Long-acting Naltrexone for Pre-release Prisoners: A Randomized Trial of Mobile Treatment
Phase: PHASE3
Conditions: Opiate Addiction
Sponsor: Friends Research Institute, Inc.

P a g e  | 1 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 
Protocol Cover Page 
 
Protocol Title: 
Long-acting naltrexone for pre-release prisoners:  A randomized trial of mobile 
treatment 
 
Sponsor: 
National Institute on Drug Abuse (Grant # R01DA040636-01) 
 
Study Drug: 
VIVITROL® (naltrexone for extended-release injectable suspension, 
Alkermes) 
 
Project Leader (s):  
Michael S. Gordon, DPA (Principal Investigator) 
 
 
 
 
Senior Research Scientist 
 
 
 
 
Friends Research Institute, Inc. 
 
 
 
 
Frank J. Vocci, PhD (Co-Investigator) 
 
 
 
 
President, Senior Research Scientist 
 
 
 
 
Friends Research Institute, Inc. 
 
 
 
 
 
 
 
 
 
Terrence T. Fitzgerald, MD (Co-Investigator) 
Medical Director 
Glenwood Life Counseling Center (GLC) 
            
 
 
 
 
 
 
 
 
Chuck O’Brien, MD, PhD (Medical Consultant) 
 
 
 
 
Kenneth E Appel Professor 
 
 
 
 
Department of Psychiatry 
 
 
 
 
Center for Studies of Addiction 
 
 
 
 
 
FRI Protocol Number: 
 
 
16-05-237 
 
Initial Version/Number Date: 
v. 0.1 
2   June 2016 
Revised Version/Number Date: 
v. 1.0 
28 June 2016 
 
v. 2.0 
18 August 2016 (#1 Amendment) 
 
v. 3.0 
26 January 2017 (#2 Amendment) 
 
v. 4.0 
2 February (#3 Amendment) 
 
v. 5.0 
22 February 2017 (#4 Amendment) 
 
v. 6.0 
19 May 2017 (#5 Amendment) 
 
v. 7.0 
23 May 2017 (#6 Amendment) 
 
v. 8.0 
29 June 2017 (#7 Amendment) 
 
v. 9.0 
1 Nov 2017 (#8, #9 Amendment) 
 
v. 10.0 
4 Dec 2017 (#10 Amendment) 
 
v.11.0 
29 Mar 2018 (#11 Amendment) 
 
v. 12.0 
2 Nov 18 (#12 Amendment) 
 
 
CONFIDENTIAL 
This material is the property of Friends Research Institute (FRI). Do not disclose or use except as authorized in writing by the study sponsor. 
 

P a g e  | 2 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 
 
 
TABLE OF CONTENTS 
 
Study Contact List ................................................................................................................................................................... 5 
Protocol Synopsis ................................................................................................................................................................... 6 
List of Abbreviations ................................................................................................................................................................ 8 
Schematic of Study Design ..................................................................................................................................................... 9 
Statement of Compliance ...................................................................................................................................................... 10 
1.0 SPECIFIC AIMS .............................................................................................................................................................. 11 
1.1. Design ............................................................................................................................................................... 11  
1.2. Specific Aims ....................................................................................................................................................  11 
1.3. Significance and Public Health Impact .............................................................................................................. 11 
2.0 SIGNIFICANCE ............................................................................................................................................................... 12 
2.1. Opioid Use Disorder (OUD) among Incarcerated Individuals ........................................................................... 12 
2.2. Untreated Opioid Use Disorders among Inmates: Adverse Consequences ..................................................... 12 
2.3. Need for Continuity of Care for Inmates with Opioid Use Histories .................................................................. 12 
2.4. Pharmacotherapy in Criminal Justice Settings ................................................................................................. 12 
2.5. Long-acting Injectable Naltrexone .................................................................................................................... 12 
2.5.1. Why Long-Acting Injectable Naltrexone? .......................................................................................... 13 
2.6. Mobile Medical Treatment ................................................................................................................................. 13 
2.6.1. Why an XR-NTX mobile medical treatment study is needed ............................................................ 13 
2.7. Efficacy of Naltrexone with Criminal Justice Populations: Research by the Current Investigators .................. 13 
2.7.1. XR-NTX Among Parolees, Probationers Pilot Study ........................................................................ 13 
2.7.2. Treatment Study Using Depot Naltrexone (5/6) Baltimore Protocol Treatment Site ........................ 14 
2.7.3. A Phase 4, Pilot, Open-label Study of VIVITROL® in the Prevention of Re-arrest and Re-
incarceration ................................................................................................................................................ 14 
2.8. Efficacy of Naltrexone with Criminal Justice (CJ) Populations: Other Research .............................................. 14 
2.9. Major Differences between Individuals in Prisons, Jails, and Community Corrections .................................... 15 
3.0. INNOVATION ................................................................................................................................................................. 15 
4.0. APPROACH ................................................................................................................................................................... 15 
4.1. Study Overview ................................................................................................................................................. 15 
4.2. Design Considerations ...................................................................................................................................... 16 
4.3. Investigators ...................................................................................................................................................... 16 
4.4. Successes in Research Implementation ........................................................................................................... 17 
4.4.1. Pilot Study on Naltrexone with Prisoners .......................................................................................... 17 
4.4.2. Recruitment and Follow-up of Drug-Involved Research Participants ............................................... 17 
5.0. Specific Approach .......................................................................................................................................................... 17 
5.1. Maryland Department of Public Safety and Correctional Services (MDPSCS) ................................................ 17 
5.2. Participant Eligibility: Inclusion/Exclusion Criteria ............................................................................................. 17 
5.3. Participant Recruitment Procedures ................................................................................................................. 18 
5.4. Random Assignment Procedure ....................................................................................................................... 18 
5.5. Participant Attrition ............................................................................................................................................ 18 
5.6. Medical Services in Prison ................................................................................................................................ 18 
5.6.1. Treatment Clinic ................................................................................................................................ 18 
5.6.2. Pre-release extended-release XR-NTX ............................................................................................ 18 
5.6.3. Overdose Prevention ........................................................................................................................ 19 
5.7. XR-NTX Treatment in the Community .............................................................................................................. 19 
5.7.1 Glenwood Life Counseling Center for XR-NTX injections ................................................................. 19 
5.7.2. Place of Residence for XR-NTX injections ....................................................................................... 19 
5.7.3. Missed XR-NTX Injections ................................................................................................................ 20 
5.7.4. Withdrawal from Naltrexone: Treatment Safety ................................................................................ 20 
5.7.5. Additional Medical Concerns (Safety) ............................................................................................... 20 
5.8. Measures .......................................................................................................................................................... 21 
5.8.1. XR-NTX Adherence .......................................................................................................................... 21 

P a g e  | 3 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
5.8.2. Addiction Severity Index (ASI) with Timeline Follow-Back (TLFB) ................................................... 21 
5.8.3. Biological Assays .............................................................................................................................. 21 
5.8.4. Risk Assessment Battery (RAB) ....................................................................................................... 21 
5.8.5. Opioid Overdose Scale ..................................................................................................................... 21 
5.8.6. Visual Analogue Scale (VAS) ........................................................................................................... 21 
5.8.7. Health Related Quality of Life (QOL) ................................................................................................ 22 
5.8.8. Official Records ................................................................................................................................. 22 
5.8.9. Biometric Measures .......................................................................................................................... 22 
5.8.10. Data Management/Quality Control.................................................................................................. 22 
5.9. Study Aims, Hypothesis, Rationale ................................................................................................................... 22 
5.9.1. Aims .................................................................................................................................................. 22 
5.9.2. Hypothesis ........................................................................................................................................ 22 
5.9.3. Rationale ........................................................................................................................................... 22 
6.0. Statistical Analyses ........................................................................................................................................................ 24 
6.1. Guiding Principle ............................................................................................................................................... 24 
6.2. Intent-to-Treat Approach ................................................................................................................................... 24 
6.3. Outcome Measures ........................................................................................................................................... 24 
6.4. Explanatory Variables ....................................................................................................................................... 24 
6.4.1. Covariates ......................................................................................................................................... 24 
6.4.2. Control Variables............................................................................................................................... 24 
6.4.3. Time .................................................................................................................................................. 24 
6.5. Statistical Method .............................................................................................................................................. 24 
6.6. Missing Data ..................................................................................................................................................... 25 
6.7. Power ................................................................................................................................................................ 25 
6.8. Supplementary Analyses .................................................................................................................................. 25 
6.9. Additional Process Data .................................................................................................................................... 26 
6.10. Follow-up Analyses ......................................................................................................................................... 26 
7.0. Project Timeline ............................................................................................................................................................. 26 
8.0. Impact ............................................................................................................................................................................. 26 
9.0. PROTECTION OF HUMAN SUBJECTS   ..................................................................................................................... 26 
9.1. Potential Risks .................................................................................................................................................. 26 
9.1.1. Extended-Release Naltrexone (XR-NTX) ......................................................................................... 26 
9.1.2. Other Risks ....................................................................................................................................... 27 
9.2. Protection Against Risks ................................................................................................................................... 27 
9.2.1. Risks Associated with XR-NTX ......................................................................................................... 27 
9.2.2. Vivitrol: Medication Guide Required for Patients .............................................................................. 27 
9.2.3. Risks Associated with Loss of Confidentiality ................................................................................... 27 
9.2.4. Risks Associated with Emotional Discomfort .................................................................................... 28 
9.3. Risk/Benefit Ratio .............................................................................................................................................. 28 
9.4. Importance of the Knowledge to be Gained ..................................................................................................... 28 
9.5. Participation of Prisoners .................................................................................................................................. 28 
9.6. Data and Safety Monitoring Plan ...................................................................................................................... 29 
9.6.1. Responsibility for Safety Oversight ................................................................................................... 29 
9.7. Report of Safety-Relevant Information to NIDA ................................................................................................ 29 
9.8. Adverse Event Reporting .................................................................................................................................. 29 
9.9. Relatedness ...................................................................................................................................................... 29 
9.10. Reporting of Unanticipated Risks or New Findings ........................................................................................ 30 
9.11. Quality Control of Data .................................................................................................................................... 30 
9.12. Data and Safety Monitoring Board (DSMB) .................................................................................................... 31 
9.13. Criteria for Suspending or Terminating the Study ........................................................................................... 31 
9.13.1. Termination Due to Safety/Adverse Events .................................................................................... 31 
9.13.2. Termination Due to Favorable Benefit-Risk Ration ........................................................................ 31 
9.13.3. Termination Due to Unfavorable Benefit-Risk Ration ..................................................................... 31 
9.13.4. Termination Due to Inability to Answer Trial Question.................................................................... 31 
10.0. REFERENCES ............................................................................................................................................................. 32 
11.0. APPENDIX (screening forms, medical forms, research instruments) ......................................................................... 38 

P a g e  | 4 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 

P a g e  | 5 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
LIST of FIGURES 
 
Figure 1. Schematic of Study Design ...................................................................................................................................... 9 
Figure 2. Data Collection Schedule ...................................................................................................................................... 23 
Figure 3. Biometric Measures ............................................................................................................................................... 23 
 
 

P a g e  | 6 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
Study Contact List 
 
For questions regarding the conduct of this study, please contact: 
 
 
 
Principal Investigator: 
Michael S. Gordon, DPA 
Friends Research Institute 
E-mail: 
mgordon@friendsresearch.org 
Telephone: 410-837-3977 ext. 251 
Mobile: 
410-978-2241 
Fax:  
410-752-4218 
Co-Investigator: 
Frank J. Vocci, PhD 
Friends Research Institute 
E-mail: 
fvocci@friendsresearch.org 
Telephone: 410-837-3977 ext.  
Fax:  
410-752-4218 
Co-Investigator/Medical 
Director: 
Terrence T. Fitzgerald, MD 
Glenwood Life Counseling Center 
E-mail: 
ttfitzgerald@stanford.edu 
Telephone: 410-323-9811 
Mobile: 
410-925-1220  
Fax:  
410-323-9077 
Medical Consultant: 
Chuck O’Brien, MD, PhD 
Kenneth E Appel Professor 
Department of Psychiatry 
Center for Studies of Addiction 
3900 Chestnut Street 
Philadelphia, PA 19104 
E-mail: 
obrien@upenn.edu 
Telephone: (215) 222-3200 
Fax:  
Fax: 215-386-6770 
 
 

P a g e  | 7 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
Protocol Synopsis 
TITLE 
Long-acting naltrexone for pre-release prisoners:  A randomized trial of mobile treatment 
Investigational site: 
Project implementation will occur at seven pre-release prisons: 1) Brockbridge Correctional 
Facility (BCF); 2) Dorsey Run Correctional Facility (DRCF); 3) Baltimore City Correctional 
Center (BCCC); 4) Maryland Correctional Institution (MCIW) for Women; 5) Central Maryland 
Correctional Facility (CMCF), 6) Maryland Correctional Training Center (MCTC); and 7) 
Roxbury Correctional Institution (RCI) 
Investigators: 
Michael S. Gordon, DPA, Frank J. Vocci, PHD, Terrence T. Fitzgerald, MD 
Sponsor: 
National Institute on Drug Abuse (NIDA); Grant # R01DA040636-01 
Protocol number: 
16-05-237 
Objectives/Outcomes: 
Aim1. To compare the two study conditions in terms of: a) XR-NTX treatment adherence; b) 
opioid use; c) criminal activity; d) re-arrest; e) re-incarceration; and f) HIV risk-behaviors (i. 
needle use; and ii. risky sexual behaviors). Aim 2. To determine if the number of months of 
post-release XR-NTX treatment is related to outcomes (a-f above), and if so, is there a point at 
which XR-NTX v. Non-XR-NTX equilibrates. Such a finding could be potentially important 
because it would be informative about the needed length of XR-NTX treatment 
Study Design: 
The study is a parallel two-group randomized controlled trial in which 240 (120 per condition) 
incarcerated men and women will be randomly assigned within gender to one of two conditions: 
Condition 1. XR-NTX-OTx. One injection of XR-NTX in prison, followed by 6 monthly injections 
post-release at a community opioid treatment program. Condition 2.  XR-NTX+ MMTx. One 
injection of XR-NTX in prison followed by 6 monthly injections post-release at the participant’s 
place of residence utilizing mobile medical treatment. All participants will be evaluated at 1-, 2-, 
3-, 4-, 5-, 6-, 7- (safety visit) and 12-months after release from prison.  
Subjects: 
Inclusion Criteria: (1) adult male or female inmate at BCF, DRCF, BCCC, MCIW CMCF, 
MCTC, or RCI and be eligible for release within 30 days; (2) history of opiate disorder [meeting 
DSM-5 criteria of dependence at the time of incarceration; individuals who do not meet criteria 
at time of incarceration and become addicted during incarceration will be eligible]. Inmates not 
meeting the opioid-dependence criterion will be eligible if they were treated in an opioid agonist 
treatment program during the year before incarceration (3) suitability for XR-NTX treatment as 
determined by medical evaluation; (4) currently opioid-free by history, with negative urine for all 
opioids and no signs of opiate withdrawal; (5) willingness to enroll in XR-NTX treatment in 
prison [not currently in or planning to pursue agonist (methadone, buprenorphine) treatment at 
release]; and (6) planning to live in Baltimore City or County (individuals planning to live outside 
of Baltimore City/county will be allowed to participate as long as they agree to travel to the 
treatment clinic if randomized to OTX. Exclusion Criteria: (1) Liver function test levels greater 
than three times normal (if a blood sample is not obtained at baseline participants will still be 
eligible for participation); (2) Active medical illness that may make participation hazardous (e.g., 
unstable diabetes, heart disease). Adequately treated medical conditions are acceptable; (3) 
Untreated psychiatric disorder that may make participation hazardous (e.g., untreated 
psychosis, bipolar disorder with mania). Adequately treated psychiatric disorders and 
appropriate psychotropic medications will be allowed; (4) History of allergic reaction to XR-NTX; 
(5) Current chronic pain diagnosis for which opioids are prescribed; (6) creatinine above normal 
limits; (7) pregnancy (for women); (8) Breast-feeding (for women); (9) suicidal ideation (within 
the past 6-months); and (10) Body Mass Index (BMI) > 40  
Study Product: 
Vivitrol ® (naltrexone for extended release injectable suspension) 380 mg per month 
delivered in monthly intramuscular injections 
Duration: 
7 months (1 injection in prison and 6 in the community.  
Sample Size: 
240 subjects 
Statistical 
Methodology: 
A Generalized Linear Mixed Model (GLiMM) will be used to conduct all analyses. 

P a g e  | 8 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 
List of Abbreviations 
 
Abbreviation/specialist term 
Explanation 
XR-NTx 
Long acting naltrexone 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
MTC 
Metropolitan Transition Center 
BPRU 
Baltimore Pre-Release Unit 
JPRU 
Jessup Pre-Release Unit 
BCCC 
Baltimore City Correctional Center 
MCIW 
Maryland Correctional Institute 
CMCF 
Central Maryland Correctional Facility 
MCTC 
Maryland Correctional Training Center 
RCI 
Roxbury Correctional Institution 
GLiMM 
Generalized Linear Mixed Model 
MMTx 
Medical Mobile Treatment 
OTx 
Opioid Treatment Program 
CJ 
Criminal Justice 
PI 
Principal Investigator 
Co-I 
Co-Investigator 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
FRI 
Friends Research Institute 
GLCC 
Glenwood Life Counseling Center 
ASI 
Addiction Severity Index 
TLFB 
Time Line Follow Back 
UDS 
Urine Drug Screen 
OOS 
Opioid Overdose Scale 
VAS 
Visual Analog Scale (Craving) 
RAB 
Risk Assessment Battery 
 
 
 

P a g e  | 9 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 
 
Schematic of Study Design 
 
 
In Prison (Research):  

Screening 

Consent 

Baseline assessments 

Physical examination 
XR-NTX-OTx 
(n=120) 
XR-NTX+MMTx 
(n=120) 
Post Release Activities (In Community)  
1-,2-,3-,4-,5-,6-,7-,12-month follow-up 

XR-NTX injections, months 1-6 

Self-report assessments 

Urine drug screen 

Biometric measures 

Records review 
7 MARYLAND 
Randomize (N=240) 
Opioid Tx Program 
Mobile Medical Tx 
Figure 1. Study Flow 

P a g e  | 10 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
Statement of Compliance 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), and the <NIH IC> Terms of Award. The Principal Investigator will assure 
that no deviation from, or changes to the protocol will take place without prior agreement from the sponsor and 
documented approval from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have completed 
Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments.  
Principal Investigator: 
 
Michael S. Gordon, DPA Michael S. Gordon 
                                       Print/Type Name  
 
 
Signed:  
_____________________________________ Date: ______________  
 

P a g e  | 11 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
1.0 SPECIFIC AIMS 
 Heroin use has risen significantly over the past 11 years1 with heroin overdoses increasing by 23%.2 Opioid 
use disorders are a severe problem among jail and prison inmates throughout the world.3-7 In the United 
States, there are over 1.5 million state and federal prisoners,8 of whom an estimated 12-15% have histories of 
OUDs.9 Moreover, scarce resources are provided for corrections-based substance use treatment in many 
nations, and many inmates with OUDs remain untreated;7,10 and less than .1% receive agonist treatment.11 
Correctional health officials, treatment providers, and policy makers need innovative, effective, and cost-
beneficial approaches to help inmates with OUD successfully transition to the community. 
 We recently completed a Phase 4 pilot, open-label study of long-acting injectable naltrexone (XR-NTX), 
funded by Alkermes, with prisoners with pre-incarceration OUD. In this study, involving one XR-NTX injection 
in prison followed by 6 monthly injections in the community, XR-NTX was feasible; all 27 participants got their 
first injection.12 XR-NTX was acceptable to correctional officials; it did not disrupt security and other prison 
routines and there was no concern about its diversion. An expected benefit of XR-NTX was opioid blockade for 
30 days; there were no overdoses in the first month post-release. However, an important challenge was that 
while 78% of participants received their first community injection, only 37% received their 5th and 6th injections. 
In our multi-site study of parolees/probationers funded by NIDA,13 308 participants were randomized to XR-
NTX across five sites in which 95% received the first injection; 65% received their 5th and 59% received their 
6th injections. XR-NTX adherence rates were higher in parolees and probationers and roughly equal to opioid 
agonist treatment but still dropped off by month 6. Also, most parole/probation participants were recruited from 
community treatment programs and were nearing completion of treatment at study entry, which meant that 
they were more likely to have more stable lives than newly released prisoners. These results and many 
stressors faced by newly released prisoners, noted below, suggest that enhancements to prison initiation of 
XR-NTX are needed in order to ensure continued adherence to XR-NTX treatment. 
 Many of our XR-NTX prisoners left treatment because of the need for stable housing, legitimate employment, 
child care, securing health benefits, addressing medical and psychiatric issues, and meeting requirements 
regarding criminal justice supervision interfered with continued treatment. Thus, a Mobile Medical Treatment 
approach that will provide medication at the client's place of residence might improve adherence and expand 
capacity and treatment access by reducing travel time and cost.14  Many programs have implemented mobile 
services, including for opioid addiction using LAAM,15 methadone,14,16,17 HIV education and testing,18 HIV 
treatment,19 for mental health services20 and cancer information and support.21,22 In summary, the above 
studies were successful in increasing access and engaging clients in treatment.  
1.1. Design   
 The proposed study is a parallel two-group randomized controlled trial in which 120 incarcerated men and 
120 incarcerated women will be randomly assigned within gender, to one of two conditions: (1) XR-NTX+ 
MMTx. One injection of XR-NTX in prison followed by 6 monthly injections post-release at the participants’s 
place of residence utilizing mobile medical treatment; or, (2) XR-NTX-OTx. One injection of XR-NTX in prison, 
followed by 6 monthly injections post-release at a community opioid treatment program. All participants will be 
confirmed opiate-free prior to XR-NTX injection, and evaluated at 1-, 2-, 3-, 4-, 5-, 6-, 7- (safety visit) and 12-
months after release from prison.  
1.2. Specific Aims 
 Aim1. To compare the two study conditions in terms of: (a) XR-NTX treatment adherence; (b) opioid use; (c) 
criminal activity; (d) re-arrest; (e) re-incarceration; and (f) HIV risk-behaviors (i. needle use; and ii. risky sexual 
behaviors).  
 
 Aim 2. To determine if the number of months of post-release XR-NTX treatment is related to outcomes (a)-
(f), and if so, is there a point at which XR-NTX v. Non-XR-NTX equilibrates. Such a finding could be potentially 
important because it would be informative about the needed length of XR-NTX treatment. 
1.3. Significance and Public Health Impact 
 The proposed study is innovative because it would be the first randomized clinical trial in the US assessing 
effectiveness of receiving XR-NTX using mobile medical treatment compared to XR-NTX at an opioid 
treatment program. The public health impact of the study will be highly significant and far-reaching because 
most individuals with OUD do not receive treatment while incarcerated, thereby substantially raising their 

P a g e  | 12 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
likelihood of re-addiction, overdose death, HIV/AIDS infection, and re-incarceration. Finally, many individuals in 
the criminal justice system drop out of treatment and therefore increasing ways to improve adherence by 
attempting to: 1) expand capacity; and 2) implement access by providing treatment at their place of residence 
may positively impact outcomes. 
 
2.0. SIGNIFICANCE 
2.1. Opioid Use Disorder (OUD) among Incarcerated Individuals 
 OUD is a severe problem among jail and prison inmates. Inmates in the US, Canada, Australia, and many 
European and Asian nations have disproportionately higher rates of OUDs than their general populations.3-7 In 
the US, there are over 1.5 million state and federal prisoners,8 of whom an estimated 12-15% have histories of 
OUD.9 Moreover, few resources are provided for corrections-based substance use treatment in many nations, 
and many inmates with OUDs remain untreated;7,10 and less than .1% receive agonist treatment.11  
2.2. Untreated Opioid Use Disorders among Inmates: Adverse Consequences 
  Scarce resources are available for corrections-based substance use treatment in many nations, and many 
inmates with OUD remain untreated.3,6,7,23  As a consequence, opioid use either continues or resumes rapidly 
after release from incarceration,3,7,24 placing newly released inmates at  extremely higher risk for death from 
drug overdose25-32 and for infections with human immunodeficiency virus (HIV) and hepatitis B and C.3,5,33 
Opioid use among newly released inmates also has adverse public safety consequences, as it typically results 
in increased criminal activity33-36 and re-incarceration.34,37,38 Individuals with OUD regularly engage in criminal 
activity, mainly illicit drug trafficking, often on a daily basis; such trafficking, in turn, typically leads to higher 
rates of violent crime.39-42  
2.3. Need for Continuity of Care for Inmates with Opioid Use Histories 
 Extensive evidence documents that continuity of substance treatment from prison to the community is 
associated with superior treatment outcomes.3,7,33,37,43-50 Continuity of care provides ongoing treatment, 
reduces rates of opioid and other illicit drug use and crime, as well as valuable support for newly released 
individuals to cope with problems related to re-entry into the community: unstable housing, unemployment, and 
pressure from drug-using peers to resume drug use.7,33,51 
2.4. Pharmacotherapy in Criminal Justice Settings  
 A growing body of evidence supports the effectiveness of opioid agonist pharmacotherapy in jail and prison 
settings for both inmates who were using opioids at initiation of maintenance treatment37,52-57 and inmates who 
were previously, but not currently, opioid-dependent.43,45-47,58 However, many American prison and jail 
administrators are opposed to opioid agonist medication in their facilities, largely because of their preference 
for drug-free interventions59-63 and concerns about diversion of medication, especially buprenorphine.64  
2.5. Long-acting Injectable Naltrexone 
 The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release 
prisoners.  Naltrexone blocks the intoxicating and reinforcing effects of opioids, but has no opioid-like effects. 
When taken regularly, it reduces opiate-taking behavior. VIVITROL® (naltrexone for extended-release 
injectable suspension, XR-NTX) is supplied as a microsphere formulation of naltrexone for suspension and is 
to be administered by intramuscular (IM) gluteal injection every 4 weeks (once a month). In 2010, it was 
approved for the prevention of relapse to opioid dependence, following opioid detoxification. Administered as a 
monthly injection, long-acting naltrexone eliminates the need for adherence to daily oral therapy, and thus has 
the potential to improve clinical outcomes for this indication. Moreover, monthly administration avoids the daily 
plasma concentration fluctuations associated with daily oral administration of naltrexone and its major 
metabolite, 6β-naltrexol. Its lower frequency of administration, the fact it has no opioid-like effects and cannot 
be diverted by patients, may make long-acting naltrexone more acceptable to corrections officials than 
methadone or buprenorphine. The primary reason for failure of oral naltrexone treatment for both opioid 
addiction and alcoholism has been failure on the part of patients to adhere to the daily medication regimen.65,66  
Long-acting naltrexone reduces the adherence problem as confirmed by studies showing blockade of injected 
opiates for over 30 days. Importantly, a sustained release medication may protect participants from overdose 
death within the critical one month post-release period.25,31 Long-acting naltrexone may also be more attractive 
to correctional officials than methadone or buprenorphine because there is no potential for abuse or diversion. 

P a g e  | 13 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
Because naltrexone has no abuse potential, and is not a controlled substance, there is greater flexibility in 
settings in which naltrexone can be prescribed, including correctional settings. Moreover, controlled 
environments offer an excellent opportunity to initiate long-acting, injectable naltrexone because individuals 
with OUD have a higher likelihood of being abstinent from opioids for the required length of time in the 
controlled correctional environment prior to initiating naltrexone treatment. Extended-release injectable 
naltrexone has been found effective in reducing opiate use compared to control participants for community 
corrections populations in the US;67,68 jail inmates in the US69 and for Russian heroin-dependent individuals.70 
Results from Russia are especially noteworthy given that in a nation with one of the highest rates of heroin 
addiction in the world, methadone and buprenorphine are not available.70 
 2.5.1. Why Long-Acting Injectable Naltrexone? Research has provided substantial evidence that the first 
month, and particularly the first week, after release from prisons is associated with extremely high death rates 
for former prisoners, mainly from drug overdoses.27,29-31,71  Although methadone maintenance, initiated 3 
months before release and continued in the community, is effective in reducing heroin use,43,45,72-74 individuals 
still have to regularly go to treatment programs despite clients’ lack of transportation and responsibilities 
regarding child care and employment. Furthermore, many are homeless, and finding safe and secure shelter is 
often a priority over attending drug treatment. There is also a need to take medication on a daily or near-daily 
basis. In contrast, with XR-NTX, medication is administered monthly and daily or near-daily attendance at drug 
treatment programs is not mandatory. Also, newly released prisoners, including those with pre-incarceration 
heroin addiction, face considerably more challenges to successful re-entry than in previous years, specifically 
regarding unemployment, lack of job skills/education, and fulfilling criminal justice related requirements.75,76 
2.6. Mobile Medical Treatment 
  Mobile treatment for chronic diseases have been implemented in a variety of settings. Mobile treatment 
provides an opportunity to expand outreach to surmount barriers to traditional clinic treatment for chronic 
disease. A number of programs have implemented mobile services including for opioid addiction using 
LAAM,15 methadone,14,16,17 HIV education and testing,18 HIV treatment,19 for mental health services20 and for 
cancer information and support.21,22 In summary, the above-mentioned studies have been successful in 
increasing access and engaging clients in treatment. More importantly, the Greenfield et al.,14 study indicated 
patients in the methadone mobile treatment group were retained in treatment for a median of 15.5 months 
compared to a median of 3.9 months for the patients at the fixed sites. It is well known that, regardless of type 
of treatment, greater treatment duration is associated with reduced substance use and criminal activity.  
 2.6.1 Why an XR-NTX mobile medical treatment study is needed. As emphasized by Hall et al.,17 we 
need additional strategies that state and local governments can use to increase opioid treatment participation 
by broadening its reach to different types of patients such as pre-release prisoners, community corrections 
populations that are often socially disenfranchised and have high opioid use. Furthermore, the stigmatization of 
methadone and the difficulty for certain individuals to enter and continue treatment based on restrictions for 
individuals in the criminal justice system61,62,77 might make mobile medical XR-NTX treatment more appealing 
to criminal justice professionals that have to monitor the movement and activities of parolees in the community. 
2.7. Efficacy of Naltrexone with Criminal Justice Populations: Research by the Current Investigators 
 The current Investigators have considerable experience conducting pharmacotherapy trials with criminal 
justice populations using different medications.  The three most relevant studies are: 1. XR-NTX among 
Parolees, Probationers Pilot Study (Dana Foundation); 2. Treatment Study Using Depot Naltrexone (5/6) 
Baltimore Protocol Treatment Site (NIDA# R01 DA024556); and 3. A Phase 4, Pilot, Open-label Study of 
VIVITROL® in the Prevention of Re-arrest and Re-incarceration (Alkermes). 
 2.7.1. XR-NTX Among Parolees, Probationers Pilot Study. During 2007-2008, a multi-site pilot study (lead 
site PI Charles O’Brien of the University of Pennsylvania) examined depot naltrexone (Depotrex®) among 
opioid-dependent parolees and probationers. This feasibility study provided monthly injections to volunteers for 
6 months. Sixty-one participants were recruited across five sites, including the present FRI research team site. 
Six-month outcomes showed that those who completed naltrexone treatment had significantly fewer opioid-
positive urines and were less likely to have been re-incarcerated than participants who had not completed 
treatment.67 There were a number of study limitations. There was a lack of a comparator group. There was a 
overall low follow-up rate of 66%, which varied considerably across sites. We compared a 3-month XR-NTX 

P a g e  | 14 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
treatment protocol from 1 site with a 6-month protocol from the other 4 sites. The statistical tests were bivariate 
with no control variable used in the analyses regarding outcomes.  
 2.7.2, Treatment Study Using Depot Naltrexone (5/6) Baltimore Protocol Treatment Site. The same 
investigators from the pilot study recently completed a 5-year multi-site study that examined the extent to which 
a monthly XR-NTX injection prevents relapse compared to treatment-as-usual (TAU) among probationers and 
parolees.78 This 5-site open-label RCT compared 24 weeks of XR-NTX (n=153) to usual treatment (n=155). 
Participants randomized to XR-NTX had a longer median time-to-relapse (10.5 vs. 5.0 weeks, p<0.001), were 
less likely to relapse (43% vs. 64% of participants, p<0.001), and provided more opioid-negative urines (74% 
vs. 56%, p<0.001). There were several limitations to this study. An open-label effectiveness design increases 
generalizability yet is subject to increased attention, recall, and assessment bias.  The agreement between this 
study’s results and those of other recent trials are reassuring regarding validity. Eligibility criteria did not 
distinguish by disease severity or active vs. prior opioid use.   
 2.7.3. A Phase 4, Pilot, Open-label Study of VIVITROL® in the Prevention of Re-arrest and Re-
incarceration. This was a Phase 4B, open-label, longitudinal, single cohort, pre-post study. Pre-release 
opioid-dependent inmates from four Maryland area prisons (three for men and one for women) receive one 
injection of XR-NTX prior to release from prison and are then offered six monthly injections of XR-NTX for six 
months post-release. Following prison release, participants were seen for study visits and receive XR-NTX at 
Glenwood Life Counseling Center in Baltimore, MD. Participants were assessed at 10 time points: at screening 
(study entry: approximately one month prior to release from prison), at baseline (approximately 1 week prior to 
release), and then monthly for 6 treatment visits, an end-of-treatment visit, and a safety follow-up visit following 
their release from prison. . We provided XR-NTX to 27 prisoners, of whom 100% received their first injection in 
prison; 21/27 (77.8%) received their first community injection, 18/27 (67%) received their second community 
injection; 13/27 (48%) received their third community injection; 11/27 (41%) received their 4th community 
injection, 10/27 (37%) received their 5th community injection, and 10/27 (37%) received their 6th community 
injection. Over the one–year enrollment period in this study, 97 individuals were screened for interest; 23 were 
initially not eligible, and 74 consented. Of these 74, 9 refused, 6 were released early and/or transferred to other 
prisons; 2 failed to meet the OUD criteria and 3 were positive for buprenorphine (all would have been ineligible 
for the presently proposed study). Fifteen inmates were excluded for medical reasons, 7 for psychiatric 
reasons and 5 for both psychiatric and medical reasons. According to the study physician and Co-I on the 
proposed study, Dr. Fitzgerald, most, if not all, of these 27 excluded for medical and/or psychiatric reasons 
would have been eligible for the presently proposed study, as the proposed study would not exclude 
individuals with appropriately treated medical and/or psychiatric conditions. Results indicate participants 
completing 6 compared to participants completing less than 6 injections were less likely to test positive for 
opioids in the community (0% vs. 63%, respectively; p=.003). Although not statistically significant, individuals 
who did not complete all 6 injections were more likely to be re-arrested compared to those completing all 6 
community injections (31% vs. 0%, respectively; p=.12).12 The limitations of this study included a small sample 
size which was highly selective and lack of a comparator group.  Finally, because the rather long list of 
exclusion criteria were mandated by the funding agency, the ability to generalize results is limited. The 
proposed study will have a larger sample size, comparator group, and less stringent exclusion criteria.  
2.8. Efficacy of Naltrexone with Criminal Justice (CJ) Populations: Other Research  
  To date, we are aware of only two RCTs using oral naltrexone with cj populations and one study using long-
acting naltrexone with individuals leaving jail. Cornish et al.79 randomly assigned federal probationers to 
receive either oral naltrexone or TAU. Probationers randomized to the naltrexone condition had fewer opiate-
positive urines (8%) compared to the TAU group (30%), and lower rates of re-incarceration (26% v. 56%). 
More recently, Coviello et al.80 randomly assigned 111 probationers/parolees to oral naltrexone or TAU. They 
found no significant differences between conditions in terms of both retention and negative opioid urine tests. 
Lee et al.13 conducted an 8-week open-label randomized trial and randomized to XR-NTX (n=17) versus no 
medication (n=17) within 10 days prior to jail release. Acceptance of XR-NTX was high; with 15/17 initiating 
XR-NTX treatment. Rates of opioid relapse were lower among XR-NTX participants: 38% versus 88% (p<.004) 
and more XR-NTX urine samples were negative for opioids, 59% versus 29% (p<.009). 
 

P a g e  | 15 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
2.9. Major Differences between Individuals in Prisons, Jails, and Community Corrections 
 There are major differences between prisoners and offenders on community supervision. The criminal history 
of prisoners is more serious, frequent, and varied.33,76 Therefore, the crime-reduction potential of XR-NTX may 
be greater when used with prisoners than with other criminal justice clients. Furthermore, and especially 
significant, there are extremely important physiological differences between prisoners compared to other 
offenders (those in jail and on community corrections). In contrast to parolees and probationers, who are at 
large in the community, who have full opportunity to use opioids and other illicit substances, most prisoners in 
the United States with histories of OUD do not have full opportunity to use drugs in prison (although use of illicit 
substances does occur, it is typically more occasional than on a regular basis).7,81 Therefore, and unlike most 
jail inmates, who have relatively short incarceration stays and do not lose their tolerance to opioids, most such 
prisoners lose their tolerance to the respiratory depressant effects of opioids during incarceration. This 
distinction is critical, given the overwhelming evidence for the extremely high death rate from drug overdose 
among newly released prisoners.27 Monthly XR-NTX injections, begun in prison, have the advantage of 
protecting such individuals from relapse to addiction, overdose death, HIV infection, increased criminal activity, and 
re-incarceration. In addition, most prisoners do not receive substance use counseling while in prison, as options in 
correctional institutions are limited compared to in the community. It is particularly noteworthy that the proposed 
sample and settings in which XR-NTX treatment is administered are distinctly different from that of the multi-
site study (PI O’Brien) in which the current investigators participated. In PI O’Brien’s study, participants were 
recruited in the community, not in a controlled environment (a prison), and must have had some criminal justice 
involvement (parole, probation, jail, arrest) during the past year. Further, all XR-NTX injections in the O’Brien 
study occurred in the community, while in the proposed study, the first injection will take place in prison.   
3.0. INNOVATION 
 The proposed study is innovative because it would be the first randomized controlled trial (RCT) in the US 
assessing effectiveness of receiving XR-NTX using medical mobile treatment compared to XR-NTX at an 
opioid treatment program. The public health impact of the proposed study will be highly significant and far-
reaching because most individuals with OUDs do not receive treatment while incarcerated, thereby 
substantially raising their likelihood of re-addiction, overdose death, HIV/AIDS infection, and re-incarceration 
following release. Furthermore, many individuals in the criminal justice system drop out of treatment; therefore, 
offering opportunities to improve adherence by attempting to: 1) expand capacity; and 2) implement access by 
providing treatment at their place of residence may positively impact outcomes. The proposed study is 
significant as to our knowledge it would be the first RCT with long-acting naltrexone in a prison population. 
While other investigations have reported that naltrexone is effective among parolees and probationers and pilot 
studies have found that it is feasible with prison inmates, the present study will focus on whether the addition of 
mobile XR-NTX treatment will increase adherence and thus efficacy of the medication. Finally, the importance 
of finding a point of equilibration will provide evidence of how many monthly XR-NTX injections will be needed.  
More importantly, there is a continuing need for RCTs to further examine the efficacy and effectiveness of 
opioid maintenance therapies within specific incarcerated populations such as prisoners because different 
criminal justice populations could respond to treatment differently and we could adapt treatment to work better 
for specific populations.82 
4.0. APPROACH 
4.1. Study Overview 
 This proposed five-year study will focus on whether the addition of mobile medical XR-NTX treatment will 
increase adherence and thus efficacy of the medication for pre-release prisoners. Project implementation will 
occur at four pre-release prisons: 1) Brockbridge Correctional Facility (BCF); 2) Dorsey Run Correctional 
Facility (DRCF); 3) Baltimore City Correctional Center (BCCC);4) Maryland Correctional Institution (MCIW) for 
Women; 5) Central Maryland Correctional Facility (CMCF); 6) Maryland Correctional Training Center (MCTC); 
and 7) Roxbury Correctional Institution (see Maryland Department of Public Safety and Correctional Services 
Letter of Support). Two of these Maryland prisons were sites in our recently completed XR-NTX pilot study 
(see Research Strategy, above). Following initial screening, informed consent, and medical examination, 
consenting prisoners at each facility will be block randomized within gender, to either: (See Figure 1 below): 
XR-NTX-OTx: One injection of XR-NTX in prison, followed by six monthly injections in the community post-

P a g e  | 16 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
release at an opioid treatment program; or XR-NTX+MMTx:  One injection of XR-NTX in prison, followed by six 
monthly injections in the community post-release at the participant’s place of residence. All participants will be 
confirmed opiate-free by urine (all participants will receive two urine drug screens after consent) test and 
negative naloxone and oral naltrexone tests, and evaluated monthly for 7 months with follow up at 1-, 2-, 3-, 4-, 
5-, 6-, 7- (safety visit) and 12-months after release from prison. We consider the proposed follow-up schedule 
advantageous from both a treatment and research perspective. Regarding treatment, it allows for quicker 
"rescue" for those overdue for XR-NTX injections. Concerning research, it enables us to stay in closer contact 
with participants and enhances post-release follow-up assessment completion rates, leading to greater 
generalizability of findings. The proposed study has two specific aims: Aim 1. To compare the two study 
conditions in terms of: (a) XR-NTX treatment adherence; (b) opioid use; (c) criminal activity; (d) re-arrest; (e) 
re-incarceration; and (f) HIV risk-behaviors (i. needle use; ii. risky sexual behaviors). Aim 2. To determine if the 
number of months of post-release XR-NTX treatment is related to outcome (a)-(f), and if so, is there a point at 
which XR-NTX v. Non-XR-NTX equilibrates. 
4.2. Design Considerations 
 We considered XR-NTX vs. treatment as usual but it was felt strongly that it would not be ethical to deny 
services to participants during this crucial transition period from prison to community. We also considered XR-
NTX vs. placebo but still were of the opinion of denying newly released prisoners access to an intervention was 
not ethical. While the methods of this particular design are very strong, the ethics of providing no treatment to 
newly released inmates can be called into question. Furthermore, although we do not know for pre-release 
prisoners, past research suggests that XR-NTX is efficacious for probationers. Therefore, it would be unethical to 
*withhold what we would assume to be an efficacious treatment from some participants. Moreover, our interest 
was not in whether XR-NTX worked in this population, but to address the unanswered question of whether 
mobile medical services (XR-NTX) increased medication compliance, thereby reducing opioid use, HIV risk 
behaviors, and re-arrest, and re-incarceration. While we understand a control group that did not receive XR-NTX 
might be considered a potent comparator, we chose XR-NTX without a mobile component as the control group 
for two reasons: (a) it was the ‘obvious’ comparison group to our XR-NTX mobile intervention, because we 
would be able to determine the added benefit of mobile treatment above and beyond XR-NTX alone; (b) Other 
control groups would not be feasible [methadone or buprenorphine, due to medication regulations, daily 
dosing, need for increased staffing, and problem with diversion; or unethical (no treatment)]. 
4.3. Investigators  
  The proposed research is a natural outgrowth and extension of the work conducted by the current 
investigators at FRI. This application for a Phase III RCT seeks to build on the investigators’ ground-breaking 
research using pharmacotherapies with prisoners, probationers, and parolees with histories of opioid addiction.  
 PI Gordon has substantial experience conducting pharmacotherapy trials with opioid-dependent prisoners, 
parolees, and probationers. Dr. Gordon was PI on a XR-NTX for prisoners pilot study funded by Alkermes. He 
is PI on a five-year NIDA-funded Seek, Test, and Treat: HIV in CJS grant (R01DA030771). Importantly, he was 
Co-I on four NIDA-funded studies highly relevant to the present application: 1) Buprenorphine for Prisoners 
(R01 DA 021579); 2) Prevention of Relapse to Opioid Addiction Using XR-NTX for probationers/parolees (R01 
DA 02455301); 3) a 2-year study, CJ DATS 2: Implementing treatment Initiatives for CJ Clients (R01 UO1 
D025233) examining the implementation of pharmacotherapies with cj populations; and 4) Testing Client 
Linkage to Buprenorphine Treatment from Community Corrections (R01 DA021579-04S1). Dr. Gordon was 
project manager on the first RCT in the US examining the benefits of prison-initiated methadone;43,45-47 and the 
first investigation of the feasibility of BUP-naloxone provided to pre-release prison inmates in Puerto Rico.83 
Furthermore, Dr. Gordon was Co-I of a pilot study examining the feasibility of XR-NTX with probationers and 
parolees67 funded by the Dana Foundation.  
   Co-I Vocci is President of FRI, supervising 10 investigators researching substance abuse treatment. He has 
more than 30 years-experience in medication development and multi-site clinical trial research, and he 
administered NIDA's medication development program before accepting the position of President with FRI. Dr. 
Vocci has published over 100 articles in neuropharmacology and the treatment of substance use disorders.  
   Co-I Fitzgerald is a physician with over 15 years-experience in the treatment and study of pharmacotherapy 
for OUD. His research experience includes his collaboration with Drs. Gordon and Kinlock on the all of above-

P a g e  | 17 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
mentioned investigations. 
 
  Consultant O’Brien is Kenneth Appel Professor and Vice Chair of Psychiatry at the University of 
Pennsylvania, Vice Director of the Institute of Neurological Sciences, as well as Director of the Center for 
Studies of Addiction. As Chief of Psychiatry at the Philadelphia VA Medical Center, his research has been 
responsible for numerous discoveries on the nature of addiction and improved the results of treatment for 
addictive disorders.  
4.4. Successes in Research Implementation 
 4.4.1. Pilot Study on Naltrexone with Prisoners. In our pilot study conducted in Maryland prisons,12 we 
achieved three main objectives: 1) we demonstrated that formerly opioid-dependent prisoners would accept 
XR-NTX treatment, beginning in prison; 2) strengthened our collaboration with the Maryland Division of 
Correction (DOC) custodial and medical staff by establishing logistics with correctional staff regarding XR-NTX 
administration; and 3) worked out logistics with our community treatment provider in terms of in-prison and 
community treatment, thus assuring continuity of care from prison to the community.  
 4.4.2. Recruitment and Follow-up of Drug-Involved Research Participants. We have been exceptionally 
successful in obtaining voluntary consent and cooperation of individuals with OUD to participate in research 
projects. In our previous study of methadone treatment for prisoners, 99% of eligible clients consented to 
participate, and over 95% of 1-, 3-, 6-, and 12-month post-release interviews were completed.43,45-47 In our 
study of Buprenorphine for Prisoners, we have achieved follow-up rates exceeding 92% of study participants at 
1-, 3-, 6-, and 12-months after release from prison. In our study of XR-NTX for Probationers/Parolees, we have 
achieved follow-up rates over 90% at 6-, 12-, and18-months. In our ongoing study involving HIV testing of 
parolees/probationers, we consented over 2000 probationers/parolees for testing and 100 for our HIV-positive 
intervention study; follow-up rates are 95% for each of our follow-up periods (1-,6-, 12-, and 15-months).  
5.0 SPECIFIC APPROACH 
5.1. Maryland Department of Public Safety and Correctional Services (MDPSCS) 
 Male and female inmates recruited for participation will be drawn from the following seven prisons: 1) 
Brockbridge Correctional Facility (BCF); 2) Dorsey Run Correctional Facility (DRCF); 3) Baltimore City 
Correctional Center (BCCC); 4) Maryland Correctional Institution (MCIW) for Women;5) Central Maryland 
Correctional Facility (CMCF) 6) Maryland Correctional Training Center (MCTC); and 7) Roxbury Correctional 
Institution (See Letter of Support from MDPSCS). The seven facilities are administered by the Maryland 
Division Department of Correction (DOC), and are staffed by administrative and custodial personnel and by 
case managers, who provide referral services and are responsible for preparing reports concerning inmates’ 
institutional progress and adjustment. MDPSCS and FRI investigators have an extensive history of 
collaborating on pharmacotherapy studies for opioid-dependent prisoners. 
5.2. Participant Eligibility: Inclusion/Exclusion Criteria 
 Eligible inmates must meet the following criteria: (1) adult male or female inmate at BCF, DRCF,  BCCC, 
MCIW, CMCF, MCTC, or RCI and be eligible for release within 30 days; (2) history of opiate disorder [meeting 
DSM-V criteria of dependence at the time of incarceration; individuals who do not meet criteria at time of 
incarceration and become addicted during incarceration will be eligible];]; Inmates not meeting the opioid-
dependence criterion will be eligible if they were treated in an opioid agonist treatment program during the year 
before incarceration. (3) suitability for XR-NTX treatment as determined by medical evaluation; (4) currently 
opioid-free by history, with negative urine for all opioids and no signs of opiate withdrawal; (5) willingness to 
enroll in XR-NTX treatment in prison [not currently in or planning to pursue agonist (methadone, 
buprenorphine) treatment at release]; and (6) planning to live in Baltimore City or County(individuals outside of 
Baltimore City/county will be allowed to participate as long as they agree to travel to the treatment clinic if 
randomized to OTX. Inmates with one or more of the following conditions will be excluded from the study: (1) 
Liver function test levels greater than three times normal (note: if a blood specimen is unable to be drawn the 
individual will not be excluded from participation); (2) Active medical illness that may make participation 
hazardous (e.g., unstable diabetes, heart disease). Adequately treated medical conditions are acceptable; (3) 
Untreated psychiatric disorder that may make participation hazardous (e.g., untreated psychosis, bipolar 
disorder with mania). Adequately treated psychiatric disorders and appropriate psychotropic medications will 
be allowed; (4) History of allergic reaction to XR-NTX; (5) Current chronic pain diagnosis for which opioids are 

P a g e  | 18 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
prescribed; (6) creatinine above normal limits; (7) pregnancy (for women); (8) Breast-feeding (for women) (9) 
suicidal ideation (within the past 6-months); and (10) Body Mass Index (BMI) > 40.   
5.3. Participant Recruitment Procedures 
 The study will employ the following procedures, which have been successfully utilized in Friends Research 
Institute’s (FRI’s) previous randomized trials implementing pharmacotherapy with prisoners. Maryland 
Department of Correction (DOC) personnel will schedule project orientation appointments with research staff 
for the Baltimore area prison inmates with less than 60-90 days to serve. Group orientation sessions will be 
conducted at each prison, in which research staff will explain study procedures and eligibility requirements. 
Potentially interested inmates will then meet individually with research staff for an in-depth discussion of the 
purposes, procedures, risks, and benefits, of study participation, and to make a preliminary determination of 
eligibility, subject to confirmation during the physical examination (see below). Immediately after providing 
informed consent, each potential participant is scheduled for administration of the baseline measures. 
Following baseline assessment, which is used, in part, to confirm eligibility regarding histories of opioid 
addiction and nature and severity of medical and psychiatric problems, each potential participant will meet with 
the project medical staff for a medical history, physical examination, and laboratory tests to confirm eligibility 
and suitability for XR-NTX administration, and to discuss the potential risks and benefits of study participation. 
Individuals who do not meet medical eligibility based on physical examination or do not wish to initiate XR-NTX 
following a discussion of this treatment with the study physician will not be enrolled into the study. Potential 
participants who are determined medically eligible and remain interested in participating in the study will then 
be randomly assigned to one of the two treatment conditions (see Random Assignment, below).  Finally, 
because of the possibility of coercion when working with prisoners, the study RAs will emphasize that the 
decision to participate or not will not affect the prisoner's status, institutional privileges, or release date. In 
addition to group orientations we will post IRB approved study flyers in the five prisons (these will be pre-
approved locations decided upon by prison administration at each prison). 
5.4. Random Assignment Procedure  
 Participants will be assigned to one of two conditions (XR-NTX-MMTx or XR-NTX+OTx) using a random 
permutation procedure, such that, within gender for each block of 2, 4, or 6 participants, half will be assigned at 
random to the XR-NTX-MMTx Condition [n=120: 60 men, 60 women] and half to the XR-NTX+OTx condition 
[n=120: 60 men, 60 women], ensuring that both male and female participants have an equal chance of being 
assigned to either condition.85 [Random block sizes will be used in order to conceal allocation to treatment 
condition. Sealed envelopes will be prepared for the study physician based on this block randomization 
procedure so that he can explain the condition to which a participant has been assigned. He will open the 
designated envelope and inform the participant to which one of the two conditions s/he has been assigned. 
This assignment procedure will be performed by the study physician so that, immediately after assignment to 
treatment condition, consent to medication initiation can be obtained from participants.  
5.5. Participant Attrition 
 Consistent with our previous studies, we will collect detailed locator information that has enabled us in the 
past to successfully locate participants for follow-up. Thus, we anticipate follow-up rates well over 90%, which 
is consistent with our previous studies conducted at FRI.43,45-47,74,81  
5.6. Medical Services in Prison 
 5.6.1. Treatment Clinic. Glenwood Life Counseling Center (GLCC) has been in continuous operation for 41 
years.  It is a State of Maryland- and CARF-certified outpatient drug treatment program that treats over 600 
patients. GLC provides individual and group drug abuse counseling, HIV assessment and risk-reduction 
counseling, and a limited amount of family-based therapy. Its medical director, Dr. Fitzgerald, served as the 
study physician on the PI’s prison methadone, buprenorphine, and XR-NTX studies. The clinic is well-suited to 
continue its collaboration on the proposed study, in which it will provide XR-NTX services in the prison as well 
as in the community. Dr. Fitzgerald will perform all prison medical examinations and the nursing staff will 
provide prison-based injections under his supervision within10 days of release.  
 5.6.2. Pre-release extended-release XR-NTX. XR-NTX treatment will likewise be administered by the 
nursing staff of GLCC under Dr. Fitzgerald’s supervision. Participants will receive one injection within 10 days 
prior to release.  Long-acting, injectable naltrexone (Vivitrol ®) will be used, at a dose of 4cc (380mg of 

P a g e  | 19 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
naltrexone), administered by intramuscular injection to the buttocks (alternating sides monthly). Note: 
Participants can request to receive the intramuscular injection to the buttocks on the same side at each 
monthly visit. VIivivtrol® has the advantage of being FDA-approved for treatment of alcohol and opioid 
dependence, hence commercially available with strong safety data.  Participants who deny opioid use in the 
past 10 days and who provide a specimen that tests negative for opioids on an instant urine test will receive a 
naloxone challenge test (Note: participants will receive two urine drug screens after consent: 1) one within 7-10 
days of the injection; and 2) on the day of the injection). Naloxone is a short-acting opioid antagonist. This test 
consists of an intravenous (or intramuscular for participants’ without venous access) injection of a 1.0mg of 
short-acting naloxone followed by a 20-minute observation period. A positive test will cause the temporary (up 
to 40 minutes) appearance of opioid withdrawal symptoms. Following a negative naloxone test, participants will 
be administered a low dose of oral naltrexone (12.5 mg) to further determine whether they will be able to 
tolerate depot naltrexone. If the participant has withdrawal symptoms in response to either the naloxone test or 
the oral naltrexone dose, the study physician will treat these symptoms with other medications. The medical 
staff of all prisons are highly experienced in treating opioid withdrawal, will be fully aware of the ongoing study, 
and will be able to provide symptomatic treatment to participants in the unlikely event that it is needed when 
study staff are not on the premises. Such issues may consist of the following: 1) withdrawal; and/or 2) injection 
site reaction. Prior to discharge, participants will receive an information card about naltrexone to carry with 
them at all times which will alert any medical providers about the characteristics of naltrexone. Ten days before 
anticipated release from prison, each participant will have an exit interview with the study’s Research Assistant 
(RA). The RA will provide each such participant with a card with the address of GLCC outlining their schedule 
for their six monthly injections in the community.  In addition, those randomized to XR-NTX+MMTx will receive 
a pamphlet 10 days before from the study RA detailing the procedures and operations of receiving medication 
at their place of residence. Follow-up injections will be scheduled 28 days (4 weeks) after first prison injection. 
 5.6.3. Overdose Prevention. The study physician and nurse will provide overdose prevention education at 
the time of XR-NTX injection in prison. We will use the overdose prevention video, “Staying Alive on the 
Outside” created by Green, Rich et al.86 that was developed specifically for incarcerated populations and is 
currently used in Rhode Island Department of Corrections and other prison facilities. This video will be shown 
to all participants prior to release from prison. In addition, at each monthly follow-up visit in the community, the 
study nurse will provide prevention education information that was developed by the Substance Abuse and 
Mental Health Services Administration (SAMHSA). SAMHSA’s Overdose Toolkit87 is a guideline and checklist 
focusing on the following: 1) how to avoid overdose, 2) what is naloxone, 3) preventing overdose, and 4) 
reporting side effects. This checklist will be reviewed with all participants at their monthly visits with the study 
nurse. 
5.7. XR-NTX Treatment in the Community 
 5.7.1. Glenwood Life Counseling Center for XR-NTX injections. The participants randomized to XR-NTX-
OTx will go to GLCC only to receive injections under the direction of Dr. Fitzgerald and the study nurse from 
prison in order to ensure continuity of care for those receiving XR-NTX in the community (injections will occur 
every 28 days). The study RA will be in close contact upon release and will provide the client with reminder 
calls and/or visits prior to each XR-NTX appointment. Prior to each injection (at GLCC and place of residence), 
the nurse will administer: 1) a drug use questionnaire, and 2) an instant urine drug screening test. If negative 
for opioid use participants will be administered XR-NTX.  If the participant reports using opioids in the past 7-10 
days or tests positive on the urine drug screen they will not be administered XR-NTX (see procedures below 
for missed XR-NTX injections). Once the participant receives the injection, he/she will be monitored for up to 
1½ hours. In addition, the nurse will provide the participant with the Naltrexone Medication Card, and tell the 
participant that he/she should keep it at all times. The nurse or physician will follow the same procedures as in 
prison. 
 5.7.2. Place of Residence for XR-NTX injections. For those randomized to receive XR-NTX at their place 
of residence, specific procedures will be implemented. First, the study nurse will be accompanied by the study 
RA so two staff members are always physically present. The study RA will confirm the place of residence prior 
to release from prison using our locator form. Contact will be made with the participant immediately following 
prison release and subsequently one week before each scheduled injection to verify his/her home address as 

P a g e  | 20 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
many newly released inmates have difficulty acquiring stable housing. The study nurse/RA will make sure the 
scheduled injection will be at a date/time that is convenient for the participant. In addition, the nurse/RA will 
reiterate to the participant that they will be asking sensitive questions and providing long-acting naltrexone so 
the participant may want to make sure they will have privacy. If the scheduled date/time is not convenient or 
the client feels as they will not have privacy the appointment will be rescheduled for a more convenient 
date/time. The nurse will be responsible for making sure the study team  have all the necessary medical 
equipment. The nurse and RA will first knock on the door of the participant’s residence and explain who they 
are and ask if the participant is there. If upon entering the residence, the nurse, RA or client feel that privacy is 
not possible they will reschedule another date/time that is convenient for both parties within 7 days.  Moreover, 
if upon arriving the client is not present we will not disclose the reason for our appointment. The nurse/RA will leave a 
business card/appointment card to reschedule. At the place of residence, the nurse will administer XR-NTX and 
follow the same procedures as they would at the clinic (See above). Participants who enter a semi-controlled 
environment, such as residential or inpatient treatment, will still be eligible to receive XR-NTX if the program 
continues to allow them to receive it. We have fostered a relationship with many of the Baltimore City treatment 
programs and we will coordinate with them to continue to provide XR-NTX whenever possible. Individuals that 
are homeless or become homeless during the course of treatment will be offered the opportunity to receive 
XR-NTX at GLCC or FRI field office. Based on our previous prison studies with medication we anticipate no 
more than 4-6 participants will be homeless. Participants who are receiving XR-NTX at their place of residence 
who require additional medical care will be referred by the study nurse or physician based on their level of 
need, similar to as they would at a standard outpatient opioid treatment program. Participants will also be 
encouraged access to individual and group drug abuse counseling, HIV assessment and risk-reduction 
counseling, and family-based therapy on an as needed basis. The study nurse will follow the Department of 
Health and Human Services, National Institute for Occupational Safety and Health Hazards Review manual 
(NIOSH)88. This manual documents procedures and guidelines for providing medical care at a person’s place 
of residence.  
 5.7.3. Missed XR-NTX Injections. Participants who miss a monthly appointment will be contacted by the 
study RA within 24 hours of missing their appointment. The participant will be strongly encouraged to receive 
their next injection. If they miss a dose and return for a subsequent dose more than 7 days after their missed 
scheduled injection they will receive the following: 1) drug use questionnaire; 2) urine rapid test; and 3) 
naloxone challenge before the naltrexone injection. Everyone who reports opioid use or has a positive urine 
test for opioids during days 29-37 will be given the naloxone test and then the oral naltrexone (12.5mg) prior to 
the Vivitrol injection. If a participant misses a scheduled injection, he/she will have up to 37 days to receive 
their next XR-NTX injection. We will also record the number of successful rescues and number of delayed 
returns to XR-NTX treatment. Participants will no longer receive XR-NTX if they become incarcerated in jail or 
prison (if incarcerated less than 37 days, they will still be eligible receive their injection).  
 5.7.4. Withdrawal from Naltrexone: Treatment Safety. Participants may voluntarily stop taking XR-NTX 
doses at any time without penalty. Naltrexone is an opioid antagonist with no opioid agonist properties and no 
withdrawal upon discontinuation. Potential side effects relate to the medication itself and to the injection. The 
most frequent side effects of the medication include opioid withdrawal symptoms for those participants who still 
have some trace of opioids in their system. There had been reports of increased liver enzymes in individuals 
receiving high doses of oral NTX in a study of obesity. For this reason, we have an exclusion criterion 
regarding elevated liver function tests at baseline. The injection can lead to local irritation, infection, and 
potentially abscesses, which in the most extreme circumstance may require surgical debridement. Participants 
receiving XR-NTX who require acute treatment of pain will be told that they need to inform their physicians that 
they are on XR-NTX because XR-NTX is an antagonist and will block the effects of opioid-agonist pain 
medications. In addition, each participant will also receive a laminated card that indicates they are on XR-NTX 
that can be provided to their health care provider.  
 5.7.5. Additional Medical Concerns (Safety). Adverse events (AEs) and Serious Adverse Events (SAEs) 
will be tracked monthly at each follow-up appointment. In addition, in cases where participants have elevated 
liver enzymes and will be discontinued on XR-NTX, they will be linked with follow-up medical services to 
monitor liver function. All participants requiring additional medical or psychiatric care will be monitored and 

P a g e  | 21 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
followed up and be referred for additional care on a case-by-case basis. All participants are under the care of 
the study physician and GLC and will be monitored monthly through treatment phases. Where further medical 
treatment is required, appropriate referrals and consultation will be ongoing. Our study physician will follow the 
recommendations in the SAMHSA (2015) Clinical Use of Extended-Release Injectable Naltrexone in the 
Treatment of opioid Use Disorder: A Brief Guide by referring a patient for more intensive or specialized care. 
5.8. Measures 
 Assessment of participant characteristics and/or performance will involve a multidimensional set of 
instruments administered by trained research interviewers. See Figure 2, for a schematic of measures and 
when they are administered. Sources of information will include: (1) self-report; (2) official records; (3) urine 
drug screening results; and (4) treatment program records. Assessment at baseline will provide information on 
participant characteristics and pre-incarceration histories of substance use, substance use treatment, crime, 
incarceration, and HIV risk behavior. Participants in both conditions will be paid $50 cash for each follow-up 
visit. Participants 
 will not be paid for baseline assessments in prison due to the fact that such payments may be viewed as 
coercion.  
   5.8.1. XR-NTX Adherence. Data on post-release treatment status will be obtained from GLCC records. 
Treatment status will be measured at each follow-up point by whether or not a participant received an injection 
of XR-NTX at each follow-up point (yes v. no). We will also collect data on whether a person entered outpatient 
treatment (yes v. no) and the type of services utilized. Treatment duration for individuals who end treatment will 
be calculated based on the last date of clinic attendance (if a participant fails to receive his/her injection by day 
37 s/he would be considered a drop-out). Thirty seven days is used in our current XR-NTX studies as this is 
how long the medication typically protects the participant. We will also collect data on whether or not 
participants entered other types of treatment. Follow-up assessments will collect self-report data on reasons 
why participants entered, did not enter, or dropped out of treatment.  
  5.8.2. Addiction Severity Index (ASI) with Timeline Follow-Back (TLFB).  The ASI is a standardized 40-60 
minute measure widely used in research to quantify problem areas in substance-using populations.89,90 This 
instrument has excellent inter-rater and test-retest reliability.89,90 We will also collect data on substance use 
frequency and criminal activity to cover the entirety of the follow-up periods post-baseline. In addition, we will 
use the DSM-5 opioid-related-disorder classification91 to assess opioid use severity (mild, moderate, severe). 
In addition to the ASI, we will collect baseline data on crime severity which is determined on the basis of a 7-
point scale (a higher number indicating greater severity of criminal involvement) and classifies crime severity 
according to the most serious level of criminal activity in their lifetime prior to the index incarceration.92 
 5.8.3. Biological Assays. Urine will be tested on-site with CLIA waived QuikScreen cups using an 
immunochromatographic assay for rapid (2-5 minute) qualitative results based on SAMHSA-standard cutoffs 
for alcohol (20mg/dl or 0.02% BAC), amphetamine/methamphetamine (1,000 ng/ml), cannabis (50 ng/ml), 
cocaine/ benzoylecgonine (150 ng/ml), and opiates/morphine (2000 ng/ml). In addition, we will test for 
methadone and buprenorphine, and for commonly abused prescription drugs (oxycodone, hydrocodone, and 
codeine) (100 ng/ml), and for Fentanyl (10ng/ml). Results will be used as outcome measures of heroin and 
other opioid use as well as to check on the validity of self-reported drug use information. Urine samples will not 
be obtained on the approximately 10% of participants who we expect to be re-incarcerated. Those participants 
in methadone or buprenorphine treatment who screen positive only on their respective treatment medication 
will be counted as negative for their urine drug screening results.     
 5.8.4. Risk Assessment of Battery (RAB). This self-administered questionnaire, designed to identify 
individuals engaging in acts that could transmit HIV and other infectious diseases,93 contains 45-items 
consisting of three scales: a drug risk, sexual behavior risk, and an overall scale. 
 5.8.5. Opioid Overdose Scale. This self-administered questionnaire will ask participants to report the 
number of opiate overdoses where they did and did not receive medical attention.  The questionnaire 
administered at baseline will cover the period prior to the instant incarceration while the questionnaire follow-up 
in the community, will cover post-release months 1-12. 
 5.8.6. Visual Analogue Scale (VAS). Participants are asked to place a mark across the line at the point that 
corresponds to their immediate craving for opioids. Anchors included 0 mm – ‘no cravings’ to 100 mm – ‘most 

P a g e  | 22 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
extreme cravings possible’.94,95 Participants will be assessed at baseline and at each follow-up visit and asked 
about peak cravings during the preceding 24 hours.  
   5.8.7. Health-related quality of life will be measured by the EuroQol 5D (EQ-5D).108, 109 The preference 
weights obtained from the EQ-5D will be used to calculate quality-adjusted life-years (QALYs; see section D.4). 
The EQ-5D is the most widely used generic, preference-based health-related quality of life instrument.110 
  5.8.8. Official Records. As in our previous research,96 official record data will be obtained from the MDPSCS 
at 12-months. Data will include type (e.g., charges involved) and number of arrests, convictions, and 
incarcerations; and the number and length of time of each imposed disciplinary period. Criminal record data 
will be used to assess the validity of self-report criminal activity data. 
   5.8.9. Biometric Measures. All participants will complete the following biometric measures for 
inclusion/exclusion criteria, participant monitoring, and serious adverse event (SAE) and adverse event (AE) 
reporting. The following biometric measures will be completed (see Figure 3): 1) history and physical; 2) liver 
function tests (note: if a blood specimen is unable to be drawn the individual will not be excluded from 
participation), hepatitis profile; 3) vital signs; 4) concomitant medications; 5) pregnancy, 6) HIV; 7) Urine 
toxicology; and 8) AEs.     
   5.8.10. Data Management/Quality Control. Assessments will be administered by trained RAs, and closely 
supervised by the PI. RAs will receive training concerning: (a) initiating and developing rapport; (b) sensitivity 
regarding culture, gender, and sexual orientation; (c) forms administration; (d) serious adverse event reporting; 
(e) responsibility for maintaining participant confidentiality; and (f) follow-up procedures. 
5.9. Study Aims, Hypothesis, Rationale 
 5.9.1. Aims. The proposed study has two specific aims: Aim 1. To compare the two study conditions in terms 
of: a) XR-NTX treatment adherence; b) opioid use; c) criminal activity; d) re-arrest; e) re-incarceration; and f) 
HIV risk-behaviors (i. needle use; ii. risky sexual behaviors). Aim 2. To determine if the number of months of 
post-release XR-NTX treatment is related to outcome (a-f above), and if so, is there a point at which XR-NTX 
v. Non-XR-NTX equilibrates. 
 5.9.2. Hypothesis. Based on data from the research team’s current studies (see above), It is anticipated that 
the XR-NTX+MMTx condition will have superior outcomes compared to the XR-NTX+OTx condition in terms of 
outcomes (a)-(f).   
 5.9.3. Rationale. We are not aware of RCTs using mobile medical treatment for the provision of XR-NTX. 
However, based on studies utilizing mobile treatment for HIV services, and methadone, which increased 
access, engagement, and retention, we believe the provision of medical treatment, provided at a participant’s 
place of residence, is expected to yield better adherence, subsequently, improving outcomes mentioned 
above. If we find a point of equilibration it will tell us how many months we will need to provide mobile 
treatment (XR-NTX) and at what point it impacts on outcomes-significant given the cost of the medication. It is 
difficult to provide firm conjectures on this latter question given the lack of research in this area. 
 
 
 
 

P a g e  | 23 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
Figure 2:  Data Collection Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Figure 3:  Biometric Measures 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measures 
Source 
Interval 
Operational Definition 
Aim 1: Outcomes (a)-
(f)  
 
 
 
a. XR-NTX adherence  
Clinic records 
B, 1-6 
• # of injections due/completed 
b.  opioid use 
ASI/TLFB/UDS  
B, 1-6, 7, 12 
• days of opioid use  
• positive opioid urine drug 
screen 
c. criminal activity 
ASI/TLFB 
    B, 1-6, 7,12 
• days of crime 
d. re-arrest 
Official records 
12 
• time to re-arrest 
e. re-incarceration 
Official records 
12 
• time to re-incarceration 
f. HIV risk behaviors 
   i. needle use 
   ii. risky sex behaviors 
RAB/TLFB 
 
B, 1-6, 7,12 
 
• scored 0-22 (higher risk) 
• scored 0-18 (higher risk) 
Aim 2:  Outcomes (a)-
(f) 
Source 
Interval 
Operational Definition 
(a)-(f) equilibrates 
Above 
1-6,12 
Time to relapse 
Supplementary  
Source 
Interval 
Operational Definition 
other treatment 
ASI 
B, 1-6, 7,12 
• Days in other treatment 
opioid overdose 
OOS 
B, 1-6, 7, 12 
• # of times overdosed 
opioid craving 
VAS 
B, 1-6, 7, 12 
• 0-100 (higher cravings) 
Quality of Life 
QOL 
B, 1-6, 7, 12 
 
Measures 
Data Collection Point 
Biometric Measures (for 
inclusion/exclusion criteria, patient 
monitoring and AE determination) 
Baseline 
in prison 
1mo 
2mo 
3mo 
4mo 
5mo 
6/7mo 
History & Physical 
 
 
 
 
 
 
 
(7only) 
Liver Function Tests, Hepatitis Profile 
 
 
 
 
 
 
 
(7only) 
Vital signs 
 
 
 
 
 
 
 
Concomitant medication 
 
 
 
 
 
 
 
Pregnancy 
 
 
 
 
 
 
 
HIV   
 
 
 
 
 
 
 
(7only) 
Urine toxicology 
 
 
 
 
 
 
 
Adverse Events 
 
 
 
 
 
 
 

P a g e  | 24 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
6.0. Statistical Analyses 
 6.1. Guiding Principle.  Although the description of the statistical approach that follows is more in line with 
the language associated with a ‘traditional’ superiority trial, we endorse the “sensible formulation of the 
significance test” proposed by Jones and Tukey.97  These authors outline an approach to significance testing 
that focuses not on the rejection of a null hypothesis, but on determining whether the data favor a 
determination of superiority or inferiority.  As part of their approach, they suggest reporting not only a test 
statistic and its associated probability value but also a confidence interval and an effect size related to the 
determination of any difference.  It would be our intention in reporting our results to adhere to Jones and 
Tukey’s suggestions. 
 6.2. Intent-to-Treat Approach.  All analyses will be conducted on available study-related data from all 
participants, regardless of whether or when they drop out of treatment; i.e., the intent-to-treat population is all 
persons consented and randomized to the study.  
 6.3. Outcome Measures.  Except for criminal justice records, collected at study conclusion, outcome data 
will have been collected monthly during the project: at baseline (study entry), and at 1, 2, 3, 4, 5, 6, 7, and 12 
months following release from prison (see Figure 2, above). The resulting dependent variables will be of three 
distinct types: 1) continuous random variables (e.g., RAB scale scores), assumed to follow a normal 
distribution; 2) discrete random variables (e.g., number of days of criminal activity), assumed to follow a 
Poisson distribution; and, 3) dichotomous variables (e.g., treatment adherence, urine drug screening results), 
assumed to follow a binomial distribution. [All distributional assumptions will be evaluated prior to the conduct 
of all analyses, and if such assumptions are not met, assumptions will be modified and statistical methods 
chosen accordingly, and/or outcome measures transformed appropriately. For example, it may be necessary to 
allow for under- or over-dispersion in the logistic and Poisson regression analyses, or use zero-inflated 
Poisson or negative binomial models rather than a Poisson model for the count variables.]  
 6.4. Explanatory Variables.  The predictor variables in all statistical models can be categorized as either 
Treatment Variables, Covariates, or Control Variables.  (From a statistical viewpoint, this categorization is 
arbitrary and is utilized here simply for ease of presentation.) 
Treatment Variables.  There will be a single treatment variable: Treatment Condition (XR-NTX-MMTx v. XR-
NTX+OTx). 
 6.4.1.Covariates. Three additional predictor variables – Age, Gender, and age of onset of criminal activity – 
will be included as “main effects” in all analyses.  These “main effects” test for the unique contribution of each 
of these variables in predicting outcome, above and beyond the effects of Treatment Condition.  Each of these 
variables, as well as its respective interaction with Treatment Condition, will be included as a predictor in order 
to examine for potential differences in treatment outcome as a function of each covariate, and whether any of 
these three covariates moderate treatment efficacy.   
 6.4.2. Control Variables.  Finally, because participants may know one another through contact at their 
respective prison, it is possible that participants' responses within a given prison will not be entirely 
independent of each other.  This potential lack of independence must be controlled for by including Prison 
nested within Treatment Condition and Participants nested within Prison nested with Treatment Condition as 
random factors.  [Although neither of these two effects represents a substantive effect of interest, both must be 
included in order to produce unbiased estimates and tests of significance for Treatment Condition.] 
 6.4.3. Time.  Finally, the “repeated factor” in the statistical analysis of all outcome variables measured 
repeatedly will be assessment Time point, which will allow for the evaluation of both differential course and 
impact of the interventions as a function of the “between-subjects” Treatment Condition factor. (For information 
regarding which outcome variables are measured at what assessment time points, see Figure 2, above.) 
 6.5. Statistical Method.  A Generalized Linear Mixed Model (GLiMM) will be used to conduct all analyses.  
[For the case in which the outcome is measured only at the end of study participation (e.g., reincarceration), 
GLiMM reduces to the generalized linear model (GLiM).] It is not necessary that the within-subjects set of 
observations either be complete or collected at the same points in time for GLiMM models.  GLiMM will make 
use of all available data, and hence, is an ideal statistical procedure for “intent-to-treat” approaches to data 
analysis, as occurs in the study proposed herein.    

P a g e  | 25 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 6.6. Missing Data. GLiMM is quite flexible in the presence of missing data for outcome variables, and it is 
not necessary for participants to have complete outcome data to be included in GLIMM analyses; in general, 
GLMM will make use of all available data, and hence, is an ideal statistical procedure for intent-to-treat 
approaches to data analysis in the case of ignorable missingness (ie, MCAR and MAR).  However, a pattern 
mixture model approach98 to modeling the missingness as part of statistical estimation will be utilized if there 
are a sufficient number of identifiable patterns to the missingness.  The potential impact of missingness and 
the operation of the missing data mechanism(s) will be examined from a multiple imputation perspective.99,100 
 6.7. Power. Stroup101 (also see Littell et al.102) has outlined a four-step procedure to estimate power for 
general linear mixed models, which can also be applied to generalized linear mixed models as occur in the 
proposed study.  This procedure was implemented in the current case.  For each of the number of Times 
outcomes were measured (4, 5, 6, 7, or 9), three datasets for each hypothesis were created, assuming the 
dependent variable was continuous and normally distributed, discrete and Poisson distributed, or dichotomous 
and binomially distributed.  For the normally distributed case, the only non-null effect in the model was the 
hypothesized effect of interest, with the XR-NTX-OTx condition mean set at 1 at Time 1, decreasing by .1 at 
each subsequent Time point, while the XR-NTX+MMTx condition means were set at 1 at Time 1, and then 
adjusted to reflect “small”103 mean differences (.2 of the standard deviation at subsequent Time points) 
consistent with the hypothesis of interest.  [Time was not included in the estimation of power for the criminal 
justice outcomes because these outcomes are measured only at 12-month post-baseline assessment.]    
Similar specifications were made for the datasets with outcomes following the Poisson and binomial 
distributions.  Finally, observations were dropped from the data consistent with the expected loss of 
approximately 10% of participants at the 12-month assessment (see Participant Attrition, above).  Hence, 
power was estimated for a design in which the effects were unbalanced in a manner similar to what was 
expected to occur in the proposed research.  Therefore, simulations were conducted under what might be 
considered “worst-case scenarios.”  Power was then estimated for three different covariance structures 
(compound symmetric heterogeneous, first-order autoregressive heterogeneous, and unstructured) of the 
observations over Time.  [Covariance structures can be specified for GLiMM models independent of the 
location (e.g., mean) structure, so it was only necessary to create a single dataset for the three cases.]   
Assuming a sample size of 240 and α=.05, the resulting power values (1 – β) for the Treatment Condition X 
Time effect varying between .81 and .85 in the simulations. From a more rudimentary and slightly less accurate 
perspective, assuming the primary outcome measures follow a normal distribution rather than binomial or 
Poisson distributions, power calculations based on the set correlation method104 can be used to calculate effect 
sizes for desired power, including under the extremely conservative assumption that no other effect in the 
model is significant (with the resulting effect size estimates likely to be slight underestimates). In this case, 
assuming α=.05 and N=216 due to attrition (see Participant Attrition, above) in order to remain conservative, 
an effect size of f2=.037 in the population associated with a Treatment Condition main effect for statistical 
models in which there is no Time effect (e.g., reincarceration) and  effect sizes ranging from a minimum 
f2=.046 to a maximum f2=.072 for the Treatment Condition X Time effects associated with the 4,  5, 6, 7, or 9 
Time points for statistical models in which there is a Time effect, would yield a power of .8 for the respective 
effect. These effect sizes fall toward the “small-to-medium” range, with f2=.02 considered a “small” effect and f2 
= .15 a “medium” effect.103  In other words, and imprecisely, under the assumption that the effect in the 
population was ≥ .037 or ≥ .072, for the Treatment Condition and Treatment Condition X Time effects, 
respectively, there is an 80% chance of concluding that effect is significant if α is set to .05 and 216 
participants are assessed at 12-month follow-up. Power calculations do not utilize any estimates of treatment 
efficacy from prior studies. This latter approach to power analysis, although once popular, is often quite limited, 
as is the case for the proposed study, in that prior studies may have examined populations that are not 
comparable to the population in the proposed study and/or do not include the same experimental or control 
conditions, and in all cases, the effect sizes reported in prior studies are generally subject to wide fluctuation 
due to sampling variability.105  Power was calculated to detect a stated effect size, as detailed in the proposal, 
an approach consonant with more recent writings regarding power analysis. 
 6.8. Supplementary Analyses. We will tabulate (and test for treatment condition differences) for the relative 
frequency of each adverse event (AE) in each condition, where the examination is based on the proportion of 

P a g e  | 26 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
individuals who experience the AE, and the number of that AE reported. In addition, we will tabulate and test 
for treatment condition differences) for the relative frequency of opioid overdoses in each condition, where the 
examination is based on the proportion of individuals who report overdoses during the 12-months post-release. 
We will also calculate mean scores of cravings at each follow-up. 
 6.9. Additional Process Data We will collect three additional process variables: (1) data on housing stability 
at each follow-up visit that will utilize a checklist to describe the participant’s place of residence and the level of 
stability; (2) data on the distance travelled from place of residence to Glenwood Life Counseling Center (GLC) 
for participants randomized to TAU; and (3)  data on the number of counseling sessions received during the 
course of the study (this will account for any community counseling received during treatment).   
 6.10. Follow-up Analyses. Follow-up analyses will include select covariates in the model, with a focus on 
the covariate X BI Intervention Condition (X Time, if an outcome is measured repeatedly).These follow-up 
analyses can be viewed as either sensitivity analyses or as subgroup analyses106,107 intended to map the 
population(s) for which the intervention is maximally useful and/or examine the robustness of the findings 
under uncertainty in the model.  Possible covariates include:  (1) crime severity, (2) opioid severity, (3) housing 
stability, (4) distance travelled from place of residence to treatment clinic; and (5) number of counseling 
sessions received. 
7.0. Project Timeline  
 Months 1-5 will be devoted to start-up activities, including confirming logistic arrangements, recruiting and 
training staff, and developing detailed procedures with prison and treatment personnel, and obtaining IRB and 
OHRP approval. Recruitment of participants and delivery of interventions will begin in month 6. Five to six 
prison inmate/participants are projected to be enrolled per month, yielding a total of 240 participants (120 per 
condition), at the end of recruitment (month 40). Follow-up assessments will be completed by month 53. 
Months 54-60 will be devoted to dissemination activities (e.g., publication of the primary outcomes paper).  
8.0. Impact 
 This proposed intervention addresses several public health and public safety problems. First, it will likely 
impact the problem that a substantial number of prisoners with histories of OUD are released to the community 
and untreated by treating their addictions. Second, by eliminating transportation costs and time, and the 
requirement that reliable transportation is required for treatment adherence, the treatment comes to the patient 
rather than the patient must go to treatment. This is likely to improve adherence, which tends to reduce the 
possibility of addiction. Third, by substantially impacting addiction, in turn, it has increased chances of reducing 
death from overdose, HIV and hepatitis infection, the frequency of criminal activity, and the likelihood of re-
incarceration. 
 
9.0. PROTECTION OF HUMAN SUBJECTS 
 
This Human Subjects Research involves an NIH-Defined Phase III Clinical Trial. 
 
9.1. Potential Risks  
 
 
9.1.1. Extended-Release Naltrexone (XR-NTX). Participants may experience brief withdrawal symptoms 
with the naloxone test, although this will be uncommon as only patients with a history of no opiate use and 
negative urine for opiates will be given the test. Those receiving an XR-NTX intramuscular injection may 
experience side effects consisting of pain at the site of injection, nausea, or other opioid withdrawal symptoms. 
In rare cases, an infection at the site of injection has occurred. XR-NTX has been reported to cause increased 
liver enzymes when it was given in high dose oral form, but this has not been reported with the dose used in 
the injection. Participants in both conditions carry the risk of relapse to opioid dependence, as is the case for all 
individuals who have a history of opioid use disorder. Relapse to opioid dependence after a detoxification and 
opioid-free period, or after discontinuing depot naltrexone, carries a risk of opioid overdose and death because 
tolerance after a period of abstinence is low. Participants will be informed of these risks and of treatment 
alternatives, including agonist maintenance.  

P a g e  | 27 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 
XR-NTX injections will block the effects of opioid pain medication and all participants randomized to the 
naltrexone condition will receive a card to present in case of emergency need for opioid analgesia. General 
anesthetics, nerve blocks, and non-steroidal pain medications are not affected. All individuals who will be 
administered depot naltrexone will be informed as follows: “You should carry identification to alert medical 
personnel to the fact that you are taking depot naltrexone. A depot naltrexone medication card has 
been supplied to you for this purpose. Carrying the identification card should help to ensure that you 
can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the 
treating physician that you are receiving depot naltrexone therapy”.   
 
 
 
9.1.2. Other Risks. Other risks are expected to be minimal.  Participants will be asked to provide sensitive 
information regarding a number of behaviors, including deviant and criminal behaviors, and are thus exposed 
to the risks associated with the potential for disclosure of confidential information outside the research context.  
Because participants will be discussing personal information, including information on psychological 
functioning, some participants may experience emotional discomfort. 
 
9.2. Protection Against Risks 
 
 
 
9.2.1. Risks Associated with XR-NTX. Participants may experience symptoms of opioid withdrawal from 
the naloxone challenge, oral naltrexone, or XR-NTX injection. In order to minimize the likelihood of withdrawal 
symptoms, potential participants will be carefully screened with exclusion criteria which include recent opiate 
use history and a urine test prior to naloxone administration. The study design was carefully crafted to 
minimize risk of withdrawal by first administering the short-acting naloxone followed by a small oral dose of 
naltrexone prior to XR-NTX administration. Individuals who do experience opiate withdrawal symptoms from 
the administered opioid antagonists will be treated symptomatically by the study’s medical personnel.  
 
To protect against risks of increase in liver enzymes, study applicants will be excluded if their liver enzymes 
are greater than triple the normal levels. Also, liver enzyme tests will be repeated during the course of the 
study and doses withheld if indicated.  
 
Participants will be warned of the risk of opioid overdose should they discontinue XR-NTX and will be 
informed of alternative treatment, including methadone or buprenorphine treatment. Finally, participants will be 
informed that they should carry their study identification card with them and provide it to any medical personnel 
that will be treating them in the future so they can be aware of the need to provide appropriate alternatives to 
opioids for pain relief. 
 
The study physician has extensive experience in the injection technique.  This should minimize the 
likelihood of injection site reactions. Nonetheless, the FDA has provided the following information for 
healthcare professionals with regard to Naltrexone Injection Site Reaction [naltrexone for extended-release 
injectable suspension (marketed as Vivitrol)] FDA Alert [08/12/08] Vivitrol injections may be followed by pain, 
redness, itching, bruising, and swelling.  Sometimes reactions at the injection site can quickly worsen and skin 
and other tissue can be permanently damaged and require surgery.  If an injection site reaction does not 
improve within two weeks following the injection, or it worsens sooner than 2 weeks, the participant will be 
instructed to see his/her doctor.  The dose of Vivitrol® (380mg) selected for this research has been studied in 
both normal healthy adults as well as in individuals who were using opioids, alcohol, and stimulants.  
 
9.2.2. Vivitrol (naltrexone for extended-release injectable suspension): Medication Guide Required 
for Patients. Some people on Vivitrol treatment have had severe reactions at the site of the injection (injection 
site reactions), including tissue death (necrosis). Some of these injection site reactions have required surgery. 
The participant will be instructed to seek medical attention immediately if he or she has any of the following 
things happen at any of the injection sites: intense pain; an open wound the area feels hard; a dark scab large 
area of swelling; lumps; and blisters. FDA requires that a Medication Guide, which communicates this and 
other important information about treatment, be provided to all participants. 
 
9.2.3. Risks Associated with Loss of Confidentiality.  To assure participant confidentiality, as in our 
previous and ongoing research, we will obtain a federal Certificate of Confidentiality to protect all data against 
subpoena and criminal justice investigation; we will provide training to all research staff regarding 

P a g e  | 28 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
responsibilities for maintaining and protecting participant confidentiality.  To ensure confidentiality, we will use 
of unique participant identifiers in the database.  Baseline and follow-up measures will be linked by the unique 
identifiers employed and will be stored in the locked files to which only the Principal Investigator, Co-
Investigators, and Project Manager have access. Study findings will make use of aggregate data only and 
publication or presentation of findings will not involve use of any individual or personalized information. 
 
9.2.4. Risk Associated with Emotional Discomfort.  All instruments to be employed have been used 
frequently and without incident with individuals who are using illicit substances.  Research interviewers will be 
trained to be alert to indication of participant discomfort and will discontinue administration of research 
instruments if a study participant shows discomfort.  In such cases occurring at baseline assessment, referral 
will be made to institutional medical/case management personnel as appropriate.  For follow-up assessments, 
appropriate referral sources will be available to the interviewer in the event of an adverse reaction that requires 
intervention, and a clinical appointment to deal with this issue will be scheduled if the participant requests.  
 
9.3. Risk/Benefit Ratio 
 
Every effort will be made to minimize the risks to participants in this study.  Exclusion criteria, (e.g., medical 
status), voluntary participation, and careful and constant medical monitoring and protection of confidentiality 
will help minimize risk to subjects.  With regard to study benefits, all participants will receive long-acting 
naltrexone  in prison and will be referred to substance use treatment in the community.  In addition, participants 
will also receive treatment services in prison that may increase entry and retention into community-based 
treatment following release and thus decrease the likelihood of readdiction and its negative consequences.  
Results from this study may help determine the utility of administering long-acting naltrexone to inmates in 
prison with pre-incarceration opioid addiction histories prior to release and continued post-release either at a 
standard opioid treatment program or utilizing medical mobile treatment. 
 
9.4. Importance of the Knowledge to be Gained   
 
Although progress has been made in the development of effective treatments for opioid addiction that 
begin during incarceration and continue during the critical period of transition back to the community, further 
improvement in efforts at treatment entry and engagement is clearly needed.  The development of effective 
treatment strategies for these individuals with histories of pre-incarceration opioid addiction, who are at 
especially high risk for HIV infection and death from overdose, is of high public health and safety importance.  
Therapeutic research that has established the effectiveness of XR-NTX in other settings and with other 
populations, suggests that the proposed intervention holds considerable promise for effectively treating 
inmates with histories of opioid addiction who are released to the community. It is especially significant that the 
proposed study is the first to examine naltrexone using mobile health strategies among soon-to-be released 
prison inmates with regard to a number of post-release outcomes: XR-NTX adherence, opioid use, criminal 
activity, and HIV risk behaviors. 
 
9.5. Participation of Prisoners 
 
The proposed study involves research on prisoners and therefore is subject to DHHS regulations that 
provide additional protections for research involving prisoners as research participants.  In keeping with their 
vulnerable status as prisoners, all study participants will receive treatment prior to release (XR-NTX) in prison 
and in the community and information on how to access various treatment resources in the community. XR-
NTX is approved by the FDA for the prevention of relapse to opioid dependence. Both treatment conditions will 
be receiving study medication. Thus, the study will not employ a “no treatment” control condition, inasmuch as 
all participants will receive an active substance use treatment (i.e., XR-NTX).   
 
We are sensitive to the possibility that, given the limited financial resources of many prisoners at this point 
in time, providing cash compensation at baseline could unduly influence inmates to participate in this 
intervention study.  Furthermore, we consider that the treatment that participants receive is ample 
compensation for the time that they devote to research procedures at baseline.  Therefore, no cash 
compensation will be provided for baseline assessments.  Cash compensation will be provided for follow-up 
interviews conducted following release in recognition of participants’ contribution of their time and efforts to the 
research. 

P a g e  | 29 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
 
We are also sensitive to ensuring that participants are not being coerced to enroll in the study. Thus, the 
process of participant enrollment (including participant screening, informed consent, baseline assessment, and 
medical examinations) will take place without correctional staff present, in private discussions with the research 
and medical staff of the study. Furthermore, as mentioned above, because of the possibility of coercion when 
working with prisoners, the study RAs will emphasize that the decision to participate or not will not affect the 
prisoner's status, privileges, or release date. 
 
9.6. Data and Safety Monitoring Plan 
 
9.6.1. Responsibility for Safety Oversight. As in our past and ongoing clinical trial of prison-initiated 
methadone and buprenorphine treatment, the Principal Investigator and his study staff, the FRI Institutional 
Review Board (IRB), and a Data Safety Monitoring Board (DSMB) will provide safety oversight for the project. 
In addition, an external medical safety monitor (an independent physician with expertise in pharmacotherapy 
and opioid addiction) will report his/her review of adverse events to the PI, the project’s medical staff, and the 
FRI’s IRB.  The medical safety monitor will review reports on the study and be informed by the PI of any 
information that has bearing on the safety of the participants.  Finally, the PI will be responsible for conducting 
a literature search on XR-NTX no less frequently than every six months to identify any emerging research 
findings that might influence study procedures.  Finally, the PI and external medical safety monitor will stay 
alert to any changes in the labeling of naltrexone.  
 
9.7. Report of Safety-Relevant Information to NIDA 
 
The Principal Investigator is responsible for informing NIDA of any safety-relevant actions taken by the 
FRI’s Institutional Review Board as a result of its regular semi-annual reviews and any special reviews of this 
project.  In addition, the PI will inform NIDA of any major changes in the protocol or its status including:  
protocol amendments; procedural changes; suspension or termination of subject accrual or of the protocol 
itself; changes in the informed consent or IRB approval status; and other problems or issues that could have a 
significant impact on individuals’ consent to participate. 
 
9.8. Adverse Event Reporting 
 
As in our other clinical trials, adverse event reporting will follow the usual FRI policy.  Serious adverse 
events (SAEs) include any of the following outcomes for the participant: 1) death; 2) acute life-threatening 
incidents; 3) hospitalization or the prolongation of a hospitalization; 4) persistent or significant disability or 
incapacity; or, 5) birth defects.  Should they occur, these events may be communicated to the PI by participants 
and/or staff, or may be observed directly by the PI.  SAEs will be reported regardless of whether they are 
considered study related. Adverse events will be monitored by nursing and medical staff and will include:  
nasopharyngitis, insomnia, and injection site pain among other more frequently reported reactions. 
The completed Serious Adverse Event Form will contain: subject’s ID#, gender, age, the title and date of the 
Serious Adverse Event, and narrative explanation. The Serious Adverse Event Report Form tracks how the 
research staff was notified of the event, dates of consent, study medication, study screening for 
inclusion/exclusion, study treatment received, outcome of study treatment (e.g., was participant using illicit 
substances or abstinent, other relevant clinical information), dates and circumstances of the 
hospitalization/death, whether alcohol or illicit substances were known to be involved, and participant status at 
last clinical or research contact. In cases of participant death, the report also includes appropriate 
substantiation from clinic records, as well as copies of the death certificate, autopsy report, or medical record. 
The Principal Investigator will address whether there is a need to redesign or amend the protocol, and/or to 
inform current and future subjects of a change in description of risk (in consent form and protocol or other). The 
Principal Investigator will state whether the event was "expected" and assess its "relatedness" to the study 
medication or intervention. 
 
9.9. Relatedness 
 The Principal Investigator (Dr. Gordon), Medical Co-I (Dr. Fitzgerald), and Medical Consultant (Dr. O’Brien) 
will review the information and offer an educated opinion about the relatedness of the event to the study drug. 
1 = Definitely – The adverse event: 
a) Follows a reasonable temporal sequence from drug administration. 

P a g e  | 30 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
b) Abates upon discontinuation of the drug (de-challenge). 
c) Is confirmed by reappearance of the reaction on repeat exposure (re-challenge). 
2 = Probably – The adverse event: 
a) Follows a reasonable temporal sequence from drug administration. 
b) Abates upon discontinuation of the drug (de-challenge). 
c) Cannot be reasonably explained by the known characteristics of the patient’s clinical state. 
3 = Possibly – The adverse event: 
a) Follows a reasonable temporal sequence from drug administration. 
b) Could have been produced by the patient’s clinical state or by other modes of therapy administered to 
the patient. 
4 = Remotely – The temporal association between the adverse event and the drug is such that the drug is not 
likely to have had any reasonable causal relationship with the observed event. The assessment of whether 
the drug was present prior to the reaction or event could be made by history or by blood level. 
5 = Definitely not – The adverse event is definitely produced by another known cause, and is not temporally 
associated with the drug. 
9 = Unknown – only used while awaiting further information. 
 In any given case, the Ps will make an initial SAE report to the FRI IRB and the study’s medical safety 
monitor within 48 hours. The PI will submit follow-up reports on participants who have experienced an SAE 
until the outcome of the event is known. This follow-up information will be reported to the external medical 
safety monitor and FRI’s IRB.  A summary of SAEs will be reported to NIDA Program staff through the annual 
non-competing renewal application mechanism.  AEs will be aggregated weekly by nursing staff and reported 
to the PIs. The PIs will report these AEs in aggregate to the DSMB and IRB on a regular basis. 
 In addition to the above actions, all regulatory reporting required by the FDA will be closely followed. 
 
9.10. Reporting of Unanticipated Risks or New Findings  
 Any unexpected Serious Adverse Events which occur during the course of this investigation and follow-up 
period, whether or not related to the study protocol, will be reported within 24 hours by telephone to NIDA 
(NIDA program official TBN), and the FRI IRB. The telephone report will be followed within 2 days by sending a 
completed Serious Adverse Event Form with demographic information and a narrative explanation of the 
event. The narrative will also provide details of relevant screening measures, medical history & physical, 
treatment compliance, participant reports of Serious Adverse Events and any other information the Principal 
Investigator deems appropriate. Attached to the Serious Adverse Event Form will be photocopies of relevant 
source documents (Case Report Forms). The Principal Investigator will address whether there is a need to 
redesign or amend the protocol, and/or to inform current and future participants of a change in description of 
risk, either in the consent form and protocol, or by other written or verbal communication. The written Serious 
Adverse Event report will also be sent to the FRI Institutional Review Boards. 
 The PI will also report any new information that may change the risk-benefit ratio to the FRI’s IRB, medical 
safety monitor, and the NIDA Program Official.  This information may consist of findings from the current study 
or other studies.  Any changes in the protocol or informed consent as a result of this information will be 
promptly reported to the NIDA Program Official. 
 
 The PI will also report any irregularities in the conduct of the study, such as improper participant enrollment, 
obtaining of informed consent, and data collection or processing to the FRI’s IRB, medical safety monitor, and 
the NIDA Program Official. 
 
9.11. Quality Control of Data 
 Interviewers will be thoroughly trained regarding administration of interviews and completion of forms and 
their work will be reviewed on an ongoing basis.  Interviewers will review case report forms (CRFs) for 
completeness and accuracy.  Data processing staff will review CRFs the next day.  The Project Manager will be 
advised of any forms needing correction, and he/she will bring these to the attention of the interviewer. 
Prior to the conduct of inferential analysis, the raw data will undergo extensive examination for completeness 
and accuracy by the data entry staff, under direction of the project’s statistician. 
 

P a g e  | 31 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
9.12. Data and Safety Monitoring Board (DSMB) 
 As in our previous clinical trials of prison-initiated opioid agonist maintenance treatment, a DSMB of outside 
experts in clinical trials, biostatistics, and criminal justice (prisoner advocate) will be created to review the 
progress of the study and monitor subject intake, outcomes, adverse events and other safety related matters.  
The DSMB will meet at the start of study enrollment and every six months for the first year of enrollment and 
annually thereafter.  Members will include a physician expert in the opioid treatment of opioid disorder, a 
statistician, and a criminal justice expert (prisoner advocate).  The DSMB will review all SAEs.  The project’s 
statistician will perform interim analyses, at times determined by the DSMB, to determine whether the study 
should be terminated early as a result of preliminary findings.  The Board will also review study enrollment and 
feasibility as well as the nature and frequency of SAEs in reviewing the safety of the study.  DSMB meetings 
will be convened as needed to discuss new findings, unexpected SAEs related to the interventions under 
study, or results of any other new findings in the literature that pertain to this study.  All DSMB reports will be 
sent to the PI who will forward copies to the IRB and to NIDA.  
 
9.13. Criteria for Suspending or Terminating the Study 
 The study may be modified, suspended, or terminated at the recommendation of the PI, DSMB, or by the FRI 
IRB in the interests of protecting study participants.  The study will be modified to comply with any labeling 
changes for long-acting naltrexone administration made by its manufacturer or by the Food and Drug 
Administration.  The PI, medical safety monitor, DSMB and/or IRB may recommend modifying, suspending, or 
terminating the study based on the SAE reports. Trials may be terminated for any one or more of four classes 
of reasons as determined by the DSMB, as specified below: 1) safety/adverse events; 2) favorable benefit-risk 
ratio; 3) unfavorable benefit-risk ratio; and 4) inability to answer questions regarding trial efficacy. 
 
9.13.1.Termination Due to Safety/Adverse Events. The DSMB’s decision to stop the study with regard to 
safety/adverse event considerations will be based on the number and severity of study-related adverse events, 
particularly those determined to be fatal and/or extreme.  The study may also be terminated if the DSMB 
decides that there has been an emergence of an unexpected serious adverse event or events. 
 
9.13.2. Termination Due to Favorable Benefit-Risk Ratio. If the results of an interim analysis of post-
release outcome data performed by the DSMB provides compelling evidence for the efficacy of the 
experimental intervention(s), early termination may be recommended. Such a recommendation would not be 
made without consideration of other relevant information related to the trial and an assessment of the strength 
of evidence of benefit. 
 
9.13.3. Termination Due to Unfavorable Benefit-Risk Ratio. If the interim efficacy analysis results show 
compelling evidence for a lack of clinically relevant outcomes, early termination may be recommended by the 
DSMB. Such a recommendation would not be made without consideration of other relevant information related 
to the trial (e.g., safety/adverse event issues). 
 
9.13.4. Termination Due to Inability to Answer Trial Question. If there are serious flaws in the data or 
the implementation of the study, the DSMB may recommend termination because the questions concerning 
efficacy are unable to be adequately addressed. These problems include serious problems in the 
recruitment/enrollment of participants; threats to internal validity, external validity, construct validity, and/ or 
statistical conclusion validity. As with the other types of reasons for study termination, noted above, the DSMB 
will make this decision in consideration with other relevant information regarding the trial. 
 
 

P a g e  | 32 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
10. References 
 
1. 
Lipari RN, Hughes A. The NSDUH Report: Trends in Heroin Use in the United States: 2002 to 2013. 
Rockville, MD: Substance Abuse and Mental Health Services Administration, Center for Behavioral 
Health Statistics and Quality;2015. 
2. 
Larochelle MR, Zhang F, Ross-Degnan D, Wharam JF. Rates of opioid dispensing and overdose after 
introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene. JAMA 
Intern Med. 2015;175(6):978-987. 
3. 
Dolan K, Khoei EM, Brentari C, Stevens A. Prisons and drugs: A global review of incarceration, drug 
use and drug services. Oxford: Beckley Foundation;2007. 12. 
4. 
Fazel S, Bains P, Doll H. Substance abuse and dependence in prisoners: a systematic review. 
Addiction (Abingdon, England). 2006;101(2):181-191. 
5. 
Kanato M. Drug use and health among prison inmates. Current opinion in psychiatry. 2008;21(3):252-
254. 
6. 
Kastelic A, Pont J, Stöver H. Opioid Substitution Treatment in Custodial Settings. A Practical Guide. 
BIS-Verlag: Oldenburg; 2008  
7. 
Kinlock TW, Gordon MS, Schwartz RP. Incarcerated populations. In: Ruiz P, Strain E, eds. Lowinson & 
Ruiz’s Substance Abuse: A Comprehensive Textbook. Fifth ed. Philadelphia, PA: Lippincott Williams & 
Wilkins; 2011:881-891. 
8. 
Carson EA, Golinelli D. Prisoners in 2012: Advance counts. Washington, D.C.: Department of Justice, 
Bureau of Justice Statistics; 2013. 
9. 
Mumola CJ, Karberg JC. Drug Use and Dependence, State and Federal Prisoners, 2004. Washington, 
D.C.: U.S. Department of Justice, Bureau of Justice Statistics (NCJ 213530);2006. 
10. 
Kinlock TW, Gordon MS, Shabazz H. Pharmacotherapy for incarcerated individuals with histories of 
heroin addiction. Hauppauge, NY: Nova Science Publishers, Inc.; In Press. 
11. 
Fox AD. Opioid Addiction and Criminal Justice Systems: Opportunities to Break the Cycle of 
Incarceration. SGIM Forum. 2015;38(1). 
12. 
Gordon MS, Kinlock TW, Vocci FJ, Fitzgerald TT, Memisoglu A, Silverman B. A Phase 4, Pilot, Open-
Label Study of VIVITROL(R) (Extended-Release Naltrexone XR-NTX) for Prisoners. Journal of 
substance abuse treatment. 2015;59:52-58. 
13. 
Lee JD, McDonald R, Grossman E, et al. Opioid treatment at release from jail using extended-release 
naltrexone: a pilot proof-of-concept randomized effectiveness trial. Addiction (Abingdon, England). 
2015;110(6):1008-1014. 
14. 
Greenfield L, Brady JV, Besteman KJ, De Smet A. Patient retention in mobile and fixed-site methadone 
maintenance treatment. Drug and alcohol dependence. 1996;42(2):125-131. 
15. 
Kuo I, Brady J, Butler C, et al. Feasibility of referring drug users from a needle exchange program into 
an addiction treatment program: experience with a mobile treatment van and LAAM maintenance. 
Journal of substance abuse treatment. 2003;24(1):67-74. 
16. 
Buning EC, Van Brussel GH, Van Santen G. The 'methadone by bus' project in Amsterdam. British 
journal of addiction. 1990;85(10):1247-1250. 
17. 
Hall G, Neighbors CJ, Iheoma J, et al. Mobile opioid agonist treatment and public funding expands 
treatment for disenfranchised opioid-dependent individuals. Journal of substance abuse treatment. 
2014;46(4):511-515. 
18. 
O'Connor CA, Patsdaughter CA, Grindel CG, Taveira PF, Steinberg JL. A mobile HIV education and 
testing program: bringing services to hard-to-reach populations. AIDS patient care and STDs. 
1998;12(12):931-937. 
19. 
Dube C, Nozaki I, Hayakawa T, Kakimoto K, Yamada N, Simpungwe JB. Expansion of antiretroviral 
treatment to rural health centre level by a mobile service in Mumbwa district, Zambia. Bulletin of the 
World Health Organization. 2010;88(10):788-791. 

P a g e  | 33 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
20. 
Suggett J, Lloyd C, Meehan T, King R. Is there a difference? A comparative study of Mobile Intensive 
Treatment Team and Continuing Care Team consumers' clinical and other characteristics. Advances in 
Mental Health. 2012;10(3):293-297. 
21. 
Foster C, Scott I, Addington-Hall J. Who visits mobile UK services providing cancer information and 
support in the community? European journal of cancer care. 2010;19(2):221-226. 
22. 
Iredale R, Hilgart J, Hayward J. Patient perceptions of a mobile cancer support unit in South Wales. 
European journal of cancer care. 2011;20(4):555-560. 
23. 
Taxman FS, Perdoni ML, Harrison LD. Drug treatment services for adult offenders: the state of the 
state. Journal of substance abuse treatment. 2007;32(3):239-254. 
24. 
Strang J, Gossop M, Heuston J, Green J, Whiteley C, Maden A. Persistence of drug use during 
imprisonment: relationship of drug type, recency of use and severity of dependence to use of heroin, 
cocaine and amphetamine in prison. Addiction (Abingdon, England). 2006;101(8):1125-1132. 
25. 
Binswanger IA, Stern MF, Deyo RA, et al. Release from prison--a high risk of death for former inmates. 
The New England journal of medicine. 2007;356(2):157-165. 
26. 
Binswanger IA, Merrill JO, Krueger PM, White MC, Booth RE, Elmore JG. Gender differences in 
chronic medical, psychiatric, and substance-dependence disorders among jail inmates. American 
journal of public health. 2010;100(3):476-482. 
27. 
Binswanger IA, Blatchford PJ, Lindsay RG, Stern MF. Risk factors for all-cause, overdose and early 
deaths after release from prison in Washington state. Drug and alcohol dependence. 2011;117(1):1-6. 
28. 
Bird SM, Hutchinson SJ. Male drugs-related deaths in the fortnight after release from prison: Scotland, 
1996-99. Addiction (Abingdon, England). 2003;98(2):185-190. 
29. 
Farrell M, Marsden J. Acute risk of drug-related death among newly released prisoners in England and 
Wales. Addiction (Abingdon, England). 2008;103(2):251-255. 
30. 
Krinsky CS, Lathrop SL, Brown P, Nolte KB. Drugs, detention, and death: a study of the mortality of 
recently released prisoners. Am J Forensic Med Pathol. 2009;30(1):6-9. 
31. 
Merrall EL, Kariminia A, Binswanger IA, et al. Meta-analysis of drug-related deaths soon after release 
from prison. Addiction (Abingdon, England). 2010;105(9):1545-1554. 
32. 
Stewart LM, Henderson CJ, Hobbs MS, Ridout SC, Knuiman MW. Risk of death in prisoners after 
release from jail. Australian and New Zealand journal of public health. 2004;28(1):32-36. 
33. 
Inciardi JA. The War on Drugs IV: The continuing saga of the mysteries and miseries of intoxication, 
addiction, crime and public policy. Boston, MA: Allyn and Bacon; 2008. 
34. 
Hough M. Drug user treatment within a criminal justice context. Substance use & misuse. 2002;37(8-
10):985-996. 
35. 
Kinlock TW, O'Grady KE, Hanlon TE. Prediction of the criminal activity of incarcerated drug-abusing 
offenders. Journal of Drug Issues. 2003;33:897-920. 
36. 
Kinlock TW, O'Grady KE, Hanlon TE. The effects of drug treatment on institutional behavior. The Prison 
Journal. 2003;83:257-276. 
37. 
Dolan KA, Shearer J, White B, Zhou J, Kaldor J, Wodak AD. Four-year follow-up of imprisoned male 
heroin users and methadone treatment: mortality, re-incarceration and hepatitis C infection. Addiction 
(Abingdon, England). 2005;100(6):820-828. 
38. 
Metz V, Matzenauer C, Kammerer K, et al. Evaluation of Opioid-Dependent Prisoners in Oral Opioid 
Maintenance Therapy. Heroin Addiction and Related Clinical Problems. 2010;12(1):5-16. 
39. 
Brownstein HH. Contemporary Drug Policy. New York: Routeledge; 2013. 
40. 
Latkin CA, Yang C, Tobin KE, German D. Injection drug users' and their risk networks' experiences of 
and attitudes towards drug dealer violence in Baltimore, Maryland. International Journal of Drug Policy. 
2013;24(2):135-141. 
41. 
Lobmaier PP, Kunoe N, Waal H. Treatment research in prison: Problems and solutions in a randomized 
trial. Addiction Research and Theory. 2009;18(1):1-13. 
42. 
Yang C, German D, Webster D, Latkin C. Experiencing violence as a predictor of drug use relapse 
among former drug users in Baltimore, Maryland. Journal of Urban Health. 2011;88(6):1044-1051. 

P a g e  | 34 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
43. 
Gordon MS, Kinlock TW, Schwartz RP, O'Grady KE. A randomized clinical trial of methadone 
maintenance for prisoners: findings at 6 months post-release. Addiction (Abingdon, England). 
2008;103(8):1333-1342 [PMCID: PMC2582162]. 
44. 
Inciardi JA, Martin SS, Butzin CA. Five-year outcomes of therapeutic community treatment of drug-
involved offenders after release from prison. Crime & Delinquency. 2004;50:88-107. 
45. 
Kinlock TW, Gordon MS, Schwartz RP, O'Grady K, Fitzgerald TT, Wilson M. A randomized clinical trial 
of methadone maintenance for prisoners: results at 1-month post-release. Drug and alcohol 
dependence. 2007;91(2-3):220-227 [PMCID: PMC2423344]. 
46. 
Kinlock TW, Gordon MS, Schwartz RP, O'Grady KE. A study of methadone maintenance for male 
prisoners: 3-month postrelease outcomes. Criminal justice and behavior. 2008;35(1):34-47 [PMCID: 
PMC24423939]. 
47. 
Kinlock TW, Sears EA, O'Grady KE, Callaman JM, Brown BS. Treatment retention and changes in 
motivation among drug court probationers. Journal of Offender Rehabilitation. 2009;48:1-18. 
48. 
Prendergast M, Hall E, Wexler H, Melnick G, Cao Y. Amity prison-based therapeutic community: Five-
year outcomes. Prison Journal. 2004;84(1):36-60. 
49. 
Prendergast ML, Campos M, Farabee D, Evans WK, Martinez J. Reducing Substance Use in Prison: 
The California Department of Corrections Drug Reduction Strategy Project. The Prison Journal. 
2004;84(2):265-280. 
50. 
Wexler HK, Prendergast ML. Therapeutic communities in United States’ Prisons: Effectiveness and 
Challenges. Therapeutic Communities. 2010;31(2):157-175. 
51. 
Chandler RK, Fletcher BW, Volkow ND. Treating drug abuse and addiction in the criminal justice 
system: improving public health and safety. JAMA. 2009;301(2):183-190. 
52. 
Dolan KA, Shearer J, MacDonald M, Mattick RP, Hall W, Wodak AD. A randomised controlled trial of 
methadone maintenance treatment versus wait list control in an Australian prison system. Drug and 
alcohol dependence. 2003;72(1):59-65. 
53. 
Hedrich D, Alves P, Farrell M, Stover H, Moller L, Mayet S. The effectiveness of opioid maintenance 
treatment in prison settings: a systematic review. Addiction (Abingdon, England). 2012;107(3):501-517. 
54. 
Magura S, Rosenblum A, Lewis C, Joseph H. The effectiveness of in-jail methadone maintenance. 
Journal of Drug Issues. 1993;23:75-99. 
55. 
Magura S, Lee JD, Hershberger J, et al. Buprenorphine and methadone maintenance in jail and post-
release: a randomized clinical trial. Drug and alcohol dependence. 2009;99(1-3):222-230. 
56. 
Stover H, Michels, II. Drug use and opioid substitution treatment for prisoners. Harm reduction journal. 
2010;7:17. 
57. 
Tomasino V, Swanson AJ, Nolan J, Shuman M. The Key Extended Entry Program (KEEP): A 
methadone treatment program for opiate-dependent inmates. The Mount Sinai Journal of Medicine. 
2001;68:14-20. 
58. 
Dole VP, Robinson JW, Orraca J, Towns E, Searcy P, Caine E. Methadone treatment of randomly 
selected criminal addicts. The New England journal of medicine. 1969;280(25):1372-1375. 
59. 
Friedmann PD, Hoskinson R, Gordon M, et al. Medication-assisted treatment in criminal justice 
agencies affiliated with the criminal justice-drug abuse treatment studies (CJ-DATS): availability, 
barriers, and intentions. Subst Abus. 2012;33(1):9-18. PMCID: PMC3295578. 
60. 
Nunn A, Zaller N, Dickman S, Trimbur C, Nijhawan A, Rich JD. Methadone and buprenorphine 
prescribing and referral practices in US prison systems: results from a nationwide survey. Drug and 
alcohol dependence. 2009;105(1-2):83-88. 
61. 
Rich JD, Boutwell AE, Shield DC, et al. Attitudes and practices regarding the use of methadone in US 
state and federal prisons. J Urban Health. 2005;82(3):411-419. 
62. 
Rich JD, McKenzie M, Shield DC, et al. Linkage with methadone treatment upon release from 
incarceration: a promising opportunity. Journal of addictive diseases. 2005;24(3):49-59. 
63. 
Zaller N, McKenzie M, Friedmann PD, Green TC, McGowan S, Rich JD. Initiation of buprenorphine 
during incarceration and retention in treatment upon release. Journal of substance abuse treatment. 
2013;45(2):222-226. 

P a g e  | 35 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
64. 
Wish ED, Artigiani E, Billing A, et al. The emerging buprenorphine epidemic in the United States. 
Journal of addictive diseases. 2012;31(1):3-7. 
65. 
Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance 
treatment for opioid dependence. Cochrane Database of Systematic Reviews 2006(Issue 1. Art. No.: 
CD001333. DOI: 10.1002/14561858.CD001333.pub.2). 
66. 
Pettinati HM, Volpicelli JR, Pierce JD, Jr., O'Brien CP. Improving naltrexone response: an intervention 
for medical practitioners to enhance medication compliance in alcohol dependent patients. Journal of 
addictive diseases. 2000;19(1):71-83. 
67. 
Coviello DM, Cornish JW, Lynch KG, et al. A multisite pilot study of extended-release injectable 
naltrexone treatment for previously opioid-dependent parolees and probationers. Subst Abus. 
2012;33(1):48-59. 
68. 
Cornish JW, Langleben DD, Nordeck CD, et al. Six-Month Depot Naltrexone Treatment Reduces 
Relapse in Parolees Formerly Addicted to Opioids. Poster presented at 51st Annual Meeting of the 
American College of Neuropsychopharmacology; December 2-6, 2012, 2012; Hollywood, Florida. 
69. 
Lee S, Klein-Schwartz W, Welsh C, Doyon S. Medical outcomes associated with nonmedical use of 
methadone and buprenorphine. The Journal of emergency medicine. 2013;45(2):199-205. 
70. 
Krupitsky E, Zvartau E, Woody G. Use of naltrexone to treat opioid addiction in a country in which 
methadone and buprenorphine are not available. Current psychiatry reports. 2010;12(5):448-453. 
71. 
Binswanger IA, Nowels C, Corsi KF, et al. Return to drug use and overdose after release from prison: a 
qualitative study of risk and protective factors. Addiction science & clinical practice. 2012;7(1):3. 
72. 
Kinlock TW, Battjes RJ, Schwartz RP. A novel opioid maintenance program for prisoners: report of 
post-release outcomes. The American journal of drug and alcohol abuse. 2005;31(3):433-454. 
73. 
Kinlock TW, Schwartz RP, Gordon MS. The significance of interagency collaboration in developing 
opioid agonist programs for prisoners. Corrections Compendium. 2005;30:6-9, 28-30. 
74. 
Kinlock TW, Gordon MS, Schwartz RP, Fitzgerald TT. Developing and Implementing a new prison-
based buprenorphine treatment program. J Offender Rehabil. 2010;49(2):91-109 [PMCID: 
PMC2868193]. 
75. 
Lurigio AJ. An evaluation of a safe haven’s workshop for Illinois parole agents. Chicago: Loyola 
University of Chicago; 2009. 
76. 
Schmalleger F. Criminal Justice Today: An introductory text for the 21st century 10th ed. Upper Saddle 
River, NJ: Pearson Prentice Hall; 2010. 
77. 
McKenzie M, Nunn A, Zaller ND, Bazazi AR, Rich JD. Overcoming obstacles to implementing 
methadone maintenance therapy for prisoners: implications for policy and practice. Journal of opioid 
management. 2009;5(4):219-227. 
78. 
Lee JD, Friedmann PD, Boney TY, et al. Extended-release naltrexone to prevent relapse among opioid 
dependent, criminal justice system involved adults: rationale and design of a randomized controlled 
effectiveness trial. Contemporary clinical trials. 2015;41:110-117. 
79. 
Cornish JW, Metzger D, Woody GE, et al. Naltrexone pharmacotherapy for opioid dependent federal 
probationers. Journal of substance abuse treatment. 1997;14(6):529-534. 
80. 
Coviello DM, Cornish JW, Lynch KG, Alterman AI, O'Brien CP. A randomized trial of oral naltrexone for 
treating opioid-dependent offenders. The American journal on addictions / American Academy of 
Psychiatrists in Alcoholism and Addictions. 2010;19(5):422-432. 
81. 
Gordon MS, Kinlock TW, Schwartz RP, Couvillion K, Schwartz RP, O'Grady KE. The severity, 
frequency and variety of crime in heroin-dependent prisoners enrolled in a buprenorphine clinical trial. 
The Prison Journal. in press. 
82. 
Pecoraro A, Woody GE. Medication-assisted treatment for opioid dependence: making a difference in 
prisons. F1000 Med Rep. 2011;3:1. 
83. 
Garcia CA, Correa GC, Hernandez Viver AD, et al. Buprenorphine-naloxone treatment for pre-release 
opioid-dependent inmate in Puerto Rico. Journal of Addiction Medicine. 2007;1(3):126-132. 
84. 
Kinlock TW, Battjes RJ, Schwartz RP. A novel opioid maintenance program for prisoners: preliminary 
findings. Journal of substance abuse treatment. 2002;22(3):141-147. 

P a g e  | 36 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
85. 
Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. 
Lancet. 2002;359(9306):614-618. 
86. 
Green TC, Bowman SE, Ray M, McKenzie M, Lord SE, Rich JD. Development of an incarceration 
specific overdose prevention video: Staying Alive on the Outside. Health Education journal. 2014:1-11. 
87. 
SAMHSA. SAMHSA Opioid Overdose Prevention Toolkit. 2016; 
http://store.samhsa.gov/shin/content//SMA16-4742/SMA16-4742.pdf. 
88. 
DHHS. NIOSH Hazard Review: Occupational Hazards in Home Healthcare. 2010; Publication No. 210-
125:http://www.cdc.gov/niosh/docs/2010-125/pdfs/2010-125.pdf. 
89. 
McLellan AT, Kushner H, Metzger D, et al. The Fifth Edition of the Addiction Severity Index. Journal of 
substance abuse treatment. 1992;9(3):199-213. 
90. 
McLellan AT, Luborsky L, Woody GE, O'Brien CP. An improved diagnostic evaluation instrument for 
substance abuse patients. The Addiction Severity Index. The Journal of nervous and mental disease. 
1980;168(1):26-33. 
91. 
Association AP. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC 2013. 
92. 
Kinlock TW. Precursors and correlates of serious criminal behavior over a narcotic addiction career 
[Doctoral Dissertation.]. College Park, MD, University of Maryland, 1993; 1995. 
93. 
Metzger D, Woody GE, McLellan AT, Navaline H, O'Brien CP, International Conference on AIDS. 
Measuring risk behavior among IDUs: validation of the risk for AIDS behavior (RAB) scale. Paper 
presented at: Int Conf AIDS; Jul 19-24, 1992; University of Pennsylvania, Philadelphia. 
94. 
Kaplan RF, Cooney NL, Baker LH, Gillespie RA, Meyer RE, Pomerleau OF. Reactivity to alcohol-
related cues: physiological and subjective responses in alcoholics and nonproblem drinkers. J Stud 
Alcohol. 1985;46(4):267-272. 
95. 
Childress AR, McLellan AT, O'Brien CP. Conditioned responses in a methadone population. A 
comparison of laboratory, clinic, and natural settings. Journal of substance abuse treatment. 
1986;3(3):173-179. 
96. 
Schwartz RP, Jaffe JH, O'Grady KE, et al. Interim methadone treatment: impact on arrests. Drug and 
alcohol dependence. 2009;103(3):148-154 [PMCID: PMC2699328]. 
97. 
Jones LV, Tukey JW. A sensible formulation of the significance test. Psychological methods. 
2000;5(4):411-414. 
98. 
Hedeker D, Gibbons RD. Application of random-effects pattern-mixture models for missing data in 
longitudinal studies. Psychological methods. 1997;2:64-78. 
99. 
Carpenter J, Kenward M. Multiple Imputation and its Application. New York, NY: Wiley; 2013. 
100. 
Carpenter J, Kenward M. Missing data in randomised controlled trials - a practical guide. Birmingham: 
National Institute for Health Research;2008. 
101. 
Stroup WW. Mixed model procedures to assess power, precision, and sample size in the design of 
experiments. Lincoln, NE: University of Nebraska, American Statistical Association; 1999:19-24. 
102. 
Littell RC, Milliken GA, Stroup WW, Wolfinger RD, Schabenberger O. SAS for mixed models. Second 
ed. Cary, NC: SAS Institute, Inc.; 2006. 
103. 
Cohen J. Statistical power analysis for the behavioral sciences (Second edition) Hillsdale, NJ: LEA; 
1988. 
104. 
Borenstein M, Cohen J. Statistical power analysis. Hillsdale, NY: Erlbaum; 1988. 
105. 
Miller J, Schwarz W. Aggregate and individual replication probability within an explicit model of the 
research process. Psychological methods. 2011;16(3):337-360. 
106. 
Thabane L, Mbuagbaw L, Zhang S, et al. A tutorial on sensitivity analyses in clinical trials: the what, 
why, when and how. BMC Med Res Methodol. 2013;13:92. 
107. 
Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine--reporting of subgroup 
analyses in clinical trials. The New England journal of medicine. 2007;357(21):2189-2194. 
108. 
Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997;35(11):1095-1108. 
109. 
The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health 
policy. 1990;16(3):199-208. 

P a g e  | 37 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
110. 
Richardson J, Mckie J, Bariola E. Multiattribute utility instruments and their use. In: Culyer AJ, ed. 
Encylopedia of Health Economics: Elsevier; 2014:341-357. 
 
 
 
 
 

P a g e  | 38 
 
 
 
Protocol Version Number/Date: V.12.0 2 Nov. 2018 
11.0 APPENDIX (screening forms, medical forms, research instruments)