Conditions: Opioid-use Disorder Hiv
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
The Primary Objective of this study is to compare the effectiveness of HIV clinic-based extended-release Naltrexone (XR-NTX) in decreasing substance use and increasing HIV viral suppression in HIV-infected participants with opioid use disorder to Treatment as Usual in this population.

Detailed description:
The CTN-0055 CHOICES pilot study demonstrated the feasibility of extended-release naltrexone (XR-NTX) for treatment of opioid use disorder in HIV primary care. The CTN-0067 CHOICES scale-up study builds on lessons learned from the pilot and uses the Consolidated Framework for Implementation Research to advance understanding of XR-NTX adoption in HIV primary care clinics. The study is an open-label, randomized, comparative effectiveness trial of office-based XR-NTX for 24 weeks (6 monthly injections) versus treatment as usual (TAU) in HIV-infected participants with untreated opioid use disorder. Each participant will be engaged in the overall study for 25 to 28 weeks, depending on the speed of screening and enrollment procedures.

Arms:
arm 1: Extended-release naltrexone arm 2: Treatment as usual

Interventions: intervention 1: Naltrexone Injectable Suspension intervention 2: Treatment as usual
Intervention descriptions: intervention 1: Six monthly injections of extended-release naltrexone intervention 2: Standard treatment for opioid use disorder provided at each HIV clinic

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
NIDA CTN Protocol 0067 
Comparing Treatments for  
HIV-Infected Opioid 
Users in an Integrated Care Effectiveness 
Study (CHOICES) Scale-Up 
 
Lead Investigator: Todd Korthuis, MD, MPH 
Co-LI: Dennis McCarty, PhD 
 James Sorensen, PhD 
Protocol Manager: Lynn Kunkel, MS, CCRP 
 
January 30, 2019 
Version 5.0 
NCT03275350 
 


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PROTOCOL DEVELOPMENT TEAM: 
Daniel J. Feaster, PhD (Florida Node Alliance) 
Kim A. Hoffman, PhD (Western States Node) 
P. Todd Korthuis, MD, MPH (Western States Node) 
Paula Lum, MD, MPH (Western States Node) 
Dennis McCarty, PhD (Western States Node) 
Lisa Metsch, PhD (Florida Node Alliance)  
Edward Nunes, MD (Greater New York Node) 
John Rotrosen, MD (Greater New York Node)  
James Sorensen, PhD (Western States Node) 
 
Emmes: 
Eve Jelstrom, CRNA, MBA 
Robert Lindblad, MD 
Neal Oden, PhD 
Paul Van Veldhuisen, PhD 
Lauren Yesko 
 
NIDA CCTN: 
Petra Jacobs, PhD (CCTN Scientific Liaison) 
Geetha Subramaniam, MD (CCTN co-Scientific Liaison) 
 
HIV/AIDS: 
Lynda Erinoff, JD, PhD  
Jacques Normand, PhD 
 
PROTOCOL MANAGER: 
Lynn E. Kunkel, MS, CCRP 
 
 
 


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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS ..................................................................................................... 1 
2.0 
STUDY SYNOPSIS AND SCHEMA ......................................................................................... 4 
 
Figure 1.  Study Schema ...................................................................................................... 5 
3.0 
STUDY FLOW CHART ............................................................................................................ 6 
4.0 
INTRODUCTION ...................................................................................................................... 7 
 
Background and Rationale ................................................................................................... 7 
 
Figure 2.  Conceptual Model ........................................................................................ 11 
 
Naltrexone (NTX) and Extended-Release Naltrexone (XR-NTX) ....................................... 11 
 
Treatment as Usual (TAU) ................................................................................................. 12 
 
Significance to the Field ..................................................................................................... 14 
5.0 
OBJECTIVES ......................................................................................................................... 16 
 
Primary Objectives ............................................................................................................. 16 
 
Secondary Objectives ........................................................................................................ 16 
6.0 
STUDY DESIGN .................................................................................................................... 17 
 
Overview of Protocol Study Design .................................................................................... 17 
 
Study Duration and Visit Schedule ..................................................................................... 17 
 
Justification of 24 weeks active treatment and timing of ART initiation .............................. 18 
 
Justifcation of Implementation Study Procedures .............................................................. 18 
7.0 
STUDY POPULATION ........................................................................................................... 20 
 
Inclusion Criteria................................................................................................................. 20 
 
Exclusion Criteria ............................................................................................................... 20 
 
Recruitment ........................................................................................................................ 21 
 
Special Populations to Consider ........................................................................................ 22 
 
Site Characteristics ............................................................................................................ 23 
 
Rationale for Site Selection ................................................................................................ 24 
 
Collaboration with CTSA for Site Recruitment .................................................................... 24 
8.0 
OUTCOME MEASURES ........................................................................................................ 25 
 
Primary Outcome Measures ............................................................................................... 25 
 
Secondary Outcome Measures .......................................................................................... 25 
9.0 
STUDY PROCEDURES ......................................................................................................... 26 
 
Duration of Participant Study Procedures .......................................................................... 26 
 
Pre-screening ............................................................................................................... 26 
 
Figure 3.  Study Duration ............................................................................................. 26 
 
Screening and Enrollment Procedures (1-4 weeks duration) ....................................... 26 


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Informed Consent Process ........................................................................................... 26 
 
Locator Form ................................................................................................................ 26 
 
Medical Record Release Form ..................................................................................... 27 
 
Collection of Biological Specimens .............................................................................. 27 
 
Baseline Assessment ................................................................................................... 27 
 
Randomization ............................................................................................................. 27 
 
Treatment Conditions ......................................................................................................... 28 
 
HIV Usual Care (Both Arms) ........................................................................................ 28 
 
Medical Management (when applicable) ...................................................................... 28 
 
Clinic-based Extended-Release Naltrexone (XR-NTX) ................................................ 29 
9.2.3.1 
XR-NTX Detoxification and Induction (0 - 4 weeks duration, during active treatment 
phase) ...................................................................................................................... 29 
9.2.3.2 
Active Treatment with XR-NTX (Treatment Initiation through Week 20) .................. 29 
9.2.3.3 
Handling of Missed XR-NTX Doses, Lapses, and Relapses .................................... 29 
9.2.3.4 
Dispensing of XR-NTX ............................................................................................. 30 
 
Treatment as Usual (TAU) ........................................................................................... 30 
 
Ancillary Treatments ........................................................................................................... 30 
 
Provisions for Access to Treatment after Study ................................................................. 31 
 
Drug Packaging / XR-NTX ................................................................................................. 31 
 
Participant Discontinuation ................................................................................................. 31 
 
Blinding .............................................................................................................................. 31 
 
Participant Compensation .................................................................................................. 31 
 
Long Term Mortality Follow-up ........................................................................................... 31 
10.0 
STUDY ASSESSMENTS AND INSTRUMENTS .................................................................... 33 
 
List of all CRFs and Table of Assessments ........................................................................ 34 
11.0 
HIV-RELATED MEASURES .................................................................................................. 37 
 
Antiretroviral Medication Prescription and Adherence ........................................................ 37 
 
HIV Care Utilization ............................................................................................................ 37 
 
HIV Risk Assessment Battery ............................................................................................ 37 
 
VACS Index ........................................................................................................................ 37 
 
Table 1:  Point Values Used to Calculate VACS Index ....................................................... 38 
12.0 
GENERAL MEASURES ......................................................................................................... 39 
 
Inclusion/Exclusion ............................................................................................................. 39 
 
Locator Form ...................................................................................................................... 39 
 
PhenX Core Tier 1 Forms .................................................................................................. 39 


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Demographics Form ........................................................................................................... 39 
 
Treatment Satisfaction Survey ........................................................................................... 39 
 
Treatment Plan ................................................................................................................... 39 
 
Medication Adherence ........................................................................................................ 40 
 
End of Treatment Form ...................................................................................................... 40 
 
Study Completion Form ...................................................................................................... 40 
 Treatment Initiation and XR-NTX Non-Initiation ................................................................. 40 
13.0 
SAFETY AND MEDICAL MEASURES .................................................................................. 41 
 
Medical and Psychiatric History ......................................................................................... 41 
 
Physical Examination ......................................................................................................... 41 
 
Vital Signs .......................................................................................................................... 41 
 
DSM-5 Checklist................................................................................................................. 41 
 
Clinical Laboratory Tests .................................................................................................... 41 
 
Pregnancy and Birth Control Assessment .......................................................................... 42 
 
Injection Site Examination .................................................................................................. 42 
 
Pain Assessment................................................................................................................ 42 
14.0 
SUBSTANCE USE AND MENTAL HEALTH COVARIABLES .............................................. 44 
 
Urine Drug Screen .............................................................................................................. 44 
 
Addiction Severity Index-Lite (ASI-Lite) Drug and Alcohol Use .......................................... 44 
 
Timeline Follow Back (TLFB) ............................................................................................. 44 
 
Visual Analog Craving Scale (VAS).................................................................................... 44 
 
Treatment Services Review (TSR), Version 6 (28 days) .................................................... 45 
 
Medication-Assisted Treatment .......................................................................................... 45 
 
Quality of Life ..................................................................................................................... 45 
 
Participant Treatment Preference ...................................................................................... 45 
15.0 
SAFETY ASSESSMENTS ..................................................................................................... 46 
 
Adverse Events, including Serious Adverse Events, and Protocol Deviations ................... 46 
 
Non-Fatal Overdose ........................................................................................................... 46 
 
Fatal Overdose ................................................................................................................... 46 
 
Precipitated Withdrawal ...................................................................................................... 46 
 
Concise Health Risk Tracking - Self Report (CHRT-SR) Suicidal Behavior Evaluation ...... 46 
 
Concise Health Risk Tracking - Clinician Rated ................................................................. 47 
 
Patient Health Questionnaire (PHQ-9) Depression Symptoms .......................................... 47 
 
Suicidal Risk ....................................................................................................................... 47 
16.0 
STUDY CONDITIONS ............................................................................................................ 48 
 
Clinic-Based XR-NTX ......................................................................................................... 48 


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TAU .................................................................................................................................... 48 
 
Training .............................................................................................................................. 48 
 
Concomitant Medications ................................................................................................... 48 
17.0 
STATISTICAL ANALYSIS ..................................................................................................... 49 
 
Primary Objective of the Analysis ....................................................................................... 49 
 
Primary Outcome Measure ................................................................................................ 49 
 
Secondary Outcome Measures .......................................................................................... 50 
 
Sample Size and Duration of Recruitment Phase .............................................................. 50 
 
Substantive Justification for a Non-Inferiority Design. ........................................................ 51 
 
Justification of the Non-Inferiority Margin ........................................................................... 51 
 
Rationale for Sample Size .................................................................................................. 51 
 
Figure 4.  Non-inferiority margins granting power = 0.8 and 0.9 as a function of sample 
size ............................................................................................................................... 52 
 
Figure 5.  Implications for probabilities of fixing RR = 0.75 versus fixing a probability 
difference of 0.14 ......................................................................................................... 53 
 
Duration of Recruitment Period .......................................................................................... 54 
 
Figure 6.  Simulated times to enrollment of 350 participants from 8 sites like CORE 
Center. ......................................................................................................................... 54 
 
Analysis of secondary outcomes ........................................................................................ 55 
 
Additional Statistical Tests of the Secondary Outcomes .............................................. 56 
 ITT and Per-Protocol Analyses, Missing Data and Dropouts ............................................. 57 
 Interim Monitoring of Primary Efficacy Endpoint ................................................................. 57 
 Figure 7.  Information Fraction and Fraction of Target Enrollment for Proposed Sample 
Size Re-Estimation Based on Months from Start of Enrollment ................................... 58 
 Conditional Power and Futility ............................................................................................ 58 
 Safety Analysis ................................................................................................................... 59 
18.0 
REGULATORY COMPLIANCE AND SAFETY ...................................................................... 60 
 
Regulatory Compliance ...................................................................................................... 60 
 
Statement of Compliance ................................................................................................... 60 
 
Confidentiality ..................................................................................................................... 60 
 
Health Insurance Portability Accountability Act (HIPAA) .................................................... 61 
 
Investigator Assurances ..................................................................................................... 61 
 
Research Advisory Panel of California ............................................................................... 61 
 
Financial Disclosure ........................................................................................................... 61 
 
DEA Registration ................................................................................................................ 61 
 
Drug Accountability ............................................................................................................ 61 
 Inclusion of Women and Minorities..................................................................................... 61 


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 IND Requirement................................................................................................................ 62 
 Regulatory Files ................................................................................................................. 62 
 Records Retention and Requirements ............................................................................... 62 
 Audits ................................................................................................................................. 62 
 Reporting to Sponsor ......................................................................................................... 62 
 Informed Consent ............................................................................................................... 62 
 Clinical Monitoring .............................................................................................................. 63 
 Study Documentation ......................................................................................................... 64 
19.0 
SAFETY MONITORING ......................................................................................................... 65 
 
Data and Safety Monitoring Board (DSMB) ........................................................................ 65 
 
Protocol Deviations Reporting and Management ............................................................... 65 
 
Adverse Events (AEs) ........................................................................................................ 65 
 
Adverse Events ............................................................................................................ 66 
 
Serious Adverse Events ............................................................................................... 66 
 
Known Potential Toxicities of Study Drug/Intervention ....................................................... 66 
 
Known Potential Adverse Events Related to the Underlying Clinical Condition and/or Study 
Populations ........................................................................................................................ 66 
20.0 
DATA SAFETY MANAGEMENT AND PROCEDURES ........................................................ 67 
 
Design and Development ................................................................................................... 67 
 
Site Responsibilities ........................................................................................................... 67 
 
Data Center Responsibilities .............................................................................................. 67 
 
Data Collection ................................................................................................................... 67 
 
Data Acquisition and Entry ................................................................................................. 67 
 
Data Editing ........................................................................................................................ 67 
 
Database Lock and Transfer .............................................................................................. 68 
 
Data Training ...................................................................................................................... 68 
 
Data QA ............................................................................................................................. 68 
21.0 
PROTOCOL SIGNATURE PAGE .......................................................................................... 69 
22.0 
REFERENCES ....................................................................................................................... 70 
23.0 
APPENDIX A - ADVERSE EVENT REPORTING DEFINITIONS AND PROCEDURES ....... 79 
 
Definition of Adverse Events and Serious Adverse Events ................................................ 79 
 
Definition of Expectedness ........................................................................................... 79 
 
Pregnancy .......................................................................................................................... 79 
 
Medical and Psychiatric History ......................................................................................... 80 
 
Site’s Role in Eliciting and Reporting Adverse Events ........................................................ 80 
 
Site’s Role in Assessing Severity and Causality of Adverse Events .................................. 80 


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Guidelines for Assessing Severity ...................................................................................... 81 
 
Guidelines for Determining Causality ........................................................................... 81 
 
Site’s Role in Monitoring Adverse Events .................................................................... 81 
 
Sponsor’s Role in Safety Management Procedures of AEs/SAEs ............................... 81 
 
Regulatory Reporting for an IND study ............................................................................... 82 
 
Reporting to the Data and Safety Monitoring Board ........................................................... 82 
 
Participant Withdrawal ........................................................................................................ 82 
 Adverse Event Reporting Chart .......................................................................................... 83 
24.0 
APPENDIX B - DATA SAFETY AND MONITORING PLAN (DSMP) .................................... 84 
 
Brief Study Overview .......................................................................................................... 84 
 
Oversight of Clinical Responsibilities .................................................................................. 84 
 
Site Principal Investigator ............................................................................................. 84 
 
Medical Monitor/Safety Monitor .................................................................................... 84 
 
Data and Safety Monitoring Board (DSMB) ................................................................. 84 
 
Quality Assurance (QA) Monitoring .............................................................................. 85 
 
Management of Risks to Participants ........................................................................... 85 
24.2.5.1 Confidentiality .......................................................................................................... 85 
24.2.5.2 Information Meeting Reporting Requirements .......................................................... 85 
24.2.5.3 Human Subject Protection ....................................................................................... 85 
24.2.5.4 Pregnancy ................................................................................................................ 85 
24.2.5.5 Study Specific Risks................................................................................................. 86 
 
Data Management Procedures .......................................................................................... 86 
 
Data and Statistics Center Responsibilities ........................................................................ 86 
 
Data Collection and Entry ................................................................................................... 86 
 
Data Monitoring, Cleaning and Editing ............................................................................... 86 
 
Database Lock and Transfer .............................................................................................. 87 
25.0 
APPENDIX C - “RANDOM ASSIGNMENT BOOTSTRAPPING” .......................................... 88 
 
Table 1: Some Parameters Necessary to Simulate Realistic Data for CTN-0067 .............. 88 
 
Table 2: CTN-0055 Treatment Assignment and Suppression ...................................... 89 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Aminotransferase 
AOR 
Adjusted Odds Ratio 
ART 
Antiretroviral Therapy 
ARV 
Antiretroviral 
ASI-Lite 
Addiction Severity-Index-Lite 
AST 
Aspartate Aminotransferase 
BHIVES 
Buprenorphine HIV Evaluation and Support Collaborative 
BMI 
Body Mass Index 
BUP 
Buprenorphine 
BUP/NX 
Buprenorphine Naloxone (Suboxone®) 
CCC 
Clinical Coordinating Center 
CFIR 
Consolidated Framework for Implementation Research 
CCTN 
Center for the Clinical Trials Network 
CFR 
Code of Federal Regulations 
CHRT 
Concise Health Risk Tracking 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTN 
Clinical Trials Network 
CTSA 
Clinical and Translational Science Award 
DEA 
Drug Enforcement Agency 
DSC 
Data and Statistics Center 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice  
HAART 
Highly Active Antiretroviral Therapy 
HCV 
Hepatitis C Virus 
HHS 
HIPAA 
Department of Health and Human Services 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRSA 
Health Resources and Services Administration 
IEC 
Institutional Ethics Committee 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LFTs 
LI 
Liver Function Tests 
Lead Investigator 
MAT 
Medication-Assisted Treatment 
MAR 
Missing at Random 
Mg 
Milligrams 
MM 
Medical Management 
MMT 
Methadone Maintenance Treatment 
MNAR 
Missing not at Random 
MOP 
Manual of Operating Procedures 
NDA 
New Drug Application 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
NTX 
Naltrexone 
NX 
Naloxone 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health and Science University 
ORT 
Opioid Replacement Therapy 


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Abbreviation 
Definition 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PLWHA 
Persons Living with HIV/AIDS 
PLG 
Polylactide-co-glycolide 
PWID 
People Who Inject Drugs 
QA 
Quality Assurance 
RAB 
Risk Assessment Battery 
RMVL 
Repeated Measure of Viral Load 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAMHSA 
Substance Abuse and Mental Health Services Administration 
SC 
Subcutaneous 
SOP 
Standard Operating Procedures 
TAU 
Treatment as Usual 
TLFB 
Timeline Follow-Back 
UDS 
Urine Drug Screen 
VACS 
Veterans Aging Cohort Study 
XR-NTX 
Extended-Release Naltrexone (Vivitrol®) 


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2.0 
STUDY SYNOPSIS AND SCHEMA 
Substance use disorders are common in HIV-infected individuals [1-5]. Untreated substance use 
disorders are associated with increased HIV risk behaviors [6-8], decreased receipt of 
antiretroviral therapy (ART) [9], [7], [10-12], decreased ART adherence [7, 13-16], decreased HIV 
viral suppression [13, 17-20], greater HIV-related symptoms [21, 22], and higher hospitalization 
rates [23, 24]. Compared to other HIV risk groups, people who inject drugs (PWID) are less likely 
to engage in HIV care and achieve HIV viral suppression [13, 17, 25] or sustained viral 
suppression [26, 27]. 
Treatment of substance use disorders can increase engagement in HIV care [28, 29]. Opioid 
replacement therapy (ORT) with methadone [30] and sublingual buprenorphine/naloxone 
(BUP/NX) [31] decreases HIV transmission risk behaviors and improves HIV outcomes, yet 
access to these medication-assisted therapies is limited and requires adherence to daily dosing. 
HIV providers are well-positioned to integrate pharmacotherapy for substance use disorders into 
HIV treatment settings, but thus far only BUP/NX has been adopted in HIV practice. In the 
Buprenorphine-HIV Evaluation and Support (BHIVES) Collaborative (a demonstration of 
integrated care for HIV and opioid dependence), HIV-infected individuals with opioid dependence 
who received office-based BUP/NX from an HIV clinic provider decreased opioid use [32], 
increased ART use [29], experienced higher quality of HIV care [33] and reported better quality 
of life [34]. HIV treatment guidelines now recommend opioid agonist therapy as a key treatment 
strategy for engaging PWID in HIV treatment [35]. Retention on agonist therapy remains limited, 
however, due to daily dosing requirements, and some patients would prefer alternatives to agonist 
treatment. 
Long-acting antagonist treatment may provide an alternative to daily agonist therapy for patients 
with opioid use disorder, though its ability to facilitate closing gaps in HIV treatment retention 
and outcomes is unknown. Extended-release naltrexone (XR-NTX), a deep muscle injection that 
lasts 28 days, eliminates the need for daily dosing. XR-NTX improves alcohol dependence 
treatment adherence and retention when integrated into primary care clinics [36, 37], but has 
not been tested in people living with HIV who are having difficulty engaging in HIV treatment. 
XR-NTX may also be preferred by some HIV-infected patients seeking a non-narcotic treatment 
option and/or once a month dosing. 
The CTN-0055 CHOICES pilot study demonstrated the feasibility of extended-release naltrexone 
(XR-NTX) for treatment of opioid use disorder in HIV primary care at two HIV clinic pilot sites. The 
CTN-0067 CHOICES scale-up study builds on lessons learned from the pilot and uses the 
Consolidated Framework for Implementation Research to advance understanding of XR-NTX 
adoption in HIV primary care settings. CTN-0067 CHOICES scale-up study is conducted in no 
more than 8 HIV primary care clinics. It is an open-label, randomized, comparative effectiveness 
trial of office-based XR-NTX for 24 weeks (approximately 6 monthly injections) (n = 175) versus 
treatment as usual (TAU) (n = 175) in HIV-infected participants with untreated opioid use disorder 
and HIV RNA PCR > 200 copies/ml at baseline (Figure 1). The primary outcome is HIV viral 
suppression (HIV RNA PCR ≤ 200 copies/mL) at 24 weeks. Secondary outcomes include VACS 
Index, CD4 count, HIV care engagement, and ART adherence mediation. The trial will be powered 
as a non-inferiority trial because the overall goal of the research is to add to rather than supplant 
currently available effective treatments. An implementation assessement documents best 
practices. Each participant will be engaged in the overall study for 25 to 28 weeks, depending on 
the speed of screening and enrollment procedures.  
 
 


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Figure 1.  Study Schema 
 
 
 
Specific Aim: The specific aim is to compare the effect of office-based extended-release 
naltrexone (XR-NTX) versus treatment as usual (TAU) on HIV viral suppression at 24 weeks from 
randomization for HIV-infected participants with untreated opioid use disorder and HIV RNA PCR 
> 200 copies/ml at baseline. 
Secondary Specific Aims: Secondary aims compare the effectiveness of XR-NTX versus TAU in 
1) other HIV outcomes (VACS Index, CD4 count), 2) engagement in HIV care (receipt of ART, 
ART adherence, retention in HIV care, HIV risk behaviors), 3) ART adherence as mediated by 
number of opioid use days at 24 weeks, and 4) qualitiative interviews with participants, providers, 
and staff to document the HIV primary care treatment environment and describe XR-NTX 
formative implementation strategies, challenges, and best practices. 
 
 
Recruitment, 
Screening, 
and Consent 
Randomization 
(n=350) 
XR-NTX 
(n=175) 
Study Drug Exposure (24 wk) 
 
Primary Outcome 
HIV viral suppression 
 
Secondary Outcomes 
a) VACS Index 
b) CD4 Count 
c) Engagement in HIV care 
d) ART adherence mediation 
 
TAU 
(n=175) 
Qualitative Interviews, (n=up to 120) 
Clinic Providers and Staff, up to 60 across sites 
Randomized Participants, up to 60 across sites 
Secondary Outcome: Implementation facilitators and barriers 


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3.0 
STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment: HIV providers, clinic staff, and intake coordinators refer and research staff approach HIV clinic patients with 
opioid dependence interested in learning about the study. Potential participants receive detailed information about XR-NTX, 
agonist, and non-pharmacological treatment (10 minutes/ppt) 
Informed Consent: HIV-infected participants who pre-screen eligible will complete the written consent process and HIPAA 
authorization. (20-30 minutes/ppt) 
Verbal Consent for Pre-Screening: After hearing a brief overview of the study, potential participants provide verbal 
informed consent with HIPAA Authorization/Waiver. (5 minutes/ppt and 5 minutes/ppt, respectively)  
Pre-Screening Interview: After providing verbal consent and HIPAA Authorization/Waiver, potential participants complete a 
brief pre-screening interview to determine eligibility for trial, attitudes toward opioid antagonist treatment and willingness to 
be randomized. (10 minutes/ppt) 
Randomization: Upon completion of Baseline Assessment, participants will be randomly assigned to XR-NTX or TAU, 
provide a blood specimen, and discuss their Treatment Plan with the provider (20-30 minutes/ppt)  
Baseline Assessment: After study enrollment/screening, participants complete the baseline assessment.  
(60-90 minutes/ppt) 
Screening and Enrollment: After completing the informed consent and HIPAA authorization process, participants will 
complete the locator information form and screening procedures, provide a urine specimen, and provide blood draw for 
eligibility criteria if not available from medical records abstraction. (60-90 minutes/ppt) 
Group 1: Office-Based XR-NTX 
 (# of medical appointments will vary; 
 ~ 25 minutes per appointment/ppt) 
Group 2: TAU 
(# of medical appointments will vary; 
 ~25 minutes per appointment/ppt) 
On-Treatment Study Visits: Treatment initiation visit; safety visit 1 week after treatment initiation; follow-up visits 4, 8, 12, 
16, 20 and 24 weeks post-randomization. Interview and specimen collection (urine [all visits for Group 1; all visits except the 
treatment initiation visit and safety visit for Group 2] and blood [Week 12 and 24 only]) will be conducted. (45-60 and  
5 minutes/ppt, respectively) 


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4.0 
INTRODUCTION 
 
Background and Rationale 
Opioid Use Disorders in People Living with HIV. Opioid use disorders are common in HIV- 
infected individuals [3, 38, 39]. Patients with opioid use disorder experience wide gaps in the HIV 
care cascade. Only 21% of HIV-infected individuals referred are established and retained in 
ongoing HIV care [25] and PWID are least likely to engage in HIV care and achieve HIV viral 
suppression compared to other HIV risk groups [13, 17, 25]. 
When untreated, opioid use disorder in people living with HIV is associated with decreased receipt 
of antiretroviral therapy (ART) [9, 40], decreased ART adherence [14], and decreased HIV viral 
suppression [13, 17-19]. Other adverse outcomes include decreased health-related quality of life 
[34], greater HIV-related symptoms, [21], higher hospitalization rates [23], and greater HIV 
disease progression and death [41]. Opioid use disorder is also associated with increased HIV 
risk behaviors [8]. 
Opioid Use Disorder Treatment and HIV Outcomes. Treatment of opioid use disorders with 
methadone or buprenorphine can improve engagement and retention in care, receipt of ART, 
ART adherence, and HIV viral suppression. The International Association of Providers of AIDS 
Care guidelines recommend scale-up of evidence-based medication-assisted treatments for 
substance use disorders for optimizing the HIV care continuum [42]. Over four decades of 
evidence demonstrate that methadone maintenance therapy (MMT) is both efficacious in clinical 
trials and effective in the community in promoting and sustaining abstinence and reducing risks 
associated with opioid use disorders [39, 43]. In a cohort of HIV-infected PWID in Vancouver, 
British Columbia, MMT was associated with greater ART adherence (AOR 1.52; 95% CI 1.16-
2.00), HIV-1 RNA suppression (AOR 1.34; 95% CI 1.00-1.79), and CD4 cell count rise (AOR 1.58; 
95% CI 1.26-1.99) over time [44]. 
The approval of buprenorphine for office-based treatment of opioid dependence expanded patient 
treatment options and access to addiction care. In a pilot trial (n=93) of clinic-based buprenorphine 
vs. referral for methadone maintenance, HIV-infected participants randomized to clinic-based 
buprenorphine treatment were more likely to engage in treatment for opioid dependence 
compared to those referred for methadone (74% vs. 41%, p<.001); however, ART receipt, HIV 
RNA and CD4 counts did not differ at 12 months [28]. In the Buprenorphine HIV Evaluation and 
Support Collaborative (BHIVES), HIV-infected individuals with opioid dependence who received 
clinic-based buprenorphine/naloxone (BUP/NX) from an HIV clinic provider decreased opioid use 
[32], experienced higher quality of HIV care [33] and reported better quality of life [34]. A majority 
(60%) of BHIVES participants were already on ART at baseline. Participants initiating clinic-based 
BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 
counts over time compared with baseline. Retention on BUP/NX for three or more quarters was 
associated with increased likelihood of initiating ART (β = 1.34 [95% CI 1.18, 1.53]) and achieving 
viral suppression (β = 1.25 [95% CI 1.10, 1.42]) among the 64 of 119 (54%) participants not on 
ART at baseline compared with the 55 participants not retained on buprenorphine [29]. 
Opioid agonist therapy with methadone [30] or sublingual BUP/NX [31] is associated with 
decreases in HIV risk behaviors. A meta-analysis of 12 studies assessing the impact of opioid 
substitution treatment on HIV transmission showed a 54% reduction in HIV infection among PWID 
[45]. 
Need for Expanded Opioid Treatment Options in HIV Clinics. Despite the availability of MMT 
in most communities and recent adoption of office-based buprenorphine in some HIV practices, 


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an expanded palette of treatment options for opioid use disorder in HIV clinics is greatly needed. 
Only a minority of HIV-infected patients with substance use disorders receive addiction treatment 
[3, 46]. For those who receive pharmacologic treatment for opioid use disorder, treatment success 
is often limited by the need for daily dosing adherence for both methadone and buprenorphine. 
MMT is tightly regulated and requires provider or self-referral to federally certified treatment 
centers for management. Some patients may prefer a once monthly treatment that can be 
administered in a primary care setting. Furthermore, HIV-infected participants receiving 
antiretroviral therapy with efavirenz or certain protease inhibitors can experience clinically 
significant reductions in methadone levels [47-49] and increases in buprenorphine levels [50, 51] 
that complicate methadone and buprenorphine dosing and ART choice. HIV providers are well-
positioned to integrate novel treatments for substance use disorders, such as XR-NTX, into 
outpatient HIV practice. For example, BHIVES demonstrated that HIV providers and their patients 
readily adopted use of office-based buprenorphine for treatment of opioid dependence [32]. 
Naltrexone Treatment of Opioid Use Disorder. Naltrexone (NTX), a full mu-opioid antagonist, 
has been FDA-approved for opioid pharmacotherapy since the 1980s. Though highly efficacious 
when taken as prescribed, oral daily dosing requirements limit its effectiveness due to lack of 
adherence. Consequently, it is rarely used as first-line treatment for opioid use disorders in the 
community [52, 53]. Two recent studies of XR-NTX: 1) Comer et al. [54], testing Depotrex®, 
Biotech Inc., in New York City and Philadelphia; and 2) Krupitsky et al. [55], testing Vivitrol®, 
Alkermes Inc., in Russia, support efficacy of XR-NTX compared to placebo injections. In October 
2010, largely on the basis of the Russian trial and an earlier U.S. safety study (Alkermes ALK21-
006 and ALK21-006EXT), the FDA approved Vivitrol® for the prevention of relapse to opioid 
dependence. Patients and providers now have a remarkable opportunity to choose between two 
pharmacologically distinct treatment approaches, XR-NTX and BUP/NX, each with established 
efficacy, to expand options for medication-assisted recovery. 
Yet little is known about XR-NTX implementation in U.S. office-based settings, and the FDA’s 
decision has been criticized insofar as (1) the FDA “accepted a single trial of injectable naltrexone 
in Russia, unpublished at the time, as primary evidence of efficacy,” and (2) “the study did not 
adequately assess risk of post-treatment overdose” [56]. Because agonist therapy is prohibited in 
Russia, these authors question the use of these data to gain approval in the USA where 
methadone and buprenorphine are widely available. Regardless of the merit of these concerns, 
the data from the Russian placebo-controlled efficacy trial do not directly address the 
effectiveness, implementation issues, safety, and costs of XR-NTX in U.S. HIV-infected 
populations. 
Naltrexone for Treatment of Comorbid Alcohol Use Disorder. The CTN-0055 CHOICES pilot 
study demonstrated that 16% of participants with opioid use disorder had comorbid alcohol use 
disorder. Oral naltrexone received FDA approval in 1994 for treatment of alcohol use disorders 
and systematic reviews support its efficacy compared to placebo [57-61]; however, its success is 
limited by suboptimal adherence to daily dosing requirements [62, 63]. XR-NTX, which lasts 28 
days, has improved response rates in alcohol-dependent patients. In a 6-month, multicenter trial 
of XR-NTX for alcohol dependence, those randomized to receive 380mg XR-NTX experienced a 
25% greater decrease in heavy drinking day event rate compared to placebo [64], improved 
quality of life [65], and decreased holiday drinking [66]. In a post-hoc analysis limited to those with 
higher severity alcohol dependence, XR-NTX reduced heavy drinking days by 37% and compared 
with a 27% reduction for placebo-treated participants’ improved maintenance of abstinence [67]. 
Treatment responses were highest among participants with at least 4 days of voluntary alcohol 
abstinence prior to their first dose of XR-NTX [64, 68], and were rapid in onset, with significant 
reductions in alcohol use observed after only 2 days [69]. XR-NTX did not significantly increase 
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An open-label implementation study evaluating XR-NTX treatment of alcohol dependence in 
primary settings demonstrated that integrating XR-NTX was feasible and associated with marked 
reductions in drinking days and heavy drinking days, and improved abstinence [36, 37]. 
Participants completed a median 38 weeks (range 16-72) of treatment, with a median 8 monthly 
injections (range 4-15). 
Naltrexone in HIV-infected populations. The CHOICES study is the first to assess XR-NTX in 
an HIV-infected clinic-based population. Daily oral naltrexone has been safely used to treat opioid 
and alcohol use disorders in HIV-infected persons. Tetrault, et al. assessed changes in liver 
enzymes and HIV biomarkers in 114 HIV-infected U.S. veterans 365 days before, during, and 365 
days after treatment with oral naltrexone [70]. Co-morbidities common among the participating 
veterans were: opioid dependence (32%), alcohol dependence (89%), and hepatitis C (53%). 
About half (52%) received antiretroviral therapy during naltrexone treatment. Participants were 
prescribed naltrexone for a median 49 days (interquartile range 30-83 days). Mean AST and ALT 
levels decreased during and after naltrexone treatment. Two of 114 participants (1.8%) 
experienced mild liver enzyme elevations during naltrexone treatment, less than 5-times the upper 
limit of normal, which resolved upon treatment discontinuation. Mean HIV RNA levels decreased 
after naltrexone treatment and mean CD4 count remained stable throughout. This study suggests 
the risk of hepatotoxicity is minimal in HIV-infected participants treated with naltrexone, and that 
there are no adverse immunologic or virologic effects of treatment. 
XR-NTX safety in HIV-infected populations is further demonstrated in HIV-infected persons 
randomized to XR-NTX following release from prison, who experienced no change in hepatic 
enzymes compared to those receiving placebo [71]. HIV/HCV co-infection has no effect on XR-
NTX hepatic safety [72]. 
Naltrexone has been associated with risk-taking behavior. When combined with behavioral 
therapies, naltrexone was associated with reduced use of benzodiazepines and injection of 
buprenorphine among opioid injecting people in the Republic of Georgia [73].  
Naltrexone and potential for ART Drug-Drug Interactions. Naltrexone is metabolized through 
both hepatic glucuronidation and minor extra-hepatic metabolism. When taken orally, it undergoes 
extensive first-pass metabolism, with reduction of naltrexone to the active metabolite 6-beta-
naltrexol by dihydrodiol dehydrogenase. 6-beta-naltrexol levels are much lower with injectable 
extended-release naltrexone [74-76]. Elimination of conjugated naltrexone and 6-beta-naltrexol 
is through renal excretion. Naltrexone has no effect on Cytochrome P450 metabolism. It is thus 
unlikely to have clinically significant drug-drug interactions with antiretroviral medications. There 
are theoretical interactions possible between naltrexone and antiretrovirals that undergo 
glucuronidation, such as raltegravir (a substrate of UDP-glucuronosyltransferase [UGT] 1A1) and 
zidovudine (a substrate of UGT 2B7). A pharmacokinetic study of oral zidovudine administered to 
15 participants taking oral naltrexone revealed no change in area under the curve (AUC) for 
zidovudine compared to controls [77]. 
Potential Effect of Naltrexone on HIV Viral Suppression and Immune Function. In the 
observational study of HIV-infected veterans receiving oral naltrexone for opioid or alcohol 
dependence, mean HIV RNA levels decreased after naltrexone treatment and mean CD4 count 
remained stable throughout [70]. While the majority of decline in HIV viral load is likely due to 
increased receipt of or adherence to antiretroviral therapy, declines persisted even after adjusting 
for antiretroviral use in this study. This raises the possibility that naltrexone may have direct effects 
on HIV-1 viral activity. CD4+ lymphocytes express µ, ĸ, and delta opiate receptors that interact 
with opioid antagonists [78, 79]. In vitro studies suggest that naltrexone inhibits alcohol-mediated 
HIV entry and replication in T-lymphocytes [80]. Gekker, et al. demonstrated naltrexone 
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[81] and hypothesized potential synergism between naltrexone and antiretrovirals for reducing 
viral load. 
Furthermore, naltrexone has non-opioid receptor activity that may have beneficial effects for HIV-
infected participants. Toll-like receptors (TLR), a class of cell surface proteins that modulate 
innate immune responses, are expressed in many cells important to HIV pathogenesis and 
activated by opioid ligands. For example, activation of TLR 4 and TLR 8 by morphine in microglial 
cell cultures promotes inflammatory cytokine production and release of neurotoxic substances 
that may contribute to HIV-associated neural deficits when exposed to a bacterial challenge [82]. 
Morphine and bacterial challenge in microglia cultures from TLR4/TLR8 knock-out mice showed 
no increase in inflammatory cytokines or neurotoxins. Blocking these receptors with opioid 
antagonists suggests they may be important modulators of pain perception [83]. Naloxone and 
naltrexone are TLR 4 receptor antagonists that alleviate rat models of acute and chronic 
neuropathic pain [83] and reverse pain responses in microglial cell cultures [84]. Little is known 
about the effect of opioid antagonism on immune function, but CD4 cells express several TLRs 
and TLR activation appears to suppress innate immune responses that promote chronic viral 
infection with HIV [85] and HSV-2 [86], in vitro. The in vivo effect of TLR blockade with opioid 
antagonists on immune function and HIV viral activity is unknown. The CTN-0067 CHOICES study 
provides an opportunity to investigate novel direct effects of chronic opioid blockade on immune 
function and HIV viral suppression in a clinical population of HIV-infected participants. 
Conceptual Model. Substance use disorders impair patient engagement and retention in HIV 
care, contributing to gaps in the HIV care cascade and suboptimal HIV viral suppression [87, 88]. 
The CHOICES study seeks to compare office-based XR-NTX vs. TAU for treating opioid use 
disorder in HIV-infected participants to improve engagement and retention in HIV treatment 
required for HIV viral suppression. Patient and provider attitudes assessed in the pilot study 
influence adoption of new treatment modalities [89]. The Consolidated Framework for 
Implementation Research (CFIR) suggests that patient, provider, and organizational attributes 
are key inputs to adoption of new evidence-based technologies in healthcare settings [90]. A CFIR 
analysis of the adoption of XR-NTX identified features of the technology (e.g., complicated 
ordering process, cold shipping requirements, preparation requirements, and cost), 
environmental issues (e.g., patient needs, health plan policies and reimbursements), practice 
setting concerns (e.g., changes in workflow, program culture, and communication requirements), 
and clinician characteristics (e.g., attitudes and self-efficacy) as potential barriers to routine use 
of the medication in routine practice [91].   
CTN-0067 CHOICES Scale-up study compares the effectiveness of office-based XR-NTX versus 
TAU in achieving virologic suppression and decreasing opioid use. Virologic suppression reduces 
HIV associated morbidity, prolongs survival, restores and preserves immunologic function and 
decreases HIV transmission [92]. As shown in the conceptual model (Figure 2), HIV viral 
suppression is achieved through decreased use of opioids, which improves engagement in HIV 
care, receipt of ART, and ART adherence. Most HIV-infected patients with opioid use disorder 
who begin ART should be able to achieve virologic suppression if they continue in HIV care and 
adhere to ART [14, 93]. In this model, treatment of opioid use disorder is hypothesized as an 
important mediator of HIV viral suppression. HIV-infected participants with a history of substance 
use treatment are more likely to use HIV primary care and receive ART [94], [95]. The model also 
includes other covariates that may be related to engagement in HIV primary care or substance 
use treatment. Patient participant and provider qualitative interviews collected in parallel with 
outcome data enhance understanding of intervention characteristics with other CFIR domains, 
including the outer setting, inner setting, characteristics of the individuals involved, and the 
process of implementing XR-NTX in HIV clinic settings [90]. 


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Figure 2.  Conceptual Model 
 
 
Naltrexone (NTX) and Extended-Release Naltrexone (XR-NTX) 
NTX is a potent opioid antagonist with high affinity for the mu-opioid receptor. In the U.S., it is 
approved for use in treating opioid dependence and alcohol dependence. It is highly efficacious 
in preventing relapse to opioid dependence provided that it is taken as prescribed, but adherence 
with oral naltrexone is problematic and leads to extremely high dropout rates, with the occasional 
exception of treatment in criminal justice and other settings where relapse may be linked to severe 
adverse consequences [96-98]. This has led to intensive efforts – including NIDA- and NIAAA- 
funded grants to small businesses – to develop long-acting naltrexone preparations that can be 
administered as an injection or placed as an implant once per month or less frequently [99, 100]. 
XR-NTX (Vivitrol®, NTX-containing polylactide-co-glycolide [PLG] biodegradable sterile 
microspheres suspended in a diluent) is delivered by monthly injection into the muscles of the 
upper outer quadrant of the buttock. Each vial of microspheres contains 380 mg NTX which are 
suspended by adding a diluent that comes with the product and shaking for about a minute prior 
to injection of the full (less dead-space) content of the vial. Plasma concentrations of NTX and 6-
beta-naltrexol (its main active metabolite) after a single XR-NTX injection are detectable for at 
least 30 days. Consistent with this, in human laboratory studies with Vivitrol® and Depotrex®, an 
essentially complete blockade of opioid agonist effects is seen for 30 days [101, 102]. To maintain 
blockade beyond 30 days, XR-NTX must be re-administered. Long-term use of NTX and XR-NTX 
is not associated with tolerance, dependence, addiction or withdrawal on discontinuation. NTX 
and XR-NTX will, however, precipitate withdrawal in individuals physiologically dependent on 
opioids and decrease opioid tolerance. 
As a consequence of its extended duration of action and assured treatment adherence, XR- NTX 
may dramatically and favorably alter the limited effectiveness profile associated with orally 
administered NTX. By ensuring 30-day medication adherence with a single injection, and thereby 
establishing a ~30 day mu-opioid antagonist blockade, the likelihood of an individual re- 
establishing opioid dependence during this period is very low. Two clinical trials support efficacy 
for XR-NTX preparations compared to placebo injections [54, 55]. 
The 2006 Comer et al. study [54] was a proof-of-concept, 2-month randomized, placebo-
controlled trial with a subcutaneously administered product (Depotrex®, Biotek Inc.), and showed 
that long-acting injectable naltrexone in conjunction with outpatient counseling produced superior 
treatment retention to placebo, providing evidence of the feasibility, efficacy, and tolerability of 
long-lasting antagonist treatments for opioid dependence. 
The Krupitsky et al. study [55] was conducted in 2008 and 2009 in 13 sites in Russia, and was 
sponsored by the manufacturer, Alkermes, Inc. Following inpatient detoxification, 250 opioid-
dependent participants were randomized to XR-NTX or placebo, double-blind monthly injections, 
• Primary Outcome
• Proximal Outcome
• Mechanism of Main Effect 
Potential Covariates
- Sociodemographics
- Housing
- Mental Health Status
- Alcohol & Drug Use Severity 
- History of Substance Abuse Treatment
Patient Attitudes
XR-NTX vs. TAU
Provider Attitudes
Substance 
Use
Receipt    
of ART
ART 
Adherence
Virologic 
Suppression


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for 6-months, during which all participants received outpatient counseling. The percent of opioid 
abstinent weeks, by weekly urine toxicology, was the primary outcome. A response profile 
analysis compared the cumulative percent of participants at each level of the outcome (percent 
opioid-free weeks) between the active XR- NTX and placebo conditions. The difference between 
the response profiles was significant (p < .0002), with the median participant on XR-NTX having 
90% abstinent weeks compared to 35% abstinent weeks for the median participant on placebo. 
Total abstinence (100% opioid-free weeks) was reported in 45 (35.7%) participants in the XR-
NTX group versus 28 (22.6%) participants in placebo group (p < .03). Retention in treatment for 
the full 6 months was 53% on XR-NTX, compared to 38% on placebo (p < .02). The 6-month 
retention rate in the 50% range is similar to that observed in clinical trials of buprenorphine [103]. 
Participants treated with XR-NTX showed an approximately 50% sustained reduction in craving 
compared to no change in craving in the placebo group (p < .005). XR-NTX was generally well 
tolerated. Data from this trial supported Alkermes’ supplemental NDA for treatment of opioid 
dependence. 
Prescribing 
and 
Safety: 
Details 
on 
XR-NTX 
prescribing, 
pharmacokinetics 
and 
pharmacodynamics, metabolism and elimination, safety and toxicity are in the XR-NTX package 
insert. 
 
Treatment as Usual (TAU) 
The current standard of care for treatment of opioid use disorders in HIV clinics is opioid agonist 
therapy. Recent HIV treatment guidelines recommend office-based BUP/NX or referral for 
methadone maintenance for HIV-infected patients with opioid use disorders [35, 104]. Through 
the efforts of the Health Resources and Service Administration (HRSA)-funded Buprenorphine 
and HIV Evaluation Study (BHIVES) and Substance Abuse and Mental Health Services 
Administration (SAMHSA)-funded Physician Support Service for Buprenorphine, on-site 
treatment with office-based buprenorphine is increasingly being offered in HIV clinics. A recent 
HRSA HIV/AIDS Bureau monograph promotes adoption of office-based buprenorphine in HIV 
primary care [105]; see Section 4.1 for evidence of effectiveness of methadone and 
buprenorphine. Office-based BUP/NX, together with referral for methadone maintenance therapy, 
is now the standard of care for treatment of opioid use disorders in many U.S. HIV clinics [104]. 
Many HIV clinics in the U.S., including those associated with NIDA CTN nodes, receive Ryan 
White Care Act funding to provide ancillary services for under-insured and uninsured Persons 
Living with HIV/AIDS (PLWHA). These services typically include on-site case managers, social 
workers, and substance use counselors who provide critical treatment, referral, and support 
services for HIV-infected patients with substance use disorders. The site selection process will 
include a thorough review of existing treatment services. 
PRELIMINARY DATA: CTN-0055 CHOICES Pilot: The CTN-0055 CHOICES pilot study tested 
patient and provider acceptability and feasibility of XR-NTX versus TAU for treatment of opioid 
and/or alcohol use disorder at two HIV clinic pilot sites (St. Paul’s Hospital, Vancouver, B.C. and 
Core Center, Chicago, IL). Participants were enrolled without regard to baseline HIV viral 
suppression and opioid and/or alcohol use. The study was designed to continue until 50 
participants were enrolled or 12 months elapsed, whichever came first.  
Pilot study primary outcomes focused on 5 feasibility primary outcomes, which support the 
feasibility of a multi-site scale-up trial to assess the effectiveness of XR-NTX in HIV practice: 
1) Provider Acceptability. HIV provider acceptability of XR-NTX was high in a survey of 
107 HIV providers – more than 90% reported willingness to refer patients to a clinical 
trial of XR-NTX [106].  


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2) Patient Acceptability. Patients were interested in XR-NTX treatment, as well. The study 
site in Vancouver, B.C. conducted a survey of 657 persons who inject opioids as part of 
their site selection application. About half (52%) of the survey participants expressed 
willingness to receive XR-NTX treatment for opioid use disorder. Daily heroin injection 
was associated with increased willingness to try XR-NTX (OR 1.53, 95% CI 1.02, 3.12) 
[107]. Prospective CTN-0055 CHOICES pilot study participants (n=112) were asked 
about their willingness to participate in a trial of XR-NTX during pre-screening. Ninety-
eight percent of prospective participants interested in reducing opioid use (n=60) and 
99% of those interested in reducing alcohol use (n=82) were definitely or maybe willing 
to consider enrolling in a clinical trial of XR-NTX. 
3) Randomization Rate. The CTN-0055 CHOICES pilot study enrolled 51 HIV-infected 
patients receiving care at two pilot site HIV clinics (mean age 46 years, mean CD4 count 
620; 43% women). The trial achieved 155% actual versus expected randomizations, 
reaching randomization targets 4 months ahead of schedule and enrolling 22 (43%) 
participants with opioid and 29 (57%) with alcohol as their primary use disorder. Sixteen 
percent of randomized participants met criteria for both opioid and alcohol use disorders. 
Overall, the pilot study enrolled a mean of 3 participants per month per site.  
4) Treatment Initiation. The majority (68%) of participants assigned to XR-NTX initiated 
treatment. Five of 12 (42%) participants with any OUD assigned to XR-NTX initiated XR-
NTX within 4 weeks of randomization. The CTN-0055 CHOICES pilot study randomized 
participants prior to detoxification and provides the first benchmark for XR-NTX 
treatment initiation in community-dwelling people with opioid use disorder. Both of the 
two clinical trials of XR-NTX for opioid use disorder that led to FDA approval required 
successful residential detoxification prior to randomization and did not report treatment 
initiation rates [54, 55]. The CTN-0067 scale-up trial seeks to increase the rate of 
treatment initiation for participants with OUD with a modified naltrexone induction 
protocol (Section 9.2.3.1). 
5) Treatment Retention. Of those initiating XR-NTX treatment, 88% were retained on XR-
NTX at 16 weeks. Five of 5 (100%) participants with OUD who initiated XR-NTX were 
retained on XR-NTX at 16 weeks and received all four doses. This exceeds rates 
reported in the two previously reported clinical trials of XR-NTX for opioid use disorder 
that observed 68% retention on XR-NTX at 8 weeks in a U.S.-based study [54] and 
57.9% at 24 weeks in a study of Russian PWID [55]. 
The CTN-0055 CHOICES pilot study documents the feasibility of XR-NTX treatment for opioid 
and/or alcohol use disorder in HIV clinics, but was not powered to assess the effect of XR-NTX 
on secondary outcomes, including HIV viral suppression and substance use.   
 
 


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Secondary outcomes generated point estimates for a multi-site trial: 
1) HIV Viral Suppression. Overall, 80% of participants had a suppressed viral load (HIV 
RNA PCR ≤ 200 copies/mL) at baseline, and 84% were suppressed at 16 weeks. 
Among those with OUD, HIV viral suppression improved from 67% to 80% for XR-NTX 
and 58% to 75% for TAU. Among those with AUD, HIV viral suppression changed from 
92% to 82% for XR-NTX and 100% to 100% for TAU. The very high proportion of 
participants with HIV viral suppression at baseline, particularly among those with only 
alcohol use disorder, has implications for design of a multi-site non-inferiority trial. 
Inclusion of participants suppressed at baseline in the scale-up study potentially biases 
scale-up results toward the alternative (i.e., non-inferiority) hypothesis. In other contexts, 
non-inferiority trials that cannot distinguish effective from ineffective treatments are said 
to lack assay sensitivity, jeopardizing the validity of a non-inferior result [108]. Pilot 
participants with OUD had lower baseline rates of viral suppression and substantial room 
for improvement. We also anticipate lower baseline HIV viral suppression rates in a 
scale-up to HIV clinics throughout the U.S., where HIV suppression rates are lower for 
persons who inject drugs than those observed at the two pilot sites [27, 109, 110]. The 
CTN-0067 CHOICES scale-up multi-site study seeks to limit the potential for a baseline 
ceiling effect by excluding participants with only alcohol use disorder and including 
participants with a non-suppressed HIV viral load at baseline. 
2) Substance Use Outcomes. Among participants with OUD, mean days of opioids use in 
past 30 days decreased from 19 to 10 for TAU (n=12) and from 18 to 13 for XR-NTX 
(n=10). Among those with AUD, mean days of drinking to intoxication in the past 30 days 
decreased from 18 to 7 for TAU (n=11) and 13 to 6 for XR-NTX (n=12). 
 
Significance to the Field 
Expanding HIV providers’ armamentarium for treating opioid use disorders and improving viral 
suppression in HIV-infected patients advances the three major goals of the National HIV/AIDS 
Strategy for the United States, updated for 2020, including 1) reducing new HIV infections in 
communities where HIV is most concentrated, 2) increasing access to care and improving health 
outcomes for people living with HIV, and 3) reducing HIV-related disparities and health 
inequalities [111]. The primary driver of HIV transmission is HIV viral load. If XR-NTX is effective 
in increasing viral suppression, fewer new HIV infections will occur among the sexual and drug- 
using partners of opioid and alcohol dependent individuals [112-114]. The CHOICES scale-up 
study increases access to care by engaging HIV-infected participants with suboptimal viral 
suppression to initiate and adhere to ART, and improves health outcomes by increasing viral 
suppression with resultant improvements in health outcomes and decreased mortality. The 
CHOICES scale-up study reduces HIV-related disparities and health inequalities by seeking to 
engage opioid-dependent participants in HIV treatment — a vulnerable population with 
persistently suboptimal access to high quality HIV care and outcomes, compared with other HIV 
risk behavior groups. The CHOICES scale-up study also advances the science of opioid use 
disorders treatment by directly comparing antagonist therapy with TAU in a comparative 
effectiveness trial to assess the implementation of a novel therapy into HIV clinical practice. 
CTN-0067 is well-aligned with three NIH Office of AIDS Research high priority areas for HIV 
research funding:  
1) Reducing Incidence of HIV: developing, testing, and implementing strategies to improve 
HIV testing and entry into prevention services. Opioid use disorders are barriers to 
engagement and retention in HIV care, and consequently HIV-infected patients with 


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these comorbid disorders are less likely to achieve HIV viral suppression compared with 
those without. Recruitment strategies will emphasize linkage with local HIV testing 
outreach efforts affiliated with HIV clinics to encourage entry into HIV treatment of 
substance users who are newly diagnosed with HIV.   
2) Next generation of therapies-implementation research to ensure initiation of treatment as 
soon as diagnosis has been made, retention and engagement in these services, and 
achievement and maintenance of optimal prevention and treatment responses. 
CHOICES scale-up study will provide data on the effect of treating substance abuse on 
the HIV continuum of care stages: linkage, engagement, retention, and viral 
suppression. Treatment of underlying opioid use disorders with XR-NTX is likely to 
increase engagement and retention in HIV care, with consequent HIV viral suppression 
— the primary outcome for CHOICES scale up. The data gathered by the 
implementation component of CHOICES scale-up study should facilitate widespread 
adoption of XR-NTX by HIV clinics following the completion and publication of the study 
results. 
3) Research to reduce health disparities in the incidence of new HIV infections and 
treatment outcomes. Seventy-three percent of CHOICES pilot participants were of 
minority race ethnicity. Scale-up sites will be predominately located in cities with local 
HIV epidemics that disproportionately affect African-American and Hispanic populations. 
CTN-0067 CHOICES scale-up study intervention is designed to increase engagement in 
HIV care leading to ART treatment (a secondary outcome) and HIV viral suppression 
(the primary outcome) for a predominantly minority race-ethnicity study population. 
Study outcomes and implementation lessons-learned will directly inform efforts to close 
race-ethnicity gaps in HIV treatment. 
 
 


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5.0 
OBJECTIVES 
 
Primary Objectives 
The overarching goal of the CHOICES scale-up study is to determine the effectiveness of HIV 
clinic-based XR-NTX therapy in achieving HIV viral suppression in HIV-infected patients with 
opioid use disorder. Specific measures of study objectives outcomes are defined in Section 8.0. 
Specific Aim: Compare HIV viral suppression (HIV-1 RNA ≤ 200 copies/ml) among study 
participants randomized to XR-NTX versus TAU at 24 weeks from time of randomization. 
 
Secondary Objectives 
Secondary Specific Aims: Secondary aims compare the effectiveness of XR-NTX versus TAU 
in 1) other HIV outcomes (VACS Index, CD4 count), 2) engagement in HIV care (receipt of ART, 
ART adherence, retention in HIV care, HIV risk behaviors), and 3) ART adherence as mediated 
by number of opioid use days at 24 weeks. An additional secondary aim assesses barriers and 
faciliators of implementing XR-NTX for retaining patients in HIV primary care.   
1) Secondary HIV Outcomes 
a. Change in VACS Index at 24 weeks, compared with randomization. 
b. Change in CD4 count at 24 weeks, compared with randomization. 
2) Engagement in HIV Care: 
a. Proportion of participants prescribed ART within 24 weeks following randomization. 
b. Proportion of participants taking 100% of prescribed ART doses in the past month at 
24 weeks for those prescribed ART at any point during the 24 week trial. 
c. Retention in HIV Care: Proportion of participants with at least 1 HIV primary care visit 
in the past 12 weeks, measured at week 24. 
d. HIV Risk Behaviors, as measured by the RAB at week 24. 
e. Quality of life as measured by EQ-5D at week 24, compared to baseline. 
3) ART Adherence Mediation Variables: 
a. Number of days of opioid use since baseline, measured by Timeline Follow Back 
(TLFB) at 24 weeks. 
b. Past 30 day opioid abstinence (by Addiction Severity Index (ASI)-lite self-report, 
Timeline Follow Back (TLFB) and urine drug screen (UDS) confirmation at 24 weeks. 
4) Assess barriers and facilitators of XR-NTX implementation to improve retention in 
HIV primary care: 
Qualitative interviews with participants, providers, and staff to document the HIV primary 
care treatment environment and describe XR-NTX formative implementation strategies, 
challenges, and best practices.  
 


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6.0 
STUDY DESIGN 
 
Overview of Protocol Study Design 
The CHOICES scale-up (CTN-0067) study is designed to compare the effectiveness of HIV clinic-
based XR-NTX versus TAU in engaging HIV-infected persons with opioid use disorder in care to 
improve HIV viral suppression. The CTN-0067 CHOICES scale-up study builds on lessons 
learned from the pilot and uses the Consolidated Framework for Implementation Research [90] 
to advance understanding of XR-NTX adoption.  
HIV clinics will serve as primary care clinic settings for CTN-0067. Eligible study sites must a) 
provide HIV primary care, b) have a sufficient population of potential participants to achieve study 
enrollment goals, c) have providers willing to be trained in use of XR-NTX for management of 
opioid use disorder, d) have the capacity to prescribe ART to participants, regardless of CD4 
count, e) offer on-site addiction counseling services as part of usual care, and f) offer access to 
opioid agonist treatment, either on-site or by referral. 
The CTN-0067 CHOICES scale-up study will utilize no more than 8 HIV primary care clinics to conduct 
the trial. The study is an open-label, randomized, comparative effectiveness implementation trial of 
office-based XR-NTX for 24 weeks (approximately 6 monthly injections) (n = 175) versus TAU (n = 
175) in HIV-infected participants with untreated opioid use disorder (Figure 1).  
In the pilot, 60 (85%) of 71 pre-screened individuals who reported using opioids in the past year 
said they were interested in stopping opioid use. Of these, 59 (98%) were willing to enroll in a 
clinical trial of XR-NTX for treatment of OUD, and 24 (41%) of those willing to try XR-NTX were 
randomized. Thus, 24 (34%) of 71 pre-screened individuals with past year illicit opioid use were 
ultimately randomized. Nine (38%) of these had an unsuppressed HIV viral load at baseline. 
Assuming the same proportion of pre-screened as randomized opioid users will be unsuppressed 
at prescreening, enrolling 350 participants in the scale-up may require pre-screening of about 
2,709 [350/(0.34*0.38)] patients with past year opioid use.  
The trial will be powered as a non-inferiority trial since the overall goal of the research is to add 
to rather than to supplant currently available effective opioid agonist treatment options. The 
primary outcome is the proportion of participants who achieve HIV viral suppression (HIV-1 RNA 
≤ 200 copies/ml), measured at 24 weeks. Secondary outcomes include 1) other HIV outcomes 
(VACS Index, CD4 count), 2) engagement in HIV care (receipt of ART, ART adherence, retention 
in HIV care, HIV risk behaviors), and 3) ART adherence as mediated by number of opioid use 
days at 24 weeks. A fourth secondary objective documents facilitators and barriers of 
implementing XR-NTX to improve retention in HIV primary care (Figure 1). 
 
Study Duration and Visit Schedule 
The CTN-0067 CHOICES scale-up study will target enrolling 350 participants over approximately 
22 months at no more than 8 HIV clinic sites. Each participant will be engaged in the overall study 
for an expected duration of 25-28 weeks (Figure 3) as follows: 
• 
Weeks 1-4: consent, screening, randomization. 
• 
24 weeks: Active treatment with study visits every 4 weeks. 
• 
Week 24: A single follow-up visit at the end of active treatment. 
 


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Justification of 24 weeks active treatment and timing of ART initiation 
Assessment of the primary outcome of HIV viral suppression requires a minimum of 6 months, 
given the high potency of currently available ART regimens. While longer follow-up periods are 
required to assess sustained viral suppression, nearly all people initiating ART can now achieve 
an HIV viral RNA ≤ 200 copies/mL within 6 months of ART initiation. Participants not already 
taking ART at study enrollment will be encouraged to begin ART as soon as possible following 
enrollment. The timing of XR-NTX initiation or ART initiation is up to the discretion of the HIV 
provider on the basis of the patient’s clinical priorities. Finally, previous efficacy trials of XR-NTX 
for opioid use disorder [55] and alcohol use disorder [64] provided 24 weeks of XR-NTX. 
 
Justifcation of Implementation Study Procedures 
Overview. The HIV primary care treatment environment is likely to change during the course of 
the study, reflecting broader healthcare policy changes in society. Documenting the HIV primary 
care treatment environment and describing XR-NTX formative implementation strategies, 
challenges, and best practices is crucial both for interpreting study findings and advancing 
understanding of generalizability and sustainability in other settings. A mixed-methods 
implementation analysis of HIV providers, staff, administrators, and study participants enrolled in 
CTN-0067 assesses barriers and facilitators to the use of XR-NTX in participating HIV clinics. 
Results inform policy-making for dissemination of clinic-based XR-NTX to other settings. 
Qualitative Interview Justification. Qualitative interviews provide critical detail for enhanced 
understanding of the findings from the comparative effectiveness trial (Secondary Aim). Using the 
Taxonomy of Mixed Method Designs [115-117], our design has a QUAN + qual structure with 
simultaneous data collection and emphasis/weight placed on the quantitative (comparative 
effectiveness trial) efforts. Recurrent themes extracted from key informant interviews document 
provider, organizational, and participant experiences over time to examine these findings in 
parallel with staff surveys and study participant outcomes data (i.e., HIV viral suppression). This 
approach is consistent with Type I hybrid implementation study designs recommended for 
comparative effectiveness trials [118]. HIV clinic characteristics and provider attitudes (inner 
setting), as well as detail about the use of XR-NTX (intervention characteristics), and community 
awareness, linkage across service settings, and policy support (outer setting) help identify the full 
range of complex variables associated with implementation of clinic-based XR-NTX. This 
approach represents an innovative strategy to integrate available quantitative study results 
(Secondary Aim) to examine the provider, patient, organizational, and policy-level changes that 
influence the uptake of XR-NTX in HIV clinics. Corresponding with the CFIR, we identify 
individual, organizational and contextual characteristics that influence uptake of XR-NTX. We will 
particularly explore barriers to XR-NTX adoption identified in substance abuse treatment center 
setting using a CFIR framework, such as cost, complexity of prescribing, health plan policies, and 
reluctance to change [91]. Mixed-methods including QUAN + qual data are well suited for studying 
implementation of clinic-based XR-NTX and assessing the influence of individual and 
organizational characteristics on utilization.  
Data Collection and Management. Lead Node investigators will conduct audio-recorded key 
informant interviews with HIV clinic providers, staff and administrators (up to 60 total across sites) 
over the study period. A convenience sample of CTN-0067 study participants assigned to XR-
NTX (up to 60 total across sites) will be approached by site research staff and consented for 
participation in qualitative interviews. Interview guides use the CFIR framework to probe 
participant perceptions of the characteristics of XR-NTX and TAU (e.g., intervention quality, 
advantage, adaptability), outer setting (e.g., resources, social support, social interactions, 
external policies and incentives), inner setting (e.g., clinic organization, networks and 


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communication, practice culture, and implementation climate), provider characteristics (e.g., self-
efficacy for XR-NTX treatment) and the implementation process (e.g., engaging, executing, 
evaluating) [90, 119]. Not all questions will be asked of all informants.   
Audio-recorded interviews will be professionally transcribed, reviewed and summarized. 
Transcriptions will be password protected, stored on a secure network and uploaded into 
qualitative analysis software (Atlas.ti) which organizes data and facilitates coding and thematic 
analysis.  
Qualitative data will be supplemented with a brief survey of participating sites (n = no more than 
8), completed prior to study initiation, to document local treatment environment (e.g., availability 
of clinic-based buprenorphine, state Medicaid support for medication-assisted treatment, amount 
of Ryan White Care Act funding, community referral resources, etc.). 
 
 


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7.0 
STUDY POPULATION 
 
Inclusion Criteria 
Individuals participating in the clinical trial must: 
 
1) Be at least 18 years old. 
2) Be willing and able to provide written informed consent and HIPAA Authorization (if 
applicable) for medical record abstraction. 
3) Meet DSM-5 criteria for moderate or severe opioid use disorder. 
4) Be willing to be randomized to antagonist-based therapy or TAU. 
5) Have an HIV viral RNA count > 200 copies/ml. HIV viral RNA may be drawn with 
screening blood draw or abstracted from medical records if drawn in the 90 days prior to 
the date of consent. 
6) Be willing to establish ongoing HIV care at the site if not already receiving ongoing care. 
7) If female, be willing to take at least one evidence-based measure to avoid becoming 
pregnant.  
 
Exclusion Criteria 
Participants will be excluded if they: 
 
1) Have a severe medical, psychiatric or substance use disorder that, in the opinion of the 
study physician, would make study participation hazardous to the participant, 
compromise study findings, or prevent the participant from completing the study due to 
imminent risk of death. Hospitalized patients who do not meet these conditions remain 
eligible for participation. 
 
Examples include: 
 
a. Acute life-threatening medical illness (e.g., uncompensated heart failure, end-stage 
liver disease, acute hepatitis or moderate to severe renal impairment) as assessed 
by medical history, review of systems, physical exam and/or laboratory 
assessments; 
b. Severe, inadequately-treated mental health disorder in need of immediate 
treatment (e.g., active psychosis, uncontrolled manic-depressive illness) as 
assessed by history and/or clinical interview; 
c. Suicidal or homicidal ideation requiring immediate attention. 
2) Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) liver 
enzymes greater than 5 times upper limit of normal on screening phlebotomy. Results 
from tests conducted within the past 30 days from date of consent may be abstracted 
from medical records. 
3) Have INR > 1.5 or platelet count <100k. Results from tests conducted within the past 30 
days from date of consent may be abstracted from medical records. 


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4) Have known allergy or sensitivity to naloxone, naltrexone, polylactide-co-glycolide, 
carboxymethylcellulose, or other components of the Vivitrol® diluents. 
5) Anticipate undergoing surgery during study participation. 
6) Have chronic pain requiring ongoing pain management with opioid analgesics. 
7) If female, currently (at time of consent) pregnant or breastfeeding or planning on 
conceiving in the coming months. 
8) Body habitus that, in the judgment of the study physician, precludes safe intramuscular 
injection of XR-NTX (e.g., excess fat tissue over the buttocks). 
9) Received methadone or buprenorphine maintenance therapy for treatment of opioid use 
disorder in the 4 weeks prior to consent (medically supervised withdrawal therapy is 
allowed). 
10) Received ongoing XR-NTX injections as maintenance therapy for opioid or alcohol use 
disorder in the 4 weeks prior to consent (does not exclude individuals leaving 
incarceration with a single injection and no specific follow up). 
11) Have taken an investigational drug in another study within 30 days of study consent. 
12) Are currently in jail, prison or any overnight facility as required by court of law or have 
pending legal action that could prevent participation in study activities. 
 
Recruitment 
HIV-Infected Participant Recruitment: 
Study participants will be recruited from participating HIV outpatient clinics. HIV clinics likely to 
participate in CTN-0067 typically serve as patient-centered medical homes for HIV-infected 
participants, offering a broad array of on-site case management, social work, and counseling 
support services to engage and retain patients in care. All members of the HIV clinic care team 
will be educated regarding the study and asked to refer potential participants who are interested 
in learning more about the study to clinic research staff for screening. The site PI will either be an 
attending HIV provider in the HIV clinic or have strong relationships with HIV providers, so we 
anticipate excellent cooperation in approaching potential participants. Because the study seeks 
to improve engagement in HIV care, the HIV clinic care team and research staff will interact with 
community and hospital-based outreach services to identify and engage potential participants 
who are not currently engaged in HIV care. Outreach to and screening of hospitalized patients is 
encouraged, since they represent an enriched population of people with untreated HIV and opioid 
use disorder. If a participant is interested in learning more about the study, a study staff member 
will meet with the participant to discuss the study. Potential participants will be briefly instructed 
regarding opioid agonist and antagonist therapy and complete a survey demonstrating 
understanding as part of the consent process prior to enrollment. Specific recruitment procedures 
(e.g., local educational activities, community outreach, print- and web-based advertisements, etc.) 
will vary by site according to local needs. Strict ethical guidelines regarding professional conduct 
and confidentiality will be enforced for all study staff. Particular populations of interest to be 
targeted for recruitment include: 
• 
Hospitalized patients. HIV outpatient clinic sites will be encouraged to partner with their 
affiliated inpatient institutions for recruiting these patients. 


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• 
Emergency Departments (EDs). Clinics will be encouraged to partner with local EDs for 
direct referral of patients presenting to the ED with opioid overdose. 
• 
Persons utilizing local needle exchange and other sites that provide HIV testing for 
persons who inject opioids. 
• 
Detox/addiction treatment facilities with HIV testing services. 
• 
Local syringe exchange programs. 
• 
People receiving services from community-based AIDS service outreach organizations. 
• 
People being released from local criminal justice systems. 
Enrolling participants in clinical settings poses many challenges to screening and interviewing 
potential participants [120-123], including the rapid pace of care, interruptions, clinic productivity 
requirements, space limitations, participants not feeling well enough, and the presence of multiple 
HIV care team staff members. To minimize the impact of these challenges, research staff will 
spend considerable time in participating HIV clinics interacting with staff, familiarizing themselves 
with clinic patient flow, and learning how to communicate and negotiate with clinic staff regarding 
the necessary space and time to conduct interviews. 
Site PIs, who are HIV clinic providers or someone who has strong relationships with HIV providers, 
will facilitate negotiation of space and time requirements and be a resource to research staff 
regarding participating HIV clinic procedures. Staff and sites with experience and expertise in 
conducting research studies in outpatient HIV clinic settings will be prioritized for site selection. A 
review of 13 clinical trials conducted in the University of North Carolina Infectious Disease Clinic 
suggested that integrating a dedicated research screener in clinic operations facilitates trial 
enrollment [123]. The Lead Investigator’s research team has experience successfully integrating 
clinical trial research teams with outpatient HIV clinic staff, enrolling 82% of HIV providers and 
73% of their eligible participants in one recent trial [122]. 
The interviewer will negotiate the location of the interview as necessary to protect confidentiality 
and respect HIV clinic patient flow. If necessary, the potential participant will be given the option 
to participate in screening, consent, and interview procedures in a nearby exam room or 
staff/patient lounge if it is unoccupied, or to reschedule the interview at another time. If a 
participant feels ill during the interview, the interview will stop and be rescheduled. In the Lead 
Investigator’s team’s prior experience conducting research interviews in outpatient HIV clinics, 
the team found this level of flexibility achieved high levels of participation and did not impede the 
flow of usual HIV clinic activities [3, 29, 124]. 
Participants may undergo repeat screening within the appropriate amount of time after an initial 
screen-fail, per the discretion of the site PI and in accordance with the Manual of Operating 
Procedures. 
 
Special Populations to Consider 
This study is likely to enroll persons involved in the criminal justice system who are receiving 
HIV care at participating sites. The study will not recruit persons incarcerated/detained in a 
correctional facility or currently considered “prisoners” by local or state laws, but will not exclude 
parolees or probationers. At screening, prisoner status will be assessed using a streamlined 


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assessment based on the definition of a prisoner in 45 CFR 46.303(c). Throughout the study, prisoner 
status will be documented on the Criminal Justice case report form (CRF). 
Those participants who become incarcerated during the course of their involvement with this study 
will continue to be followed to ensure safety and data integrity. All study interventions (XR-NTX 
or TAU) will be discontinued while the participant is incarcerated. If necessary for safety and with 
the permission of the participant, correctional facility officials will be informed of study 
participation. When possible, participants will be contacted to complete questionnaires and 
surveys, which would include safety checks. These visits can occur over the telephone or as in-
person visits, whichever is more appropriate for the local research site and the correctional 
facilities’ policies. The visits will only occur if confidentiality can be maintained. This generally 
assumes that in-person visits will be done in private rooms and that recording equipment 
(regardless of type of visit) can be turned off or destroyed. No biospecimens will be collected 
(blood or urine) during any visit that occurs with an incarcerated prisoner. If necessary, specific 
documents for incarcerated participants will be developed and approved by the IRB of record. All 
local guidelines will be followed, including any required reporting to the IRB or other institution 
when a participant becomes incarcerated. Despite the use of a central IRB for this study, local 
IRBs may be notified if a participant becomes incarcerated. Appropriate progress notes will be 
written to ensure complete documentation of any interaction with an incarcerated participant, 
specifically mentioning confidentiality procedures.  
An Office for Human Research Protections (OHRP) Prisoner Research Certification Letter will be 
filed through the IRB of record and distributed to the sites that cede review. Sites that are not 
ceding review to the IRB of record will be responsible for obtaining an OHRP Prisoner Research 
Certification Letter. Local sites will be covered by the OHRP Prisoner Certification to enable 
follow-up of study participants who may become incarcerated. 
Number of Sites 
No more than eight HIV outpatient clinics will serve as sites for this study. 
 
Site Characteristics 
HIV clinics will be selected primarily on the basis of the following characteristics: 
1) Provide HIV primary care. 
2) Have a sufficient population of potential participants to achieve study enrollment goals. 
3) Have providers willing to be trained in use of XR-NTX for management of opioid use 
disorder. 
4) Capable of prescribing ART to participants, regardless of CD4 count. 
5) Access to addiction counseling services as part of usual care. 
6) Clinic offers access to opioid agonist treatment, either on-site or by referral. 
We will specifically target HIV clinics in areas that have local prevalence of untreated opioid use 
disorder and HIV that support feasibility of enrollment. 


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Rationale for Site Selection 
Sites that have access to an adequate number of HIV-infected participants with suboptimally 
controlled HIV and untreated opioid use disorder will be selected for participation. In order to 
achieve target enrollment for this study, we anticipate that most (but not all) participating HIV 
clinics will need to see >1,000 unduplicated HIV-infected potential participants per year. This 
number is based on enrollment rates observed in the pilot study and experience of CHOICES 
pilot study investigators in enrolling subjects in the BHIVES study [29]. We have also included 
site selection criteria that attempt to limit site variability in treatment effects (e.g., capacity for 
prescribing ART regardless of CD4 count; access to addiction counseling services). 
 
Collaboration with CTSA for Site Recruitment 
Site recruitment will explore opportunities to partner with the NIH-funded Clinical and Translational 
Science Award (CTSA) consortium. CTSA institutions work to transform local, regional, and 
national environment to increase the efficiency and speed of clinical and translational research. 
Potential opportunities for collaboration between CTN-0067 and affiliated CTSAs include CTSA 
assistance with community-based recruitment and/or some aspects of study implementation. 
 
 


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8.0 
OUTCOME MEASURES 
 
Primary Outcome Measures 
The primary outcome variable for CTN-0067 CHOICES scale-up study is HIV viral suppression. 
HIV viral suppression is defined as an HIV-1 RNA < 200 copies/ml at 24 weeks. We are aware 
that, for participants on therapy, the goal of antiretroviral therapy is achieving a viral load “below 
the limit of detection of the assay” which currently is usually < 40 copies/ml. However, we have 
chosen to define “suppression” for this study as less than or equal to 200 copies/ml to be 
consistent with the January 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected 
Adults and Adolescents [92]. The rationale for this definition is to avoid the influence of “blips” in 
HIV RNA viral load which commonly occur at levels between 40 and 200 copies/mL using current 
PCR assays and which are of limited clinical significance [125, 126]. 
 
Secondary Outcome Measures 
1) Secondary HIV outcomes: 
a. VACS Index. Change in VACS Index at 24 weeks compared with randomization. 
(score; derived from screening and week 24 laboratory and demographic data). 
b. CD4 Count.  Change in CD4 count at 24 weeks compared with randomization (count; 
laboratory assay). 
2) Engagement in HIV Care: 
a. ART Prescribed. Proportion of participants prescribed ART within 24 weeks following 
randomization (binary; medical record abstraction). 
b. ART Adherence. Proportion of participants taking 100% of prescribed ART doses in 
the past month at 24 weeks for those prescribed ART at any point during the 24 
week trial (binary; self-reported VAS medication adherence measure). 
c. Retention in HIV Care. Proportion of participants with at least 1 HIV primary care visit 
in the past 12 weeks, measured at week 24 (binary; medical record abstraction). 
d. HIV Risk Behaviors. Past 30 day injection drug use, unprotected sex, multiple sexual 
partners as measured by the RAB at week 24 (binary; self-report). 
e. Quality of life. Past 30 day health-related quality of life as measured by EQ-5D at 
week 24, compared to baseline. 
3) ART Adherence Mediation Variables: 
a. Days of Opioid Use.  Number of days of opioid use since baseline, as measured by 
Timeline Follow Back (TLFB) at 24 weeks (count; self-report). 
b. Opioid Abstinence. Past 30 day opioid abstinence (by Addiction Severity Index (ASI)-
lite self- report, Time-Line Follow-Back (TLFB) and urine drug screen (UDS) 
confirmation) in the final 30 days of the 24 week trial (binary; self-report + UDS). 
 
 


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9.0 
STUDY PROCEDURES 
 
Duration of Participant Study Procedures 
 
Pre-screening 
Individuals will be approached by study staff in HIV clinic settings or referred to study staff by HIV 
clinical care and outreach teams. Study staff will provide a brief verbal overview of the study to 
the individual and provide written information regarding XR-NTX. Individuals will provide verbal 
consent and HIPAA Authorization/Waiver as necessary for pre-screening and will be asked to 
complete the Pre-Screening Interview. This verbal consent and HIPAA Authorization/Waiver will 
only apply for the Pre-Screening visit. The Pre-Screening Interview will elicit information about the 
potential participant’s demographics and drug use. The Pre-screening informed consent, HIPAA 
Authorization/Waiver (if necessary), and pre-screening interview will take approximately 5, 5, and 
10 minutes to complete, respectively. Individuals who undergo pre-screening will be captured on 
the Pre-Screening Log.  
 
Figure 3.  Study Duration 
Activity: 
Screening & 
Enrollment 
Active 
Treatment 
Total 
Participant 
Time in Study 
Duration: 
1-4 weeks 
24 weeks 
25-28 weeks 
 
 
Screening and Enrollment Procedures (1-4 weeks duration) 
Once a person has completed the Pre-Screening Interview process and meets basic eligibility 
criteria, they will either be asked to stay for the Screening Visit or scheduled to come back for the 
visit (based on staff and candidate's availability). It is expected that the screening and enrollment 
phase will take approximately 1-4 weeks; however, participants will have 60 days from the date 
of consent to complete screening and be randomized before being considered a screen failure. 
 
Informed Consent Process 
Study procedures and the potential risks and benefits of participating in the trial will be explained 
by research staff. Staff will be available to answer questions about the consent form and consent 
quiz while participants are reviewing them. After signing the consent form, participants will be 
given a copy of the form to keep for their records. The process will take approximately 20-30 
minutes. 
 
Locator Form 
Participants will complete a locator information form which will be used to contact them to remind 
them of follow-up visits, as well as to locate participants who may not have attended 
appointments. When completing this form, participants provide their names, addresses, and 
telephone numbers as well as contact information for at least two other persons. Permission will 
also be requested to obtain locating information from additional agencies and publicly accessible 
databases or search engines including, but not limited to, Medicare/Medicaid and Social Security 
offices, department of motor vehicles, local jail logs, white pages, and Facebook. Locator 
information will be reviewed at each visit and updated as needed during the study. The locator 


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information form will take approximately 5-10 minutes to initially complete and content will be 
checked at future study visits. 
 
Medical Record Release Form 
Participants will complete the form(s) as applicable during screening and throughout the study to 
grant permission to study staff to review inpatient, outpatient, mental health, and substance use 
treatment clinic records as needed. The purpose of medical record review at the end of study 
participation is to document information needed to evaluate secondary outcomes. Specifically, 
study staff will abstract medical record information to corroborate participants’ self-report of 
information including, but not limited to the following: HIV viral load and CD4 count, liver enzymes, 
hepatitis B and C serologies, CBC, metabolic panel, INR, utilization of HIV primary care, utilization 
of HIV and addiction treatment services, and opioid overdose events. Records review/abstraction 
will occur throughout the study (as needed) and up to 52 weeks post-randomization. 
 
Collection of Biological Specimens 
Study staff will collect blood specimens at screening, randomization, 12 weeks, and 24 weeks to 
confirm eligibility and assess the primary outcome of HIV-1 RNA PCR and secondary outcomes 
of CD4 count, VACS Index, and hepatotoxicity. CBC, serum creatinine, LFTs (AST, ALT), INR, 
and HIV-1 RNA blood specimens will be collected during screening. CD4, Hepatitis C, Hepatitis 
B, and PBMC specimens will be collected and processed only after the participant has been 
randomized. Study staff will collect urine specimens during screening and at treatment initiation 
(XR-NTX arm only), safety visit (XR-NTX arm only), and at 4, 8, 12, 16, 20, and 24 weeks to 
confirm eligibility and assess secondary outcomes and pregnancy. Screening and randomization 
labs (CD4, HIV-1 RNA, and hepatitis B and C serologies) drawn in the 90 days prior to date of 
informed consent may be abstracted from participant medical records, when available. Other 
screening lab tests may be abstracted from medical records if drawn within 30 days prior to the 
date of informed consent, with the exception of urine specimens, which must be collected by study 
personnel. Some participating sites may require that copies of some or all lab results collected for 
study purposes be filed in participants’ medical records. 
 
Baseline Assessment 
After the enrollment process is complete, study staff will prepare a new data record for the 
participant and the baseline assessments will be administered either through a computer-assisted 
data collection instrument or a paper version of the CRF. The baseline assessments are detailed 
in Section 10.0 and capture participant medical, psychiatric, and drug use history, HIV status and 
care, quality of life, current health status, and other baseline characteristics. The baseline 
assessment will take approximately 60-90 minutes to complete. 
 
Randomization  
The timing of randomization will follow shortly after baseline assessments and final confirmation 
of eligibility. Participants will be encouraged to initiate treatment within 28 days of randomization. 
If a participant is unable to initiate treatment within 28 days, he or she may initiate XR-NTX study 
drug at any time until week 20 and may initiate TAU at any time during the trial. Initiation of 
assigned treatment will be tracked. 
Participants will be randomized in a 1:1 fashion to either office-based XR-NTX or TAU using a 
permuted block design with randomly-sized blocks. Randomization will be stratified only by site. 
Participants who meet DSM-5 criteria for both opioid and alcohol use disorder (16% of CTN-0055 
CHOICES pilot study participants) will be included, in addition to participants with OUD, alone. 


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Concomitant alcohol use disorder will be considered as a potential covariate [31], [127, 128]. 
Participants need not be abstinent from opioids at the time of randomization. 
The randomization procedure will be conducted in a centralized process through the Data and 
Statistics Center (DSC). Specifically, randomization schedules will be created by the study 
statistician for each site. The randomization schedules will be of a randomized-block nature to 
ensure relative equality of assignment across condition across the recruitment period and to 
prevent the potential for study staff guessing the next assignment, which is heightened when a 
fixed block-size is used. After the baseline assessment is successfully completed, a designated 
site study staff member will perform the randomization. Randomization for each participant is 
done over the internet using the Enrollment Module in Advantage eClinical. 
The DSC statistician will review the randomization data on a regular basis to ensure that the 
scheme is being implemented according to plan. If a participant drops out of the study at any point 
after randomization, the randomization slot will not be re-allocated to a new participant due to the 
intent-to-treat nature of the study. 
 
Treatment Conditions 
 
HIV Usual Care (Both Arms) 
All participants will receive comprehensive HIV primary care, case management, addiction 
counseling, and social support services from HIV clinics as they would regardless of study 
participation. As part of protocol training, HIV clinic providers will be encouraged to offer ART 
within 4 weeks of randomization for participants not already prescribed ART. Current guidelines 
recommend offering ART to all HIV-infected participants, regardless of CD4 count [35]. The 
schedule of medical care provided will be as deemed appropriate by the treating provider. HIV-
infected participants are typically seen at least twice within the first month of initiating ART, and 
at least every 3 months thereafter for monitoring. Medical visits will not be considered study visits, 
though they may coincide with study visits. HIV clinic treatment will also include usual addiction 
counseling services, which are offered as a part of usual care in most large U.S. HIV clinics. As 
part of protocol training, HIV clinic providers will be asked to refer study participants to existing 
addiction counseling services in their clinic, as they would do regardless of study participation. 
Throughout the course of the trial, HIV clinics will be monitored for any potential changes that 
might occur in standard practice around medical management of HIV infection or addiction 
treatment services. Throughout study participation, HIV clinic medical visits will be tracked 
through medical record abstraction, and counseling visits will be tracked through participant self-
report (See Section 10, Assessments). 
 
Medical Management (when applicable) 
Study clinicians will be trained in medical management (MM). MM is a brief counseling 
intervention delivered by non-addiction medical providers to improve response to medication-
assisted addiction treatments delivered in medical settings [129] [130]. It has augmented care for 
medication-assisted treatment of alcohol dependence with acamprosate and oral naltrexone in 
the COMBINE study [131], integration of XR-NTX treatment of alcohol dependence in primary 
care settings [36], and integration of BUP/NX for treatment of opioid dependence in primary care 
[132]. Since MM is meant to facilitate medication-assisted addiction treatment, it will be performed 
only for participants offered medication-assisted treatment in the HIV clinic (e.g., participants with 
opioid use disorders randomized to XR-NTX and TAU participants receiving clinic-based 
buprenorphine/naloxone or methadone for opioid use disorder). TAU participants referred for off-
site methadone maintenance or buprenorphine/naloxone will not receive MM since medical 


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oversight is the responsibility of the treating provider. TAU participants who receive non-
medication-assisted treatments such as 12-step groups or psychosocial counseling will not 
receive MM. During brief MM sessions, study clinicians will review recent drug and alcohol use, 
recommend abstinence, review medication side effects, and encourage adherence to medication-
assisted treatment and participation in clinic and/or community support groups.  
 
Clinic-based Extended-Release Naltrexone (XR-NTX) 
9.2.3.1 XR-NTX Detoxification and Induction (0 - 4 weeks duration, during 
active treatment phase) 
Following randomization, participants assigned to office-based XR-NTX will undergo 
detoxification and naltrexone induction in accordance with the package insert and published 
guidelines [133-136]. Participating HIV providers will be trained to manage outpatient 
detoxification procedures for participants with mild to moderate anticipated opioid withdrawal 
severity. Provider training reviews a range of detox options outlined in the Manual of Operating 
Procedures [137, 138]. Participants failing an induction regimen and those with anticipated severe 
withdrawal may be referred to local detox facilities for medication-assisted inpatient detoxification.  
9.2.3.2 Active Treatment with XR-NTX (Treatment Initiation through Week 
20)  
XR-NTX (4cc, ~380mg of naltrexone base) will be administered approximately every four weeks 
(treatment initiation visit and weeks 4, 8, 12, 16, and 20) for an approximate maximum of 6 doses 
in the form of Vivitrol®, which will be obtained by NIDA or the NIDA contractor for distribution to 
the sites. Administration of XR-NTX more frequently will require approval by the Lead 
Investigators and will be provided on a case-by-case basis. XR-NTX will be administered by 
intramuscular injection to the buttocks (alternating sides monthly) according to the injection 
preparation and administration procedures specified in the Vivitrol® product package insert. These 
procedures are designed to minimize the risk of injection site reactions. 
9.2.3.3 Handling of Missed XR-NTX Doses, Lapses, and Relapses  
Use of illicit opioids presents different concerns in the management of participants receiving XR- 
NTX maintenance, compared to those participants receiving agonist therapy. A participant 
receiving XR-NTX may miss a scheduled injection and resume opioid use. However, because of 
the long duration of action of XR-NTX (full blockade out to 5 weeks after the last injection [101]), 
a grace period of at least 7 days after the scheduled injection can be expected during which repeat 
XR-NTX injection can be rescheduled without risk of relapse. If the participant misses a scheduled 
injection and uses opioids during at least two of the seven days following the date of the scheduled 
injection, relapse will be suspected and the provider will perform a repeat naloxone challenge as 
described in the Manual of Operating Procedures. If the challenge is negative, XR-NTX 
administration will be resumed. If positive, then XR-NTX administration would risk precipitating 
withdrawal. However, because naltrexone blood levels remain and there is partial blockade 
beyond week 5, vulnerability to relapse may be more gradual, and the possibility of mild or 
equivocal reactions to naloxone challenge more common. In this instance, a second challenge 
within 72 hours will be attempted, and, if tolerated, the next injection can be given. Missing a 
scheduled XR-NTX injection is the most important threat to the success of naltrexone 
maintenance. In the event that a participant misses a scheduled injection, clinic study staff will 
contact the participant for follow-up. The goal of these contacts is to re-establish commitment to 
XR-NTX treatment and schedule the next injection as soon as possible. Participants who miss a 
scheduled XR-NTX dose but remain abstinent (i.e., return to clinic reporting no opioid use, urine 
negative for all opioids, and passing naloxone challenge), may be restarted on XR-NTX up to 3 
weeks after the scheduled dose. 


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Among the 9 individuals in the pilot study who had opioid use disorder and were unsuppressed 
at baseline, 6 (17%) of the 36 subsequent viral load values were missing. In the pilot, viral load 
was measured monthly, increasing the opportunity for missing data, whereas CTN-0067 collects 
follow-up viral loads only at 12 and 24 weeks and will likely have fewer missing viral loads. The 
primary outcome analysis will be carried out using the binary repeated measures of viral load 
(RMVL) framework of Rose et al., a type of time series model. In theory, time series models can 
accommodate missing data better than non-longitudinal models by using all non-missing data 
points. However, this approach assumes that missing data are not informative, that is, that 
missing values are probably similar to corresponding non-missing values with the same set of 
other predictors. For substance-use trials, missing at random (MAR) is less likely than missing 
not at random (MNAR) alternative: if data are missing, it is probably because the participant is 
unsuppressed. So, for the primary analysis, “unsuppressed” will be substituted for missing 
suppression status values. Since death is at least as undesirable as lack of suppression, 
“unsuppressed” will be assigned as a status value for visits subsequent to death. A secondary 
sensitivity analysis will explore the extent to which trial conclusions need to be changed as the 
missingness assumption approaches MAR. 
9.2.3.4 Dispensing of XR-NTX 
Study medication (XR-NTX) will be provided by the study at no cost to the participant. XR-NTX 
will be administered in clinic at the Treatment Initiation Visit and at treatment weeks 4, 8, 12, 16 
and 20.  
 
Treatment as Usual (TAU) 
Participants assigned to the TAU group will receive the standard treatment for opioid use disorder 
provided at each HIV clinic. The standard of care in U.S. HIV clinics is currently to link with opioid 
agonist treatment services. Opioid substitution therapy is recommended for HIV-infected 
participants with opioid dependence [35, 104], and many HIV practices are being encouraged to 
adopt clinic-based BUP/NX [105]. Assessment of TAU includes assessing use of medication-
assisted treatments for alcohol use disorder as well as opioid use disorder since we anticipate some 
participants with OUD will also have AUD. TAU assessment will also include characterization of 
usual counseling services and linkages with local detox programs available at each site. 
Many HIV clinics receive funding from the Ryan White Care Act for case management and 
addiction/mental health counseling services to facilitate engagement of HIV-infected patients with 
substance use disorders in treatment. In a 6-month randomized trial of methadone maintenance 
referral strategies, passive referral of heroin users resulted in 8% methadone maintenance 
enrollment at 6 months vs. 29% enrollment among those randomized to case-management 
assisted referrals (p = .006) [139].  
During the formal site selection process, a thorough assessment will be conducted of each site’s 
standard practice for linkage to addiction treatment services. Throughout the course of the trial, 
HIV clinics will be monitored for any potential changes that might occur in standard practice 
around linking HIV-infected clinic patients to substance use treatment. 
 
Ancillary Treatments 
Participants who experience withdrawal symptoms or nausea associated with detoxification and 
induction may be treated with ancillary medications (see guidelines in study Manual of Operating 
Procedures (MOP)). Depression is also common in opioid-dependent participants and, though 
not causally related to XR-NTX use, may adversely affect prognosis of naltrexone treatment [140, 


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141]. Participants who show depressive symptoms may be treated by their HIV clinic providers 
with antidepressants and/or referred for mental health evaluation and treatment. 
 
Provisions for Access to Treatment after Study 
Prior to the conclusion of the 24 week active treatment phase, the research team will make an 
effort to arrange for continued treatment with XR-NTX as locally available and appropriate. In 
most cases, the study physician will continue to prescribe this FDA-approved study medication 
as the participant’s HIV primary care provider. Where this is not possible (due to insurance or 
availability of treatment resources, etc.), alternative treatment referrals (e.g., methadone 
maintenance, intensive outpatient psychosocial aftercare), special access programs, and 
manufacturer medication assistance plans will be made as appropriate. 
 
Drug Packaging / XR-NTX 
XR-NTX will be supplied in single use kits. Each kit will contain one 380 mg vial of Vivitrol® 
microspheres, one vial containing 4 mL (to deliver 3.4 mL) diluent for the suspension of Vivitrol®, 
one 5-mL prepackaged syringe, one 1-inch 20-gauge needle, two 1.5-inch 20-gauge needles and 
two 2-inch 20-gauge needles with needle protection devices. The lot number will be included on 
the kit labels as supplied by the manufacturer.  
 
Participant Discontinuation 
All participants will be followed for the duration of the study (25-28 weeks, depending on length 
of time required for completion of screening and enrollment procedures) unless they withdraw 
consent, or the investigator or sponsor decides to discontinue their enrollment. Reasons for the 
investigator or sponsor terminating a participant from the study may include, but are not limited 
to, the participant becoming a threat to self or others, lack of funding, or DSMB early termination 
of the study for safety or effectiveness reasons. 
 
Blinding 
CTN-0067 is an unblinded study. 
 
Participant Compensation 
Participants will be compensated for their time and effort for baseline and follow-up visits. 
Participants may receive a maximum amount of up to approximately $510.00 U.S. Dollars for 
completing the following activities: screening interview, baseline assessment, and visits at 1, 4, 
8, 12, 16, 20, and 24 weeks. The specific amounts and format (e.g., cash, debit card, voucher, 
etc.), and distribution schedule will be determined by the participating site with the approval of the 
Lead Investigator or Co-Lead Investigators and the IRB. All compensation will be recorded and 
tracked in the Compensation Log.  
 
Long Term Mortality Follow-up 
In the future, we will attempt to account for all participants who may have died after the study 
ends.  We will do this by sending participant data to the National Center for Health Statistics’ (part 
of the Centers for Disease Control and Prevention) National Death Index. This is a list of all 
persons who have died in the U.S. Data, if available, will be abstracted from the Locator Form 
and other CRFs and may include name, date of birth, sex, race/ethnicity, social security number, 
state of residence, date of last contact, and date of death. The date and cause of death identified 


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by the National Death Index will be entered into a secure database at OHSU. Information 
regarding persons presumed to still be alive in the National Death Index will be destroyed. 


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10.0 STUDY ASSESSMENTS AND INSTRUMENTS 
The selected assessments attempt to balance the value of comprehensive data against the 
costs of data collection in terms of staff time, feasibility of completing assessments in an 
outpatient HIV clinic setting, financial cost, and response burden. Therefore, assessments have 
been limited to those that contribute directly to the study objectives or that are necessary for 
reasons of safety or regulatory compliance. When choosing between comparable instruments, 
we have chosen instruments for which CRFs have already been built for other recent CTN trials 
to minimize the cost of new CRF construction. 


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List of all CRFs and Table of Assessments 
Assessment/Activity 
Pre-
Screening 
Screening 
Baseline 
Random-
ization^^ 
Treatment 
Initiation 
 
Safety 
Visit 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
End of 
Study 
(≠Week 
24) 
As 
Needed  
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Screening Verbal Consent and 
HIPAA Authorization/Waiver 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Screening Interview 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (from PhenX) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Master Enrollment Log++ 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/HIPAA 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Checklist 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Locator Form++ 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Medical Release++ 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Study Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inventory Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pre-screening Log++ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secure Document Upload 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Missed Visit Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Progress Note Checklist++ 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Protocol Deviation  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Visit Compensation Log++ 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
End of Treatment 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Study Completion 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Safety and Medical Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ARV Medication Log 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
 
Concomitant Medications 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
CD4 Count 
 
 
 
x 
 
 
 
 
x 
 
 
x 
x 
 
Serum Creatinine 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
Confirmed Pregnancy and Outcome  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Detoxification  
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Fatal Opioid Overdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 


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Assessment/Activity 
Pre-
Screening 
Screening 
Baseline 
Random-
ization^^ 
Treatment 
Initiation 
 
Safety 
Visit 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
End of 
Study 
(≠Week 
24) 
As 
Needed  
Vital Signs (blood pressure, pulse, 
temperature, height and weight) 
 
x 
 
 
 
 
 
 
 
 
 
x± 
x± 
 
Hepatitis B surface antigen (HBs AG) 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Hepatitis C virus antibody (HCV ab) 
 
 
 
x 
 
 
 
 
 
 
 
x** 
 
 
Hepatitis C PCR confirmation, 
 when HCV ab + 
 
 
 
x** 
 
 
 
 
 
 
 
x** 
 
 
HIV-1 RNA PCR 
 
x 
 
 
 
 
 
 
x 
 
 
x 
x 
 
LFT (AST, ALT) and INR 
 
x 
 
 
 
 
 
 
x 
 
 
x 
x 
 
Medical and Psychiatric History 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Adherence 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Pain Assessment 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Non-Fatal Opioid Overdose  
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
 
PBMC 
 
 
 
x 
 
 
 
 
x 
 
 
x 
x 
 
Physical Examination  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy and Birth Control 
Assessment (including urine 
pregnancy test) 
 
x 
 
 
x*,^ 
x*,^ 
x 
x 
x 
x 
x 
x 
x 
 
Naloxone Challenge* 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
XR-NTX Administration Log* ++ 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
XR-NTX Injection* 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
Injection Site Abnormality* 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Injection Site Examination* 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
ASI Lite Drug/Alcohol Use 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
 
Concise Health Risk Tracking – Self 
Report 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Concise Health Risk Tracking – 
Clinician Rated 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
DSM-5 Substance Use Disorders 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
 
x 
 
 
x* 
x* 
x 
x 
x 
x 
x 
x 
x 
 
HIV Care Utilization 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
 
Buprenorphine and Methadone Chart 
Abstraction 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Quality of Life, from PhenX 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life, from EQ-5D 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
 


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Assessment/Activity 
Pre-
Screening 
Screening 
Baseline 
Random-
ization^^ 
Treatment 
Initiation 
 
Safety 
Visit 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
End of 
Study 
(≠Week 
24) 
As 
Needed  
Risk Assessment Battery 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Tobacco Use History and Substance 
Use History, from PhenX 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
 
Timeline Follow Back 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Treatment Plan 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Treatment Initiation*** 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
XR-NTX Non-Initiation* 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Treatment Satisfaction Survey 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Treatment Services Review 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
VACS Index 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
 
Visual Analog Scale 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
PHQ-9 Depression Symptoms 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
 
Suicidal Risk 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Criminal Justice 
 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
 
Participant Treatment Preference 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
* Only for participants randomized to the XR-NTX arm. 
**At randomization, HCV PCR confirmation is required when HCV ab is positive. At 24 weeks, collect HCV ab if participant tested HCV ab negative at 
randomization or if HCV ab result was not obtained at randomization. At 24 weeks, collect HCV PCR confirmation if: HCV antibody is positive at 
randomization, but HCV PCR was not obtained at randomization or HCV antibody was negative at randomization, but HCV antibody is positive at 
Week 24.  
*** Only for participants randomized to TAU arm. 
± Height and weight only for BMI calculations. 
++ Not captured in eClinical. 
 
^Urine pregnancy test required for XR-NTX group only; remainder of Pregnancy and Birth Control Assessment required for all participants.  
 
^^Assessments performed at randomization correspond with Week 0 requirements in the eClinical system.


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11.0 HIV-RELATED MEASURES 
 
Antiretroviral Medication Prescription and Adherence 
Since HIV viral suppression is most strongly influenced by optimal use of ART, evaluation of 
adherence to one’s ART regimen is essential. Self-reported antiretroviral use and adherence will 
be assessed using a Medication Adherence questionnaire with visual analogue scale [142, 143] 
that is administered at baseline, treatment initiation, and weeks  4, 8, 12, 16, 20 and 24 weeks or 
the end of study visit (if not week 24) for assessment of secondary outcome if participant is 
prescribed ART at the time of follow-up visits. The Medication Adherence questionnaire asks the 
participant about adherence to HIV medications in the past month. We will assess the proportion 
of participants taking 100% of prescribed ART doses, based on visual analogue scale responses, 
in the past month at baseline, treatment initiation, and weeks 4, 8, 12, 16, 20, and 24 for those 
prescribed ART (proportion; self-reported medication adherence measure). 
Because self-reported use of specific antiretrovirals has limited reliability when compared with 
medical record review [144, 145], we will confirm ART use with medical record review at baseline 
and 24 weeks (or the end of study visit, if not week 24) using the ARV Medication Log to assess 
the secondary outcome of ART prescription. Specifically, we will assess change in the proportion 
of participants prescribed ART within 24 weeks following randomization, compared to baseline 
(binary; medical record abstraction). 
 
HIV Care Utilization 
Study staff will assess the number of HIV primary care visits at baseline and 24 weeks, or the end 
of study visit, if not week 24 (count, chart abstraction). 
 
 
HIV Risk Assessment Battery 
The Risk Assessment Battery (RAB) [146] is a self-administered assessment of engagement in 
activities that increase the likelihood of HIV transmission. Only sexual and drug-related HIV risk 
behavior items will be included, in an effort to limit instrument redundancy and participant 
response burden. Several scores that measure drug risk, sex risk, and total risk will be computed. 
It will be assessed at baseline and at weeks 4, 8, 12, 16, 20, and 24 (or the end of study visit, if 
not week 24). 
 
 
VACS Index 
The VACS Index is a validated biomarker score that reflects overall health and is a potent 
predicator of mortality in HIV-infected patients [147, 148]. The VACS Index is calculated by 
summing scores for age, CD4 count, HIV-1 RNA, hemoglobin, liver fibrosis (FIB-4), renal function 
(eGFR), and HCV status (Table 11.1) [148, 149]. It is responsive to abstinence among HIV-
infected patients receiving opioid agonist treatment even when they enter such treatment with an 
undetectable HIV viral load [150]. A clinically meaningful difference is 5 points as it relates to a 
20% change in 5-year mortality risk [147-149]. It will be assessed at randomization and week 24, 
or the end of study visit, if not week 24. 
 
 


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Table 1:  Point Values Used to Calculate VACS Index 
Component 
VACS Index 
Age 
<50 
0 
50-64 
12 
≥65 
27 
CD4 
≥500 
0 
350 to 499 
6 
200 to 349 
6 
100 to 199 
10 
50 to 99 
28 
<50 
29 
HIV-1 RNA 
<500 
0 
500-1x105 
7 
>1x105 
14 
Hemoglobin 
≥14 
0 
12 to 13.9 
10 
10 to 11.9 
22 
<10 
38 
FIB-4 
<1.45 
0 
1.45 to 3.25 
6 
>3.25 
25 
eGFR 
≥60 
0 
45 to 59.9 
6 
30 to 44.9 
8 
<30 
26 
Hepatitis C 
5 
 
Definitions: 
• 
FIB-4 = (years of age x AST in U/L) ÷ (platelets in 109/L x square root of ALT in U/L) 
o 
Measure of liver fibrosis 
• 
eGFR = 186.3 x (serum creatinine-1.154) x (age-0.203) x (0.742 for women) x (1.21 if black) 
o 
Estimated glomerular filtration rate; Measure of renal function 
 
 


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12.0 GENERAL MEASURES 
 
Inclusion/Exclusion 
This form will include each inclusion and exclusion criterion to document eligibility. Eligibility will 
be assessed prior to randomization, and then continually as appropriate. Only participants who 
continue to meet study eligibility criteria will be allowed to continue with the screening process 
and randomization. 
 
Locator Form 
A locator form will be used to obtain information to assist in finding participants during 
screening/baseline and at follow-up. This form will collect participants’ current address, email 
address, and phone number(s). In order to facilitate locating participants if direct contact efforts 
are unsuccessful, we will attempt to collect addresses and phone numbers of 2-3 family/friends, 
who may know how to reach the participant, as well as information such as Social Security 
number, driver’s license number, social media, and other information to aid in searches of public 
records. This information will be collected at screening and will be updated at each visit. No 
information from this form will be used in data analyses. 
 
PhenX Core Tier 1 Forms 
The Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org) 
includes highly recommended measures that are being adopted across NIDA-funded research. 
The Core Tier 1 collection includes measures for demographics (age, ethnicity, sex, race, 
educational attainment, employment status and marital status), BMI, quality of life, and HIV Risk 
& Status; substance use measures include age of onset, past 30-day quantity and frequency, 
lifetime use for alcohol, tobacco and other substances. We will delete Core Tier 1 items regarding 
HIV testing, since only HIV-infected participants are eligible for the current study. Core Tier 1 
assessments will be completed at baseline only, with BMI and tobacco use questions repeated at 
week 24 or the end of study visit, if not week 24. 
 
Demographics Form 
The demographics form will collect information about demographic characteristics of the 
participant, including sex, date of birth, ethnicity, race, education, employment pattern, and marital 
status. The PhenX Core Tier 1 form will be completed during the screening process to collect 
demographic data. 
 
Treatment Satisfaction Survey 
Satisfaction with treatment will be recorded on the Treatment Satisfaction Survey completed at 
week 24 visit or the end of study visit, if not week 24. 
 
Treatment Plan 
This form will be used once the participant is randomized. After randomization, the participant will 
meet with the study clinician to develop a plan that will determine the activities the participant 
should engage in, including addiction pharmacotherapy (e.g., methadone, buprenorphine, XR-
NTX) during the active treatment phase of the protocol. This meeting and form should be 
completed the same day the participant is randomized. The Treatment Plan will be reviewed at 
follow-up visits 4, 8, 12, 16, 20, and 24 or the end of study visit, if not week 24. 


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Medication Adherence 
This form will track the participant’s adherence to recommended addiction pharmacotherapy (i.e., 
methadone, buprenorphine, or XR-NTX) as described in the Treatment Plan.  
 
End of Treatment Form 
This form tracks the participant’s status with regards to the study intervention/medication or 
treatment(s) received as part of TAU. It will be completed if the participant permanently stops 
treatment early or at the week 24 visit (for participants who complete study participation) or at the 
end of study visit (for participants who permanently stop the study trial early). 
 
Study Completion Form 
This form tracks the participant’s status in the study. It will be completed at the week 24 visit, once 
the week 24 visit window elapses for participants who do not complete this final visit or after the 
week 24 visit is completed for participants who complete the final visit, or once the site confirms 
that a participant is permanently done with the study (i.e., participant died or withdrew consent). 
This form will be used in data analyses to address variables such as treatment retention and 
completion. 
 Treatment Initiation and XR-NTX Non-Initiation 
The Treatment Initiation form will track participants randomized to the TAU arm only and will track 
initiation of TAU. This form will be completed once the participant reports that they have intitated 
TAU treatment. If treatment is not initiated, the form must be completed by end of study.  
The XR-NTX Non-Initiation form will track non-initiation of XR-NTX injections for participants 
randomized to the XR-NTX treatment arm. This form will be completed as needed if a participant 
does not receive any XR-NTX injections. If the participant receives at least one injection, this form 
will not be completed. 
 
 


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13.0 SAFETY AND MEDICAL MEASURES 
The study clinician must review and approve all safety and eligibility assessments to confirm 
participant eligibility prior to randomization. 
 
Medical and Psychiatric History 
The study clinician will obtain a medical and psychiatric history from the participant covering past 
and present health conditions to help determine eligibility and to provide baseline information. 
This form will be collected during screening. Information from this form may be used in data 
analyses. 
 
Physical Examination 
The study clinician will complete a physical examination at screening, to ensure that there are no 
medical concerns regarding participation and to gather baseline information regarding the 
participant’s physical health. During the screening physical exam, a description of the participant’s 
body habitus will be documented, and the study clinician will examine the planned injection sites 
to ensure adequacy for XR-NTX gluteal intramuscular injection of naltrexone with the supplied 
needle. 
 
Vital Signs 
Study personnel will complete vital signs (blood pressure, pulse, temperature, height, and weight) 
at screening to inform overall medical fitness for participation, along with the physical exam. 
Height and weight only will be collected at week 24 or the end of study visit, if not week 24.  
 
DSM-5 Checklist 
The DSM-5 Checklist is a semi-structured, interviewer-administered instrument that provides 
current diagnoses for substance use disorders based on DSM-5 diagnostic criteria. The DSM-5 
Checklist will be completed at screening to determine eligibility.  
 
Clinical Laboratory Tests 
Trained staff will be responsible for collecting and processing biologic specimens. Local 
laboratories at participating sites will be used to conduct all laboratory tests with the exception of 
the PBMCs. Laboratories must participate in the Clinical Laboratory Improvement Act of 1998 
(CLIA) or be accredited by the College of American Pathologists (CAP). If neither CLIA nor CAP 
is available, equivalent evidence of laboratory certification may be acceptable and must be 
discussed on a case-by-case basis with the Lead Team. Laboratories should provide reference 
ranges and proof of laboratory certification. 
HIV-1 RNA PCR: will be drawn at screening, 12, and 24 weeks (or the end of study visit, if not 
week 24) for outcomes assessment. At screening, results of laboratory tests conducted within 90 
days prior to date of informed consent will be acceptable. 
CD4 Count (T-helper cells): will be drawn at randomization and at 12 and 24 week visits or the 
end of study visit, if not week 24, for secondary outcomes assessment. At randomization, results 
of laboratory tests conducted within 90 days prior to date of informed consent will be acceptable. 
Peripheral Blood Mononuclear Cells (PBMCs): For all randomized participants (both TAU and 
XR-NTX), we will collect four 8mL or eight 4mL CPT tubes for PBMC analysis at randomization, 


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12, and 24 (or end of study visit if not week 24). Blood draws may coincide with other research 
blood draws. PBMC analysis will be conducted in a related NIH application to assess the effects 
of opioid blockade on TLR mediated immune responses at a later time. PBMC samples will be 
shipped to a lab at Oregon Health & Science University and kept indefinitely. PBMC samples will 
be used for immunologic testing. It is also possible that banked PBMC specimens will be shared 
with other investigators for performance of genetic testing in the future.  
Safety labs: AST, ALT, CBC, INR, serum creatinine, and urine pregnancy test (for all females) 
will be performed to help determine eligibility at screening. Receipt and review of laboratory test 
results is necessary before confirming eligibility, conducting randomization and starting study 
medication. Results of laboratory tests (not including urine pregnancy) conducted within 30 days 
prior to date of informed consent (e.g., collected as part of routine detoxification admission) will 
be acceptable. Urine pregnancy test will be repeated at the Treatment Initiation Visit (required for 
XR-NTX arm only), the safety visit (required for XR-NTX arm only), and weeks 4, 8, 12, 16, 20, 
and 24 (or the end of study visit, if not week 24). AST, ALT, CBC, INR and serum creatinine will 
be repeated at week 24 or the end of study visit, if not week 24. 
Liver profile: AST, ALT, and INR will be repeated at the Week 12 and Week 24 visits (or the end 
of study visit, if not Week 24). This is consistent with recent studies supporting the lack of 
hepatotoxicity in patients receiving XR-NTX that led to dropping of the previous FDA black box 
warning regarding hepatoxicity. 
Hepatitis: Blood will be collected at randomization for Hepatitis B surface antigen (HBsAG) and 
Hepatitis C virus antibody (HCVab) with reflex hepatitis C RNA PCR testing if antibody positive. 
These tests do not determine eligibility. Results of laboratory tests conducted within 90 days prior 
to date of informed consent (e.g., collected as part of routine detoxification admission) will be 
acceptable.  
 
Pregnancy and Birth Control Assessment 
This form will document the administration of pregnancy tests, test results, and female 
participants’ self-reports of an acceptable method of birth control. The pregnancy and birth control 
assessment form, including on-site urine pregnancy tests, will be collected at screening. Birth 
control assessment and a urine pregnancy test will be repeated at the Treatment Initiation Visit 
prior to study drug induction (urine pregnancy test required for XR-NTX arm only), the safety visit 
(urine pregnancy test required for XR-NTX arm only) and the 4, 8, 12, 16, 20, and 24 week visits 
or the end of study visit, if not week 24. This will correspond to medical visits for repeat study drug 
dosing and a final assessment at week 24 or the end of study visit, if not week 24. 
 
Injection Site Examination 
The study clinician will examine the injection site on the next visit following each XR-NTX 
administration and document this on the Injection Site Examination form. The study clinician will 
also examine the injection site per standard of care before administering a new injection. 
Participants will be asked to immediately report any injection site reactions to study staff for 
evaluation, monitoring, and possible referral, as needed. Injection site reactions will be 
documented on the Injection Site Abnormality Log. 
 
Pain Assessment 
Pain assessment will occur at baseline, 4, 8, 12, 16, 20, and 24 weeks (or the end of study visit, 
if not week 24). Participants will be assessed for experiences of pain during the past 4 weeks 


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using the 3-item PEG [151]. The PEG asks respondents to estimate on a scale of 0 to 10 their 
average pain intensity (P), interference with enjoyment of life (E), and interference with general 
activity (G). Participants will also be asked how pain was managed. 
 
 


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14.0 SUBSTANCE USE AND MENTAL HEALTH COVARIABLES 
 
Urine Drug Screen 
Urine drug screens will be collected at screening, study drug induction (Treatment Initiation Visit 
– required for XR-NTX arm only), safety visit (required for XR-NTX arm only), and 4, 8, 12, 16, 
20, and 24 weeks (or the end of study visit, if not week 24) for assessment of secondary outcomes. 
All urine specimens will be collected using FDA-approved one-step temperature-controlled urine 
drug test cups following all of the manufacturer's recommended procedures. A further validity 
check will be performed using a commercially available adulterant test strip. The UDS will test for 
the presence of the following drugs: opiates, oxycodone, barbiturates, benzodiazepines, cocaine, 
amphetamines, methamphetamines, marijuana, methadone, buprenorphine, phencyclidine 
(PCP), fentanyl and ecstasy (MDMA). The PCP result will not be recorded in the data system. 
The UDS will also test for ethyl glucuronide (EtG), which is a biomarker of alcohol consumption 
in the previous 22 to 31 hours and will be used to confirm self-reported alcohol abstinence [152, 
153]. The UDS will be performed using various commercially available single or multi-panel tests. 
In the event urine specimen tampering is suspected, either based on observation or the adulterant 
tests, study staff should request a second urine sample, directly observed or according to clinic 
SOPs. 
 
Addiction Severity Index-Lite (ASI-Lite) Drug and Alcohol Use 
The ASI-Lite is derived from the Fifth Edition of the ASI [154], a structured clinical interview that 
yields scores for seven areas of functioning typically impacted by addiction, including medical 
status, employment status, drug use, alcohol use, family status, legal status, and psychiatric 
status. Only the drug use and alcohol use sections of the ASI-Lite will be used. Opioid use 
questions, including the main type of opioid used by the participant, whether a prescription opioid 
or heroin, the onset of the use, the participant’s perception of the substance that is most 
problematic, and their present treatment goal will also be assessed at baseline as part of the ASI-
Lite assessment. The ASI-Lite drug and alcohol sections will be completed at baseline and 24 
weeks (or the end of study visit, if not week 24) for assessment of secondary outcomes. 
 
Timeline Follow Back (TLFB) 
Timeline Follow Back (TLFB) assesses self-reported drug and alcohol use over the past 30 days, 
with high test-retest reliability and validity [155, 156]. Participants will be asked to report daily drug 
and alcohol use in the specified timeframe (e.g., since the last visit). TLFB will be completed at 
the following visits: baseline, treatment initiation, and weeks 4, 8, 12, 16, 20, and 24 (or the end 
of study visit, if not week 24) for assessment of secondary outcomes. Baseline TLFB assesses 
use in the 30 days prior to informed consent through to the date of the baseline visit. 
 
Visual Analog Craving Scale (VAS) 
Participants’ craving for opioids, alcohol and tobacco will be documented on a visual analog scale 
(VAS) that ranges from 0 (no craving) to 100 (most intense craving possible). Participants will be 
instructed specifically to indicate the overall intensity of craving experienced. This scale will be 
completed at baseline and at 4, 8, 12, 16, 20, and 24 weeks (or the end of study visit, if not week 
24) for assessment of secondary outcomes. 


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Treatment Services Review (TSR), Version 6 (28 days) 
Select items from the Treatment Services Review, Version 6 (TSR-6) addiction treatment modules 
will be used to collect data on the number of counseling sessions attended in the past 28 days, 
as well as detoxification, outpatient, inpatient, and medication-assisted addiction treatment 
services [157]. Participants will complete a modified TSR-6 at baseline, treatment initiation, and 
4, 8, 12, 16, 20, and 24 weeks (or the end of study visit, if not week 24) for assessment of TAU 
and counseling exposure in both TAU and XR-NTX arms. 
 
Medication-Assisted Treatment 
To assess study drug and other medication-assisted treatment exposure, TSR-6 responses will 
be augmented regarding use of medications for treatment of addiction with additional items asking 
specifically about use of methadone, buprenorphine, and extended-release naltrexone during the 
past 28 days for participants randomized to both TAU and XR-NTX arms. Participants will be 
asked to report the number of days in the past 28 days that each medication was taken at least 
once per day. This information will be collected from participants at baseline, treatment initiation, 
and weeks 4, 8, 12, 16, 20, and 24 (or the end of study visit, if not week 24). Additional information 
gleaned from medical record review to assess the dose and number of days of treatment 
prescribed for each medication will further augment this assessment. 
 
Quality of Life 
We will measure quality of life using the EuroQol Group 5D (EQ-5D), a validated, self-reported, 
5-item instrument used to measure health-related quality of life in a wide variety of populations. 
The form will be collected at the baseline and week 24 visit. [158, 159] 
 
Participant Treatment Preference 
We will collect each participant’s preference for agonist or antagonist treatment using the 
Participant Treatment Preference form. This form consists of a single item that collects participant 
treatment preference on a slider scale of 1-10, with 1 being “strongly prefer buprenorphine or 
methadone (agonist treatment),” 10 being “strongly prefer extended release naltrexone 
(antagonist treatment),” and 5 being “no preference.” The form will be collected via participant 
self-report at baseline. 


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15.0 SAFETY ASSESSMENTS 
 
Adverse Events, including Serious Adverse Events, and Protocol 
Deviations 
Adverse Events, Serious Adverse Events, and Protocol Deviations will be assessed and 
documented. 
Study staff members will assess for any medical or psychiatric side effects by asking: "How have 
you been feeling since your last visit?" AEs will be solicited at each study visit but will be recorded 
at any visit after consent when reported by the participant according to the adverse event reporting 
definitions and procedures outlined in the protocol. 
If a reported AE suggests medical or psychological deterioration, it will be brought to the attention 
of the study clinician for further evaluation. SAEs will be medically managed, reported, and 
followed in accordance with applicable regulatory requirements. Safety assessments will be 
performed at all visits. 
 
Non-Fatal Overdose 
Non-fatal opioid overdoses in the past 4 weeks will be assessed using a self-reported instrument 
used in previous studies at baseline and 24 weeks (or the end of study visit, if not week 24) [160]. 
Overdose events are sentinel events that are less likely to be prone to recall bias than other 
events. If non-fatal overdose resulted in a serious adverse event, it should also be captured on 
the AE/SAE CRF. 
 
Fatal Overdose 
We will collect data on fatal opioid overdoses using medical chart record review at 24 weeks for 
participants who are lost to follow-up. We will supplement this with information from contacts with 
persons listed on the participant’s locator form when participants are lost to follow-up throughout 
the study. If a fatal opioid overdose occurred, the event also should be captured on the AE/SAE 
CRF. 
 
Precipitated Withdrawal 
For participants assigned to XR-NTX, the study clinician will record the presence or absence of 
precipitated opioid withdrawal on the XR-NTX Administration (INJ) CRF following each XR-NTX 
injection. 
 
Concise Health Risk Tracking - Self Report (CHRT-SR) Suicidal 
Behavior Evaluation 
The CHRT-SR [161] is a 16-item participant self-report assessment of suicidality and related 
thoughts and behaviors. The scale is designed to quickly and easily track suicidality in a manner 
consistent with the Columbia Classification Algorithm of Suicide Assessment (C-CASA) [162]. 
The CHRT-SR will be assessed at screening, treatment initiation, the safety visit, and weeks 4, 
8, 12, 16, 20, and 24 (or the end of study visit, if not week 24). The CHRT-SR will assess high 
risk suicidal ideation by a positive response (Agree or Strongly Agree) on any of the last three 
questions (thoughts of, thoughts of how and/or a specific plan to commit suicide) and prompt a 
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Concise Health Risk Tracking - Clinician Rated 
The Clinician Rated (CHRT-CR) [161] assessment will be performed by the study clinician only 
if a participant answers any of questions 14-16 on the CHRT-SR as “Agree” or “Strongly Agree” 
as described in Section 15.5. 
 
Patient Health Questionnaire (PHQ-9) Depression Symptoms 
We measure depression symptoms using the self-reported PHQ-9, a 9-item scale validated for 
screening, diagnosing, and assessing the severity of depression symptoms in diverse populations 
[163]. The PHQ-9 will be administered at baseline, 12, and 24 weeks (or the end of study visit, if 
not week 24). Endorsements of suicidality on the PHQ-9 will be addressed locally at each site.  
 
Suicidal Risk 
This assessment will be performed by research staff if the participant endorses suicidality on the 
PHQ-9 by answering Q9 (“Thoughts that you would be better off dead, or of hurting yourself in 
some way”) as “Several days”, “More than half the days” or “Nearly every day.” 


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16.0 STUDY CONDITIONS 
The two study conditions are: 1) office-based XR-NTX, and 2) TAU. Study conditions are 
discussed in detail in section 4.2, 4.3, and 9.0. 
 
Clinic-Based XR-NTX 
The office-based XR-NTX study condition is discussed in detail in Sections 4.2 and 9.0. 
 
TAU 
The TAU study condition is discussed in detail in Sections 4.3 and 9.0. 
 
Training 
Training in study-specific assessments will be provided as specified in a comprehensive training 
plan that will be developed by the Lead Team, which includes the Lead Node, CCTN, CCC and 
DSC staff. The training sessions will include modules targeting all research team members 
conducted via web, telephone and/or in-person training sessions. Training will cover standard 
NIDA training for all CTN Trials (e.g., Human Subjects Protection and Good Clinical Practices), 
as well as protocol specific training as needed (e.g., assessments, study intervention, fidelity to 
the protocol, safety procedures, data management and collection, research procedures). 
Attention will be given to provide the study clinic staff providers training in management of opioid 
and alcohol withdrawal, XR-NTX induction and maintenance, and to familiarize study personnel 
with study procedures. Support mechanisms are identified (e.g., who to contact for aid, questions, 
resources) as well as re-training procedures. All study staff will be required to complete any local 
training requirements per study site and IRBs. Further details are presented in the study Training 
Plan. 
 
Concomitant Medications 
Participants will be instructed to contact the study clinician at their research site if they plan on 
taking any concomitant medications (including prescription, over-the-counter, and herbal 
supplements) during the course of the study. Concomitant medications will also be assessed at 
screening. 
As described in the eligibility criteria, participants will be excluded if there is a need for ongoing 
opioid analgesic treatment. The study clinician may also exclude any participant taking 
medications that could interact adversely with study drugs, at his/her clinical discretion. 
Study screening and treatment induction procedures (requirement for negative UDS for opioids 
on day of induction – XR-NTX arm only) are anticipated to greatly decrease the risk of precipitating 
opioid withdrawal. In the event a participant experiences opioid withdrawal following XR-NTX 
injection, the study clinician may dispense symptomatic treatments (e.g., oral clonidine, 
prochlorperazine, ibuprofen, etc.) to alleviate symptoms of opioid withdrawal, according to local 
SOPs. XR-NTX can also be associated with transient nausea unrelated to opioid withdrawal, 
typically lasting 2-8 hours. Should participants develop nausea or vomiting during naltrexone 
induction, this will be treated with oral anti-emetics (e.g., prochlorperazine) as needed. 
 
 


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17.0 STATISTICAL ANALYSIS 
 
Primary Objective of the Analysis 
The Primary objective of the CTN-0067 CHOICES scale-up study is to discover whether HIV 
clinic-based XR-NTX is non-inferior to TAU with respect to HIV viral suppression in HIV-infected 
participants with opioid use disorder. We have chosen a non-inferiority margin of 0.75. That is, 
we will reject the null hypothesis of inferiority of XR-NTX to TAU in favor of non-inferiority if the 
lower 95% confidence limit for the ratio 
Pr൫𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠ห𝑁𝑁𝑁𝑁𝑁𝑁൯
Pr൫𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠ห𝑇𝑇𝑇𝑇𝑇𝑇൯is strictly greater than 0.75. We 
anticipate a sample size of 350 (175/arm) will grant at least 80% power for the non-inferiority 
conclusion. 
 
Primary Outcome Measure 
The primary outcome measure for CTN-0067 CHOICES scale-up study is HIV viral suppression. 
HIV viral suppression is defined as an HIV-1 RNA ≤ 200 copies/ml at 24 weeks from time of 
randomization. 
The binary RMVL model of Rose et al. will be used to predict the log of the risk ratio (not the log 
of the odds) for suppression via a generalized estimating equation with an exchangeable 
covariance structure for all the values of a single participant. Baseline alcohol use disorder and 
sites are included as fixed effects. The fixed effects part of the model is thus: 
log൫𝑝𝑝𝑖𝑖𝑖𝑖൯= 𝛼𝛼+ 𝛽𝛽∗𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖+ 𝛾𝛾∗𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑗𝑗+ 𝜃𝜃∗𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖∗𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑗𝑗+ 𝜏𝜏∗𝑎𝑎𝑎𝑎𝑐𝑐𝑖𝑖+ 𝛿𝛿1 ∗𝑠𝑠𝑠𝑠𝑠𝑠𝑒𝑒1𝑖𝑖+ ⋯+ 𝛿𝛿𝑘𝑘∗𝑠𝑠𝑠𝑠𝑠𝑠𝑒𝑒𝑘𝑘𝑘𝑘 
where 𝑝𝑝𝑖𝑖𝑖𝑖 is the probablility of suppression of participant i in month j, trt is the indicator for 
treatment, months enter linearly, there is a time by treatment interaction, alc is an indicator for 
baseline alcohol use disorder, and 𝑠𝑠𝑠𝑠𝑠𝑠𝑒𝑒1, … , 𝑠𝑠𝑠𝑠𝑠𝑠𝑒𝑒𝑘𝑘 are site indicator variables. The model will 
incorporate 2 time points for each patient (months 3 and 6), with a contrast used to estimate the 
treatment effect at month 6. The following SAS fragment shows how to implement this analysis: 
 
proc genmod data = visits descending; 
class suppressed trt site projid alc base; 
model suppressed = trt | month alc site / dist = bin link = log; 
repeated subject = projid / type = exch; 
estimate "6M trt eff" trt 1 -1 trt * month 6 -6  
run; 
Note that the estimate statements assumes the following coding: trt= (ntx, tau) month = (3, 6).  
 
The RMVL is a type of longitudinal model. In theory, longitudinal models can accommodate 
missing data better than non-longitudinal models because they incorporate all non-missing data 
points. But this approach assumes that missing data are not informative, that is, that missing 
values are probably similar to corresponding non-missing values with the same set of other 
predictors. For trials of substance-using individuals, missing at random (MAR) is less likely than 
missing not at random (MNAR) alternative: if data are missing, it is probably because the 
participant is unsuppressed. So, for the primary analysis, “unsuppressed” will be substituted for 
missing suppression status values. An exception is that, if missing data are flanked on both sides 
by “suppressed” values, we will impute the missing data to be suppressed. Since death is at least 


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as undesirable as lack of suppression, “unsuppressed” will be assigned as a status value for visits 
subsequent to death. A secondary sensitivity analysis will explore the extent to which trial 
conclusions need to be changed as the missingness assumption approaches MAR. 
 
Secondary Outcome Measures 
1) Secondary HIV outcomes variables: 
a. VACS Index. Change in VACS Index score at 24 weeks compared with randomization 
(continuous; laboratory assays and demographics). 
b. CD4 Count. Change in CD4 count at 24 weeks following treatment initiation compared 
with randomization (count; laboratory assay). 
2) Engagement in HIV Care Variables: 
a. ART prescribed. Proportion of participants prescribed ART within 24 weeks following 
randomization (binary; medical record abstraction). 
b. ART Adherence. Proportion of participants taking 100% of prescribed ART doses in the 
past month at 24 weeks for those prescribed ART at any point during the 24 week trial 
(binary; self-reported medication adherence measure). 
c. Retention in HIV Care: Proportion of participants with at least 1 HIV primary care visit in 
the past 12 weeks, measured at week 24. Adherence to HIV clinic visits in the year after 
ART initiation predicts HIV disease progression and death [164] (binary; medical record 
abstraction). 
d. HIV Risk Behaviors. Past 30 day injection drug use, unprotected sex, multiple sexual 
partners as measured by the RAB at week 24 (binary; self-report). 
e. Quality of life. Past 30 day health-related quality of life as measured by EQ-5D at week 
24. 
3) ART Adherence Mediation Variables: 
a. Days of Opioid Use. Number of days of opioid use since baseline, measured by Timeline 
Followback at 24 weeks (count; self-report). 
b. Opioid Abstinence. Past 30 day opioid abstinence (by Addiction Severity Index (ASI)-lite 
self- report, Time-Line Follow-Back (TLFB) and urine drug screen (UDS) confirmation) in 
the final 30 days of the 24 week trial (binary; self-report + UDS). 
 
Sample Size and Duration of Recruitment Phase 
The CTN-0067 CHOICES scale-up trial will randomize 350 participants with opioid use disorder 
who are unsuppressed at baseline from no more than 8 sites over approxmiately 22 months for a 
power of 80%. Justification for this decision follows. 
The trial will be powered as a non-inferiority trial since the overall goal of the research is to add 
to rather than to supplant the available effective opioid agonist treatment options currently 
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Substantive Justification for a Non-Inferiority Design. 
A non-inferiority trial and the attendant choice of margin must be justified not just statistically, but 
also on substantive grounds. A non-inferiority trial design is justified when the active control is 
well-established and effective, and when a non-active control would be unethical, as in the case 
of treatments for HIV infection [165]. Both conditions are salient to the CTN-0067 CHOICES scale-
up study in that opioid agonist therapy with buprenorphine or methadone is considered the 
standard of care for treatment of opioid dependence in HIV infected patients [104], and placebo 
treatments for either opioid use disorder or HIV infection are unethical. 
Reporting of non-inferiority methods must include [165, 166]:  
• 
Non-inferiority margin (delta) 
• 
Sample size calculation must take into account the margin 
• 
Both ITT and per-protocol analyses must be presented 
• 
Confidence intervals for the results must be presented 
• 
Justification of the margin 
The first 4 points have been addressed in other parts of this statistical section. The following 
section describes the justification for the margin. 
 
Justification of the Non-Inferiority Margin 
Little data exist to inform justification of non-inferiority margins. Given that our primary outcome 
measure is viral suppression, we reviewed recent non-inferiority trials comparing two antiretroviral 
regimens with viral suppression as the outcome. Noninferiority margins in these trials ranged from 
10% to 15% [114, 167-169], though no published justification is provided for these estimates. 
The only study to estimate virologic suppression in HIV-infected participants receiving BUP/NX 
was the BHIVES collaborative. BHIVES was an observational study of HIV-infected participants 
with opioid use disorder receiving office-based BUP/NX from their HIV providers. Participants not 
already on ART baseline were offered ART regimens available in 2004-2007, which were less 
potent than currently available regimens. Among 64 participants who were not prescribed ART at 
baseline and who were prescribed BUP/NX for at least 3 quarters, 57.3% achieved HIV viral 
suppression by 6 months (a timeframe comparable to CHOICES 24-week outcome) [29]. More 
information about the choice of margin is given in the following section on Power results. 
 
 
Rationale for Sample Size 
Figure 4 shows the non-inferiority margin required for power of (0.8, 0.9) (using the lower tail of 
the two-sided 95% confidence interval) as a function of the sample size for the non-inferiority test 
of XR-NTX versus TAU at 4 months, as estimated from data “random-assignment-bootstrapped” 
from the (opioid + overlap) group who were unsuppressed at baseline in the pilot study (CTN-
0055). There are only 9 participants in the bootstrap population: 7 in Core and 2 in UBC. The 
random-assignment bootstrap approach was used at 4 months as a conservative way to estimate 
power in the scale-up (see appendix). The margin is expressed in terms of the risk ratio (RR), that 


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is, Pr(suppressed | XR-NTX) / Pr(suppressed | TAU)1. A horizontal reference line in Figure 4 
marks RR = 0.75, and vertical reference lines mark the intersection of the horizontal line with the 
power curves for (0.8, 0.9). The vertical lines intersect the N axis at sample sizes of about (350, 
480). For a given sample size, use of a margin at or below the one specified by the relevant 
curved line will grant power in excess of that depicted by the line. For example, an RR margin 
less than or equal to 0.75 will grant a power of at least 90% for total sample size (both arms 
together) of about 480, and will grant a power of at least 80% for total sample size of 350. We 
have chosen this last point upon which to base our sample size. 
This particular example is calculated using the Rose et al. binary RMVL model. The fixed effects 
in the model are treatment, visit number (continuous), time by treatment interaction, baseline 
alcohol, and site (categorical). The data for each participant are assumed to have an 
exchangeable correlation structure. Missing data are assumed to be unsuppressed. Note that 
cases in which the model failed to converge or converged but SAS flagged the result as 
questionable have been dropped from this analysis. The number of analyzed iterations was (9020, 
9492, 9696, 9819, 9848, 9869, and 9911) for n = (200, 250, 300, 350, 400, 450, 500), respectively. 
With the assumptions above, a non-inferiority sample size calculation was performed using 
commercial software PASS and got very similar results. 
 
Figure 4.  Non-inferiority margins granting power = 0.8 and 0.9 as a 
function of sample size 
 
 
Additional Comments Concerning Choice of RR margin 
The reasoning in the non-inferiority margin calculation of a RR of 0.75 is as follows: 
                                                
 
 
 
1 As we define it here, RR might better be termed a “benefit ratio,” but we shall retain the common usage. 


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Recall from above that, in BHIVES, 57.3% achieved HIV viral suppression. Let us assume that, 
in the absence of any treatment for OUD, the suppression rate will be about 15%, so that the 
treatment effect of the active control in CHOICES is about 42%. It makes intuitive sense that the 
non-inferiority margin should be some fraction of this, and this general approach is discussed by 
the FDA in their Guidance for Industry on Non-inferiority Clinical Trials [170]. We have chosen 
1/3 as the clinically reasonable fraction. That is, if XR-NTX preserves 2/3 or more of the effect of 
BUP/NX over placebo, we will consider XR/NTX to be non-inferior to BUP/NX. This implies a 
margin of 14%. With this margin, we are implicitly saying that, if the true suppression probability 
for BUP/NX is 57%, then we consider any true XR/NTX suppression probability greater than 43% 
to indicate that XR/NTX is not inferior to BUP/NX. 
To turn this reasoning into a RR calculation, NTX is non-inferior if the observed risk ratio 
significantly exceeds 43/57=0.75. 
The RR we can be derived from the pilot study data. There are 9 in the opioid + overlap group 
who started out unsuppressed. Their last non-missing suppression status is as follows: 
 
TAU NTX 
Suppressed 
3 
2 
Unsuppressed 
2 
2 
The suppression rates from the CTN-0055 pilot study are (TAU, NTX) = (60%, 50%). To call NTX 
non-inferior, NTX needs to preserve at least 14 percentage points of the TAU suppression rate, 
which means an NTX suppression rate of at least 60%-14% = 46% is needed. This means a RR 
of at least 46/60 = 77%. This is not much different from the 43/57 = 75% discussed above. Note 
that data paucity militates against a more precise calculation of pilot study RR. 
 
Figure 5.  Implications for probabilities of fixing RR = 0.75 versus 
fixing a probability difference of 0.14 
 


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How different are the implications for probabilities if one fixes an RR at 0.75 versus a probability 
difference of 0.14? Figure 5 shows, p (suppressed | NTX) as a function of p (suppressed | TAU) 
for a risk ratio of 0.75 (red dashed line) and a probability difference of 0.14 (blue solid line), with 
a vertical reference line at p(suppressed | TAU)=0.57, where the two lines intersect. In the 
neighborhood of p (suppressed | TAU) = 0.57 (from, say 0.4 to 0.8), differences appear to be less 
than 0.05.   
 
Duration of Recruitment Period 
An enrollment simulation based on CTN-0055 data was run using only times from the study 
population of interest (opioid + overlap, not suppressed at baseline). Use of the pilot data for 
estimating duration of recruitment period is limited by the fact that the CTN-0055 CHOICES pilot 
study sites were encouraged to enroll both participants with OUD and also those with AUD. 
Enrollment of both groups occurred faster than anticipated, but the opportunity cost of enrolling 
AUD participants may have limited the observed pace of enrollment of OUD participants. 
Additionally, no attempt was made in CTN-0055 to enroll only participants with unsuppressed HIV 
viral loads. Using the pilot study data for only participants with OUD and non-suppressed HIV viral 
loads, times to recruitment assuming a target sample size of 350, drawn from sites that match the 
experience of the CTN-0055 sites (one site like UBC and 9 like CORE), are depicted in Figure 6. 
The intersecting reference lines for a sample of size 350 show that simulation suggests a 
recruitment period of about 1324 days = 44 months. We anticipate that expanding CTN-0067 to 
include 6-8 sites with a higher prevalence of HIV viral non-suppression among patients with 
untreated opioid use disorder will allow recruitment of 2 to 3 participants per month per site, thus 
requiring 22 months to recruit 350 participants. 
 
Figure 6.  Simulated times to enrollment of 350 participants from 8 
sites like CORE Center. 
 
 
 


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Analysis of secondary outcomes 
Secondary outcomes will be analyzed as indicated in the italicized text describing each secondary 
endpoint. 
 
1) Secondary HIV outcomes: 
a. Change in VACS index at week 24 compared with randomization (score based on lab 
measurements). T-test.   
b. Change in CD4 count at 24 weeks following randomization compared with 
randomization (count; laboratory measurement). T-test. 
2) Engagement in HIV Care: 
a. ART prescribed Change in the proportion of study participants prescribed ART within 
24 weeks following randomization, compared to baseline (binary; medical record 
abstraction). Each individual can be scored either 0 (not prescribed ART) or 1 
(prescribed ART) at both baseline and follow-up, after which his or her outcome score 
will be the follow-up score minus the baseline score. Outcome scores will be analyzed 
via rank-based methods such as Wilcoxon rank-sum tests. Covariates can be 
considered via the cumulative logit model. 
b. ART Adherence Proportion of participants taking 100% of prescribed ART doses in the 
past month at 24 weeks for those prescribed ART at any point during the 24 week trial 
(proportion; self-reported medication adherence measure). Chi-squared test comparing 
proportion to treatment assignment, for those prescribed ART.  
c. Retention in HIV Care Number of HIV primary care visits at 24 weeks (count, chart 
abstraction). Outcome scores will be analyzed via rank-based methods such as 
Wilcoxon rank-sum tests. 
d. HIV Risk Behaviors Past 30 day injection drug use, unprotected sex, multiple sexual 
partners as measured by the RAB at week 24 (binary; self-report). Chi-squared test 
comparing proportion to treatment assignment. 
e. Quality of life Past 30 day health-related quality of life as measured by EQ-5D at week 
24. Change from baseline in mean EQ5D score assessed by treatment group using 
paired t-test, or analysis of change via ordinary least squares. 
3) ART Adherence Mediation Variables and Mediation Analysis: 
a. Days of Opioid Use Number of days of opioid use between baseline and 24 weeks, 
measured by TLFB (count; self-report), will be used to compare opioid use by treatment 
group.   Confirmatory analysis will assess opioid use by the number of days of opioid 
use in the last 30 days of the study (by ASI-lite; count; self-report) and the number of 
monthly urine drug screen (UDS) negative for opioids between baseline and 24 weeks 
(count; laboratory data). Analyzed using rank-based methods such as Wilcoxon rank-
sum tests. 
b. Opioid Abstinence Past 30 day opioid abstinence (by Addiction Severity Index (ASI)-
lite self-report, Time-Line Follow-Back (TLFB) and urine drug screen (UDS) 
confirmation) in the final 30 days of the 24 week trial (binary; self-report + UDS). 


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Analyzed via rank-based methods such as Wilcoxon rank-sum tests. Covariates can be 
considered via the cumulative logit model. 
Mediation Analysis   
Mediation will be tested using structural equation 
modeling with Mplus 7.3. These models estimate 
the effect of the intervention on the potential 
mediator (path a, e.g., the effect of intervention 
on substance use) and the effect of the mediator 
on the outcome or next proximal intermediate 
outcome (path b, e.g., the effect of substance 
use on HIV medication adherence). Longer 
mediation pathways can also be tested (e.g., 
a*b*c), and therefore the entire mediational path 
depicted in section 1.2.1 can be assessed in this 
framework. There is significant mediation if the 
product of these two paths (a*b) is greater than 
zero (or the product of more pathways in a longer mediational chain). Statistical significance will 
be assessed using bias-corrected bootstrap confidence intervals on the product terms [171]. This 
test is by far the most powerful test of mediation [172] and can test multiple mediating pathways 
within a single structural model. Using the tables in Fritz and MacKinnon [171], we should have 
over 80% power for mediation when the standardized path coefficients (a and b) are .164, which 
corresponds to approximately 2.7% shared variance between the outcome and predictor variable 
(e.g., treatment and substance for the a-path in the example given above.) We will also examine 
whether there are differences in strength of mediational pathways across the opioid and alcohol 
disorder subgroups. 
Qualitative Analysis of Implementation Data The qualitative team creates a coding scheme, 
practices coding, and revises in an iterative group process. Each transcript is coded and check-
coding is completed with 20% of transcripts to ensure inter-coder reliability. The analysis uses a 
deductive approach to focus on themes related to select CFIR inner and outer setting, provider 
characteristics, and implementation characteristic domains. Iterative analyses assess 
convergence of CFIR patient, provider and organizational dimensions on study measures as well 
as the context of the policy subsystems, cross-system interactions, and resource allocation. A five 
phase strategy guides the analysis: describe themes, organize and structure data, connect codes 
and themes, corroborate and triangulate, and condense and summarize findings [173]. Site 
structural data will be triangulated with staff and patient qualitative interviews to integrate an 
environmental perspective. 
 
Additional Statistical Tests of the Secondary Outcomes 
In addition to the methods described after each secondary outcome, statistical modeling will be 
done using generalized estimating equations (GEEs) models as employed by Liang and Zeger 
[174] to allow covariate adjustment in factors such as concomitant alcohol use disorder and 
severity of opioid and alcohol use disorder. Those secondary outcomes that are binary will be 
tested with a binomial distribution and logit link as implemented in SAS; whereas those secondary 
outcomes that involve either continuous or ordinal variables will utilize the appropriate distribution 
and link function. Note that the exact method of analysis will depend on the realized distribution 
of the particular outcome in this trial. For example, an expected count data variable may need to 
be modeled using a zero-inflated Poisson regression rather than a standard Poisson regression 
if there are too many zero observations to fit the standard Poisson. If there is over-dispersion, a 
Hypothesized
Mediator
Treatment
Group
Outcome
a
b


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negative binomial (or zero-inflated negative binomial) regression may be appropriate. For these 
secondary analyses, the overall Type I error will not be controlled. 
 ITT and Per-Protocol Analyses, Missing Data and Dropouts 
Analysis will be ITT in the sense that participants will be analyzed as being members of the arm 
to which they were originally randomized. With one exception, we plan in the primary analysis to 
recode missing data to “unsuppressed” because, in this setting, this seems more realistic than 
assuming that missingness is non-informative for suppression. The exception is that, if missing 
data are flanked on both sides by “suppressed” values, we will impute the missing data to be 
suppressed. Sensitivity analyses will secondarily explore the implications of this MNAR 
imputation, and outcomes according to treatment received. Per-protocol sensitivity analyses will 
compare outcomes among those who initiated at least one dose of XR-NTX compared with those 
who initiated at least one dose of buprenorphine or methadone. 
 Interim Monitoring of Primary Efficacy Endpoint 
Interim monitoring will be performed of the primary alternative hypothesis that XR-NTX is non-
inferior to TAU at 6 months of follow-up, using a non-inferiority risk ratio of RR = 
Pr(suppressed|NTX)/Pr(suppressed|TAU) = 0.75. There will be no interim efficacy monitoring 
before 1/3 the participants have attained 24 weeks of follow-up and a sample size-re-estimation 
is performed (see the sample size re-estimation section below). Assuming the re-estimation does 
not call for a change in sample size (which would have to be ratified by the DSMB and approved 
by NIDA), we will on every subsequent DSMB meeting perform interim efficacy monitoring. All 
interim monitoring will use an O’Brien-Fleming-type boundary with information fraction equal to 
the proportion of the target sample size with primary outcome, and alpha = 0.025, one-tailed. 
Before recommending early termination, the DSMB will consider: 
• 
Internal consistency of primary and secondary results. 
• 
Internal consistency of primary and secondary results by subgroups defined by baseline 
characteristics.  
• 
Distribution of baseline prognostic factors among the two groups. 
• 
Consistency of primary and secondary results across sites and among sites enrolling 
larger numbers of participants. 
• 
Possible bias in assessment of primary and secondary response variables. 
• 
Possible impact of missing data from missed participant visits for assessment of the 
primary and secondary response variables. 
• 
Possible differences in concomitant interventions or medications. 
Sample Size Re-estimation 
We plan to also perform a sample size re-estimation after about 1/3 off the total expected number 
of participants (n=116) attain their 24 week outcome, which is approximately 13 months into 
enrollment. The motivation for sample size re-estimation is that the original sample size 
calculation was based not only on a hypothesized treatment effect, but also on assumptions about 
nuisance parameters such as variances and attrition. In the case of CTN-0067, these nuisance 
parameter estimates are implicitly contained in the Random Assignment Bootstrapping approach 
we adopted for our sample size calculation, based on pilot data from CTN-0055. It seems 
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The Randomized Assignment part of the Bootstrap approach, when applied to these 
observations, will automatically suppress the observed treatment effect in favor of one 
representing the design alternative. 
The timing of the sample size re-estimation is based on a number of factors: recruitment rate, 
timing of primary outcome, and time to perform the sample size re-estimation. For CTN-0067, we 
use the graphical tool presented in Figure 7 to assist in assessing the appropriate timing of 
sample size re-estimation. To illustrate, Figure 7 shows in a picture the timing of re-estimation 
when 33% of the participants have outcome data [information fraction = 0.33 (N=116) on the red 
line] and assuming enrollment (blue line) in CTN-0067 of 350 participants over a 22-month period. 
This time period to perform the sample size re-estimation corresponds to approximately 13 
months after enrollment into CTN-0067 has started, at which point, the study will have enrolled 
about 60% of the target sample size. If recruitment takes longer or shorter than expected, 
modifications can be made to the timing of the sample size re-estimation. 
 
Figure 7.  Information Fraction and Fraction of Target Enrollment for 
Proposed Sample Size Re-Estimation Based on Months from Start 
of Enrollment 
 
 Conditional Power and Futility 
Unless otherwise requested, we will perform a futility/conditional power calculation every time we 
do interim monitoring. If at any DSMB meeting the conditional power falls below 0.3 (when 
hypothetical future observations are generated under the design alternative RR=1 but tested 
under the null RR ≤ 0.75), this will stimulate a discussion among the DSMB members about 
whether we should stop for futility. The conditional power calculation may be carried out via 
Random Assignment Bootstrapping, similar to the sample-size re-estimation procedure, except 
that in conditional power, one uses the data already gathered in two ways: first, one includes it in 
every iteration unchanged as part of the simulated final sample, and second, one Random-
Fraction of Target Enrolled
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from Start of Enrollment
0
12
24
36
Information Fraction
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
End of enrollment
13.3  months to hit 0.33 IF
0.33 Information Fraction. N=116
0.60 Enrollment at 0.33 IF. N=211
Fraction of Target Enrolled
Fraction of Target with Complete Follow-up


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Assignment Bootstraps from it to form the rest of the simulated final sample. In contrast, when 
one re-estimates the sample size, the entire simulated final sample of each iteration is drawn from 
the already-gathered sample via Random-Assignment Bootstrapping. 
 Safety Analysis 
Adverse events (AEs), including serious adverse events (SAEs), will be summarized by body 
system and preferred term using MedDRA (The Medical Dictionary for Regulatory Activities). 
Adverse events will be presented in two ways: (1) the number and proportion of participants 
experiencing at least one incidence of each event will be presented overall and by treatment 
group; and (2) a table displaying the total number of each event will be given overall and by 
treatment group. Listings of serious adverse events will be given, sorted by treatment, body 
system, and preferred term. Detail in these listings will include severity, relationship to study 
drug, and action taken as available. Treatment arm differences will be monitored by the DSMB. 


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18.0 REGULATORY COMPLIANCE AND SAFETY 
 
Regulatory Compliance 
This study will use a commercial IRB as the central IRB of record. Sites will be expected to 
execute an IRB Authorization Agreement between their local IRB and the central IRB. For sites 
whose IRBs will not rely on the central IRB, procedures will be developed on a case-by-case 
basis.  
Prior to local study initiation, site investigators will obtain written IRB approval (in most cases this 
will consist of an IRB Authorization Agreement) to conduct the study at their respective sites. 
When changes to the study protocol become necessary, amendments will be submitted to the 
central IRB in writing by the investigators for IRB approval prior to implementation. Annual reports 
will be submitted to local IRBs as required by local guidelines. Each site investigator is responsible 
for maintaining research files that include copies of IRB-approved consent documents and all 
IRB/IEC (Institutional Ethics Committee) approval memos for Initial and Continuing/Annual 
Reviews, protocol modifications, and any other modification made in the course of the study. All 
initial approval documents (approval memos and informed consents) must be provided to the 
Lead Node investigative team prior to the initiation of research activities at a given site and all 
regulatory documents must be available at any time for an audit. 
The study will be registered in www.ClinicalTrials.gov.  
 
Statement of Compliance 
This trial will be conducted in compliance with the current version of the protocol, current Good 
Clinical Practice (GCP), the principles of the Declaration of Helsinki, and all other applicable 
regulatory requirements. Participating sites must obtain written approval of the study protocol, 
informed consent forms, other supporting documents, and any advertising for participant 
recruitment from their local institutional review board (IRB) in order to participate in the study. This 
approval is expected to consist of an IRB Authorization Agreement between the local IRB and the 
central IRB. Prior to study initiation, the protocol and the informed consent documents will be 
reviewed and approved by an appropriate Ethics Review Committee (ERC) or IRB. Any 
amendments to the protocol or consent materials must be approved by the central IRB before 
they are implemented. Annual progress reports and local Serious Adverse Event (SAE) reports 
will be submitted to each IRB, according to its usual procedures for studies operating under an 
IRB Authorization Agreement. 
 
Confidentiality 
By signing the protocol signature page, the investigator affirms that information furnished to the 
investigator by NIDA will be maintained in confidence and such information will be divulged to the 
IRB, Ethics Review Committee, or similar expert committee; affiliated institution; and employees 
only under an appropriate understanding of confidentiality with that board or committee, affiliated 
institution and employees. This study will be covered by a federal Certificate of Confidentiality 
(CoC) protecting participants against disclosure of sensitive information (e.g., drug use). The NIH 
office that issues the CoC will be advised of changes in the CoC application information. 
Participating sites will be notified if CoC revision is necessary. 
Participant records will be kept confidential by the use of study codes for identifying participants 
on CRFs, secure and separate storage of any documents that have participant identifiers, and 
secure computer procedures for entering and transferring electronic data. 


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Health Insurance Portability Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. The Lead Node will be responsible for communicating with the 
IRB and obtaining the appropriate HIPAA approvals or waivers to be in regulatory compliance. 
 
Investigator Assurances 
Each IRB that relies on the central IRB must have on record a Federalwide Assurance (FWA) 
with the HHS Office of Human Research Protection. This sets forth the commitment of the 
organization (SITE or IRB) to establish appropriate policies and procedures for the protection of 
human research subjects, with documentation to be sent to NIDA or its designee. Research 
covered by these regulations cannot proceed in any manner prior to NIDA’s receipt of certification 
that the research has been reviewed and approved by the IRB provided for in the assurance (45 
CFR 46.103(b) and (f)). Prior to initiating the study, the principal investigator at each study site 
will sign a protocol signature page, providing assurances that the study will be performed 
according to the standards stipulated therein. 
 
Research Advisory Panel of California  
Prior to initiating the study, the sponsor or designee will obtain written approval from the Research 
Advisory Panel of California (RAP-C) if any selected sites are in California. Any planned research 
project to be conducted in California requiring the use of a Schedule I or Schedule II Controlled 
Substance as its main study medication as well as research for the treatment of controlled 
substance addiction or abuse utilizing any drug, scheduled or not must be submitted to RAP-C 
for review and approval prior to study start-up. Study approval is based on review of the study 
protocol, consent form, and other pertinent study documents. Yearly reports will be provided to 
the RAP-C by the sponsor or designee in order to obtain continuing study approval. 
 
Financial Disclosure 
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. It is the responsibility of the investigator and the entire local research team to maintain 
appropriate disclosure to their individual institution according to their requirements. 
 
DEA Registration 
XR-NTX is not a controlled substance. No DEA registration is required for facilities to receive, 
prescribe or dispense study drug. 
 
Drug Accountability 
Upon receipt, the investigator, pharmacist, or authorized designee at each site is responsible for 
taking inventory of the study drug. A record of this inventory must be kept and usage must be 
documented. Any unused or expired study drug must be accounted for. 
 Inclusion of Women and Minorities 
Unless specified in the eligibility criteria, the study enrollment is open to any gender, race, or 
ethnicity. A diverse group of study sites will be involved so that the study can enroll a diverse 
study population. If difficulties are encountered in recruiting an adequate number of women and/or 


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minorities, these will be discussed in national conference calls and face-to-face meetings, 
encouraging such strategies as linkages with medical sites and/or treatment programs that serve 
a large number of women or minorities or advertising in newspapers or radio stations with a high 
female or minority audience. 
 IND Requirement 
Medications to be used in this study will be used in accordance with their approved labeling and 
therefore there is no plan to submit an IND application. 
 Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be available at each participating site for 
inspection and compliance monitoring prior to study initiation, throughout the study, and at study 
closure. 
 Records Retention and Requirements 
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, and regulatory files) are to be maintained by the investigator in a secure location 
for a minimum of 3 years after the study is complete and closed. These records are also to be 
maintained in compliance with local IRB, state, and federal requirements, whichever is longest. 
In the case of HIPAA-protected records, this time length is six years. The sponsor and lead 
investigator must be notified in writing and acknowledgment must be received by the site prior to 
the destruction or relocation of research records. 
 Audits 
The sponsor has an obligation to ensure that this trial is conducted according to good research 
practice guidelines and may perform periodic quality assurance audits for protocol compliance. 
The Lead Investigator and authorized staff from the National Lead Study Team; the National 
Institute on Drug Abuse Clinical Trials Network (NIDA CTN, the study sponsor); NIDA’s contracted 
agents, monitors, or auditors; and other agencies such as the Department of Health and Human 
Services (HHS), the Office for Human Research Protection (OHRP) and the sites’ Institutional 
Review Board may inspect research records for verification of data, compliance with federal 
guidelines on human participant research, and to assess participant safety. 
 Reporting to Sponsor 
The site principal investigator agrees to submit accurate, complete, legible and timely reports to 
the Sponsor, as required. These include, but are not limited to, reports of any changes that 
significantly affect the conduct or outcome of the trial or increase risk to study participants. 
Adverse Event and Serious Adverse Event reporting will occur as described in Appendix A - 
Adverse Event Reporting Definitions and Procedures. At the completion of the trial, the national 
Lead Investigator will provide a final report to the Sponsor. 
 Informed Consent 
The informed consent process is a means of providing study information to each prospective 
participant and allows for an informed decision about participation in the study. All potential 
candidates for the study will be given a current IRB-approved copy of the Informed Consent Form 


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to read. Appropriately qualified and trained study personnel will explain all aspects of the study in 
lay language and answer all of the study candidate’s questions. Participants who remain 
interested after receiving an explanation of the study will be given an informed consent quiz to 
test his/her understanding of the trial, the purpose and procedures involved, and the voluntary 
nature of his/her participation. Those who cannot successfully answer the quiz questions will have 
the study re-explained by research staff with a focus on those aspects they did not understand. 
Anyone who cannot demonstrate appropriate understanding of the study will be ineligible to 
participate and will be assisted in finding other treatment resources. Those who demonstrate 
understanding of the study and voluntarily agree to participate will be asked to sign the Informed 
Consent Form. Participants will not be administered any assessments or study procedures prior 
to signing the informed consent form. 
For this study, there will be three consents. There will be two consents for the primary study: one 
for pre-screening and one for trial consent. The pre-screening consent is verbal only while the 
trial consent is written and must be signed and dated by the participant. A verbal consent (i.e., 
waiver of written consent) will also be required for the qualitative interview portion of the study. All 
consents are to be treated equally in terms of regulatory and protocol requirements (e.g., 
approved by the IRB before site initiation, etc.). 
Study sites may use the template approved by the central IRB. A copy of the IRB-approved 
consents, along with the IRB study approval, must be sent to the Clinical Coordinating Center 
(CCC) and the Lead Node prior to the site initiation visit and with each subsequent consent 
revision. The Informed Consent Form must be updated or revised whenever important new safety 
information is available or whenever the protocol is amended in a way that may affect a study 
participant’s participation in the trial. The site must maintain the original and signed Informed 
Consent Form for each participant in a locked and secure location that is in compliance with IRB 
and institutional policies. The consent forms must also be accessible for quality assurance review 
and regulatory compliance. Every study participant should be given a copy of the signed 
document to keep for their reference. Individuals who refuse to participate or who withdraw from 
the study will be treated without prejudice. 
 Clinical Monitoring 
Monitoring of the study site will be conducted on a regular basis using a combination of NIDA- 
contracted monitors and node Quality Assurance (QA) staff. Investigators will host periodic visits 
by both the NIDA-contracted monitors and local QA site managers; the purpose of which is to 
encourage and assess compliance with GCP requirements and to document the integrity of the 
trial progress. The national and local monitors will audit the following items, but not exclusively: 
regulatory documents, case report forms, Informed Consent Forms, and any corresponding 
source documents for every participant. Monitors will have the opportunity and ability to review 
any study-associated document or file. 
NIDA-contracted monitors will assess whether submitted data are accurate and in agreement with 
source documentation and will also review regulatory/essential documents such as 
correspondence with the IRB. Areas of particular concern will be participant Informed Consent 
Forms, protocol adherence, reported safety events and corresponding assessments, study drug 
accountability, and principal investigator oversight and involvement in the trial. Reports will be 
prepared following the visit and forwarded to the site principal investigator, the lead investigator 
and NIDA CCTN. 
Qualified node personnel will provide site management and monitoring for each site during the 
trial. This will take place as specified by the local protocol team, node PI, or full Lead Team and 


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will occur as often as needed to help prevent, detect, and correct problems at the study sites. 
Node (QA) staff will audit source documentation, including all Informed Consent and HIPAA forms 
(if applicable). Node QA staff will verify that study procedures are being properly followed and that 
site staff is trained and able to conduct the protocol appropriately. If the node QA staff’s review of 
study documentation indicates that additional training of study personnel is needed, node QA staff 
will undertake or arrange for that training. Details of the contract, node QA, and data monitoring 
are found in the study monitoring plan. 
 Study Documentation 
Study documentation includes all case report forms, workbooks/worksheets, source documents, 
monitoring logs and appointment schedules, sponsor-investigator correspondence, signed 
protocol and amendments, Ethics Review Committee or Institutional Review Board 
correspondence and approved current and previous consent forms and signed participant 
consent forms. 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. The original recording of an observation should be retained as the source document. If 
the original recording of an observation is the electronic record, that will be considered the 
source. 


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19.0 SAFETY MONITORING 
 
Data and Safety Monitoring Board (DSMB) 
This study will utilize the CTN DSMB to oversee ongoing trial progress to assure protection of 
participants’ safety while maintaining that the study’s scientific goals are being met. The CTN 
DSMB is responsible for conducting periodic reviews of accumulating safety and efficacy data. It 
will determine whether there is support for continuation of the trial, evidence that study procedures 
should be changed, or if the trial should be halted (for safety, efficacy, or recruitment or 
performance reasons). This process is intended to assure the IRBs, sponsor, and investigators 
that participants are provided with an accurate and ongoing risk evaluation when participating in 
CTN research trials. 
Monitoring will begin with the initial review of the protocol during the study development process 
and continue throughout the study with meetings at least annually. Recommendations and reports 
from these reviews will be distributed to the site lead investigator for submission to their IRB. 
 
Protocol Deviations Reporting and Management 
Any departure from procedures or requirements outlined in the protocol will be classified as 
protocol deviations. A protocol deviation is an action (or inaction) that alone may or may not affect 
the scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a 
study participant. In some cases, a protocol deviation may compromise participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and is cause for 
corrective action to resolve the departure and to prevent re-occurrence. Protocol deviations will 
be monitored at each site for (1) significance, (2) frequency, and (3) impact on the study 
objectives, to ensure that site performance does not compromise the integrity of the trial. The 
decision about whether a deviation from the protocol will be designated as minor or major will be 
made by the Clinical Coordinating Center (CCC) in conjunction with the protocol's Lead 
Investigator(s). The consequences will be specified and participating sites will be informed. 
All protocol deviations will be recorded in the Electronic Data Capture (EDC) system via the 
Protocol Deviation CRF. The CCC, DSC, and the Lead Investigator must be contacted 
immediately if an unqualified or ineligible participant is randomized into the study. 
Additionally, each site is responsible for reviewing the IRB of record’s (and their local IRB’s, if 
applicable) definition of a protocol deviation or violation and understanding which events need to 
be reported. Sites must recognize that the CTN and IRB definition of a reportable event may differ 
and act accordingly in following all reporting requirements for both entities. Sites must also 
recognize that operating under an IRB Authorization Agreement may not excuse them from 
reporting Protocol Deviations to their local IRBs. Sites are expected to communicate with their 
IRB as necessary, according to local guidelines.  
 
Adverse Events (AEs) 
The Lead Investigator may appoint a study clinician (MD, DO, NP or PA) for this study, who will 
review or provide consultation for each serious adverse event as needed. These reviews will 
include an assessment of the severity and causality of the event to the study intervention (drug 
or therapy) or other study procedures. The study clinician will also provide advice for decisions to 
exclude, refer, or withdraw participants as required. In addition, NIDA will assign a centralized 
Medical Monitor to this protocol to independently review the safety data, present it to the DSMB 
for periodic review, and provide PIs a Safety Letter when necessary for submission to IRBs for 


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regulatory compliance. The Medical Monitor will determine which safety events require expedited 
reporting to NIDA, the DSMB, pharmaceutical/distributors, and regulatory authorities. This will 
include events that are serious, related, and unexpected. The study staff will be trained to monitor 
for and report Adverse Events and Serious Adverse Events. 
 
Adverse Events 
For the purposes of this study, mild (Grade 1) and unrelated Adverse Events will not require 
reporting in the data system. All adverse events will be tracked on a manual (paper only) Adverse 
Event Log, regardless of severity, seriousness, relatedness, or expectedness.  
 
Serious Adverse Events 
For the purpose of this study, the following events will not be reported as an SAE, but will be 
recorded on study specific forms in the data system.   
1) 
Detox admissions (documented instead on the DTX form). 
2) 
Admission for labor and delivery (documented instead on the Confirmed Pregnancy and 
Outcomes form). 
3) 
Admission for elective or pre-planned surgery. 
The Lead Node will report all other SAEs on the Serious Adverse Event form in the data system 
Sites must determine if local IRBs will require annual or other SAE reporting. 
 
Known Potential Toxicities of Study Drug/Intervention 
Refer to the package insert for XR-NTX. 
 
Known Potential Adverse Events Related to the Underlying Clinical 
Condition and/or Study Populations 
Each of the participating research sites has established practices for managing medical and 
psychiatric emergencies, and the study staff will continue to utilize these procedures. Treatment 
providers at each research site will be responsible for monitoring participants for possible clinical 
deterioration or other problems, and for implementing appropriate courses of action. 
As this population will have significant ongoing health and substance use issues, events related 
to complications of HIV, substance use treatment or admission for substance detoxification will 
be captured on study-specific forms and not duplicately reported as an adverse or serious adverse 
event. All hospitalizations for other (non-HIV, non-substance-use related) medical, surgical and 
psychological reasons and deaths will be reported on AE/SAE forms. These data will still be 
included in the reports to the DSMB at the regular meetings. 
 
 


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20.0 DATA SAFETY MANAGEMENT AND PROCEDURES 
 
Design and Development 
This protocol will utilize a centralized Data and Statistics Center (DSC). The DSC will be 
responsible for development of the electronic case report forms (eCRFs), development and 
validation of the clinical study database, ensuring data integrity, and training site and participating 
node staff on applicable data management procedures. Advantage eClinical, a web- based 
distributed data entry system, will be implemented. This system will be developed to ensure that 
guidelines and regulations surrounding the use of computerized systems used in clinical trials are 
upheld. The remainder of this section provides an overview of the data management plan 
associated with this protocol. 
 
Site Responsibilities 
The data management responsibilities of each individual site will be specified by the DSC and 
outlined in the Advantage eClinical User’s Guide. 
 
Data Center Responsibilities 
The DSC will 1) develop a data management plan and will conduct data management activities 
in accordance with that plan, 2) provide final guided source documents and eCRFs for the 
collection of all data required by the study, 3) develop data dictionaries for each eCRF that will 
comprehensively define each data element, 4) conduct ongoing data monitoring activities on 
study data from all participating sites, 5) monitor any preliminary analysis data cleaning activities 
as needed, and 6) rigorously monitor final study data cleaning. 
 
Data Collection 
Data will be collected at the study sites either on source documents, which will be entered at the 
site into eCRFs, or through direct electronic data capture. The eCRFs will be supplied by the DSC. 
eCRFs are to be completed on an ongoing basis during the study. The medical chart and the 
source documents are the source of verification of data. Paper CRFs and eCRFs should be 
completed according to the CRF instruction manual and relevant instructions in the study 
operations manual. The investigator is responsible for maintaining accurate, complete and up- to-
date records, and for ensuring the completion of the eCRFs for each research participant. 
 
Data Acquisition and Entry 
Completed forms and electronic data will be entered into the Advantage eClinical system in 
accordance with the Advantage eClinical User’s Guide. Only authorized individuals shall have 
access to eCRFs. 
 
Data Editing 
Completed data will be entered into Advantage eClinical. If incomplete or inaccurate data are 
found, a query will be generated to the sites for a response. Site staff will resolve data 
inconsistencies and errors and enter all corrections and changes into Advantage eClinical. 


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Database Lock and Transfer 
Data will be transmitted by the DSC to the NIDA central data repository as requested by NIDA. 
The DSC will conduct final data quality assurance checks and “lock” the study database from 
further modification. The final analysis dataset will be returned to NIDA, as requested, for storage 
and archive. 
 
Data Training 
The training plan for site staff includes provisions for training on assessments, eCRF completion 
guidelines, data management procedures, and the use of Advantage eClinical. 
 
Data QA 
To address the issue of data entry quality, the DSC will follow a standard data monitoring plan. 
An acceptable quality level prior to study lock or closeout will be established as a part of the data 
management plan. Data quality summaries will be made available during the course of the 
protocol. 
 
 


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21.0 PROTOCOL SIGNATURE PAGE  
SPONSOR – CCTN SCIENTIFIC OFFICER OR DESIGNEE 
 
 
 
 
 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
• 
I am in receipt of version 5.0 of the protocol and agree to conduct this clinical study in 
accordance with the design and provisions specified therein. 
• 
I agree to follow the protocol as written except in cases where necessary to protect the 
safety, rights, or welfare of a participant, an alteration is required, and the sponsor and 
IRB have been notified prior to the action. 
• 
I will ensure that the requirements relating to obtaining informed consent and institutional 
review board (IRB) review and approval in 45 CFR 46 are met. 
• 
I agree to personally conduct or supervise this investigation at this site and to ensure that 
all site staff assisting in the conduct of this study are adequately and appropriately trained 
to implement this version of the protocol and that they are qualified to meet the 
responsibilities to which they have been assigned. 
• 
I agree to comply with all the applicable federal, state, and local regulations regarding the 
obligations of clinical investigators as required by the Department of Health and Human 
Services (HHS), the state, and the IRB. 
 
SITE’S PRINCIPAL INVESTIGATOR 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
Clinical Site Name  
 
      
Node Affiliation  
 
      
 
 


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


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during the active treatment period will be discontinued from further medication administration, 
referred for medical care, and the pregnancy followed until an outcome is known. 
 
 
Medical and Psychiatric History 
A thorough medical and psychiatric history during the screening phase should record any chronic, 
acute, or intermittent preexisting or current illnesses, diseases, symptoms, or laboratory signs of 
the participant, to avoid reporting pre-existing conditions as new AEs and to assist in the 
assessment of worsening in intensity or severity of these conditions that would indicate an AE. 
Stable chronic pre-existing conditions, such as arthritis, which are present prior to clinical trial 
entry, are not considered to be AEs unless the medical clinician deems that the condition has 
worsened in intensity and/or frequency during the course of the study. 
 
Site’s Role in Eliciting and Reporting Adverse Events 
Appropriately qualified and trained study staff will elicit participant reporting of AEs and SAEs at 
each study visit designated to collect AEs. Adverse events (medical and/or psychiatric) 
assessment will initiate with participant consent and follow-up will continue through 30 days post 
last study visit. Study staff will obtain as much information as possible about the reported AE/SAE 
to complete the AE/SAE forms and will consult with the lead team as warranted. 
Standard reporting, within 7 days of the site becoming aware of the event, is required for 
reportable AEs. Expedited reporting (within 24 hours of their occurrence and/or site's knowledge 
of the event) is required for reportable SAEs (including death and life-threatening events). Local 
sites are responsible for reporting SAEs to their IRB, per their IRB’s guidelines when operating 
under an IRB Authorization Agreement. 
Site staff is required to enter reportable AEs and SAEs in the Advantage eClinical system. The 
AE form is used to capture reportable AEs (as defined in the protocol). Additional information may 
need to be gathered to evaluate serious adverse events and to complete the appropriate CRFs 
and the summary. This process may include obtaining hospital discharge reports, medical 
records, autopsy records or any other type of records or information necessary to provide a 
complete and clear picture of the SAE as well as events preceding and following the SAE. If the 
SAE is not resolved or stable at the time of the initial report or if new information becomes 
available after the initial report, follow-up information must be submitted as soon as possible. 
Reportable adverse events will be followed until resolution, stabilization or study end. Any serious 
adverse reactions will be followed until resolution or stabilization even beyond the end of the 
study. 
 
Site’s Role in Assessing Severity and Causality of Adverse Events 
Appropriately qualified and trained medical personnel will conduct an initial assessment of 
seriousness, severity, and causality when eliciting participant reporting of adverse events. A study 
medical clinician will review reportable AEs for seriousness, severity, and causality at least on a 
weekly basis. 


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Guidelines for Assessing Severity 
The severity of an adverse event refers to the intensity of the event. 
Grade 1 
Mild 
Transient or mild discomfort (< 48 hours), no or minimal medical 
intervention/therapy 
required, 
hospitalization 
not 
necessary 
(non-
prescription or single-use prescription therapy may be employed to relieve 
symptoms, e.g., aspirin for simple headache, acetaminophen for post-
surgical pain). 
Grade 2 
Moderate 
Mild to moderate limitation in activity, some assistance may be needed; no 
or minimal intervention/therapy required, hospitalization possible. 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually required; medical 
intervention/ therapy required, hospitalization possible. 
 
 
Guidelines for Determining Causality 
The study medical clinician will use the following question when assessing causality of an adverse 
event to study drug/intervention where an affirmative answer designates the event as a suspected 
adverse reaction: Is there a reasonable possibility that the study drug/intervention caused the 
event?  
Please note that for the purposes of this protocol, events assessed to be mild (Grade 1) and 
unrelated, though reportable on the manual adverse event tracking log, are not reportable in the 
electronic data capture system.   
 
Site’s Role in Monitoring Adverse Events 
Local quality assurance monitors (Node QA staff) will visit study sites and review respective study 
data on a regular basis and will promptly advise sites to report any previously unreported safety 
issues and ensure that the reportable safety-related events are being followed to resolution and 
reported appropriately. Staff education, re-training or appropriate corrective action plan may be 
implemented at the participating site when unreported or unidentified reportable AEs or serious 
events are discovered, to ensure future identification and timely reporting by the site. 
 
Sponsor’s Role in Safety Management Procedures of AEs/SAEs 
A NIDA-assigned Medical Monitor/Safety Monitor is responsible for reviewing all serious adverse 
event reports. All reported SAEs will generate an e-mail notification to the Medical Monitor, Lead 
Investigator, and designees. All SAEs will be reviewed by the Medical Monitor/Safety Monitor in 
Advantage eClinical and, if needed, additional information will be requested. The Medical Monitor 
will also report events to the sponsor and the Data and Safety Monitoring Board (DSMB). The 
DSMB will receive summary reports of all adverse events annually, at a minimum. The DSMB or 
the NIDA-assigned Medical Monitor may also request additional and updated information. Details 
regarding specific adverse events, their treatment and resolution, will be summarized by the 
Medical Monitor/Safety Monitor in writing for review by the sponsor and DSMB.  


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Regulatory Reporting for an IND study 
Not applicable as this study is not being conducted under an IND application. 
 
Reporting to the Data and Safety Monitoring Board 
The DSMB will receive a listing of AEs and summary reports of all SAEs at a frequency requested 
by the DSMB, but at least annually. Furthermore, the DSMB will be informed of expedited reports 
of SAEs. 
 
Participant Withdrawal 
The study medical clinician must apply his/her clinical judgment to determine whether or not an 
adverse event is of sufficient severity to require that the participant is withdrawn from further study 
medication administration. Extended-release naltrexone will be discontinued in participants with 
evidence of clinically significant deterioration in hepatic function and/or acute hepatitis, as 
assessed by the study clinician. The study medical clinician should consult with the site principal 
investigator, the lead investigator and/or Medical Monitor as needed. If necessary, a study 
medical clinician may suspend any trial treatments and institute the necessary medical therapy to 
protect a participant from any immediate danger. A participant may also voluntarily withdraw from 
treatment due to what he/she perceives as an intolerable adverse event or for any other reason. 
If voluntary withdrawal is requested, or the participant has been removed from the study, the 
participant will be asked to complete an end of study visit to assure safety and to document end 
of treatment outcomes and will be given recommendations for medical care and/or referrals to 
treatment, as necessary. 
 
 


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 Adverse Event Reporting Chart 
 
 
 
 
AE Identified
Standard reporting
Notify local IRB per IRB 
requirements
Serious?
AE reviewed by 
designated staff
Complete AE eCRF 
within 7 days
Expedited initial reporting within 24 
hours via AE/SAE eCRFs in EDC
EDC system will automatically 
notify Medical/Safety Monitor, Lead 
Investigator, and designees.
Study Physician reviews all 
relevant records and completes 
SAE report and documentation 
completed 
by study staff.
Complete AE and SAE 
forms in EDC system 
within 7 days. 
NO
YES
Continue follow-up and reporting 
until event is resolved or stabilized


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24.0 APPENDIX B - Data Safety and Monitoring Plan (DSMP) 
 
Brief Study Overview 
The Primary Objective of the CTN-0067 CHOICES scale-up study is to compare the effectiveness 
of HIV clinic-based XR-NTX in decreasing substance use and increasing HIV viral suppression in 
HIV-infected participants with opioid use disorder to treatment as usual (TAU) in this population. 
Details for the definitions and reporting of safety events are found in the protocol (Appendix A). 
 
Oversight of Clinical Responsibilities 
 
Site Principal Investigator 
Each participating site’s PI is responsible for study oversight, including ensuring human research 
subject protection by designating appropriately qualified, trained research staff and medical 
clinicians to assess, report, and monitor adverse events. 
Regarding safety, all Adverse Events (AEs) occurring during the course of the clinical trial will be 
collected, documented, and reported by the investigator or sub-investigators according to the 
protocol. The assessment of Adverse Events (medical and/or psychiatric) will commence at the 
time of participant consent and will continue through 30 days post last active treatment visit. 
The occurrence of AEs and Serious Adverse Events (SAEs) will be assessed at each clinic visit 
during the study. Serious adverse events will be followed until resolved or considered stable, with 
reporting to the CCC Safety Monitor/Medical Monitor through the follow-up period. 
Standard reporting, within 7 days of the site becoming aware of the event, is required for 
reportable AEs. Expedited reporting (within 24 hours of their occurrence and/or site's knowledge 
of the event) is required for reportable SAEs (including death and life-threatening events). 
 
Medical Monitor/Safety Monitor 
The NIDA Clinical Coordinating Center (CCC) Medical Monitor/Safety Monitor is responsible for 
reviewing all adverse events and serious adverse events reported. All SAEs will be reviewed at 
the time they are reported in the EDC. The Medical Monitor will also indicate concurrence or not 
with the details of the report provided by the site PI. Where further information is needed, the 
Medical Monitor/Safety Monitor will discuss the event with the site. Reviews of SAEs will be 
conducted in the Advantage eClinical data system and will be a part of the safety database. All 
AEs are reviewed on a regular basis to observe trends or unusual events. 
Reports will be generated and presented for Data Safety Monitoring Board (DSMB) meetings. 
The DSMB will receive listings of AEs and summary reports of all SAEs at a frequency requested 
by the DSMB, but at least annually. Furthermore, the DSMB will be informed of expedited reports 
of SAEs.  
 
Data and Safety Monitoring Board (DSMB) 
The NIDA CTN DSMB affiliated with this trial will be responsible for conducting periodic reviews 
of accumulating safety, trial performance, and outcome data. The DSMB will make 
recommendations to NIDA as to whether there is sufficient support for continuation of the trial, 
evidence that study procedures should be changed, or evidence that the trial (or a specific site) 


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should be halted for reasons relating to safety of the study participants or inadequate trial 
performance (e.g., poor recruitment). 
Following each DSMB meeting, the NIDA CCTN will communicate the outcomes of the meeting, 
based on DSMB recommendations, in writing to the study Lead Investigator. This communication 
detailing study safety information will be submitted to participating IRBs. 
 
Quality Assurance (QA) Monitoring 
The monitoring of the study site will be conducted on a regular basis using a combination of NIDA 
CCC contract monitors and the local Node QA monitors. Investigators will host periodic visits for 
the NIDA CCC contract monitors and Node QA monitors. The purpose of these visits is to assess 
compliance with GCP requirements and to document the integrity of the trial progress. Areas of 
particular concern will be the review of Inclusion/Exclusion criteria, participant Informed Consent 
Forms, protocol adherence, safety monitoring, IRB reviews and approvals, regulatory documents, 
participant records, study drug accountability, and Principal Investigator supervision and 
involvement in the trial. The Monitors will interact with the sites to identify issues and re-train the 
site as needed to enhance research quality. 
QA Site Visit Reports will be prepared by the NIDA CCC contract monitors following each site 
visit. These reports will be forwarded to the site Principal Investigator, the study Lead Investigator 
and NIDA. 
 
Management of Risks to Participants 
24.2.5.1 Confidentiality 
Confidentiality of participant records will be secured by the use of study codes for identifying 
participants on CRFs, secure storage of any documents that have participant identifiers, and 
secure computing procedures for entering and transferring electronic data. No identifying 
information will be disclosed in reports, publications or presentations. 
24.2.5.2 Information Meeting Reporting Requirements 
The consent form will specifically state the types of information that are required to be reported 
and the fact that the information will be reported as required. These include suspected or known 
sexual or physical abuse of a child or elders, or threatened violence to self and/or others. 
24.2.5.3 Human Subject Protection 
The study medical clinician will evaluate all pertinent screening and baseline assessments prior 
to participant randomization to ensure that the participant is eligible and safe to enter the study. 
Adverse events (AEs) and concomitant medications will be assessed and documented at each 
clinic visit. Individuals who experience an AE that compromises safe participation will be 
discontinued from further medication administration and provided referrals for other treatment or 
to specialized care. Study personnel will request that the participant complete an end of study 
visit to assure safety and to document end of treatment outcomes. 
24.2.5.4 Pregnancy 
Pregnancy is an exclusion criterion for study participation. A positive pregnancy test post- 
randomization will result in the cessation of study medication. Participants who discontinue 
medications will be expected to continue with study visits. Pregnancy test results and related 
outcome information will be collected on a Pregnancy and Outcome CRF. The site staff will follow 
the participant until an outcome of the pregnancy is known. 


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24.2.5.5 Study Specific Risks 
XR-NTX blocks the effects of exogenous opioids after administration. After treatment, participants 
are likely to have reduced tolerance to opioids. Following Vivitrol® treatment, opioid use at the end 
of a dosing interval or after missing a dose could result in potentially life-threatening opioid 
intoxication (involving respiratory compromise or arrest, circulatory collapse, etc.) Attempting to 
overcome the blockade effects of Vivitrol® by administering large amounts of exogenous opioids 
is associated with potential risk of opioid overdose. Participants in this study will receive an 
information card that will notify clinicians that they are receiving XR-NTX as part of a research 
study. 
 
Data Management Procedures 
This protocol will utilize a centralized Data and Statistics Center (DSC). A web-based distributed 
data entry model will be implemented. This electronic data capture system (Advantage eClinical) 
will be developed to ensure that guidelines and regulations surrounding the use of computerized 
systems in clinical trials are upheld. 
 
Data and Statistics Center Responsibilities 
The DSC will: 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide source documents and electronic Case Report Forms 
(eCRFs) for the collection of all data required by the study, 3) develop data dictionaries for each 
eCRF that will comprehensively define each data element, 4) prepare instructions for the use of 
Advantage eClinical and for the completion of eCRFs, 5) conduct ongoing monitoring activities on 
study data collected from all participating sites, and 6) perform data cleaning activities prior to any 
interim analyses and prior to the final study database lock. 
 
Data Collection and Entry 
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical, or will be collected via direct entry into the eCRF. In the event that 
Advantage eClinical is not available, the DSC will provide the sites with paper source documents 
and completion instructions. Data will be entered into Advantage eClinical in accordance with the 
instructions provided during project-specific training and guidelines established by the DSC. Data 
entry into the eCRFs shall be performed by authorized individuals. Selected eCRFs may also 
require the investigator’s electronic signature. 
The investigator at the site is responsible for maintaining accurate, complete and up-to-date 
research records. In addition, the investigator is responsible for ensuring the timely completion of 
eCRFs for each research participant. 
 
Data Monitoring, Cleaning and Editing 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and forms are available to sites at all times in Advantage eClinical. These 
reports will be monitored regularly by the DSC. In addition, the DSC will identify inconsistencies 
within eCRFs and between eCRFs and post queries in Advantage eClinical on a scheduled basis.  
Sites will resolve data inconsistencies and errors by entering all corrections and changes directly 
into Advantage eClinical. As described above, the CCC will conduct regular visits to sites, during 
which audits comparing source documents to the data entered on the eCRF will be performed. 
Any discrepancies identified between the source document and the eCRF will be corrected by the 
site. 


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Trial progress and data status reports, which provide information on recruitment, availability of 
primary outcome, treatment exposure, attendance at long term follow-up visits, regulatory status, 
and data quality, will be generated daily and posted to a secure website. These reports are 
available to the site, the corresponding local Node, the Lead Investigator, the coordinating 
centers, and NIDA, to monitor the sites’ progress on the study. 
 
Database Lock and Transfer 
At the conclusion of data collection for the study, the DSC will perform final data cleaning activities 
and will “lock” the study database from further modification. The final analysis dataset will be 
returned to NIDA, as requested, for storage and archive. 
 
 


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25.0 APPENDIX C - “Random Assignment Bootstrapping” 
CTN-0055 to estimate likely power for CTN-0067 
It is harder to calculate power for a repeated-measures or time series approach than it is for an 
approach that just uses data from a single time point. The reason is that, for the time series approach, 
the model needs the entire time series, not just the concluding data point. Table 1 contains a (partial) 
list of the parameters necessary to generate realistic data for the proposed scale-up study. 
 
Table 1: Some Parameters Necessary to Simulate Realistic 
Data for CTN-0067 
Design Parameters 
total sample size 
number and spacing of time points 
number of sites 
States of Nature 
autocorrelation of suppression indicator 
monthly probability of death 
monthly probability of loss to follow-up 
monthly probability of going off treatment, ntx arm 
monthly probability of going off treatment, tau arm 
probability of initiation on ntx arm 
probability of initiation on tau arm 
monthly probability of suppression in (ntx, tau) 
standard deviation of site effect -- perhaps in (ntx, tau) 
 
Although the first 3 of these are design parameters, thus controlled by the investigators, the 
remainder are states of nature that need to either be assumed or be estimated (with attendant 
noise) from a pilot study with 51 participants. This list implicitly embodies various simplifying 
assumptions that may or may not be true. For example, it could be that the probability of dropout 
depends on whether the participant is or is not suppressed, whether the participant is alcohol-
dependent in addition to opioid-dependent, and even which site the participant comes from. 
There is an alternative approach that, while it has its own problems, avoids the necessity of 
explicitly estimating many parameters from few observations and making implicit simplifying 
assumptions. Instead, we propose to perform the power calculation by bootstrapping data from 
the pilot study. 
This works because, when calculating power for a non-inferiority design, the conventional 
approach is to calculate it under the alternative hypothesis that the two treatments are the same. 


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This is accomplished in the simulation by first pooling the two arms of the pilot (i.e., ignoring the 
treatment arm), then bootstrapping data from the pool, and finally randomly assigning the 
bootstrapped observations to the two treatment arms. We call this approach, in which a bootstrap 
sample is drawn and then treatment is randomly assigned to the bootstrapped observations, 
“Random Assignment Bootstrapping.” 
As remarked above, the Random Assignment Bootstrap approach has its own limitations. Some 
arise from the small size of the pilot study. Others have to do with differences in pilot study and 
scale-up designs. Specifically, the proposed scale-up will have VL visits at months 0, 3, and 6, 
with the primary suppression outcome being assessed at M6. The pilot study had visits at months 
0, 1, 2, 3, and 4, but in this simulation we use only visits 0, 2, and 4 to assess the outcome at M4. 
The pilot study design is less powerful than the scale-up will be because although it has the same 
number of visits, they are temporally closer together. Also, if there is an outcome difference 
between arms in CTN0055, random assignment bootstrapping will probably over-estimate the 
within-arm variance, leading to a smaller power estimate. For these reasons, scale-up power is 
expected to exceed the power calculated by Random Assignment Bootstrapping of the pilot study.  
The power calculations are performed only for the members of the opiate-only + overlap group 
who are unsuppressed at baseline. There are only 9 participants in this group, with suppression 
status values at the various visits as given in Table 2. 
 
Table 2: CTN-0055 Treatment Assignment and Suppression  
History at weeks 0, 4, 8, 12, and 16 for the 9 individuals comprising the bootstrap population for 
the power simulation 
treatment 
assignment 
00 
04 
08 
12 
16 
TAU 
No 
No 
No 
No 
No 
TAU 
No 
Yes 
Yes 
Yes 
Yes 
TAU 
No 
No 
No 
No 
No 
TAU 
No 
No 
No 
No 
Yes 
TAU 
No 
No 
Yes 
Yes 
Yes 
NTX 
No 
No 
No 
No 
No 
NTX 
No 
No 
No 
Yes 
Yes 
NTX 
No 
Yes 
Yes 
Yes 
Yes 
NTX 
No 
No 
No 
No 
No 
 
Bootstrapping depends for its validity upon the probability that the underlying bootstrap sample is 
representative of the population. This probability decreases as the size of the bootstrap population 
decreases. But a similar limitation is true of the other approach: the precision of parameter 
estimates from the pilot study also decreases as the underlying sample size decreases. 
Rose et al.’s [175] continuous method has also been implemented. Although this also can be 
used to calculate treatment effect in terms of proportions, doing so requires its own bootstrapping. 
This means that the power simulation would require both inner and outer bootstrap loops, 
resulting calculation times that are so long that the power simulation would not be practicable.