. As promising as 
this long-acting pharmacotherapy may be, however it is unlikely to be widely adopted by 
correctional agencies or community treatment systems until their expected net economic benefits 
are established.  
4.2 
Significance of the Project to the Field 
The efficacy of naltrexone has been well established in numerous controlled clinical trials 
conducted in community settings, however little research is available examining its impact among 
correctional populations. A recent study compared depot naltrexone with methadone among 
heroin-dependent inmates released from prison and found that both pharmacotherapies were 
associated with reductions in opiate use and criminal activity (Lobmaier et al., 2010). However, 
post-release retention in the methadone condition was extremely low (relative to the 100% 
adherence rate for those in the depot naltrexone group). Poor attendance/adherence is a vexing 
issue in offender treatment, with typical rates of admission of one-third to one-half of parolees 
referred to drug-free counseling programs, and about half of those referred to MAT (Cornish et 
al., 1997; Lobmaier et al., 2010; Olson, Rozan, & Powers, 2009). Vivitrol potentially obviates the 
problem of non-compliance with medication dosing, eliminates concerns about potential diversion 
as medication is provided once monthly by the medical study team, and lessens the need for 
frequent patient presentation in the clinic or primary care physician's office—issues that are 
concerns associated with oral naltrexone.  
 
The development of long-acting depot formulations of naltrexone (e.g., Vivitrol) has also provided 
a new approach for treating opioid addiction, especially in terms of preventing relapse once 
abstinence has been attained (Comer et al., 2006). Naltrexone implants reliably prevented relapse 
within one month after detoxification (Foster, Brewer, Steele, 2003), and multi-site research in 
Russia found Vivitrol effective for treating heroin addiction over six months (Krupitsky et al., 2011). 
Vivitrol was approved in 2010 by the U.S. FDA for opioid addiction.  
 
The pharmacotherapy examined in this study offers important advantages to its orally 
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compliance, maintenance of consistent plasma levels of medication, and elimination of potential 
diversion and misuse. The proposed project intends to provide new empirical data from a 
correctional population on the utility of depot naltrexone in preventing relapse and associated 
behaviors by examining the long-acting medication in a context that takes advantage of its 
strengths to bring about positive and meaningful net economic benefits. Comparisons will be 
made between two medication conditions provided with and without a Patient Navigator 
component (VI, PNV) and a drug education (DE) condition.  
4.3 
Objectives 
The project emphasizes evaluation of the clinical utility of pharmacotherapy with Vivitrol (VI) or 
Vivitrol + PN (PNV) in comparison to a drug education (DE) condition. Descriptive statistics will 
provide an overall assessment of the implementation of the protocol. The aims of this project 
include: 
 
Aim 1: Assess the feasibility and clinical utility of a 24-week protocol of long-acting naltrexone 
(by intramuscular injection; VI) provided with and without a PN component (VI, PNV). Measures 
include side effects, adverse events, retention, and acceptance of the procedures by participants 
and clinicians. Acceptance will also be assessed among correctional staff.   
Aim 2: Examine the effectiveness of Vivitrol provided with and without a PN component (VI, PNV) 
for its ability to prevent relapse to illicit opioid use, reduce drug-related criminal activity, curtail 
engagement in HIV-risk behaviors, and increase employment compared to a group receiving only 
drug education (DE) to assist in relapse prevention after release from jail. The VI and PNV groups 
will receive VI monthly for the entire 6-month intervention phase. Th PNV group will be provided 
with PN for 3 months to provide assistance in accessing community treatment after release from 
jail. Primary measures include DSM-5 diagnosis at time to relapse (defined as self-report of daily 
opioid use for one week), protocol adherence, and opioid-negative urine samples during the 
study.   
Aim 3: Collect cost data using the Drug Abuse Treatment Cost Analysis Program (DATCAP) and 
estimate savings from reduced drug use, reduced criminal activity and re-incarceration, and 
increased employment. Data will support benefit-cost and cost-effectiveness analyses of depot 
pharmacotherapy with Vivitrol for released offenders with opioid use disorders.  
4.3.1 
Primary Objectives 
The primary objective is to compare outcomes of the three intervention groups, measured a The 
opioid use and DSM-5 diagnosis of opioid use disorder via modified CIDI-2 Substance Abuse 
Module at 6-months post-intervention.  
4.3.2 
Secondary Objectives 
Secondary objectives include: (1) HIV risk behaviors (compared using repeated measures 
procedures to evaluate possible change in sexual and drug-related behaviors that may inhibit or 
promote HIV infection) measured by the HIV-GAIN; (2) Self-reported number of days incarcerated 
during the intervention and follow-up phases; (3) Self-reported number of days of opioid and other 
drug use measured by TLFB, and objective measures of drug use by urine drug screens (UDS) 
at the 6-month post-release assessment (end of the intervention phase); (4) Self-reported days 
in drug abuse treatment; (5) Self-reported number of arrests; (6) Self-reported craving for opioids, 
and (7)  Self-reported number of overdoses.  


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5.0 
STUDY DESIGN 
5.1 
Overview of Study Design 
The proposed four-year study is a randomized, open-label trial that will examine feasibility, 
efficacy, and net economic benefits of a depot medication for opioid addiction, alone or in 
conjunction with PN, and a drug-education condition receiving no medication. All participants 
receive standard medical management. Before discharge from jail, participants randomized to 
one of two medication conditions (VI, PNV) receive Vivitrol and subsequent injections every four 
weeks for 24 weeks. Those in the PNV condition will meet with a PN before discharge and 
regularly after release to discuss barriers to treatment, possible treatment program participation 
following release, and will address social support and other participant needs. Before discharge, 
the Drug Education (DE) group will participate in session(s) designed to provide a presentation 
and discussion of drug-related issues. Following release from jail, all participants will receive 
phone calls from the study team to facilitate scheduling of appointments to occur twice monthly 
for the first 3 months after release then monthly for the last 3 months of the intervention phase for 
medical management and to complete assessments. The study nurse will also contact study 
participants to assess well-being and adverse events.   
5.2 
Duration of Study and Clinic Visit Schedule 
The duration of this study will include a projected 2-4 weeks for screening/baseline assessments 
and medication induction, and a 24-week intervention phase to include, specific to assigned 
condition, medication, PN, DE, assessments, and medical management. The screening phase 
will differ in the length of time needed to complete eligibility assessments, random assignment, 
and to complete medication induction in the VI and PNV conditions. Induction will be scheduled 
to occur within 4 weeks of discharge. Screening assessments will include the collection of 
laboratory samples and medical assessments to ensure participant safety. Confirmation of opioid-
free status (UDS and naloxone challenge) before medication induction will take approximately 
two hours. Assessment visits at 1, 3, 6, 7, and 12-months will take about 30-60 minutes depending 
on the scheduled assessments. Medical management visits will last from 20–60 minutes and will 
include collection of UDS and other short measures of status and well-being. PN sessions are 
expected to take about 60 minutes. DE sessions will take about 20 minutes.  
5.3 
Study Population 
Participants will be 150 individuals meeting DSM-5 criteria for opioid use disorders who are 18 
years and older, have been detoxified from opioids in the Bernalillo County Metropolitan Detention 
Center and meet eligibility criteria.  
5.3.1 
Inclusion Criteria 
Study participants must: 
1. Be at least 18 years of age or older, 
2. Meet criteria for DSM-5 opioid use disorders, 
3. Be detained for at least 48 hours, 
4. Have an expected release date within one year, 
5. Plan to reside in area after release, 
6. Have at least one instance of relapse to opioid use after a period of abstinence. 


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5.3.2 
Exclusion Criteria 
Study participants must not: 
1.    Have a medical (e.g., liver failure, congestive heart failure) or psychiatric condition (e.g., 
suicidal ideation, psychosis) that would make participation unsafe in the judgment of the 
medical staff or the PI, 
2.    Have current or chronic pain or have plans to undergo pain treatment/therapy, 
3.    Have known sensitivity to naltrexone or naloxone,  
4.    Have participated in an investigational drug study within the past 30 days prior to 
screening, 
5.    Be a nursing or pregnant female, or not agree to use a medically acceptable form of 
birth control such as oral contraceptives, barrier (diaphragm or condom), levonorgestrel 
implant, intra-uterine progesterone contraceptives system, medroxyprogesterone 
acetate contraceptive injection, or complete abstinence. Females who become pregnant 
during the course of the study will be withdrawn from the study and, if requested, will be 
provided with referrals for drug treatment and/or medical care, 
6.    Have any pending legal action that could prohibit continued participation for the 24-week 
intervention period of the study, such as legal proceedings that could possibly result in 
incarceration, 
7.    Have a current pattern of alcohol, benzodiazepine, or other depressant or sedative 
hypnotic use, as determined by the study physician which would preclude safe 
participation in the study. 
5.4 
Participant Recruitment 
Recruitment through a close collaboration with the Bernalillo County Metropolitan Detention 
Center (BCMDC) staff, combined with IRB-approved presentations and posted announcements 
in the jail facilities will proceed until 150 participants are recruited, consented, and randomized. 
Given the potential recruitment pool of more than 80 individuals per month, it is expected that an 
average of 6-8 individuals will be randomized per month across the 20-month enrollment period. 
Based on prior evidence in similar trials, refusals and early (pre-randomization) dropouts will 
account for approximately 20% of individuals presenting for screening.  
Recruitment plans include hypervigilence to the issue of voluntariness. All BCMDC and study staff 
will be extensively trained on this issue to ensure that their actions and words do not convey any 
level of coercion. Training will include a discussion of the fact that treatment and study compliance 
are optimized when participants have the opportunity to consider the study, ask questions, and 
provide voluntary consent to participate. Furthermore, all recruitment documents and the ICF will 
emphasize that decisions whether or not to participate are solely up to the individuals, that the 
decision will not affect the treatment or possible treatment to which the individual is eligible, that 
participation/non-participation will not affect the sentence, release, probation, or any other aspect 
of the individual’s incarceration.    
 
The main method of recruitment will be announcements of the study made to inmates in the 
Bernalillo County Metropolitan Detention Center (BCMDC). An informational flyer will be provided 
to arrestees who are within 4 weeks of release and have been detoxified from opioid use. 
Individuals who convey interest in this study to jail staff will be referred to study staff. If still 
interested after receiving a description of this study, study candidates will complete a consent 
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participation is voluntary and will have no effect on a participant’s sentence, jail term, probation, 
parole, or release. 
 Treatment procedures for jail inmates: Offenders are detoxified (if necessary) under physician 
supervision within the jail setting. After this, they are moved to the general inmate population but 
have follow-up visits with the jail physicians. While in custody, they may opt to pursue participation 
in available onsite treatment programs.   
Prior to release, a case worker from Inmate Services meets with the inmate and may make a 
referral to a community-based program, which can be either drug-free residential or outpatient, 
depending on inmates’ needs and preferences. Show-up rates in the community tend to be quite 
low, but transportation directly from the jail to treatment programs has resulted in improved 
admission rates. 
5.5 
Study Sites 
UCLA Integrated Substance Abuse Program (ISAP). The leadership, data management, and 
analysis portions of the proposed project will occur at UCLA ISAP in Los Angeles.  
 
Walter Ling, MD, will be the physician PI for this study. He has extensive experience in both the 
use of Vivitrol and behavioral treatments. He will be involved in supervision of the medical aspects 
of this study, randomization, and will meet regularly with other study personnel. He has conducted 
over a dozen clinical trials using MAT and will be responsible for medical team training. More 
recently, he has conducted research using Vivitrol and has been instrumental in the training of 
other ISAP medical personnel on the Vivitrol injection. 
 
For this project, the primary sites for recruitment, data collection, and treatment services are the 
Bernalillo County Metropolitan Detention Center and the University of New Mexico, Department of 
Psychiatry. 
 
Bernalillo County Metropolitan Detention Center (BCMDC). Recruitment and induction will occur 
at the jail sites in the BCMDC System. The jail facility houses sentenced and unsentenced 
inmates. The types of inmates housed here are general population, violent/assaultive offenders, 
psychiatric, and inmates needing medical services. This facility is staffed with Sheriff Service 
Technicians, intake and release specialists, medical service staff contracted by the County 
Behavioral Health Department, and clerical support staff.  Bernalillo County opened the MDC 
facility in 2003. Currently, the MDC averages about 40,000 bookings per year, with an average 
daily population of 2,636. Males account for 87% of the inmate population. With regard to 
race/ethnicity, 54% are Hispanic, 23% White-Non-Hispanic, 12% American Indian, 9% African- 
American, 0.4% Asian, and 1.7% are categorized as “Other.” Currently the MDC detoxifies an 
average of 758 individuals monthly—412 from alcohol and 346 from opiates.  
 
The University of New Mexico Addiction Substance Abuse Program (ASAP), The University of 
New Mexico Center on Alcoholism, Substance Abuse, and Addictions (CASAA); These programs 
will be the locations for post-release assessment and medical management visits. ASAP and 
CASAA offer a range of treatment services designed to help individuals coping with substance 
use disorders. Services include screening, crisis intervention, individual, group, and family 
counseling, HIV/Hep education, assessment, and evaluation, referrals to community-based 
services, and outreach to the community. Outpatient treatment programs providing psychosocial 
interventions are located throughout the county. In the community, the MATS program provides 
comprehensive detoxification, treatment, and transitional housing services for medically indigent 


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populations in the Albuquerque area. Operated by Bernalillo County, the MATS program has 
extensive partnerships with other community medical, mental health, alcohol/drug and homeless 
service agencies. The Addictions and Substance Abuse Program (ASAP) is operated by the UNM 
Department of Psychiatry and is conveniently located adjacent to the UNM CASAA facility.  
 
 


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6.0 
OUTCOME MEASURES 
The project emphasizes evaluation of the clinical utility of the Vivitrol pharmacotherapy with and 
without a PN condition (VI, PNV), as compared to a drug education (DE) condition. Descriptive 
statistics will provide an overall assessment of the implementation of the protocol.  
6.1 
Primary Outcome Measure 
The primary outcomes will be opioid use and a DSM-5 diagnosis of opioid use disorder 6 months 
after randomization.   
6.2 
Secondary Outcome Measures 
(1) HIV risk behaviors (compared using repeated measures procedures to evaluate possible 
change in sexual and drug-related behaviors that may inhibit or promote HIV infection) 
measured by the HIV-GAIN;  
 
(2) Self-reported number of days incarcerated during the intervention and follow-up phases;  
 
(3) Self-reported number of days of opioid and other drug use measured by TLFB, and 
objective measures of drug use by urine drug screens (UDS) at the 6-month post-release 
assessment (end of the intervention phase);  
 
(4) Self-reported days in drug abuse treatment;  
 
(5) Self-reported number of arrests;  
 
(6) Self-reported craving for opioids;  
 
(7) Self-reported number of overdoses; and  
 
(8) Self-reported motivation for treatment.  
 


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7.0 
STUDY PROCEDURES   
7.1 
The Consent Process 
This study will be reviewed and approved by the Medical Institutional Review Board (M-IRB) of 
the University of California, Los Angeles, and the Institutional Review Board of the University of 
New Mexico.   
 
All participants will voluntarily sign an informed consent prior to study participation. The informed 
consent process involves a detailed verbal description of the study and the data collection 
procedures. The participant will be encouraged to ask questions about the study procedures 
throughout the process. The risks of participating in this study will be detailed in the consent form. 
Staff will emphasize that participation is voluntary and that participants may withdraw consent at 
any time without prejudice, and will be given referrals to other local treatment programs.  
 
After discussing the study procedures, potential risks and benefits, the voluntary nature of study 
participation, and that participation will have no effect on a participant’s sentence, jail term, 
probation, parole, or release, study candidates will answer a brief quiz to verify and document a 
thorough understanding of the research prior to signing the consent form. The study candidate 
will sign the consent form as witnessed by a study investigator or physician. Research staff will 
receive extensive training in the informed consent process. A copy of the signed consent form will 
be given to all participants 
7.2 
Screening  
The study team will provide a basic description of the study to interested individuals who respond 
to IRB-approved flyers and announcements at BCMDC. Study staff will verify pre-eligibility status 
of each study candidate with jail staff (e.g., has completed opioid detoxification, jail term and 
expected release date). Individuals determined as pre-eligible will be scheduled for a 
consent/screening appointment. Screening will begin with the informed consent process. A 
complete medical history and physical exam will occur after consent. Participants will be 
randomized to study condition when results of all assessments, including blood chemistries and 
ECG, are obtained and eligibility is confirmed. Screening will take ~4 hours, excluding review of 
lab results. This process may occur over multiple days.  
7.3 
Random Assignment 
Eligible participants will be randomly assigned to study condition (VI, PNV, DE ) in a 1:1:1 strategy 
using an urn randomization procedure (Stout et al., 1994) to provide multivariate balance across 
two characteristics correlated with outcomes in addiction treatment trials: type of opioid (heroin or 
prescription drug) and gender. 
 
Individuals who terminate participation before induction onto the assigned medication (or similar 
time-point for behavioral assignments) will be replaced. Those terminating after VI induction or 
provision of the first DE session will not be replaced and will be counted as "treatment failures" 
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7.4 
Medication Pre-Induction 
7.4.1 
Vivitrol Pre-Induction 
Vivitrol Pre-administration and Injection Procedures. Individuals must be free from opioids for at 
least 7 days before receiving the Vivitrol injection, which is confirmed via self-report and facility 
records. To ensure opioid abstinence at time of induction, a naloxone challenge will occur followed 
by one day of oral naltrexone before Vivitrol injection, adhering to NIDA-approved and IRB-
approved procedures. Subsequent Vivitrol injections administered every four weeks will require 
confirmation of opioid abstinence by either naloxone challenge or administration of oral 
naltrexone, as determined appropriate and necessary by the Study Physician and/or Nurse 
Practitioner (NOTE: In New Mexico, a Nurse Practitioner [NP] has virtually all the same medical 
privileges as a Physician and can function as an Physician).  
 
The pre-induction strategy includes:  
• 
Step 1. Participants must self-report no clinically significant opioid use (i.e., at any level 
that could constitute a potential risk of precipitating opioid withdrawal upon naloxone 
administration in the next step) in the previous seven days.  
• 
Step 2. A urine drug screen will be administered shortly before the naloxone challenge 
and must be negative for opioids. Individuals who are opioid-negative will continue in the 
pre-induction process. Individuals may have an additional urine drug screen on a 
subsequent day if the study medical clinician determines that a second screen is 
appropriate. 
• 
Step 3. Completion of all pertinent psychosocial and medical screening and eligibility 
assessments. 
• 
Step 4. Absence of opioids in a urine screen is not absolute proof that a patient is entirely 
opioid-free; As such a naloxone challenge will be administered. Prior to subsequent 
Vivitrol injections every four weeks, the naloxone challenge can be performed at the 
discretion of the study physician to ensure continued suitability for the Vivitrol injection. An 
example of a naloxone challenge procedure may begin with I.V., I.M., or subcutaneous 
delivery of 0.1mg naloxone. If no significant opioid withdrawal symptoms appear after a 
few minutes, a second dose of 0.3mg would then be administered followed by a brief 
observation period. With no observed discomfort, 0.8mg naloxone would then be 
administered as the final dose, followed by an observation period. A minimum 0.8mg bolus 
must be given before determining the outcome of the challenge. An alternative is to 
challenge with a single 0.8mg bolus. The determination as to whether the participant is 
eligible to continue on to VI induction will be made by the study medical clinician based on 
clinical judgment, including both objective and subjective assessments. Attention to 
individual symptoms and symptom changes should guide determination of eligibility. Signs 
of discomfort or an increase in withdrawal symptoms following naloxone administration 
should be taken as a positive result of the challenge, with induction delayed until a 
negative challenge result is achieved. 
Participants who experience withdrawal symptoms following the naloxone challenge can be 
treated with ancillary medications if appropriate, observed until symptoms resolve, and given the 
opportunity to be re-challenged on a future date. Participants who are not interested in continuing 
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7.5 
Pharmacotherapy 
7.5.1 
Extended-release Naltrexone (VI) 
Depot Naltrexone as Vivitrol. Vivitrol is a combination of naltrexone-containing microspheres that 
are delivered by injection every four weeks into the muscles of the buttock. Plasma concentrations 
of naltrexone and 6-beta naltrexol (its main metabolite) after a single Vivitrol injection are 
detectable for at least 30 days and must be re-administered to maintain its effect. Continued use 
of naltrexone is not associated with tolerance or addiction. The most common AE has been 
reaction at the injection site, reported in 50% of the placebo group and 69% of the 380mg Vivitrol 
group Physician’s Desk Reference (PDR). The most common gastrointestinal AEs are nausea 
(11% in placebo group; 33% in Vivitrol group) and vomiting (6% in placebo group; 14% in Vivitrol 
group). For pain management in an emergency situation, regional anesthesia or non-opioid 
analgesics are advised.  
 
Extended-release Naltrexone (VI) will be provided to participants as a gluteal intramuscular 
injection (380 mg) administered every four weeks. The VI injection shall be administered following 
the guidelines provided in the package insert, including the pre-induction procedures described 
above.  
Well-developed precautionary procedures will be followed to avoid adverse events associated 
with induction. For example, body habitus will be assessed during the physical exam at screening 
to assure that needle length is adequate for intramuscular administration as an inadvertent 
subcutaneous injection of VI may increase the likelihood of injection site reactions. The needle 
provided in the VI package is a customized needle required for injection of medication. Individuals 
whose body habitus precludes a gluteal intramuscular injection of naltrexone using the required 
needle will be excluded from the study. 
7.6 
Behavioral Treatment  
7.6.1 
Drug Education (DE) 
This condition is intended as an enhanced treatment-as-usual condition. Enhancements will 
include standardized materials for drug education and overdose prevention education.  
7.6.2 
Patient Navigators (PN) 
In addition to receiving Vivitrol, participants in the PNV condition will be assigned a Patient 
Navigator (PN). A PN provides one-on-one assistance to surmount barriers to entry and 
adherence with medical care for chronic disease. Originally designed to improve outcomes in 
oncology for disadvantaged female patients, the PN conceptual foundation is a strengths-based 
case management perspective to help patients keep their appointments (through scheduling, 
reminders, and accompanying the patients), improve communication between the patient and 
their providers, offer health education, provide assistance with personal barriers to treatment (e.g., 
transportation, health insurance, childcare), and offer emotional support. Clinical trials have found 
that PN increased cancer screening and follow-up rates, improved entry and adherence to HIV 
treatment, and increased adherence to medical appointments and greater likelihood of achieving 
an undetectable viral load compared to controls.  
 
Addictions treatment studies have also found positive outcomes in randomized trials for services 
comparable to PN to increase the likelihood of treatment entry from: a central drug treatment 
intake; receiving medical care at a hospital; and community outreach. Although a case 


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management approach was not found effective in linking drug users newly-released from prison 
to community treatment, that study’s sample was heterogeneous in terms of its drug use (only 
10% were opioid-dependent) and did not receive pharmacotherapy. PN has not been studied in 
re-entry into the community with treatment initiated in jail. It is our hypothesis that PN has the 
potential to assist newly-released detainees to overcome barriers to successful community 
treatment entry.  
 
In this study, the Patient Navigator (PN) will meet with PN participants to discuss barriers to 
treatment, facilitate referrals to community outpatient behavioral drug abuse treatment, and 
provide assistance with other social support-related needs.  
7.7 
Study Team Training 
Research staff will be certified in good clinical practices and will continue to receive regular 
boosters in clinical research procedures, including protection of privacy and well-being of human 
research participants.   
 
The PI and Study Physician/Nurse Practitioner and other clinical personnel will receive training in 
the medication procedures (i.e., preparation for the Vivitrol injection and its administration). The 
Study Physician will provide on-site training at BCMDC and BCMDC clinical staff may also travel 
to UCLA to observe medication procedures.  
7.8 
Medical Management  
At each clinic visit, participants will meet with study physicians and other study personnel such as 
nurses, research assistants, and counselors, to review urine results, discuss adverse events, 
consider the study medication effects and side effects, and discuss other pertinent issues in 
keeping with sound medical practice. Participants’ engagement in self-help groups such as 12-
step is permitted. Medical Management visits will occur twice-monthly during months 1-3, and 
monthly during months 4-6, and Vivitrol injections will be provided monthly to participants in the 
VI and PNV conditions. 
7.9 
"Rescue" Protocol 
Participants who develop significant problems, who cannot tolerate naltrexone, or whose pre-
existing condition worsens during the study may receive increased levels of care deemed 
necessary by the Study Physician, and they will be referred to other treatment resources. 
7.10 
Discharge, Early Termination, Taper, and Post-study Procedures 
Participants withdrawn early from the study will be referred to appropriate services. Participants 
in the VI and PNV conditions will not require any medication taper.   
7.11 
Ancillary Medications 
Ancillary medications may be provided by the study medical team for study medication-related 
side effects as clinically indicated. A range of prescription and over-the-counter ancillary 
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7.12 
Concomitant Medications 
Participants will be instructed to contact the study medical clinician before taking any non-study 
medications, including prescription drugs, over-the-counter preparations, and herbal 
supplements, during the course of the study. Participants reporting use of medications that may 
interact with naltrexone will be excluded or withdrawn based on clinical judgment.  
 
Management of Study Medications 
Appropriately qualified and trained medical personnel will maintain an accurate and current 
accounting of all study medication, which will be available for verification by study monitors. Drug-
accountability records including perpetual inventory, will include the amount of study medication 
ordered, received, transferred between areas of the study site, and those dispensed to individual 
participants.  
7.12.1 
Study Medication Storage 
Study medication will be stored in compliance with federal, state, and local laws and institutional 
policy. Study medication will be stored in a locked, secure, limited-access location under the 
conditions specified by the package insert; Vivitrol will be stored in a locked refrigerator.  
7.12.2 
Unused Medication 
Unused  expired study medication will be logged into an inventory of unused medication, and all 
medications not used by the end of the study intervention phase will be logged and returned to 
NIDA (or as directed) for destruction. Unused medications will be accurately labeled, securely 
stored, and kept separately until sent for destruction. Damaged, expired, or unused study 
medication will be accounted for by the NIDA contract monitor before being returned for 
destruction. Expired naloxone and other ancillary medications obtained for this study will be 
destroyed on site or sent for destruction per local institutional policies.  
7.12.3 
Dispensing of Study Medications 
All study medications shall be dispensed by an appropriate licensed physician/nurse practitioner 
appropriately trained and authorized to dispense study medications. Vivitrol injections will be 
administered in Week 1, and every four weeks for 24 weeks (total of 6 injections).  
7.12.4 
Drug Packaging 
Vivitrol will be supplied in single use packages. Each package will contain one 380 mg vial of 
Vivitrol® microspheres, one vial containing 4 mL (to deliver 3.4 mL) diluent for the suspension of 
Vivitrol®, one 5 mL prepackaged syringe, one 1-inch 20 gauge needle, two 1.5-inch 20 gauge 
needles, and two 2-inch 20 gauge needles with needle protection devices. Lot number and 
medication expiration date will be included on the package labels supplied by the manufacturer.  
7.13 
Participant Withdrawal 
There are no formal criteria for investigator withdrawal of a participant, however, any participant 
for whom study participation is deemed potentially unsafe as determined by the medical clinician 
will be withdrawn from participation, even if the participant would like to continue. Also, 
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 Participants will be withdrawn from medication if it is clinically determined that continuation may 
be unsafe. For example, participants who develop uncontrolled hypertension will be discontinued 
and instructed to see their private physician, or will be provided with referrals for medical care. 
Women who are assigned to one of the VI conditions and become pregnant during the intervention 
period will be withdrawn from study medication, referred for medical care, and the pregnancy will 
be followed until an outcome is known. Participants who experience intolerable side effects or 
other physical or psychiatric conditions regardless of relationship to the study medication will also 
be withdrawn from further study medication administration. 
The medical clinician may determine that a participant’s clinical condition has deteriorated during 
the course of the study. Examples of clinical deterioration that might trigger a decision to withdraw 
the participant from medication include the following: 
• 
The initiation or recurrence of risky behaviors that make further participation 
unsafe;  
• 
Overdose;  
• 
Emergence of psychosis, suicidal ideation, severe cognitive impairment or 
dangerous criminal behaviors;  
• 
Evidence of general medical deterioration; or  
• 
New onset of psychiatric or medical conditions that would require intervention that 
would preclude continued participation in the study protocol. 
In the event the participant is withdrawn from further medication administration, referrals to 
treatment programs or recommendations for medical care will be provided. The study medical 
clinician, in collaboration with the principal investigator may consult with the study medical monitor 
in making this decision. At any time, participants may decide that they no longer wish to continue 
to receive medication or to participate in the study. Those who opt out of medication will be 
allowed to continue to make clinic visits and complete assessments and will complete post-
intervention and follow-up assessments.   
7.14 
Blinding 
This is an open-label, non-blinded trial.  
7.15 
Participant Reimbursement 
Study participants will receive gift cards or cash as compensation for time, travel, parking, and 
other costs borne by the participant. Participants will be provided with medical management at no 
cost, and those in the VI and PNV conditions will receive no-cost medication.  
Incentives will be provided for participating in screening, twice-monthly medical management 
visits in months 1-3 and monthly visits in months 4-6 during the intervention phase, and 
assessment visits at months 1, 3, 6, and 12.  A $25 incentive will be provided for screening; $20 
for each of 9 medical management visits ($180), $40 for each of 3 post-release assessment visits 
($120), and $80 for a final visit at month 12. Each participant will be eligible to receive $405.  
 
 


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8.0 
STUDY ASSESSMENTS 
Measures and instruments will be used to ensure a comprehensive assessment of status and 
functioning variables. These data, along with the DATCAP, will also be used to support the 
economic analysis. (The DATCAP will be administered during Year 2.) On average, screening 
and eligibility assessments will be completed in 4-6 hours (specific to treatment group). Post-
release assessments will be completed in approximately 30- 60 minutes. Medication Management 
visits are expected to take approximately 30-60 minutes.  
 
Table 1. Data Collection Time and Event Schedule 
 
Timepoints 
Screening 
Pre-
release 
Post-release 
Clinic Visits 
 
 
Medical Mgmt 
Assessments 
 
 
 
 
Months 1, 3, 
6, 7, 12 
Measures 
 
 
 
 
Safety & Med. Measures 
 
 
 
 
Physical Exam / Med History 
X 
 
 
 
Injection site inspection 
X 
 
X 
 
Vitals 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
Clinical Lab Tests 
X 
 
 
 
HIV Test  
X 
 
 
 
Pregnancy Test 
X 
 
X 
 
Prior/Concomitant Meds 
X 
 
X 
 
AEs 
 
 
X 
X 
Drug Use Measures 
 
 
 
 
DSM-5 Checklist 
X 
 
 
 
COWS (Withdrawal) 
X 
 
 
 
SOWS (Withdrawal) 
X 
 
 
 
Urine Drug Screen (UDS) 
X 
X 
X 
X 
Substance Use Report (TLFB) 
X 
X 
X 
X 
VAS (Craving) 
X 
X 
X 
X 
Crime and Recidivism  
 
 
 
 
Self-Report Arrest/Tx History 
 
 
X 
X 
Arrest Records  
 
 
 
X 
CJ-DATS Crime Grid 
X 
 
 
 
HIV Risk Measure 
 
 
 
 
HIV-GAIN 
X 
 
 
X 
Cost 
 
 
 
 
Form 90 
 
 
 
 
 
8.1 
Safety and Medical Measures 
8.1.1 
Medical and Psychiatric History 
The participants’ medical and psychiatric history will document past and present health conditions 
at screening to help determine eligibility and to provide baseline information.  


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8.1.2 
Physical Examination 
A physical examination will be completed at screening to ensure that there are no exclusionary 
medical conditions and to gather baseline information. An examination of the participant’s body 
habitus will address appropriateness for VI gluteal intramuscular injection.    
8.1.3 
Injection Site Examination 
Appropriate medical personnel will examine the injection site on the visit following each injection 
procedures. Additional monitoring may be required. Participants will be asked to immediately 
report any site reactions to allow evaluation, monitoring, and possible referral, as needed. 
Injection site examinations will be documented. 
8.1.4 
Electrocardiogram (ECG) 
A 12-lead ECG will be administered at screening.  
8.1.5 
Clinical Laboratory Tests  
A comprehensive blood chemistry including liver function, hematology panel, and a standard 
urinalysis will help determine eligibility at screening. An accredited laboratory (College of 
American Pathologists or equivalent), that meets CLIA guidelines, will provide lab results, normal 
values, and proof of lab certifications.  
8.1.6 
HIV Testing 
On-site HIV testing will use the FDA-rapid test (INSTI™ HIV-1 Antibody Test Kit; bioLytical Labs, 
Inc.), providing results within one minute to ensure participant awareness of HIV status. 
8.1.7 
Pregnancy and Birth Control Assessment 
Pregnancy test information will be collected for female participants and include test results, and 
self-reports of birth control method(s). 
8.1.8 
Vital Signs 
Vital signs (e.g., body temperature, blood pressure, pulse, respiration rate) will be collected at 
screening, at each medical management visit throughout the intervention phase, before and after 
naloxone administration, at Vivitrol injections.   
8.1.6 
Prior and Concomitant Medications 
Information about prescription, over-the-counter medications, and herbal supplements used by 
participants will be collected at screening for medications taken in the previous 4-week period. At 
other medical management visits, the form will document medications taken since the previous 
data collection visit.  
8.1.7 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Medical or psychiatric adverse events (AEs) will be collected by inquiring of participants: “How 
have you been feeling since your last visit?” AEs will be recorded at each visit after consent 
according to the adverse event reporting definitions and procedures. If a reported AE suggests 
medical or psychological deterioration, it will be brought to the attention of the study medical 
clinician for further evaluation, and seizures will also be reported to the DSMB as they occur. 
SAEs will be medically managed, reported, and followed in accordance with applicable regulatory 
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8.2 
Drug Use Measures and Psychological Measures 
8.2.1 
Substance Use Report: Timeline Follow-Back (TLFB) 
The TLFB will be used to elicit participants’ self-reported use of alcohol and illicit substances. At 
screening, substance use reported by the participant for the prior 30-day period will be assessed. 
The TLFB will be administered at each study visit throughout the medication phase, at the post-
medication visit, and at follow-up to document the participant’s self-reported use of substances 
for each day since the previous assessment. 
8.2.2 
Urine Drug Screen (UDS) 
Urine samples will be collected at every clinic visit using FDA-approved one-step temperature-
controlled urine drug test cups following all of the manufacturer's recommended procedures. The 
UDS will test for the presence of opiates, oxycodone, barbiturates, benzodiazepines, cocaine, 
amphetamines, MA, marijuana, methadone, and Ecstasy (MDMA). A validity check may be 
performed using a commercially available adulterant test strip that indicates normal ranges for 
creatinine, pH (at minimum), nitrate, glutaraldehyde, specific gravity, bleach and pyridinium 
chloromate. Study staff may observe the collection of UDS. In the event of suspected tampering, 
the study team will request a second sample and may observe the urine collection process 
according to clinic standard operating procedures. 
8.2.3 
Visual Analog Craving Scale (VAS) 
Participants’ opioid craving will be documented on a visual analog scale (VAS) that ranges from 
0 (no craving) to 100 (most intense craving possible). The VAS will be completed at screening 
and at each Medical Management and assessment visit.  
8.2.4 
DSM-5 Checklist/Modified CIDI 
The DSM-5 Checklist is a semi-structured interviewer administered instrument that provides 
current diagnoses for substance use disorders based on DSM-5 diagnostic criteria. The CIDI will 
be modified for use in this study. Either/both measures will be completed at screening to 
determine presence and severity of opioid use disorder, and at 6 months as the primary outcome. 
8.2.5 
HIV-Gain 
The HIV-Gain will be used to assess HIV risk. It will be administered at screening and at 
assessment visits.  
8.3 
Crime and Recidivism 
8.3.1 
Arrest Records 
Arrest records will be accessed to compile information on participants’ arrests, convictions, 
sentences, and incarcerations.  
8.3.2 
CJ-DATS Crime Grid 
Criminal Justice history will be documented including information about criminal activity, arrests, 
convictions, and incarcerations with this 24-item section of the CJ-DATS intake instrument.  


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8.4 
Data Collection and Management   
Study measures will be collected using electronic data entry, and managed by ISAP’s Data 
Management Center (DMC) to manage large amounts of data. This process performs range 
checks and other verification procedures during and immediately after completion of data entry, 
thus ensuring the reliability of de-identified data transmitted to our DMC via a secure server at the 
end of each day. Upon study completion, each participant’s data record is saved to disk and 
securely stored.  
8.5 
Data Sharing   
The project will comply with NIH regulations regarding provision of access to the data set (in non-
identifiable form) after study completion. As approved by the PI, the ISAP DMC will respond to 
requests for data. Articles from the project will be made available via submittal to PubMedCentral 
after publication. 
 
 


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9.0 
TRAINING 
The study staff will be trained and certified as specified in the study Training Plan. Training will 
cover standard human subject training (e.g., Good Clinical Practices), as well as protocol-specific 
training as needed (e.g., assessments, study interventions, fidelity to the protocol and safety 
procedures, data management and collection, research procedures including understanding 
reliability and validity, and problem solving). Study Medical staff will be trained on all aspects of 
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10.0 STATISTICAL ANALYSES 
The project emphasizes evaluation of the clinical utility of Vivitrol in jail inmates as compared with 
a Drug Education condition (DE), while descriptive statistics will provide an overall assessment of 
the implementation of the protocol.  
 
Analyses will include an Intent-to-treat (ITT) design such that all randomized participants who 
received at least one dose of medication (VI, PNV), or received at least one session of drug 
education (DE) will be included who did not violate the protocol in a way that could potentially 
affect the efficacy results.  Participants will be excluded from the Protocol Population (PP) if: 
1. concomitant medication that is known to have significant clinical effect on primary or 
secondary endpoints was administered. 
2. Violations of the inclusion or exclusion criteria are judged to affect the efficacy 
evaluations. 
Subjects in the PP population will be allocated to treatment groups in the analysis based on the 
actual treatment they received. If there is substantial difference between the ITT population and 
the PP population, all analyses described below will be performed using only subjects in this 
group. 
 
All statistical tests will be performed using two-sided .05 significance levels, unless otherwise 
stated. All comparisons between treatments will be reported with parameter estimates and 95% 
confidence intervals.  For parameters measured at baseline and subsequently, the variables of 
interest are changes from baseline.  
 
Post-baseline variables will not be imputed; estimates can be obtained using the hierarchical 
models specified below under the assumption of missing at random. For the primary outcome 
measure, diagnosis at six months, subjects who have dropped out for whatever reason will be 
considered to retain the diagnosis. Other outcome measures for which data are missing will be 
imputed using multiple imputation methods. Sensitivity analyses will repeat specific analyses 
using permutation tests of at least 1000 samples. 
10.1 
Primary Outcome 
The primary outcomes of opioid use and a DSM-5 diagnosis of opiate use disorder 6 months after 
randomization.   
 
10.2     Secondary Outcomes 
 
Analyses will include descriptive, binomial and multinomial methods to address secondary 
outcomes: 
 
(1) HIV risk behaviors (compared using repeated measures procedures to evaluate possible 
change in sexual and drug-related behaviors that may inhibit or promote HIV infection) 
measured by the HIV-GAIN;  
 
(2) Self-reported number of days incarcerated during the intervention and follow-up phases;  
 
(3) Self-reported number of days of opioid and other drug use measured by TLFB, and 


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objective measures of drug use by urine drug screens (UDS) at the 6-month post-release 
assessment (end of the intervention phase);  
 
(4) Self-reported days in drug abuse treatment;  
 
(5) Self-reported number of arrests;  
 
(6) Self-reported craving for opioids;  
 
(7) Self-reported number of overdoses; and  
 
(8) Self-reported motivation for treatment.  
 
 
10.3 Power and Sample Size  
 
With the primary focus of this study on the feasibility and clinical utility of the two 
pharmacotherapies, the study is not powered to be an exhaustive comparison but to 
parsimoniously enable preliminary characterization of outcomes that will be needed to inform a 
future, larger scale multi-site trial. We expect that a baseline sample of 150 participants with 50 
participants per condition will yield a final aggregate sample of approximately 120 participants, 
assuming 10-20% dropout. (Our similar studies have had 85-90% follow-up rates.) Thus, a final 
evaluable sample size of 120 participants would permit detection of a medium-large effect size 
(~.60) between conditions for some of the outcome variables (at ~.70 power) and .5 effect size 
(at .80 power) for others. For example, we expect that the measure “time to first opioid use” will 
be markedly different among the three groups, given the difference given the expected relapse 
among the no-medication group. Over time, the total number of opioid-free urine results is 
expected be greater among the VI participants, who are likely to show less dropout and better 
long-term retention compared to the DE group. Our selection of the effect size is based on effects 
found in the literature for Vivitrol when compared against placebo, and is consistent with both 
Cohen (1988) and with more recent guidance; for example, Lipsey and Wilson (1993) did a meta 
analysis of 302 meta-analyses that included over 10,000 studies and found that the average effect 
size was .5, adding support to Cohen's recommendation that selection of the effect size of .5 is 
appropriate (Bausell & Li, 2002).    
 
10.4 Analysis Approach 
 
Analyses will employ modeling approaches that are less sensitive to biases from missing data, 
using a technique that conceptualizes missing data in two ways: intermittent missing data for 
participants active in the trial and dropouts (Shoptaw et al., 2002). Analysis of urine drug screen 
results are conducted using aggregates such as the Treatment Effectiveness Score (Ling et al., 
1997), which is tested by condition using GLM and non-parametric strategies, where appropriate. 
Retention differences between conditions will be tested using an appropriate survival analysis 
model. Counts and composites of scores on drug craving and psychological measures will also 
be analyzed by treatment condition using t-tests and ANOVAs. Secondary analyses may include 
use of longitudinal models (Diggle et al., 1994), including normal mixed-effects models (Littell et 
al., 1996; SAS Institute, 1996; Singer, 1998; MIXED; PROC MIXED, SAS Institute Inc, Cary, NC) 
for continuous measures and generalized linear mixed models (Littell et al., 1996; GLMM; 
GLIMMIX macro, SAS Institute, Inc) for categorical measures. A six-step analysis approach is 
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10.4.1 Data Screening  
 
Typical data screening activities will be conducted; univariate analyses will determine cell 
frequencies, normality, linearity, and homoscedasticity of continuous variables, and missing 
values. Variables with non-normal distributions will be transformed, when appropriate, using 
procedures recommended by Mosteller and Tukey (1977). Missing values will be handled using 
conventional case elimination, mean substitution, or estimation procedures (e.g. Cohen & Cohen, 
1983). Preliminary analyses will address baseline characteristics of the two medication conditions 
using univariate techniques to determine the adequacy of the random assignment procedures, 
and whether these procedures result in groups similar in pertinent characteristics. Any variables 
determined to differ significantly between conditions will be used as covariates. We will also 
conduct attrition analyses to determine whether participants who failed post-consent screening 
differ from those randomized.  
 
Baseline Characteristics and Treatment Group Differences 
To appraise differences in baseline characteristics of the treatment groups, continuous variables 
will utilize analysis of variance, ordinal variables will utilize the Cochran Mantel Haenszel test, and 
dichotomous variables will utilize the chi-square (χ2) test or Barnard’s test.  As appropriate, 
transformation such as log, square root or inverse may be utilized to accomplish the twin goals of 
variance stabilization across levels of the predictor variables and normal distribution of the 
outcome variable, if necessary. 
For continuous variables, the number of non-missing and missing values and the median, mean, 
standard deviation, minimum, and maximum will be obtained for each treatment group.  For 
categorical variables, the counts and proportions of each value will be tabulated.   
Differences between participants who were considered but not randomized (screen fails) will be 
compared with randomized participants on selected demographic characteristics. Summary 
tables for continuous variables include mean, standard deviation, median, min and max will be 
prepared. Outcome measures will be summarized by treatment group and by visit when 
applicable. 
Treatment group differences at the 0.10 level of significance in baseline variables may be included 
as stratification variables or covariates in efficacy analyses. 
 
10.4.2 Primary Statistical Analysis of the First Primary Outcome Measure 
 
A  mixed effects logistic regression will used to model the binary primary outcome measure; the 
diagnosis of opioid use disorder at six months post treatment. are modeled as a linear 
combination of predictor variables. A logit link function will be used to link subject covariates to 
the probability of success There will be two levels in the model: within sites and between sites. 
The model will included treatment, cluster (site) and baseline covariates as fixed effects and 
subject as a random effect. Indicator variables will identify whether a subject has received XR-
NTX, methadone and a behavioral intervention (PN.) Site by treatment interactions will be 
included in the model. Interactions that are statistically significant at the 10% level will be 
investigated and may imply that analyses of individual sites is required. In this case, relevant 
contrasts will be performed within the sites.  
 
Additional covariates will include age, gender, whether a subject had prior methadone 
maintenance treatment and baseline self-reported cocaine use. Other possibilities mediating 


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factors include opioid dependence severity at baseline, concurrent cocaine or alcohol and/or 
benzodiazepine misuse, and homelessness.   
 
SAS PROC Mixed will be used to perform the analysis. The coefficients in the model will be 
estimated by generalized least squares (GLS), with covariance parameters estimated by 
restricted maximum likelihood (REML).  Standard errors of the parameter estimates will be 
computed using the model. This procedure assumes that missing observations are ignorably 
missing or missing at random (MAR).   
The primary contrast is a comparison of the probability of a DSM-5 Opioid Use Disorder 
Diagnosis at 6 months for those on medication versus those receiving enhanced treatment as 
usual (etau.) The contrast will utilize XR NTX data from both the NYU and UCLA and Interim 
Methadone data from FRI; the medication plus PN treatment arm will not be included.  
 
Descriptive statistics will examine feasibility issues of the pharmacotherapy, analyzing AEs, side 
effects, and patient and clinician acceptance, and reasons for early termination or post-
randomization refusal of assigned condition. Single-point, between-group comparisons of these 
measures can be tested using t-tests or ANOVAs for continuous variables and chi-square for 
binary measures.  
 
10.4.3 Economic Analysis (Aim 3) 
The costs of the Vivitrol will be estimated using the Drug Abuse Treatment Cost Analysis Program 
(DATCAP[d1]; French, 2003b). The DATCAP is a data collection instrument and interview guide 
designed to estimate the costs of substance abuse treatment and related interventions. Because 
the DATCAP organizes cost data across standard categories of resources (e.g., personnel, 
buildings and facilities, supplies and materials, and miscellaneous), it can be used for other types 
of interventions including pharmacotherapies. Cost data will be obtained to calculate the total 
annual cost of Vivitrol and the average per-client cost. We will not include any costs specific to 
research conducted under this study. To ascertain the full economic impact of Vivitrol, cost data 
will be compared to changes in key clinical measures of effectiveness (e.g., time to relapse, days 
of abstinence, re-arrest) to estimate cost-effectiveness ratios. Cost-effectiveness analysis (CEA) 
is inherently an incremental analysis that compares doing a little more or a little less of something 
to capture marginal variations in costs and effectiveness across interventions (Gold et al., 1996).  
Differences in program cost are divided by differences in program effectiveness to calculate 
incremental cost-effectiveness ratios (ICERs). One can then compare the ratios of cost to 
outcome for two or more alternative programs (in this case Vivitrol) to determine which programs 
are relatively more cost-effective (i.e., have a lower cost-effectiveness ratio).  The more expensive 
pharmacotherapy will be directly assessed to see if the additional cost generates greater 
effectiveness across the key outcomes of interest. As an alternative approach to examining the 
full economic impact of this pharmacotherapy, we will estimate the economic benefits associated 
with reductions in criminal activity and criminal justice system costs, improved employment, and 
reduced health care use. The difference between economic benefits and intervention costs 
represents the net economic benefits of the interventions. The primary objectives of the benefit 
analysis are to identify important economic outcomes for Vivitrol, convert these outcomes into 
dollar equivalents, and estimate the therapy’s total and domain-specific economic benefits. 
Decreases in some measures between baseline and follow-up, such as number of arrests, 
represent improvement while other measures, such as hours worked, show improvement with 
increases. Benefit-cost analysis (BCA) expresses results as a benefit-cost ratio (benefit divided 
by cost) or a net benefit estimate (benefit minus cost) and considers an intervention cost-
beneficial if the benefit-cost ratio exceeds unity or if the net benefit estimate is positive. In 


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summary, we will be able to describe the economic impact of Vivitrol in terms of both cost-
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11.0 REGULATORY COMPLIANCE AND SAFETY MONITORING 
11.1 
Regulatory Compliance 
This study will be conducted in accordance with the current version of the protocol, in accordance 
with the ethical principles outlined in the Declaration of Helsinki, consistent with the International 
Conference on Harmonization Good Clinical Practice (GCP) Guidelines, and all other applicable 
regulatory requirements.  
11.2 
Institutional Review Board Approval 
Prior to initiating the study, written UCLA and UNM IRB approval will be obtained to conduct the 
study. Should changes to the study protocol become necessary, protocol amendments will be 
submitted in writing by the investigators for IRB approval prior to implementation. In addition, the 
UCLA and UNM IRBs will approve all consent forms, recruitment materials, and any materials 
given to the participant. Annual reports and progress reports will be submitted to the IRBs annually 
or as requested.  
11.3 
Informed Consent 
All potential candidates for the study will be given a current local IRB-approved copy of the 
Informed Consent Form to read in English. Appropriately qualified and trained study personnel 
will explain all aspects of the study in lay language and answer all of the study candidate’s 
questions. Participants who remain interested after receiving an explanation of the study will be 
given a short quiz to test his/her understanding of the project, the purpose and procedures 
involved, and the voluntary nature of his/her participation. Those who cannot successfully answer 
quiz items will have the study re-explained by research staff with a focus on aspects they did not 
understand. Anyone who cannot demonstrate appropriate understanding of the study will be 
ineligible to participate. Those who demonstrate understanding of the study and voluntarily agree 
to participate will be asked to sign the informed consent form. Participants will not be administered 
any assessments or study procedures prior to signing informed consent.  
The informed consent process is a means of providing study information to each prospective 
participant and allows for an informed decision about participation in the study. The informed 
consent form must be updated or revised whenever important new safety information is available, 
or whenever the protocol is amended in a way that may affect a study participant’s consideration 
for participation in the trial. Every study participant will be given a copy of the signed consent form 
to keep for reference. Individuals who refuse to participate or who withdraw from the study will be 
treated without prejudice.  
11.4 
Drug Accountability 
Upon receipt, the investigator, pharmacist, or authorized designee is responsible for maintaining 
written inventory of the investigational agents. A record of this inventory must be kept and usage 
must be documented. Any unused or expired investigational agent shall be accounted for. 


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11.5 
Quality Assurance and Safety Monitoring 
Protection of the rights and welfare of study participants will be a vigilant process conducted by 
the research team and by the sponsors of the research. In addition to the data and safety 
monitoring procedures described in this protocol, additional safety monitoring through the Data 
and Safety Monitoring Board will be conducted regularly throughout the duration of the study. 
11.6 
Data and Safety Monitoring Board (DSMB) 
This study will utilize a DSMB to oversee ongoing trial progress. The purpose of this board is to 
determine whether risks emerge during the conduct of the trial that make continuation unethical 
(e.g., clear and significant superiority of one condition over another). This process is intended to 
assure the IRBs, the sponsor, and investigators that participants are provided with an accurate 
and ongoing risk evaluation when participating in research trials. Safety monitoring begins with 
the initial review of the protocol during the study development process. Reports of participant 
serious adverse events (SAE) will be provided to the DSMB as they occur. The DSMB will meet 
as necessary over the study duration.  
11.7 
Medical Monitor 
A Medical Safety Monitor will be responsible for overseeing safety and for evaluating all Adverse 
Events (AEs). He/She will review all Serious Adverse Events (SAEs) within five days of their 
occurrence and all other Adverse Events on a regular basis. It is the responsibility of the Principal 
Investigator to provide this information to the medical safety monitor. It is also the Principal 
Investigators’ responsibility to inform the IRB of any reportable AE/SAE. 
11.8 
Quality Assurance Monitor 
The monitoring of the study will be conducted on a regular basis using a local quality assurance 
monitor. Investigators will host periodic visits by local QA monitors. The purpose of these visits is 
to encourage and assess compliance with GCP requirements and to document the integrity of the 
trial progress.  
Monitors will assure that submitted data are accurate and in agreement with source 
documentation and will also review regulatory/essential documents such as correspondence with 
the IRB. Areas of particular concern will be participant informed consent, protocol adherence, 
safety monitoring, IRB reviews and approvals, regulatory documents, participant records, study 
drug accountability, and Principal Investigator supervision and involvement in the trial. Reports 
will be prepared following the visit and forwarded to the Principal Investigator.  
11.9 
Statement of Compliance 
This trial will be conducted in compliance with the appropriate protocol, current Good Clinical 
Practice (GCP), the principles of the Declaration of Helsinki, and all other applicable regulatory 
requirements.  


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11.10 
Confidentiality 
By signing the protocol signature page, the investigators affirm that study information will be 
maintained in confidence and such information will be divulged to the IRBs, Ethical Review 
Committee, or similar expert committee; affiliated institution; and employees only under an 
appropriate understanding of confidentiality with such board or committee, affiliated institution and 
employees. The lead investigator will obtain a federal Certificate of Confidentiality (CoC), 
protecting participants against disclosure of sensitive information (e.g., drug use). The 
Department of Health and Human Services (HHS) office that issues the CoC will be advised of 
changes in the CoC application information. Confidentiality will be maintained in accordance with 
all applicable federal regulations and/or state/Commonwealth law and regulations. 
 
Participant records will be kept confidential by the use of study codes for identifying participants 
on CRFs, secure separate storage of any documents that have participant identifiers, and secure 
computing procedures for entering and transferring electronic data. 
11.11 
Health Insurance Portability Accountability Act (HIPAA) 
Written authorization from participants for use of protected health information will be obtained. 
Releases of participant identifying information that are permitted by the HIPAA regulations, but 
which are prohibited by other applicable federal regulations and/or state/Commonwealth law and 
regulation, are prohibited.   
11.12 
Investigator Assurances 
UCLA ISAP will maintain a Federal Wide Assurance (FWA) with the HHS Office for Human 
Research Protection setting forth the commitment of the organization to establish appropriate 
policies and procedures for the protection of human research subjects. Prior to initiating the study, 
the Principal Investigator and sub-investigators will sign a protocol signature page, providing 
assurances that the study will be performed according to the standards stipulated therein. 
11.13 
Financial Disclosure 
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. It is the responsibility of the investigator to maintain appropriate disclosure to their 
individual institution according to their requirements. 
11.14 
Inclusion of Women and Minorities 
This study should attract a diverse study population. If difficulty is encountered in recruiting an 
adequate number of women and/or minorities, the difficulties involved in recruitment will be 
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11.15 
Description of Plans to Conduct Valid Analyses of Study Results by Gender 
and Race/Ethnicity 
The association between specific demographic characteristics and outcome will be studied. The 
demographic characteristics of potential importance include: age, gender, race, and ethnicity. 
11.16 
Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be checked for regulatory document 
compliance prior to study initiation, throughout the study, as well as at study closure. 
11.17 
Records Retention and Requirements 
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, and regulatory files) are to be maintained by the investigator in a secure location 
for a minimum of 3 years after the study is completed and closed. These records are also to be 
maintained in compliance with local IRB, State and Federal requirements, whichever is longest. 
The sponsor must be notified in writing and acknowledgment must be received prior to the 
destruction or relocation of research records. 
11.18 
Audits 
The Sponsor has an obligation to ensure that this trial is conducted according to good research 
practice guidelines and may perform quality assurance audits for protocol compliance. The 
Investigator; the National Institute on Drug Abuse (the study sponsor); NIDA’s contracted agents, 
monitors or auditors; and other agencies such as the Department of Health and Human Services 
(HHS), the Office for Human Research Protection (OHRP) and the sites’ Institutional Review 
Board may inspect research records for verification of data, compliance with federal guidelines 
on human participant research, and to assess participant safety. 
11.19 
Reporting to Sponsor 
The Principal Investigator agrees to submit accurate, complete, legible and timely reports to the 
Sponsor, as required. These include, but are not limited to, reports of any changes that 
significantly affect the conduct or outcome of the trial or increase risk to study participants. 
Adverse Event reporting and Serious Adverse Event reporting will occur as previously described. 
At the completion of the trial, the PI will provide a final report to the Sponsor. 
11.20 
Study Documentation 
Study documentation includes all case report forms, data correction forms, workbooks, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence, 
and signed protocol and amendments, Ethics Review Committee or Institutional Review 
Committee correspondence and approved current and previous consent forms and signed 
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Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
The original recording of an observation should be retained as the source document. 
11.21 
Protocol Deviations, Violations, and Reporting and Management 
Any departure from procedures and requirements outlined in the protocol will be classified as 
either a protocol deviation or protocol violation. The difference between a protocol deviation and 
violation has to do with the seriousness of the event and the corrective action required. A protocol 
deviation is considered an action (or inaction) that by itself is not likely to affect the scientific 
soundness of the investigation or seriously affect the safety, rights, or welfare of a study 
participant. Protocol violations are departures that may compromise the participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and could be cause for 
corrective actions if not rectified or prevented from re-occurrence. Protocol violations will be 
monitored for (1) significance, (2) frequency, and (3) impact on the study objectives, to ensure 
that performance does not compromise the integrity of the trial. 
Additionally, the study team is responsible for reporting Protocol Violations to the IRB as required.  
11.22 
Safety Monitoring 
11.22.1 
Adverse Events (AEs) 
In accordance with FDA reporting requirements, all AEs occurring during the course of the clinical 
trial will be collected, documented, and reported by the Principal Investigator or sub-investigators 
according to the specific instructions detailed in this section of the protocol and Appendix A.  The 
occurrence of AEs will be assessed at each study visit starting at the time that informed consent 
is signed through the post-medication assessment, and study staff will follow-up on the status of 
any AEs that remain at the post-medication assessment.  
 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course of 
the clinical trial, whether or not the event is considered investigational product-related or clinically 
significant. For this study, AEs will include events reported by the participant, as well as clinically 
significant abnormal findings on physical examination or laboratory evaluation. A new illness, 
symptom, sign or clinically significant clinical laboratory abnormality or worsening of a pre-existing 
condition or abnormality is considered an AE. Stable chronic conditions, such as arthritis, which 
are present prior to clinical trial entry and do not worsen are not considered AEs.  All AEs must 
be recorded on the AE Form. The AE Form is also used to record follow-up information for 
unresolved events reported on previous visits. 
 
Each week, a study physician or investigator must review the AE Form completed for the previous 
week for any events that were reported as continuing. All AEs, including clinically significant 
abnormal findings on laboratory evaluations, regardless of severity, will be followed by study 
investigators until satisfactory resolution.  
 
A Medical Clinician will review or provide consultation for each serious event as needed. These 
reviews will include an assessment of the severity and causality to the study drug or study 
procedures. The Medical Clinician will also provide advice for decisions to exclude, refer, or 
withdraw participants as required. The medical monitor will determine which safety events require 
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This will include all suspected adverse reactions that are serious and unexpected. The study staff 
will be trained to monitor for and report adverse events and serious events. 
The BCMDC has established practices for managing medical and psychiatric emergencies, and 
the study staff will continue to utilize these procedures. Study medical clinicians will be 
responsible for monitoring participants for possible clinical deterioration or other problems, and 
for implementing appropriate courses of action. 
11.22.2 
 Definitions of Adverse Events and Serious Adverse Events 
Full definitions of adverse events and serious adverse events, their identification, characterization 
regarding severity and relationship to therapy and processing are described in Appendix A. 
11.22.3 
 Reportable Adverse Events and Serious Adverse Events 
Reporting of AEs and SAEs is described in Appendix A. The study investigators in this study have 
the responsibility of promptly reporting all SAEs to NIDA.   
Adverse Events 
For the purpose of this study, the following AE will not require reporting in the data system but will 
be captured in the source documentation as medically indicated: 
 
Grade 1 (mild) unrelated adverse events 
This would typically include mild physical events such as headache, cold, etc., that were 
considered not reasonably associated with the use of the study drug/intervention.  
Other adverse events that are deemed moderate, severe or serious, regardless of the relationship 
to the study medications, will be captured and reported in the data system.  
Serious Adverse Events 
All SAEs will be documented in the source documentation as medically indicated and reported 
through the data system.  
11.23 
Possible Risks of Study Medications 
The most serious adverse effect of naltrexone is hepatocellular injury, which has almost always 
been associated with oral doses of 1400 to 2100 mg per week. Recent study findings show that 
no evidence of liver toxicity was found in those receiving monthly Vivitrol® injections such as 
provided in this study. Participants will not be allowed to participate if there is any indication or 
report of acute symptomatic hepatitis or liver failure. 
 
Vivitrol® injections may be followed by pain, tenderness, induration, swelling, redness, bruising, 
or itching. Injection site reactions have been the most common adverse events associated with 
Vivitrol®, but the injection site will be monitored after each injections. Any participant exhibiting 
adverse events will be evaluated by the study physician for possible referral to a surgeon if 
warranted. Other side effects may include nausea and vomiting. Continued use of naltrexone is 
not associated with tolerance or addiction, but naltrexone will precipitate withdrawal if given to a 
person who is physiologically dependent on opioids. To eliminate this risk, a naloxone challenge 
will be administered to each participant in this condition before administration of each Vivitrol 
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12.0 DATA MANAGEMENT AND PROCEDURES 
This protocol will utilize the UCLA ISAP Data Management Center (DMC). A web-based 
distributed data entry model will be implemented. This electronic data capture (EDC) system will 
be developed to ensure that guidelines and regulations surrounding the use of computerized 
systems used in clinical trials are upheld.  
12.1 
Operations Manual 
An Operations Manual or Standard Operating Procedure documents will be provided for this study 
that incorporates procedures from this protocol with those procedures in more detail as necessary 
for the day-to-day conduct of the trial. The Operations Manual will be used to train study staff, to 
provide reference for study procedures, and to support quality management activities. 
12.2 
Data and Statistics Center Responsibilities 
The DMC will 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide source documents and electronic Case Report Forms 
(eCRFs) for the collection of all data required by the study, 3) develop data dictionaries for each 
eCRF that will comprehensively define each data element, 4) prepare instructions for the use of 
EDC system and for the completion of eCRFs, 5) perform data cleaning activities prior to any 
interim analyses and prior to the final study database lock.  
12.3 
Data Collection and Entry 
Data will be collected on source documents and entered by the site into eCRFs or in the EDC, or 
will be collected via direct entry into the eCRF. In the event that the EDC is not available, the DMC 
will provide paper source documents and completion instructions. Data will be entered into the 
EDC in accordance with the instructions provided during project-specific training and guidelines 
established by the DMC. Data entry into the eCRFs shall be performed by authorized individuals. 
Selected eCRFs may also require the investigator’s electronic signature.   
The investigator is responsible for maintaining accurate, complete and up-to-date research 
records. In addition, the investigator is responsible for ensuring the timely completion of eCRFs 
for each research participant.  
12.3.1 
Data Monitoring, Cleaning, and Editing 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and forms are available to sites at all times in the EDC. These reports will 
be monitored regularly by the DMC. In addition, the DMC will identify inconsistencies within 
eCRFs and between eCRFs and post queries in the EDC on a scheduled basis. Data 
inconsistencies and errors by will be corrected by entering all corrections and changes directly 
into the EDC.  
12.4 
Study Documentation and Records Retention 
Study documentation includes all data correction forms, workbooks, source documents, 
monitoring logs and appointment schedules, Sponsor correspondence and regulatory documents 
(e.g., signed protocol and amendments, IRB correspondence and approved consent form and 


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signed participant consent forms, Statement of Investigator form, and clinical supplies receipt and 
distribution records, among others). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Accordingly, source documents include, but are not limited to, laboratory reports, ECG tracings, 
X-rays, radiologist reports, participant diaries, biopsy reports, ultrasound photographs, participant 
progress notes, hospital charts or pharmacy records and any other similar reports or records of 
any procedure performed in accordance with the protocol. 
12.5 
Data Transfer and Lock 
At the conclusion of data collection for the study, the DMC will perform final cleaning activities 
and will “lock” the study database from further modification. The final data will be provided to the 
PI for analyses.   
12.6 
Confidentiality 
12.6.1 
Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the Food and Drug Administration 
(FDA) under the Freedom of Information Act providing, in part, that proprietary information 
furnished to investigators and Institutional Review Boards will be kept confidential by the FDA 
only if maintained in confidence by the clinical investigator and Institutional Review Board (IRB). 
By signing this protocol the investigator affirms to NIDA that information furnished to the 
investigator by NIDA will be maintained in confidence and such information will be divulged to the 
IRB or similar or expert committee; affiliated institution; and employees only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and employees. 


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13.0 SIGNATURES 
SPONSOR’S REPRESENTATIVE 
Typed Name 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATOR(S) 
 
I agree to conduct this clinical study in accordance with the design and specific provisions of 
this protocol and will only deviate from the protocol after notifying the sponsor except when 
necessary to protect the safety, rights, or welfare of participants. 
 
I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 
and institutional review board (IRB) review and approval in 45 CFR 46 and 21 CRF Part 56 are 
met. 
 
I agree to report to the sponsor adverse experiences that occur in the course of the 
investigation, and to provide annual reports and a final report in accordance with 45 CFR 46 
and 21 CFR 312.64. 
 
I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to 
make those records available for inspection in accordance with 45 CFR 46 and 21 CFR 312.68. 
 
I will ensure that an IRB that complies with the requirements of 45 CFR 46 and 21 CRF Part 
56 will be responsible for the initial and continuing review and approval of the clinical 
investigation. I also agree to promptly report to the IRB all changes in the research activity and 
all unanticipated problems involving risks to human participants or others. Additionally, I will 
not make any changes in the research without sponsor, lead investigator, and IRB approval, 
except where necessary to eliminate apparent immediate hazards to human participants. 
 
I agree to personally conduct or supervise this investigation and to ensure that all associates, 
colleagues, and employees assisting in the conduct of this study are informed about their 
obligations in meeting these commitments. 
 
I agree to comply with all the applicable federal, state, local, and institutional regulations 
regarding the obligations of clinical investigators and other pertinent requirements in 21 CRF 
312. 
 
 
 
 
 
 
 
 
 
 
 
Typed Name 
 
Signature 
 
Date 
 
 
 
 
 
Principal Investigator  
 
 
 
 
 
 
 
 
 
Principal Investigator 
(if applicable) 
 
 
 
 
 
 
 
 
 
Sub-Investigator  
 
 
 
 
 
 
 
 
 
Sub-Investigator 
 
 
 
 


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15.0 APPENDICES


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APPENDIX A 
Adverse Event Reporting Definitions and Procedures 
The Principal Investigator is responsible for study oversight, including ensuring human research 
subject protection by designating appropriately qualified and trained study personnel to assess, 
report, and monitor adverse events. 
 
Definition of Adverse Events and Serious Adverse Events 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered study drug/intervention related, which occurs during the conduct of a clinical trial. Any 
change from a baseline pre-existing condition based on clinical status, ECGs, lab results, x-rays, 
physical examinations, etc., that is considered clinically significant by the study medical clinician 
are considered AEs.  
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the study drug/intervention caused the adverse event. A reasonable possibility implies that there 
is evidence that the study drug/intervention caused the event. 
Adverse reaction is any adverse event caused by the study drug/intervention. 
An adverse event, suspected adverse reaction, or adverse reaction is considered “serious” 
(i.e. a serious adverse event, serious suspected adverse reaction or serious adverse reaction) if, 
in the view of either the study medical clinician or sponsor, it: 
1. Results in death: A death occurring during the study or which comes to the attention of 
the study staff during the protocol-defined follow-up period, whether or not considered 
caused by the study drug/intervention, must be reported. 
2. Is life-threatening: Life-threatening means that the study participant was, in the opinion of 
the medical clinician or sponsor, at immediate risk of death from the reaction as it occurred 
and required immediate intervention.  
3. Requires inpatient hospitalization or prolongation of existing hospitalization.  
4. Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
5. Is a congenital abnormality or birth defect. 
6. Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention to 
prevent one of the outcomes listed in the above definition of serious event.   
 
Definition of Expectedness 
Any adverse event is considered “unexpected” if it is not listed in the investigator brochure or the 
package insert or is not listed at the specificity or severity that has been observed. If neither is 
available then the protocol and consent are used to determine an unexpected adverse event. 
 
Pregnancy 
Any pregnancies that occur to a participant enrolled in the study will be captured on a pregnancy 
CRF and not separately reported as an AE or SAE. Women who become pregnant during the 


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medication period will be discontinued from further medication administration, referred for medical 
care, and the pregnancy followed until an outcome is known. 
Medical and Psychiatric History 
A thorough medical and psychiatric history during the screening phase should record any chronic, 
acute, or intermittent preexisting or current illnesses, diseases, symptoms, or laboratory signs of 
the participant, to avoid reporting pre-existing conditions as new AEs and to assist in the 
assessment of worsening in intensity or severity of these conditions that would indicate an AE. 
Stable chronic conditions, such as arthritis, which are present prior to clinical trial entry and do 
not worsen are not considered AEs.  
 
Eliciting and Reporting Adverse Events  
Appropriately qualified and trained medical personnel will elicit participant reporting of AEs and 
SAEs at each study visit designated to collect AEs. Adverse events (medical and/or psychiatric) 
assessment will initiate with participant consent and follow-up will continue through 30 days post 
last study visit. Medical personnel will obtain as much information as possible about the reported 
AE/SAE to complete the AE/SAE forms and will consult as warranted.  
Standard reporting, within 7 days of the site becoming aware of the event, is required for 
reportable AEs. Expedited reporting (within 24 hours of their occurrence and/or site's knowledge 
of the event) is required for reportable SAEs (including death and life-threatening events). Local 
sites are responsible for reporting SAEs to their IRB, per their IRB’s guidelines. 
Sites are required to enter reportable AEs and SAEs in the EDC system. The AE form is used to 
capture reportable AEs (as defined in the protocol). Additional information may need to be 
gathered to evaluate serious adverse events and to complete the appropriate CRFs and the 
summary. This process may include obtaining hospital discharge reports, medical records, 
autopsy records or any other type records or information necessary to provide a complete and 
clear picture of the serious event and events preceding and following the event. If the SAE is not 
resolved or stable at the time of the initial report or if new information becomes available after the 
initial report, follow-up information must be submitted as soon as possible. 
Reportable adverse events will be followed until resolution, stabilization or study end. Any serious 
adverse reactions will be followed until resolution or stabilization even beyond the end of the 
study.  
 
Assessing Severity and Causality of Adverse Events 
Appropriately qualified and trained medical personnel will conduct an initial assessment of 
seriousness, severity, and causality when eliciting participant reporting of adverse events.  A 
study medical clinician will review reportable AEs for seriousness, severity, and causality on at 
least a weekly basis.  
Guidelines for Assessing Severity  
The severity of an adverse event refers to the intensity of the event. 
Grade 1 
Mild 
Transient or mild discomfort (< 48 hours), no or minimal medical 
intervention/therapy required, hospitalization not necessary 
(non-prescription or single-use prescription therapy may be 
employed to relieve symptoms, e.g., aspirin for simple 
headache, acetaminophen for post-surgical pain) 


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Grade 2 
Moderate 
Mild to moderate limitation in activity some assistance may be 
needed; 
no 
or 
minimal 
intervention/therapy 
required, 
hospitalization possible. 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/ therapy required hospitalization possible. 
Guidelines for Determining Causality 
The study medical clinician will use the following question when assessing causality of an adverse 
event to study drug/intervention where an affirmative answer designates the event as a suspected 
adverse reaction: 
Is there a reasonable possibility that the study drug/intervention caused the event?  
 
Monitoring Adverse Events 
Local quality assurance monitors will review study sites and respective study data on a regular 
basis and will promptly advise sites to report any previously unreported safety issues and ensure 
that the reportable safety-related events are being followed to resolution and reported 
appropriately. Staff education, re-training or appropriate corrective action plan will be 
implemented at the participating site when unreported or unidentified reportable AEs or serious 
events are discovered, to ensure future identification and timely reporting by the site.  
 
Safety Management Procedures of AEs/SAEs 
A Medical Monitor is responsible for reviewing all serious adverse event reports. All reported 
SAEs will generate an e-mail notification to the Medical Monitor. All SAEs will be reviewed by the 
Medical Monitor and, if needed, additional information will be requested. The medical monitor will 
also report events to the sponsor and the Data and Safety Monitoring Board (DSMB). The DSMB 
will receive summary reports of all adverse events annually, at a minimum. The DSMB or the 
Medical Monitor may also request additional and updated information. Details regarding specific 
adverse events, their treatment and resolution, will be summarized by the medical monitor in 
writing for review by the sponsor and DSMB. Subsequent review by the Medical Monitor, DSMB, 
and ethics review committee or IRB, the sponsor, or relevant local regulatory authorities may also 
suspend further trial treatment. The study sponsor, DSMB and FDA retain the authority to 
suspend additional enrollment and intervention for the entire study as applicable. 
Reporting to the Data and Safety Monitoring Board:  The DSMB will receive listing of AEs and 
summary reports of all SAEs at a frequency requested by the DSMB, but at least 
annually.  Furthermore, the DSMB will be informed of expedited reports of SAEs.  
 
Regulatory Reporting for an IND study 
All serious and unexpected suspected adverse reactions are reported by the medical monitor on 
behalf of the sponsor to the FDA in writing within 15 calendar days of notification.  Suspected 
adverse reactions that are unexpected and meet the criteria for death or immediately life-
threatening also require notification of the FDA as soon as possible but no later than 7 calendar 
days of notification of the event, with a follow-up written report within 15 calendar days of 
notification of the event.  The medical monitor will prepare an expedited report (MedWatch Form 
3500A or similar) for the FDA and other regulatory authorities, DSMB and copies will be distributed 
to all sites.  Expedited reports will be placed in the site regulatory files upon receipt.  A copy of all 
expedited reports will be forwarded to the site’s local IRB, as required.   


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Participant Withdrawal 
The study medical clinician must apply his/her clinical judgment to determine whether or not an 
adverse event is of sufficient severity to require that the participant is withdrawn from further study 
medication administration. The study medical clinician should consult with the site principal 
investigator, the lead investigator and/or Medical Monitor as needed. If necessary, a study 
medical clinician may suspend the interventions and institute the necessary medical therapy to 
protect a participant from any immediate danger. A participant may also voluntarily withdraw from 
treatment due to what he/she perceives as an intolerable adverse event or for any other reason. 
If voluntary withdrawal is requested, the participant will be asked to complete an end-of-
medication visit to assure safety and to document end-of-medication outcomes and will be given 
recommendations for medical care and/or referrals to treatment, as necessary. 
 
AE Identified
Serious?
Standard reporting
Notify local IRB per IRB 
requirements
Reportable SAE
Record per site requirements 
report SAE per IRB requirements
AE reviewed by 
designated staff
Complete AE eCRF 
within 7 days
Expedited initial reporting 
within 24 hours via AE/SAE 
eCRFs in EDC
Study Physician reviews all 
relevant records and completes 
SAE report and documentation 
completed by study staff.
Continue follow-up and reporting 
until event is resolved or stabilized
 NO   
    YES
     NO
YES


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