Surmounting Withdrawal to Initiate Fast Treatment With Naltrexone: Improving the Real-World Effectiveness of Injection Naltrexone for Opioid Use Disorder (SWIFT)
Phase: NA
Conditions: Opioid-use Disorder
Sponsor: New York State Psychiatric Institute

CONFIDENTIAL 
 
 
 
 
 
NIDA CTN Protocol 0097 
 
Surmounting Withdrawal to Initiate Fast 
Treatment with Naltrexone: 
Improving the Real-World Effectiveness of Injection 
Naltrexone for Opioid Use Disorder 
(SWIFT) 
 
Lead Investigator: Adam Bisaga, MD 
Funded by: National Institute on Drug Abuse (NIDA) 
 
Version 3.0 
October 13, 2021 

CONFIDENTIAL 
1 
Lead Investigator (LI): 
Adam Bisaga, MD 
 
Greater New York Node 
 
NYS Psychiatric Institute 
 
Columbia University, Department of 
Psychiatry 
Co-LI: 
Edward V. Nunes, MD 
 
Greater New York Node 
 
NYS Psychiatric Institute 
 
Columbia University, Department of 
Psychiatry 
 
John Rotrosen, MD 
 
Greater New York Node 
 
New York University, School of Medicine 
CCTN Scientific Officer: 
Udi Ghitza, PhD 
 
National Institute on Drug Abuse 
Data and Statistics Center (DSC): 
Paul Van Veldhuisen, PhD 
 
DSC Principal Investigator 
 
Emmes 
Clinical Coordinating Center (CCC): 
Eve Jelstrom, CRNA, MBA 
 
CCC Principal Investigator 
 
Emmes 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Lead Investigator or other participating study leadership and as consistent with the NIDA 
terms of award. 
 

NIDA CTN-0097 
 
Version 3.0 
Surmounting Withdrawal to Initiate Fast nalTrexone 
 
October 13, 2021 
 
 
TABLE OF CONTENTS 
 
1.0 
LIST OF ABBREVIATIONS 
.......................................................................................................................... 1 
2.0 
STUDY SYNOPSIS 
..................................................................................................................................... 4 
2.1 
STUDY OBJECTIVES 
............................................................................................................................................ 
4 
2.2 
STUDY DESIGN AND OUTCOMES 
.......................................................................................................................... 
4 
2.3 
SAMPLE SIZE AND STUDY POPULATION ................................................................................................................. 
5 
2.4 
TREATMENT/ASSESSMENT/INTERVENTION AND DURATION ...................................................................................... 
6 
2.5 
SAFETY REPORTING 
........................................................................................................................................... 
6 
2.6 
ANALYSES ....................................................................................................................................................... 
6 
3.0 
STUDY SCHEMA 
....................................................................................................................................... 7 
3.1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................................ 
7 
3.1.1 Table 1. Schematic of study design with six study sites and five steps, each lasting 14 weeks 
............... 
7 
3.1.2 Figure 1. Schematic of the study phases and participant 
flow 
................................................................ 
7 
3.2 
KEY RESEARCH SITE ROLES ................................................................................................................................. 
8 
4.0 
INTRODUCTION 
....................................................................................................................................... 9 
4.1 
BACKGROUND AND SIGNIFICANCE TO THE FIELD 
...................................................................................................... 
9 
4.1.1 Effectiveness of XR-NTX to Prevent Relapse Following Detoxification in OUD 
........................................ 
9 
4.1.2 Addressing the Naltrexone Induction Hurdle 
........................................................................................... 
9 
4.1.3 Changing Practice for Inpatient OUD Treatment .................................................................................. 
11 
4.1.4 Study Design 
.......................................................................................................................................... 
11 
4.1.5 Duration of XR-NTX Treatment 
.............................................................................................................. 
13 
4.1.6 Evaluation of Implementation Parameters 
........................................................................................... 
14 
4.1.7 Implementation Facilitation Manual Development Process 
.................................................................. 
14 
4.2 
I
NNOVATION 
.................................................................................................................................................. 
15 
4.3 
SUITABILITY,
 FEASIBILITY,
 AND SUSTAINABILITY FOR THE CTN SITES 
.......................................................................... 
16 
4.4 
PUBLIC HEALTH I
MPACT SIGNIFICANCE TO THE FIELD 
............................................................................................. 
16 
5.0 
OBJECTIVES 
............................................................................................................................................ 
17 
5.1 
PRIMARY OBJECTIVE 
........................................................................................................................................ 
17 
5.2 
SECONDARY OBJECTIVE(
S) 
................................................................................................................................ 
17 
5.3 
EXPLORATORY OBJECTIVE(
S) 
............................................................................................................................. 
17 
5.4 
I
MPLEMENTATION OBJECTIVES 
.......................................................................................................................... 
18 
6.0 
STUDY DESIGN ....................................................................................................................................... 
19 
6.1 
OVERVIEW OF STUDY DESIGN ........................................................................................................................... 
19 
6.1.0 Overview 
................................................................................................................................................ 
19 
6.1.1 Patient-Participants 
............................................................................................................................... 
19 
6.1.2 Random Site Selection and Treatment Assignment 
............................................................................... 
19 
6.1.3 Training in SP and RP procedures 
.......................................................................................................... 
20 
6.2 
I
MPLEMENTATION FACILITATION 
........................................................................................................................ 
22 
6.2.0 Initial Elements Included in Implementation 
Facilitation ...................................................................... 
23 
6.2.1 Iterative Development of the Implementation Facilitation Package 
..................................................... 
24 
6.3 
DURATION OF STUDY AND VISIT SCHEDULE 
.......................................................................................................... 
25 
6.4 
STUDY TIMELINE 
............................................................................................................................................. 
26 
6.4.0 Table 2: Study Timeline ......................................................................................................................... 
26 
7.0 
OUTCOME MEASURES 
............................................................................................................................ 
27 
7.1 
PRIMARY OUTCOME MEASURE ......................................................................................................................... 
27 
7.2 
SECONDARY OUTCOME MEASURE(
S) 
.................................................................................................................. 
27 

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7.2.1 Table 3: Secondary Clinical Outcomes, Outcome Measures and Hypotheses ....................................... 
27 
7.3 
I
MPLEMENTATION PROCESS AND OUTCOME MEASURES 
......................................................................................... 
28 
7.3.1 Identifying Facilitators and Barriers to Implementation Success .......................................................... 
28 
7.3.2 Table 4: Implementation Measures Organized by the Consolidated Framework for Implementation 
Research Constructs 
........................................................................................................................................... 
28 
7.3.3 Implementation Related Outcome Measures 
........................................................................................ 
30 
7.3.4 Table 5: Implementation Outcome Domain 
.......................................................................................... 
30 
7.3.5 Integration Process for Iterative Improvement of Implementation Facilitation 
.................................... 
30 
8.0 
STUDY POPULATION .............................................................................................................................. 
32 
8.1 
PARTICIPANT I
NCLUSION CRITERIA ..................................................................................................................... 
32 
8.2 
PARTICIPANT EXCLUSION CRITERIA 
..................................................................................................................... 
32 
8.3 
SPECIAL POPULATIONS TO CONSIDER 
.................................................................................................................. 
33 
8.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .................................................................................................. 
33 
9.0 
SITE SELECTION 
...................................................................................................................................... 
34 
9.1 
NUMBER OF SITES .......................................................................................................................................... 
34 
9.2 
SITE ELIGIBILITY 
.............................................................................................................................................. 
34 
9.3 
RATIONALE FOR SITE SELECTION 
........................................................................................................................ 
35 
10.0 STUDY PROCEDURES 
.............................................................................................................................. 
36 
10.1 PRE-
SCREENING,
 CONSENT AND SCREENING (P
HASE 1) 
.......................................................................................... 
36 
10.1.1 Informed Consent Procedures for Participants ................................................................................. 
36 
10.1.2 HIPAA Authorization and Medical Record Release Forms 
................................................................. 
37 
10.1.3 Screening/Baseline Visit 
.................................................................................................................... 
37 
10.2 TREATMENT I
NITIATION 
................................................................................................................................... 
37 
10.3 RANDOMIZATION 
............................................................................................................................................ 
37 
10.4 I
NPATIENT TREATMENT/INTERVENTION (P
HASE 2) 
................................................................................................ 
38 
10.4.1 Standard Induction Procedure (SP) 
................................................................................................... 
38 
10.4.2 Table 6A. Standard Induction Procedures 
......................................................................................... 
38 
10.4.3 Rapid Induction Procedures (RP) 
....................................................................................................... 
38 
10.4.4 Table 6B. Rapid Induction Procedure Guidelines 
............................................................................... 
39 
10.5 POST-I
NDUCTION TREATMENT (P
HASE 3) 
............................................................................................................ 
40 
10.5.1 Psychosocial Counseling 
.................................................................................................................... 
40 
10.5.2 Medical Management 
....................................................................................................................... 
40 
10.5.3 Rapid Procedure: Adjunctive Medication Taper 
................................................................................ 
41 
10.5.4 XR-NTX Injections 
.............................................................................................................................. 
41 
10.5.5 Handling of XR-NTX Induction Procedure Intolerance 
....................................................................... 
41 
10.5.6 Handling of Missed XR-NTX Doses, Lapses, and Relapses 
................................................................. 
42 
10.5.7 XR-NTX Discontinuation Post-Induction 
............................................................................................ 
42 
10.5.8 Ancillary Medications 
........................................................................................................................ 
42 
10.5.9 Criminal Justice Involvement 
............................................................................................................. 
43 
10.6 END OF STUDY 
............................................................................................................................................... 
43 
10.7 DISPOSITION AND REFERRAL (P
HASE 4) .............................................................................................................. 
43 
10.8 STUDY I
NTERVENTION ADHERENCE 
..................................................................................................................... 
43 
10.9 PREMATURE WITHDRAWAL OF PARTICIPANTS 
...................................................................................................... 
43 
10.10 
STUDY TERMINATION 
.................................................................................................................................. 
44 
10.11 
BLINDING ................................................................................................................................................. 
44 
10.12 
PARTICIPANT REIMBURSEMENT 
..................................................................................................................... 
45 
10.13 
RETENTION PLAN 
....................................................................................................................................... 
45 
11.0 MEDICATION PACKAGING/HANDLING/STORAGE / ACCOUNTABILITY 
..................................................... 
46 
11.1 STUDY MEDICATION SOURCES 
........................................................................................................................... 
46 

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11.2 STUDY MEDICATION MANAGEMENT .................................................................................................................. 
46 
11.3 MEDICATION ACCOUNTABILITY RECORDS 
............................................................................................................ 
46 
11.4 DISPENSING OF STUDY MEDICATION .................................................................................................................. 
46 
11.5 STUDY MEDICATION STORAGE .......................................................................................................................... 
46 
11.6 USED/UNUSED MEDICATION 
............................................................................................................................ 
47 
11.7 LOST MEDICATION 
.......................................................................................................................................... 
47 
11.8 MEDICATION PACKAGING 
................................................................................................................................. 
47 
12.0 STUDY ASSESSMENTS 
............................................................................................................................. 
48 
12.1 GENERAL ...................................................................................................................................................... 
48 
12.1.1 Locator Form 
..................................................................................................................................... 
48 
12.1.2 Prisoner Status Assessment .............................................................................................................. 
48 
12.1.3 PhenX Tier 1 and Demographics 
....................................................................................................... 
48 
12.1.4 Motivation Scale 
............................................................................................................................... 
48 
12.1.5 Patient-Reported Outcomes Measurement Information System (PROMIS) 
...................................... 
49 
12.1.6 End of Medication Treatment Form 
.................................................................................................. 
49 
12.1.7 Study Completion Form 
..................................................................................................................... 
49 
12.1.8 Treatment Satisfaction Survey 
.......................................................................................................... 
49 
12.2 MEASURES OF PRIMARY AND SECONDARY OUTCOMES 
........................................................................................... 
50 
12.2.1 End of Induction Form 
....................................................................................................................... 
50 
12.2.2 The Subjective Opioid Withdrawal Scale (SOWS) 
.............................................................................. 
50 
12.2.3 Clinical Opiate Withdrawal Scale (COWS) 
......................................................................................... 
50 
12.2.4 Visual Analogue Scales (VAS) 
............................................................................................................ 
50 
12.2.5 Timeline Followback (TLFB) 
............................................................................................................... 
50 
12.2.6 Urine Drug Screen (UDS) 
................................................................................................................... 
51 
12.2.7 Patient Health Questionnaire (PHQ-9) 
.............................................................................................. 
51 
12.2.8 Low Dose Naltrexone Titration ......................................................................................................... 
51 
12.2.9 XR-NTX Administration ..................................................................................................................... 
51 
12.3 SAFETY AND MEDICAL ..................................................................................................................................... 
51 
12.3.1 Medical and Psychiatric History 
........................................................................................................ 
51 
12.3.2 PTSD Checklist for DSM-5 (PCL-5) ..................................................................................................... 
52 
12.3.3 Adult ADHD Self-Report Screening Scale for DSM-5 (ASRS-5) 
........................................................... 
52 
12.3.4 Overdose Questionnaire 
.................................................................................................................... 
52 
12.3.5 Concomitant Medications 
................................................................................................................. 
52 
12.3.6 Death ................................................................................................................................................ 
52 
12.3.7 HIV and Hepatitis Self-Report Assessments 
...................................................................................... 
52 
12.3.8 DSM-5 Criteria 
................................................................................................................................... 
52 
12.3.9 General Anxiety Disorder-7 
............................................................................................................... 
52 
12.3.10 PHQ-Panic Disorder 
........................................................................................................................... 
53 
12.3.11 Pregnancy, Birth Control, and Breastfeeding Assessment 
................................................................ 
53 
12.3.12 Mental Health Assessment ............................................................................................................... 
53 
12.3.13 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
.................................................................. 
53 
12.4 I
MPLEMENTATION RELATED OUTCOMES ............................................................................................................. 
54 
12.4.1 Quantitative Data Collection and Analysis 
........................................................................................ 
54 
12.5 QUALITATIVE DATA COLLECTION AND ANALYSIS ................................................................................................... 
55 
12.5.1 Verbal Consent for Structured Participant Interviews 
....................................................................... 
55 
12.5.2 Conduct of Structured Interviews 
...................................................................................................... 
56 
12.6 I
MPLEMENTATION PROCESS OUTCOMES MEASURES 
.............................................................................................. 
56 
12.6.1 Fidelity to Clinical Procedures ........................................................................................................... 
56 
12.6.2 Coaching Progress Notes .................................................................................................................. 
57 
12.6.3 Site Needs Assessment and Site Mapping Progress Notes 
................................................................ 
57 
12.6.4 Internal Implementation Team Meeting Notes 
................................................................................. 
57 
12.6.5 Fidelity to Implementation Procedures Checklist 
.............................................................................. 
58 

NIDA CTN-0097 
 
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October 13, 2021 
 
 
12.6.6 Treatment Utilization Measures 
....................................................................................................... 
58 
12.7 OTHER ASSESSMENTS 
...................................................................................................................................... 
58 
12.7.1 Fagerström Test for Nicotine Dependence (FTND) 
............................................................................ 
58 
12.7.2 NIDA Cannabis Assessment 
............................................................................................................... 
58 
12.7.3 Daily Medication Administration Log 
................................................................................................ 
58 
12.7.4 Non-Study Medical and Other Services (NMS) 
.................................................................................. 
58 
12.7.5 Oral Fluid Collection for Genetic Sample and Family Origin 
.............................................................. 
59 
12.7.6 Table 7: Study Assessments .............................................................................................................. 
60 
12.7.7 Table 7a: Implementation Assessments 
............................................................................................ 
63 
13.0 GENETIC SAMPLING ............................................................................................................................... 
64 
14.0 TRAINING REQUIREMENTS 
..................................................................................................................... 
65 
14.1 OVERALL 
....................................................................................................................................................... 
65 
15.0 CONCOMITANT THERAPY/INTERVENTION 
.............................................................................................. 
66 
15.1 GENERAL ...................................................................................................................................................... 
66 
15.2 MEDICATIONS PROHIBITED/ALLOWED DURING TRIAL 
............................................................................................ 
66 
16.0 STATISTICAL DESIGN AND ANALYSES 
...................................................................................................... 
67 
16.1 GENERAL DESIGN ........................................................................................................................................... 
67 
16.1.1 Study Hypothesis 
............................................................................................................................... 
67 
16.1.2 Primary and Secondary Outcomes (Endpoints) 
................................................................................. 
67 
16.1.3 Study Design ..................................................................................................................................... 
67 
16.1.4 Recruitment ...................................................................................................................................... 
67 
16.1.5 Randomization and Factors for Stratification 
................................................................................... 
67 
16.2 RATIONALE FOR SAMPLE SIZE AND STATISTICAL POWER ......................................................................................... 
68 
16.2.1 Introduction ...................................................................................................................................... 
68 
16.2.2 Table 8: Design Pattern Matrix 
......................................................................................................... 
68 
16.2.3 Values of Parameters Underlying Power Simulations 
....................................................................... 
69 
16.2.4 Power Curve 
...................................................................................................................................... 
71 
16.2.5 Power in Unforeseen Circumstances 
................................................................................................. 
72 
16.2.6 Conclusion 
......................................................................................................................................... 
75 
16.3 STATISTICAL METHODS FOR PRIMARY AND SECONDARY OUTCOMES 
......................................................................... 
75 
16.3.1 Primary Outcome Analysis 
................................................................................................................ 
75 
16.3.2 Secondary Outcome Analysis: 
........................................................................................................... 
76 
16.4 I
MPLEMENTATION OUTCOME ANALYSIS 
.............................................................................................................. 
76 
16.5 SIGNIFICANCE TESTING .................................................................................................................................... 
76 
16.6 I
NTERIM ANALYSIS 
.......................................................................................................................................... 
76 
16.7 EXPLORATORY ANALYSIS .................................................................................................................................. 
76 
16.8 PREDICTION MODELS 
...................................................................................................................................... 
77 
16.9 MISSING DATA AND DROPOUTS ........................................................................................................................ 
77 
16.10 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
.............................................................................................. 
77 
16.11 
SAFETY ANALYSIS ....................................................................................................................................... 
77 
17.0 REGULATORY COMPLIANCE, REPORTING AND MONITORING 
................................................................. 
79 
17.1 STATEMENT OF COMPLIANCE 
............................................................................................................................ 
79 
17.2 I
NSTITUTIONAL REVIEW BOARD APPROVAL 
.......................................................................................................... 
79 
17.3 I
NFORMED CONSENT 
....................................................................................................................................... 
79 
17.4 QUALITY ASSURANCE MONITORING 
................................................................................................................... 
81 
17.5 PARTICIPANT AND DATA CONFIDENTIALITY .......................................................................................................... 
81 
17.5.1 Certificate of Confidentiality 
............................................................................................................. 
82 
17.5.2 Health Insurance Portability and Accountability Act 
(HIPAA) 
........................................................... 
82 

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17.6 I
NVESTIGATOR ASSURANCES 
............................................................................................................................. 
82 
17.6.1 Financial Disclosure/Conflict of Interest 
............................................................................................ 
82 
17.7 CLINICAL MONITORING 
.................................................................................................................................... 
82 
17.8 I
NCLUSION OF WOMEN AND MINORITIES 
............................................................................................................ 
83 
17.9 PRISONER CERTIFICATION 
................................................................................................................................. 
83 
17.10 
REGULATORY FILES 
..................................................................................................................................... 
83 
17.11 
RECORDS RETENTION AND REQUIREMENTS ..................................................................................................... 
84 
17.12 
REPORTING TO SPONSOR 
............................................................................................................................. 
84 
17.13 
AUDITS .................................................................................................................................................... 
84 
17.14 
STUDY DOCUMENTATION 
............................................................................................................................. 
84 
17.15 
PROTOCOL DEVIATIONS 
............................................................................................................................... 
85 
17.16 
SAFETY MONITORING 
.................................................................................................................................. 
85 
17.16.1 Data and Safety Monitoring Board (DSMB) 
...................................................................................... 
86 
17.16.2 Safety Monitor/Medical Monitor 
...................................................................................................... 
86 
17.16.3 Safety Events 
..................................................................................................................................... 
86 
17.16.4 Serious Adverse Events (SAEs) 
........................................................................................................... 
87 
17.16.5 Known Potential Toxicities of Study Medication/Intervention 
.......................................................... 
87 
18.0 DATA MANAGEMENT 
............................................................................................................................. 
88 
18.1 DESIGN AND DEVELOPMENT 
............................................................................................................................. 
88 
18.2 SITE RESPONSIBILITIES ..................................................................................................................................... 
88 
18.3 DATA CENTER RESPONSIBILITIES 
........................................................................................................................ 
88 
18.4 DATA COLLECTION 
.......................................................................................................................................... 
88 
18.5 DATA ACQUISITION AND ENTRY 
......................................................................................................................... 
88 
18.6 DATA EDITING ............................................................................................................................................... 
89 
18.7 DATA TRANSFER/LOCK 
.................................................................................................................................... 
89 
18.8 DATA TRAINING ............................................................................................................................................. 
89 
18.9 DATA QUALITY ASSURANCE 
.............................................................................................................................. 
89 
19.0 PUBLIC ACCESS AND DATA SHARING PLAN 
............................................................................................. 
90 
20.0 PROTOCOL SIGNATURE PAGE 
................................................................................................................. 
91 
21.0 REFERENCES 
........................................................................................................................................... 
92 
22.0 APPENDIX A: ADVERSE EVENT REPORTING AND PROCEDURES 
............................................................... 
96 
22.1 DEFINITION OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
............................................................................ 
96 
22.2 DEFINITION OF EXPECTEDNESS .......................................................................................................................... 
96 
22.3 PREGNANCY .................................................................................................................................................. 
97 
22.4 MEDICAL AND PSYCHIATRIC HISTORY 
.................................................................................................................. 
97 
22.5 SITE’
S ROLE IN ELICITING AND REPORTING SAFETY EVENTS ..................................................................................... 
97 
22.6 SITE’
S ROLE IN ASSESSING SEVERITY AND CAUSALITY OF ADVERSE EVENTS 
................................................................. 
98 
22.7 GUIDELINES FOR ASSESSING SEVERITY 
................................................................................................................. 
98 
22.8 GUIDELINES FOR DETERMINING CAUSALITY 
.......................................................................................................... 
98 
22.9 SITE’
S ROLE IN MONITORING SAFETY EVENTS 
....................................................................................................... 
98 
22.10 
SPONSOR’
S ROLE IN SAFETY MANAGEMENT PROCEDURES OF AES/SAES 
.............................................................. 
98 
22.11 
REGULATORY REPORTING FOR A NON-IND
 STUDY 
............................................................................................. 
99 
22.11.1 Reporting to the Data and Safety Monitoring Board 
........................................................................ 
99 
22.12 
PARTICIPANT WITHDRAWAL 
......................................................................................................................... 
99 
22.13 
ADVERSE EVENT REPORTING (C
HART) 
.......................................................................................................... 
100 
23.0 APPENDIX B: DATA AND SAFETY MONITORING PLAN 
........................................................................... 
101 
 

NIDA CTN-0097 
 
Version 3.0 
Surmounting Withdrawal to Initiate Fast nalTrexone 
 
October 13, 2021 
 
 
1.0 LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUP 
Buprenorphine 
BUP-NX 
Buprenorphine-Naloxone (Suboxone®) 
CAP 
College of American Pathologists 
CCC 
Clinical Coordinating Center 
CCTN 
Center for the Clinical Trials Network 
CFIR 
Consolidated Framework for Implementation 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendment of 1988 
CNS 
Central Nervous System 
CoC 
Certificate of Confidentiality 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Form 
CTN 
Clinical Trials Network 
CTP 
Community Treatment Program 
DEA 
Drug Enforcement Agency 
DSC 
Data and Statistics Center 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Record 
EOS 
End of Study 
EMT 
End of Medication Treatment 
ERC 
Ethics Review Committee 
FDA 
Food and Drug Administration 
FTND 
Fagerström Test for Nicotine Dependence 
FWA 
Federalwide Assurance 
GAD-7 
Generalized Anxiety Disorder Screener 
GCP 
Good Clinical Practice 
HCV 
Hepatitis C Virus 
HHS 
Department of Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 

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Abbreviation 
Definition 
HR 
Heart Rate 
HSP 
Human Subjects Protection 
ICC 
Intraclass Correlation Coefficient 
IF 
Implementation Facilitation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IM 
Intramuscular 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LI 
Lead Investigator 
MD 
Medical Doctor 
MDMA 
Methylenedioxymethamphetamine (Ecstasy) 
MDD 
Maximum Daily Dose 
MedDRA 
The Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mL 
Milliliters 
MM 
Medical Management 
MOP 
Manual of Operations 
MOUD 
Medications for Opioid Use Disorder 
NDA 
New Drug Application 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
NMS 
Non-Study Medical and Other Services 
NP 
Nurse Practitioner 
NTX 
Naltrexone 
NX 
Naloxone 
OUD 
Opioid Use Disorder 
OHRP 
Office for Human Research Protections 
ORCA 
Organizational Readiness to Change Assessment 
PO 
per os (by mouth) 
PA 
Physician Assistant 
PCL-5 
PTSD Checklist for DSM-5 
PHQ-9 
Patient Health Questionnaire -9 
PI 
Principal Investigator 
PLG 
Polylactide-co-glycolide 
QA 
Quality Assurance 
QALYs 
Quality-Adjusted Life Year Estimates 
RAP-C 
Research Advisory Panel of California 

NIDA CTN-0097 
 
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Surmounting Withdrawal to Initiate Fast nalTrexone 
 
October 13, 2021 
 
 
Abbreviation 
Definition 
RP 
Rapid Procedure 
RRTC 
Regional Research and Training Center 
SAE 
Serious Adverse Event 
SAMHSA 
Substance Abuse and Mental Health Services Administration 
SC 
Subcutaneous 
SOWS 
Subjective Opiate Withdrawal Scale 
SP 
Standard Procedure 
SW 
Stepped-Wedge 
TAU 
Treatment as Usual 
TLFB 
Timeline Followback 
TSE 
Targeted Safety Event 
UDS 
Urine Drug Screen 
VA 
Veterans Administration 
VAS 
Visual Analog Scale 
XR-NTX 
Extended-Release Naltrexone (Vivitrol
®) 

NIDA CTN-0097 
 
Version 3.0 
Surmounting Withdrawal to Initiate Fast nalTrexone 
 
October 13, 2021 
 
 
2.0 STUDY SYNOPSIS 
2.1 Study Objectives 
The overarching objective of the SWIFT trial (CTN-0097) is to foster widespread adoption of a 
regimen for rapid initiation of treatment with extended-release injection naltrexone (XR-NTX) at 
inpatient or residential Community Treatment Programs (CTPs). If widely adopted, such a 
regimen would have a substantial public health impact by expanding medication treatment options 
offered to patients with OUD to include XR-NTX. 
In multi-site, randomized (subject level) trials, XR-NTX, once initiated, has been found to have 
similar effectiveness to sublingual buprenorphine on clinical outcomes of retention in treatment 
and abstinence from opioids. However, initiation of naltrexone often involves a significant (up to 
2 weeks) delay, which is a clinical hurdle that impedes the widespread adoption of XR-NTX as a 
treatment option. Initiation of naltrexone in patients actively using opioids requires that a patient 
be detoxified first, and the official prescribing information for XR-NTX recommends an additional 
7- to 10-day waiting period after last dose of opioid before administering XR-NTX. This standard 
initiation regimen, involving a brief period of agonist, usually buprenorphine, taper followed by a 
7- to 10-day waiting period, takes approximately two weeks. During this time, patients are 
vulnerable to drop out and relapse; further, this waiting period is problematic in the face of funding 
restrictions on the duration of inpatient stays. In a single-site randomized trial, a Rapid naltrexone 
induction method utilizing minimal buprenorphine, non-opioid medications to treat withdrawal 
symptoms, and upward titration of oral naltrexone starting with small doses, XR-NTX initiation 
was accomplished in 5 to 7 days and was found superior to the standard 14-day approach on the 
proportion of patients initiating XR-NTX. 
The primary goal of this hybrid effectiveness-implementation study is to determine whether the 
Rapid method of initiating treatment with XR-NTX is non-inferior to a standard method on the 
primary effectiveness outcome of successful initiation of XR-NTX (receiving the first injection while 
inpatient) when implemented at community-based inpatient or residential programs. Secondary 
objectives include comparing rapid versus standard method of XR-NTX initiation on: time from 
admission to first 
dose 
of 
XR-NTX while inpatient 
and 
time 
to 
dropout, 
craving, 
withdrawal 
severity, 
retention, abstinence, and safety measures, as measured during the inpatient initiation process 
and the first two months post XR-NTX induction. Other exploratory outcomes include predictors 
of initiation success, economic analyses, engagement with medical visits and receipt of MOUD 
after discharge from the inpatient unit. The implementation goal is to operationalize an 
implementation facilitation strategy that will be used to train clinical sites on the XR-NTX initiation 
method, to capture fidelity to the rapid induction process, and to study barriers and facilitators to 
implementation and refine the implementation facilitation strategy accordingly. 
2.2 Study Design and Outcomes 
The proposed study is an open-label, multi-center, stepped-wedge cluster randomized trial. It will 
be conducted in 6 CTN-affiliated CTPs that are able to provide inpatient or residential 
detoxification services and have the capacity for an ongoing outpatient treatment with 
XR-NTX. 

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As part of the stepped-wedge design proposed for this trial, one site, randomly chosen, will start 
implementing the Rapid Procedures and will remain in this arm for the rest of the study. 
The next 4 sites randomly chosen will first implement the control procedure (Standard, 13-day 
procedure; SP), to establish the within-site comparison condition, and then at selected staggered 
time-points (steps) will switch to implementing only the experimental (Rapid, 5-7-day procedure; 
RP), and the 6th site (after 5 sites have been randomized to RP) will remain in the SP arm 
throughout the whole duration of the study. Implementation of RP at study sites will be staggered 
by 14 weeks and the order in which sites will cross-over from SP to RP will be randomly chosen. 
The primary effectiveness objective of the study is to determine whether the novel RP of initiating 
treatment with XR-NTX is non-inferior to the SP induction method as implemented in community 
treatment programs. The primary outcome measure is a dichotomous measure of treatment 
success which is receipt of the first injection of XR-NTX. 
Secondary objectives are to: (1) compare RP vs. SP across a range of secondary efficacy 
domains and clinical safety measures, (2) compare retention rates to subsequent second and 
third monthly XR-NTX injections. 
Exploratory objectives include: (1) evaluation of demographic and clinical predictors of successful 
induction and moderators of differential effectiveness, (2) evaluation of whether the primary opioid 
of dependence (prescription painkillers vs heroin vs fentanyl) will interact with treatment, (3) 
evaluation whether fentanyl positive toxicology at screening and during treatment is predictive of 
relapse, (4) collection of a limited dataset to permit analyses of economic costs and benefits of 
the two treatment regimens, (5) compare time to induction failure in SP vs. RP (6) explore 
engagement with medical visits and therapy in SP vs. RP (7) compare  use of MOUD as measured 
by patient self-report by treatment arm (SP vs. RP), and (9) compare percentage of participants 
inducted onto XR-NTX (during induction and post-induction phase) in RP vs. SP (8) explore 
percentage of induction failure participants receive XR-NTX during the course of the study. 
The implementation goal is to operationalize an implementation facilitation strategy that will be 
used to train sites in the naltrexone initiation methods, evaluate implementation parameters 
including fidelity and reach, identify facilitators and barriers to implementation of RP, and refine 
the implementation facilitation strategy in an iterative process over the course of the trial. The 
ultimate goal is to emerge from the trial with an implementation facilitation strategy that can 
support widespread adoption of XR-NTX initiation across inpatients and residential treatment 
facilities. 
2.3 Sample Size and Study Population 
The projected sample size is approximately 450 participants, recruited across all study sites 
(approximately 75 at each of the six sites) over a study period of 70 weeks, at an enrollment rate 
of approximately 1-2 new participants per week per site. Study participants are treatment-seeking 
adults of all genders, at least 18 years of age or older, heroin- and/or prescription opioid-
dependent volunteers, without chronic pain requiring opioid therapy, who are willing to accept 
naltrexone-based therapy and have no contraindications to XR-NTX. 

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2.4 Treatment/Assessment/Intervention and Duration 
Two XR-NTX induction regimens will be evaluated: a Standard Procedure - SP typically a five- 
day buprenorphine taper followed by an 8-day washout period (naloxone challenge (e.g., 0.8-1.2 
mg IM) and XR-NTX injection (380 mg IM) occurs 13 or 14 days from the first dose of 
buprenorphine and a Rapid Procedure - RP typically 
one 
day 
of 
buprenorphine 
(about 
6-8mg), 
one 
day of washout, and 4-day oral naltrexone titration and XR-NTX injection occurs 6 or 7 days from 
the first buprenorphine dose. Both regimens have flexibility built into them according to clinical 
judgment, and sites will receive technical assistance and supervision according to the 
implementation-facilitation package developed for the study. All participants who complete the 
inpatient induction procedure (SP or RP) will receive the first XR-NTX injection while inpatient. 
Subsequently, all participants will enter the post-induction phase where they will be offered two 
additional XR-NTX injections, every 4 weeks, in combination with medical management clinical 
support. Participants will receive psychosocial counseling according to usual treatment at their 
participating treatment program. Study assessments will be collected at baseline, daily during the 
inpatient induction phase, and at weeks 1, 2, 3, 4, 6 and 8 during the post-induction phase. 
2.5 Safety Reporting 
At each medical management visit the study clinician will assess participants for AEs and SAEs. 
AE and SAE reporting will be in accordance with applicable regulatory requirements. As the safety 
profiles of the study medications are well established, and this trial is not powered to detect new, 
unknown safety signals, there will be no unsolicited AE collection during this study and only 
protocol-defined AEs (targeted safety events) and all SAEs will be collected. 
2.6 Analyses 
The primary outcome analysis will be performed using a generalized linear mixed effects model 
with a logistic link, a standard method for the analysis of stepped-wedge designs. 
Secondary outcomes will be modeled using mixed effects regression methods. 
Implementation outcomes will be modelled as continuous outcomes using mixed effects linear 
regression models. Additional implementation outcome measures including acceptability and 
barriers will be measured using qualitative methods. 

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3.0 STUDY SCHEMA 
3.1 Schematic of Study Design 
3.1.1 
Table 1. Schematic of study design with six study sites and five 
steps, each lasting 14 weeks 
 
 
3.1.2 
Figure 1. Schematic of the study phases and participant flow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1: Buprenorphine 
Part 2: Washout 
Part 3: Oral NTX titration 
Part 4: XR-NTX
 injection 
Part 1-4: Adjunctive
 medications 
 
– standing doses 
-Counselling 
-Medication management visits
  
-Administer additional two
 XR-NTX doses (Weeks 4
 and 
8) 
 
Post-Induction Treatment: Weeks 1-8 
Part 1: Buprenorphine taper 
Part 2: Washout 
Part 3: Naloxone challenge 
Part 4: XR-NTX
 injection 
  Part 2-4: Adjunctive 
medications - as needed 
doses 
Phase 3 
 
Post-Induction 
Phase 
 
Post  
Induction 
 
Up to 7 days prior to admission 
and during the first 4 days of 
admission, candidate is 
approached for study, signs 
Informed Consent and is 
evaluated for study eligibility.  
If eligible, will be enrolled and 
begin study assessments.  
No eligibility or study 
assessments will be completed 
prior to admission.  
Phase 2 
Induction 
Phase 
Candidate presents for an inpatient detoxification 
treatment and is evaluated for XR-NTX eligibility 
Candidate expresses interest in XR-NTX and starts SP/RP according to the clinical 
procedure implemented in the unit at the time of enrollment  
 
Continue treatment or refer to another community-based program 
Phase 4 
Referral 
Phase 1 
Consent & 
Screening 
 
Post  
Induction 
 

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3.2 Key Research Site Roles 
Each of the six research sites will require the following professionals: 
• Site Principal Investigator   
• Study Physician (NP; PA; MD; DO) 
• Site Medical Clinician (NP; PA; MD; DO) 
• Site Medical Personnel (RN; LPN; LVN) 
• Research Coordinator 
• Research Assistant 
• Pharmacy professional (pharmacist or a pharmacy technician) if needed 

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4.0 INTRODUCTION 
4.1 Background and Significance to the Field 
4.1.1 
Effectiveness of XR-NTX to Prevent Relapse Following 
Detoxification in OUD 
Two community-based effectiveness trials in the U.S. (CTN-0051) (Lee et al., 2018) and Norway 
(Tanum et al., 2017) have shown that long-acting injection naltrexone (XR-NTX; Vivitrol®) is a 
viable alternative to buprenorphine as maintenance treatment for opioid use disorder (OUD). As 
an antagonist, with a distinct mechanism of action compared to partial agonist (buprenorphine) or 
full agonist (methadone), XR-NTX has the potential to attract more patients with OUD onto 
effective medication treatment nationwide. Many patients who otherwise would not have been 
open to treatment with agonist medications may find this antagonist-based treatment acceptable. 
Ideally, patients and their clinicians would choose one of the three medication options 
(methadone, buprenorphine, or injection naltrexone) through a shared decision-making process. 
Among the medication options, extended-release injection naltrexone (XR-NTX) is currently the 
least utilized in the field as a whole. Recent large trials, including CTN-0051 (X:BOT), have shown 
that monthly XR-NTX is effective (Krupitsky et al., 2011, Lee et al., 2016), it is more effective than 
oral naltrexone (Sullivan et al., 2019), and it is similar in effectiveness to buprenorphine 
maintenance (Lee et al., 2018, Tanum et al., 2017). In addition, XR-NTX may be particularly well 
suited for patients who are seeking relapse-prevention treatment that does not include an opioid 
agonist or those that have not responded well to buprenorphine or methadone. 
However, XR-NTX remains under-utilized. An important barrier to the implementation of XR-NTX 
is the “induction hurdle,” namely the problem that among patients presenting for treatment with 
active opioid use, initiation of naltrexone requires a detoxification and transition from agonist to 
antagonist. The Official Prescribing Information for XR-NTX recommends a two-stage approach 
to naltrexone initiation, namely, an opioid detoxification followed by a 7 to 10-day delay from last 
agonist dose before starting naltrexone, to ensure that any opioids are off the receptors and 
physiological dependence is eliminated to minimize the risk of precipitated withdrawal. However, 
this involves patients tolerating acute and protracted withdrawal symptoms and a substantial 
delay to initiation of naltrexone, carrying the risk of dropout and relapse. This was the approach 
implemented in CTN-0051 (Lee et al., 2018) where substantial rates of failure to initiate naltrexone 
were observed across sites—up to 47% failure across the 8 sites, with the highest failure rate 
among sites that used methadone taper as a detoxification strategy. 
4.1.2 
Addressing the Naltrexone Induction Hurdle 
Several approaches exist for addressing the induction hurdle including methods decreasing the 
time to the injection by using minimal agonist treatment. Shorter methods minimize the drop-out 
rate during the wait period and increase the induction success rate. These “rapid methods” use 
only 1-3 days of buprenorphine at the outset 
followed by a rapid titration of oral naltrexone, starting 
at very low doses, with standing doses of adjunctive medications targeting emerging opioid 
withdrawal symptoms. The use of low doses of opioid antagonist to accelerate detoxification was 

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first proposed in 1970’s with naloxone (Kurland and McCabe, 1976), later used to facilitate 
initiation of treatment with naltrexone (Resnick et al., 1977). In this method, an antagonist, usually 
naltrexone, is administered without waiting for opioids to washout. The method starts with low 
doses of naltrexone, which do not precipitate withdrawal but prepare the system to tolerate a large 
dose of naltrexone; in this case, the first XR-NTX injection (Umbricht et al., 1999). Because of the 
relatively low-level of withdrawal, rapid methods do not require sedation or anesthesia, techniques 
which are often used in so called “ultra-rapid” (1-day) methods (Gowing et al., 2010). 
The Rapid induction method can be as short as 5 days from the day of admission to the day of 
XR-NTX injection, but it can be extended by 1-2 days depending on individual patient tolerability 
of the naltrexone titration. Using this slow titration approach minimizes the severity of opioid 
withdrawal which is comparable to residual withdrawal present during buprenorphine taper 
(Sullivan et al., 2017). The variations of this method include: duration of buprenorphine treatment 
as well as timing, starting doses, and duration of oral naltrexone treatment (Bisaga et al., 2018b, 
Mannelli et al., 2014, Sullivan et al., 2017). Non-opioid adjunctive medications targeting symptoms 
of withdrawal are given as standing doses to reduce emergent symptoms of opioid withdrawal 
(Sigmon et al., 2012). 
Risks that apply to both the Standard and Rapid initiation regimens include opioid withdrawal 
symptoms during the detoxification period, drop out from treatment prior to initiating XR-NTX and 
drop out from treatment once XR-NTX has been initiated. Opioid withdrawal symptoms may be 
unpleasant but are generally not serious, while drop out from treatment increases risk for relapse 
leading to overdose, disability and death. Risks of the Rapid method include the possibility of 
more severe precipitated withdrawal with the use of low dose oral naltrexone or after XR-NTX 
induction as well as side effects from standing doses of adjunctive medications. Although we 
expect the RP to be non-inferior to the Standard method in terms of retention and receipt of XR-
NTX, there is the possibility that increased withdrawal symptoms will lead to lower rates of 
retention. 
In a single-site randomized controlled trial conducted at an outpatient research clinic, this rapid 
induction method was found superior to the standard approach of buprenorphine taper followed 
by 7-day delay to first naltrexone dose, on proportion of patients successfully initiating XR-NTX 
(Sullivan et al., 2017). A recent study evaluated an 8-day version of the rapid XR-NTX induction 
protocol (Bisaga et al., 2018b) in outpatient community-based treatment programs. The overall 
rate of success was approximately 44% and there was no difference between participants that 
received buprenorphine and low-dose naltrexone in addition to adjunctive medications and those 
that received only adjunctive medications. The reason for not showing additional benefit of 
buprenorphine taper or low-dose NTX may include an extended duration of treatment which 
eliminates the benefits of rapid naltrexone titration (i.e., participants that received oral naltrexone 
may be able to receive XR-NTX earlier than on day 8). Clinical experience suggests that low dose 
buprenorphine at the outset is important for controlling the most severe opioid withdrawal 
symptoms over the first several days in patients with more severe physiological dependence and 
tolerance levels. The low dose naltrexone titration has a practical advantage in that it establishes 
with relative certainty that the patient’s system is ready to tolerate naltrexone and avoids the need 
for naloxone challenge. In summary, this study (Bisaga et al., 2018b)  showed that: 1) the rapid 

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method was feasible; 2) there was a higher failure rate for heroin users (suggesting that heroin 
users, who likely have greater physiological dependence and tolerance, may do better initially in 
inpatient settings where withdrawal symptoms can be managed more directly with non-opioid 
medication); and 3) experienced sites (sites with experience initiating naltrexone) enrolled more 
participants and had better success rate than inexperienced sites – suggesting a key need 
addressed by this CTN study, namely, 4) that a training and implementation package is needed 
to train and coach treatment programs to learn how to successfully initiate patients onto 
naltrexone. 
4.1.3 
Changing Practice for Inpatient OUD Treatment 
Short-term inpatient units (so-called “detoxification units”) or short-term residential treatment 
programs are an important portal of entry for patients with OUD into the treatment system, offering 
patients an opportunity for stabilization and planning a long-term outpatient treatment regimen 
post-discharge. Historically, the standard of care on these types of units has been detoxification 
from opioids, often using a brief (typically 5-day) taper with methadone, or buprenorphine. 
However, clinical experience and mounting evidence from observational studies and clinical trials 
(Lee et al., 2018, Nunes et al., 2017) have highlighted the high rate of relapse to OUD among 
patients discharged from inpatient treatment without an effective medication for OUD having been 
initiated. Observational studies have shown an elevated risk of relapse, overdose and death after 
discharge from controlled settings in which patients have been detoxified, including prison or 
residential treatment (Binswanger et al., 2013, Gossop et al., 2002, Naderi-Heiden et al., 2012, 
Pierce et al., 2016, Strang et al., 2003, Winter et al., 2015). Thus, a powerful argument can be 
made that the standard of care on these units should change from detoxification to initiation on 
one of the effective maintenance medications for OUD (Bisaga et al., 2018a). The implementation 
facilitation package for naltrexone initiation that will be developed and tested in this study should 
fill an important need in providing a blueprint for inpatient programs to follow in adopting injection 
naltrexone as part of their standard practice and treatment options. 
4.1.4 
Study Design 
The CTN trial will be a hybrid Type I implementation-effectiveness design inpatient trial that will 
compare the effectiveness of Standard Procedure (SP) (per official prescribing information) 
versus 
Rapid 
Procedure 
(RP) 
to 
initiate 
XR-NTX, 
seeking 
to 
replicate 
the findings 
of 
the 
prior 
single-
site outpatient trial (Sullivan et al., 2017) across a sample of community- based inpatient 
detoxification or short-term residential treatment units. At the same time, we will develop and test 
the implementation package that will be used to train sites in the RP. We seek to determine 
whether the RP is non-inferior to the SP in community-based treatment settings, to understand 
factors influencing its implementation, and to emerge from the study with an implementation 
package that can support the widespread adoption of RP on inpatient units. There is a large 
population of opioid-dependent patients who enter detoxification programs to which the findings 
of the trial should generalize. We propose to conduct this study first on an inpatient basis in order 
to address this important population of patients. We have observed lower injection naltrexone 
initiation success rates among heroin users when initiation is attempted on an outpatient basis 
(Sullivan et al., 2017), presumably due to the higher level of tolerance / dependence and 
correspondingly more withdrawal symptoms. This may be particularly true now that fentanyl and 

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other high potency synthetic analogs are commonly present in the heroin supply. The inpatient 
setting is likely better suited to aggressively treating withdrawal symptoms tailored to patients’ 
needs. 
4.1.4.1 
Stepped-Wedge Design 
We chose to implement stepped-wedge design after consideration of its relative strengths and 
limitations compared to patient-level randomized and program-level randomized parallel group 
designs (Handley et al., 2011). While patient-level randomization is the preferred design for 
efficacy trials, and often applied for effectiveness as well, the evidence for efficacy of the RP vs. 
SP is already established (Sullivan et al., 2017). Further, the SP and RP procedures being 
compared are service delivery interventions, involving quite different approaches to naltrexone 
initiation at the level of the treatment team and program. A patient-level randomized trial would 
have been logistically difficult to carry out at community-based treatment programs, asking 
programs and their teams to implement both procedures at the same time for different patients. 
A program (site)-level randomized, parallel group design was considered, but such designs 
typically require large numbers of sites, and only half of sites would get to implement the new RP. 
The program (site)-level randomized stepped-wedge design is appropriate for evaluation of 
service delivery interventions, where there is already evidence of effectiveness, and where there 
is an implementation aim in addition to an effectiveness aim, namely development and refinement 
of an implementation facilitation package for RP. The proposed stepped-wedge design allows 
study of implementation at each of the participating sites (except one site out of 6 sites), while 
furnishing a test of effectiveness compared to the SP naltrexone initiation approach. 
As compared to the parallel-group (patient-level randomization), the stepped-wedge design used 
in the proposed study has the following advantages: 
1. is more feasible to implement at sites with limited research infrastructure and support; 
each program will implement one regimen at a time, which is more feasible and has 
greater external validity (for other CTPs); 
2. requires fewer resources to start, as staggered implementation of the experimental 
regimen can reduce training staff effort/burden by training only 1-2 sites at a time and 
focusing on training a program’s clinical team on one naltrexone initiation method at a 
time; 
3. increased enrollment, as participants can be enrolled and receive treatment more flexibly 
with no delay due to the need for participant-level randomization which creates fewer 
barriers for the participants; 
4. fewer study implementation barriers, as there is no risk of contamination of the study 
arms. In an open label trial with similar medications but at different doses and different 
treatment durations, staff may be confused as to which study arm a participant belongs; 
further, participants, who will be housed together, will discuss/compare their treatment 
experience and may be more likely to withdraw from the study; 
5. allows for both testing the comparative effectiveness of the RP vs. SP, as well as for 
developing, improving, and evaluating the implementation facilitation package with 

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continuous quality improvement with input from stakeholders. This is important given 
that a training intervention is needed for sustainability and disseminability; 
and 
6. offering only one regimen at a time will be more naturalistic to real-world 
clinical practice, 
improving generalizability and dissemination value. 
We have also considered a cross-over study design, with half sites starting with SP arm and half 
sites starting with RP arm, with a cross-over to the other arm half-way through the trial. This 
design offers a greater power to detect hypothesized effect size however it has significant 
limitations including: 1) difficulty with implementing regimen in practice as half the sites will be 
asked to switch from the Standard Procedure to the Rapid Procedure and then back to the 
Standard Procedure with a possibility of a carry-over effect (sites may not want to change back 
to a longer, more expensive, and less effective regimen, and 2) fewer opportunities (only two 
steps) to develop and improve the Training Package using the iterative process. 
4.1.4.2 
Adjunctive Medications 
In the proposed trial we will use clonidine as the primary adjunctive medication which is one of 
several presynaptic alpha-2 adrenergic agonist which are used clinically to alleviate opioid 
withdrawal (Gowing et al., 2016). We considered an alternative choice of lofexidine. Although 
lofexidine, unlike clonidine, is FDA approved for treatment of opioid withdrawal we decided that a 
regimen that includes clonidine will have greater chance of dissemination since it is inexpensive, 
and is already in wide use, unlike lofexidine. Moreover, the package insert for lofexidine includes 
the risk of QT prolongation which is not the case for clonidine. In previous trials lofexidine has 
been used previously to facilitate rapid induction onto naltrexone (Buntwal et al., 2000, Gerra et 
al., 2001). In comparison to clonidine the data was mixed, with some trials finding lofexidine to be 
better tolerated (Carnwath and Hardman, 1998, Gerra et al., 2001) while another trial did not 
(Kahn et al., 1997). Considering the mixed trial data regarding the superiority of lofexidine over 
clonidine and significantly higher cost and implementation hurdles facing lofexidine we chose to 
use clonidine. 
Documenting effectiveness of clonidine will serve as a proof of concept for other alpha-2 
adrenergic agonist such as tizanidine (Rudolf et al., 2018) or guanfacine (San et al., 1990). We 
believe that future studies, especially those conducted in an outpatient setting, might consider 
whether lofexidine is better tolerated than clonidine. 
4.1.5 
Duration of XR-NTX Treatment 
The primary study goal is the success of XR-NTX induction, i.e., receiving the first injection. 
However, we will continue treatment by offering two additional XR-NTX injections. First, the 
acceptance of the second and third injections is an important outcome and may be reflective of 
the tolerability of the first injection and the induction procedure overall. The first three months of 
XR-NTX treatments is the time when greatest dropout is anticipated (Sullivan et al., 2019) and 
therefore providing treatment with three consecutive injections is ethically favorable. The post-
induction portion of the study will last 8 weeks, until the third XR-NTX injection is given, at which 
point participants will complete final study assessments and will transition to continuing treatment 
in the community. 

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4.1.6 
Evaluation of Implementation Parameters 
One of the main challenges in the field of medication-based treatment of OUD is the gap between 
evidence-based approaches developed and tested in research settings and real-world practice. 
Therefore, research on new methods to initiate treatment with XR-NTX should include an 
evaluation of factors that may impact successful implementation of research findings into routine 
practice. A secondary goal of the proposed study, therefore, will be to understand potential 
facilitators and barriers to implementation of rapid initiation of XR-NTX, knowledge that will be 
important in subsequent efforts to achieve widespread implementation across community-based 
treatment settings. In the proposed trial, we will focus on the inpatient setting as this is the most 
frequently used approach in addressing opioid use disorder in the community. Using the 
Consolidated Framework for Implementation Research (CFIR; (Damschroder and Hagedorn, 
2011)) to guide measurement selection, we will use mixed methods to assess the domains of 
intervention characteristics (e.g., complexity, relative advantage), inner setting (e.g., readiness, 
clinical leadership), individual characteristics (e.g., provider beliefs, self-efficacy), and 
implementation process (e.g., fidelity and feasibility).
 
4.1.7 
Implementation Facilitation Manual Development Process 
Implementation Facilitation (IF) is defined as a “process of ‘helping individuals and teams to 
understand what they need to change and how they need to change it in order to apply evidence 
to practice” (VA Mental Health Queri, 2016). 
IF is an effective approach 
that includes a “deliberate 
process of interactive problem solving and support that occurs in the context of a recognized need 
for improvement and supportive interpersonal relationship” (Stetler et al., 2011). A recent 
systematic review and meta-analysis found that IF has a positive impact on guideline adoption in 
primary care. A central aspect of IF includes the active role of the facilitator(s) working in 
partnership with relevant stakeholders, and other implementation intervention components. 
In this 
case, we will leverage experience gained in implementation of novel designs in previous work to 
develop an implementation plan that interfaces with these stakeholders through formal training 
and a “formative evaluation” to identify the specific and dynamic needs of stakeholders and the 
context (i.e., detoxification units) for implementation of evidence-based practices that may be 
specific to the site. This “diagnostic” formative evaluation informs the initial tailoring and 
refinement of the IF, which includes the “bundle” of services tailored to meet site-specific 
needs. 
Tailored implementation strategies have been found to be more effective than non-tailored 
interventions in changing practice (Baker et al., 2010) and have been applied to changing primary 
care and mental health treatment delivery (Johnson et al., 2014, Kirchner et al., 2014) IF has been 
used by large healthcare organizations including the Veterans Health Administration and is 
endorsed by the Agency for Health Care Research and Quality as a way to assist practices in 
becoming Primary Care Medical Homes. 
In this study, formative evaluation of the IF process will be iterative and will occur following each 
stepped wedge, as well as at the trial’s conclusion. Prior to the first step, a subset of the research 
team will develop an initial prototype IF process, based on current research and practice 
knowledge of implementation strategies and processes. The prototype will include approximately 
4 hours of staff education and training, academic detailing with each clinical team weekly (or more 

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frequently based on site needs), and structured 
clinical 
materials. 
Following 
each 
step 
of 
the 
study, 
relevant stakeholders including site clinicians, individuals from the research team with expertise 
in implementation, and clinical experts will meet to identify and address barriers to the 
implementation, the need to modify or adapt particular strategies, and ways to modify the IF 
manual for parsimony and efficiency. 
Given our multifaceted implementation approach, a structured framework and process will be 
used to capture adaptations or modifications to the implementation strategies throughout the IF 
process. We will combine the Framework for Reporting Adaptations and Modifications to 
Evidence-Based Implementation Strategies (FRAME-IS) (Miller et al., 2021) with additional 
tracking (informed by the Expert Recommendations for Implementing Change (ERIC) (Perry et 
al., 2019, Powell et al., 2015, Waltz et al., 2015) and Proctor et al.’s guidance on specifying 
implementation strategies (Proctor et al., 2013). Each modification or adaptation will be described 
along with the reason(s) for the change (informed by the CFIR framework). The iterative nature 
of these adaptations and use of FRAME-IS provides the opportunity to simultaneously examine 
the implementation components and feasibility of using this tool for a dynamic implementation 
facilitation approach. In this way, at the conclusion of the study, a high-quality IF manual will be 
completed that may be used for dissemination of the brief induction procedure or further 
implementation testing. In addition, this will add to the implementation science literature by 
providing a reproducible process for evaluating implementation facilitation using the ERIC 
taxonomy for strategies; although specific to the RP intervention, certain processes and 
implementation strategies are generalizable to implementation of evidence-based interventions. 
4.2 Innovation 
This would be the first community-based effectiveness-implementation trial of a method of rapid 
initiation of XR-NTX for treatment of OUD. This has the potential to move the field in a new 
direction of adopting rapid initiation of XR-NTX as standard practice in short-term inpatient units. 
Clinicians currently hesitate to consider XR-NTX in part because of lack of experience and 
concerns about the feasibility and the length of time needed to initiate XR-NTX. Clinicians are 
concerned about following the recommendation of the Official Prescribing Information, which calls 
for a waiting period of 7 to 10 days after last dose of opioid before administering XR-NTX (Vivitrol). 
Administrators and third-party payors often do not support longer inpatient stays and clinicians 
are concerned about the risk of dropout, relapse and overdose during the wait period. The 
proposed trial seeks to move the field in a new direction by showing that XR-NTX can be safely 
and effectively administered within the typical 5 to 7-day window of acute inpatient 
(“detoxification”) stays for opioid use disorder. 
The proposed trial would be among the first hybrid effectiveness-implementation trials (Curran et 
al., 2012) to be conducted by the CTN, where implementation factors at the levels of patients, 
clinicians, and treatment programs are studied in conjunction within a randomized effectiveness 
trial. A key goal of effectiveness trials conducted in CTN is to ultimately promote widespread 
dissemination and adoption of effective interventions; thus, studying the implementation 
processes should provide critical information to assist in more rapid uptake. 

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4.3 Suitability, Feasibility, and Sustainability for the CTN Sites 
We believe that a large number of inpatient treatment programs will be interested in participating 
in a trial testing a regimen for rapid XR-NTX treatment initiation. During the protocol development 
process for CTN-0051, over 30 CTN-affiliated inpatient treatment programs applied to participate 
in the trial, among which only 8 could be selected. This is consistent with the large number of 
such inpatient or residential treatment programs throughout the U.S. health system that are 
interested in implementing evidence-based medications for OUD, and the extent to which these 
programs are confronting how best to care for the many patients with OUD that they admit. The 
CTN should be able to easily supply a sample of appropriate inpatient treatment programs for the 
proposed trial and provide a vehicle for rapidly disseminating the findings across the network and 
field. 
4.4 Public Health Impact Significance to the Field 
The epidemic of OUD and opioid overdose deaths is a major public health challenge. Short-term 
inpatient addiction treatment units are a common portal of entry into treatment for patients with 
OUD. Such programs represent an important opportunity for initiating patients with OUD onto 
effective medication treatment. The current proposal seeks to facilitate the larger goal of making 
initiation of medications for OUD standard practice for inpatient treatment programs, by 
addressing the naltrexone “induction hurdle,” which is a significant barrier to the implementation 
of XR-NTX. Improving success of XR-NTX treatment initiation has important potential public 
impact via reducing barriers to the use of XR-NTX, thus potentially expanding access to this 
effective alternative across the health care system. 

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5.0 OBJECTIVES 
5.1 Primary Objective 
The primary goal of the study is to determine whether the RP method of initiating treatment with 
XR-NTX is non-inferior to the SP method recommended in the XR-NTX Prescribing Information. 
The primary outcome measure is a dichotomous measure of treatment initiation success defined 
as receipt of the first injection of XR-NTX while inpatient. Treatment initiation failure, defined as 
failure to receive first injection of XR-NTX while inpatient, can be subdivided for descriptive 
purposes into 1) decision by patient and their clinicians to abort the naltrexone initiation effort and 
change to initiation of buprenorphine or methadone maintenance; 2) dropout or discharge from 
the inpatient unit prior to receiving XR-NTX. We hypothesize that the RP will be non-inferior to 
SP in terms of proportion of successful initiations of XR-NTX. 
5.2 Secondary Objective(s) 
A key secondary objective is to summarize the below outcome to confirm expected characteristics 
of the RP compared to SP: 
1. Time to receipt of first injection of XR-NTX from day of admission for participants that 
receive first injection of XR-NTX while inpatient.  
Additional key secondary objectives are to compare the below outcomes of RP versus SP for all 
enrolled participants (ITT population). 
2. Craving for opioids measured by Visual Analog Scales (VAS). 
3. Opioid withdrawal symptoms as measured by the Subjective Opioid Withdrawal Scale 
(SOWS) and the Clinical Opiate Withdrawal Scale (COWS). 
4. Safety, as measured by overdose questionnaire, targeted safety events and serious 
adverse events. 
Other secondary objectives are to compare the below outcomes of RP vs. SP for 
participants who receive the first injection while inpatient. 
5. Retention in the trial to receive the second and the third XR-NTX injections. 
6. Craving for opioids measured by Visual Analog Scales (VAS). 
7. Opioid withdrawal symptoms following XR-NTX injection as measured by the Subjective 
Opioid Withdrawal Scale (SOWS) 
8. Safety, as measured by overdose questionnaire, targeted safety events and serious 
adverse events. 
9. Opioid abstinence, as measured by the Timeline Followback (TLFB) (self-report days 
using opioids) and proportion of opioid-positive urine tests. 
5.3 Exploratory Objective(s) 
1. Explore baseline demographic and clinical features (e.g., the primary opioid of 
dependence (heroin/fentanyl vs. prescription opioid)) as: a) predictors of induction 

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success, secondary outcomes and retention during the trial (main effect of predictors), 
and b) as moderators of differential treatment effect (moderator by treatment interaction). 
2. Compare duration of inpatient treatment and the associated costs from the time when 
detoxification is initiated to the time that XR-NTX is administered to permit analyses of 
economic costs and benefits of the two treatments. 
3. Compare RP versus SP for all enrolled participants in terms of time from day of 
admission to XR-NTX initiation failure (day of discontinuation of detoxification period that 
resulted in failure to receive 1st XR-NTX) and reasons for failure. 
4. Compare RP versus SP for all enrolled participants in terms of other depressive, anxiety, 
and subacute withdrawal symptoms as measured by the Patient Health Questionnaire-9 
(PHQ-9) and General Anxiety Disorder-7 (GAD-7). 
5. Compare RP versus SP use of alcohol and other drugs of abuse (e.g., cocaine, other 
stimulants, cannabis, benzodiazepines), by self-report and urine drug screens for all 
enrolled participants.  
6. Explore engagement with medical visits and therapy (based on Medical Management 
Log, Psychosocial Log, XR-NTX Administration Form, TLFB). 
7. Compare RP versus SP for all enrolled participants in terms of use of MOUD as 
measured by patient self-report on Timeline Followback (TLFB). 
8. Investigate the percentage of induction failure participants that receive XR-NTX during 
the course of the study overall and for each treatment arm as measured by patient self-
report on Timeline Followback (TLFB). 
9. Compare RP versus SP for percentage of participants inducted on XR-NTX (during both 
induction and post-induction phases of the trial). 
5.4 Implementation Objectives 
The objective of the implementation component of the study is to understand facilitators and 
barriers to implementation of Rapid initiation of naltrexone and to iteratively develop an 
implementation facilitation manual which can be used to disseminate XR-NTX initiation methods 
across the treatment system. Measurement will be grounded in the CFIR (Damschroder and 
Hagedorn, 2011) and will assess intervention characteristics (provider survey), inner setting 
factors (e.g., readiness, clinical leadership structure, resources; survey and environmental scan), 
individual provider characteristics (provider survey), and implementation process through fidelity 
measures. Following each stepped wedge, this information will be integrated into the IF manual 
(by adding new information and/or making modifications to existing information) to improve the 
procedures. The ultimate goal will be to produce a high quality IF manual at the conclusion of trial 
which could facilitate widespread implementation of XR-NTX induction across community-based 
treatment settings, as well as be tested within its own right in a larger implementation-focused 
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6.0 STUDY DESIGN 
6.1 Overview of Study Design 
6.1.1 
Overview 
This is a six-center, stepped-wedge, cluster randomized trial comparing effectiveness and safety 
of Rapid (5-7-day) versus Standard (13-day) XR-NTX induction procedure (RP vs. SP). Sites will 
be addiction treatment programs offering inpatient/residential “detoxification” and follow-up 
outpatient treatment (site characteristics are described in Section 9.0). Patient-participants will be 
admitted to these sites for treatment of opioid use disorder, eligible for and seeking treatment with 
XR-NTX, and consenting to research assessments during their course of XR-NTX treatment. 
Upon enrollment in the study, participants will receive the naltrexone initiation regimen being 
offered at the site at the time of admission, either SP or RP depending on the random assignment 
as per study design (Figure 1). The post-induct
ion
 phase w
i
l
l beg
in the day after receiving XR-NTX 
injection. During the 8-week post-induction phase, participants will receive medication 
management visits per the site’s standard clinical practice, plus an additional two XR-NTX 
injections, one at four weeks and one at eight weeks after the first XR-NTX injection, along with 
other psychosocial treatment as per the standard of care provided by each site. The primary 
effectiveness outcome measure is induction success defined as the administration of the first XR-
NTX injection. The primary implementation outcomes derive from the process evaluation of 
implementation using the CFIR framework and evaluation methods. 
6.1.2 
Patient-Participants 
Patients with OUD planning admission or admitted to inpatient/short-term residential treatment 
sites will participate in a shared decision-making process regarding choice of maintenance 
medication (methadone, buprenorphine, XR-NTX). All those determined to be clinically 
appropriate by their admitting clinicians for XR-NTX and choosing XR-NTX will be offered 
participation in the study and will undergo informed consent procedures before completing any 
study-related activities. 
6.1.3 
Random Site Selection and Treatment Assignment 
The study will proceed in five steps, with each step lasting 14 weeks, for a total of 70 weeks of 
the study (Table 1). At the beginning of each step 
a randomly selected site will begin implementing 
RP and will continue to offer it for the remainder of the trial, according to the optimized stepped- 
wedge study design (Thompson et al., 2017). At the outset of the trial (Step 1), one randomly 
selected site will initiate RP while the remaining five sites will continue providing XR-NTX initiation 
using the SP. At the beginning of Step 2 another randomly selected site will stop implementing 
SP and will begin implementing the RP. The same process will take place at the beginning of 
Steps 3, 4, and 5. The remaining site, one that has not been selected to transition from SP to RP 
during the five steps will be offering SP for the 70 weeks duration of the trial. After the transition 
to RP, this will be the only regimen available for patients interested in participating in the research 
study (i.e., SP will no longer be offered as a part of the study). However, standard clinical care 
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study. 
6.1.4 
Training in SP and RP procedures 
At the beginning of the trial all sites will receive training in the study procedures. In addition, the 
five sites chosen to offer SP will receive an overview training and review of practices in the SP, 
while the site selected to start with RP in Step 1 will receive an overview training in the RP. This 
didactic training will occur before the study start date. At the start date participant enrollment 
begins, the units chosen to begin by offering SP will receive academic detailing in SP, while the 
unit assigned to begin RP will receive the further targeted RP implementation facilitation 
intervention (training and academic detailing) in an 8-week pre-implementation or preparation 
phase before the start of the RP implementation step. Upon transition to RP implementation (or 
start of the step), RP academic detailing and coaching support will be held weekly or more 
frequently based on the site’s needs. After ind
iv
idua
l
 s
ite-leve
l
 coach
ing support sess
ions, a
l
l s
ites 
random
ized to RP w
i
l
l part
ic
ipate in
 co
l
laborat
ive coach
ing sess
ions that occur week
ly or more 
frequent
ly based on s
ites
’ needs. 
Study Schema 
The flow of a patient-participant through the study, at either SP or RP sites, will proceed in four 
phases (see Figure 1). 
6.1.4.1 
Phase 1 & 2 Inpatient Induction (Recruitment and 
Induction Phase) 
The clinical procedures for all individuals interested in XR-NTX will be determined by the 
assignment of the unit to either the Rapid or Standard Procedures and the clinical judgement of 
the unit staff. These will begin immediately upon admission and will be independent of study 
participation. Recruitment for research participation will occur independent of the clinical 
procedures any time from seven days before admission until the fourth day of admission. 
Research Recruitment 
The research recruitment phase begins with informed consent up to one week before or up until 
the fourth day of inpatient admission to the study site. During the inpatient admission 
intake/evaluation or the first four days of an inpatient admission, clinical staff, as part of standard 
clinical procedures, will conduct a medical and psychiatric workup, and conduct a shared –
decision-making process regarding choice of maintenance medication to be initiated during the 
inpatient stay. During this process research staff will provide information about the study to 
potential participants, describing XR-NTX as an option for relapse-prevention to opioid 
dependence following detoxification, and the study plan to monitor the progress of patients 
undergoing initiation and initial months of treatment with XR-NTX using materials prepared for the 
study. For scheduled admissions, this information may be provided in advance of the admission. 
Once a patient decides (with their clinicians) to pursue XR-NTX treatment, then the patient can 
be offered informed consent to participate in the study. 
After the participant provides written informed consent, the participant will be evaluated for study 
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on buprenorphine before study enrollment but those who received methadone at treatment outset 
(e.g., in the ER or upon arriving at the unit) are not eligible for enrollment.  
Clinical Induction Procedures 
Following the initial buprenorphine treatment, the units will provide participants with treatment 
guided by the regimen for the respective study arm as implemented by clinical staff at the 
detoxification program (Tables 6A and 6B). 
Standard Procedures: The plan is for 13-14 days from first dose of buprenorphine in the 
Standard Procedures (SP) for induction, detailed in Table 6A; this includes a 5-day buprenorphine 
taper followed by an 8-day washout before being eligible for the XR-NTX injection (as determined 
by the naloxone challenge, naltrexone titration, or toxicology). In case that participant does not 
meet criteria of eligibility by Day 14, the eligibility determination can be repeated on subsequent 
days. Since the SP 
regimen will be the standard of care for XR-NTX initiation during the SP phase 
of the participation of a Site, there will be flexibility based on clinical judgment. 
Rapid Procedures: The plan is for 5-7 days from first dose of buprenorphine in the Rapid 
Procedures (RP) 
for induction, detailed in Table 6B; this includes 1 day of buprenorphine followed 
by 1-day washout and a 4-day period of treatment with low-doses of oral naltrexone. Adjunctive 
medication will be given throughout the RP. Again, since the RP regimen will be the standard of 
care for XR-NTX initiation during the RP phase of the participation of a Site, there will be flexibility 
based on clinical judgment. For example, it is possible that some participants will not be able to 
tolerate naltrexone 6 mg on Day 6 and in those participants, XR-NTX may be administered on 
Day 7 or thereafter. 
After administration of XR-NTX participants will continue treatment per standard clinical practice. 
The day after the first XR-NTX injection is received or the day after the decision to discontinue 
XR-NTX induction is considered the Post-Induction Day 1. Participants who receive the first XR-
NTX injection will be classified as meeting criteria for “XR-NTX induction success.” Participants 
who discontinue the induction phase before receiving the XR-NTX injection will be classified as 
“XR-NTX induction failure.” These participants will continue in the study but will only follow up at 
Week 4 and Week 8. 
6.1.4.2 
Phase 3 (Post-Induction Phase): Follow-Up Treatment 
Following inpatient XR-NTX induction phase, participants will continue with the post-induction 
treatment for 8 weeks (post-induction Week 1 through Week 8; Days 1 – 55). Most participants 
will be treated on an outpatient basis during this phase, but some may be in extended residential 
or therapeutic community programs. Participants that receive first XR-NTX are expected to 
receive a second injection of XR-NTX towards the end of Week 4 and a third injection towards 
the end of Week 8 in combination with weekly Medical Management visits. The study will supply 
the three XR-NTX injections (initial and at Weeks 4 and 8). Study assessment visits occur weekly 
during this phase, with an End of Study (EOS) visit occurring at Week 8. For participants who 
request discontinuation of treatment, relapse, and/or become lost to follow up, a +14 day window 
is permissible to complete the EMT visit.   

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Patients who fail to initiate XR-NTX while inpatient will also be followed and evaluated at Week 4 
and Week 8 to determine what treatment they are receiving (for example, whether they initiated 
XR-NTX after leaving the unit or if they initiated and remained on another medication 
(buprenorphine or methadone maintenance)) and whether or not they have relapsed to opioid 
use. 
6.1.4.3 
Phase 4 (Referral Phase) Referral to continuing treatment 
During the last month of study, as part of standard clinical care, arrangements will be made by 
the clinical team for participants to either continue treatment at the same program or be referred 
to another program in the community for follow-up care, which should ideally include continuation 
of XR-NTX. The third XR-NTX injection will be administered as a part of the study in order to 
objectively assess the retention in treatment 8-weeks after the induction and to assure the 
continuation of treatment with XR-NTX during the post-study transition period. However, 
participants will not be followed with study assessments after third injection as at this point, they 
will be engaged with and 
followed 
in 
the 
community-based 
clinical 
care 
where 
they 
will 
be 
assessed 
medically 
following standard procedures. 
6.1.4.4 
Management of participants who fail to initiate XR-NTX 
Participants will be made aware, as part of standard clinical care during initial clinical evaluation 
at the site, and also at the time of study consent, that other treatment options, particularly 
buprenorphine, are available at any time if the patient is not tolerating the XR-NTX induction, or 
otherwise changes their mind and wants buprenorphine instead, or initiation and referral to 
methadone maintenance if locally available. Effort will be made to avoid having patients leave the 
inpatient-residential unit without initiating an effective medication for OUD. Patients who fail to 
initiate XR-NTX will be followed and evaluated at Week 4 and Week 8. 
6.2 Implementation Facilitation 
A secondary goal of the current study is to develop an Implementation Facilitation (IF) strategy to 
facilitate the increased adoption and implementation of Rapid Induction onto XR-NTX in inpatient 
detoxification and residential facilities. We will use IF which, as mentioned above, provides a 
“deliberate process of interactive problem solving and support that occurs in the context of a 
recognized need for improvement and supportive interpersonal relationship.” Through this 
organized and iterative process, the needed steps will be taken to support inpatient unit staff and 
to promote uptake of XR-NTX treatment initiation among enrolled participants.  
The Rapid Procedure involves systematic implementation facilitation support. The study team will 
act as external facilitators throughout the implementation process for RP and will reduce support 
as sites take lead in implementation. Before initiating the trial, we will develop a complete IF 
package for the Rapid Induction Procedure based on our prior experience training clinical teams 
for clinical trials and through the SAMHSA-funded Providers’ Clinical Support System (PCSS). 
Before each stepped wedge of the study, an 8-week pre-implementation or preparation phase will 
occur for each site randomized to RP. Note that during the pre-implementation phase the 
randomized site will continue to offer SP until the actual transition date to the next step. Pre-
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Site Mapping or an implementation needs assessment, adaptations or modifications to 
implementation strategies based on site’s needs, intensive staff training, and review of the RP IF 
package and clinical tools.  
During the implementation phase of RP, the study team will meet weekly, or more frequently if 
needed, with site’s clinical staff and other key stakeholders to provide coaching support and 
monitoring during the initial implementation of the intervention. The study team or lead 
implementation team will meet routinely to review the implementation process and identify 
modifiable barriers or facilitators to facilitate RP implementation. The study team will reduce 
coaching support as each site takes lead in implementing RP and at that point the site will shift 
into the maintenance phase. During the maintenance phase, all sites randomized to RP will meet 
routinely in a collaborative coaching session and the study team will reduce support further and 
act in a monitoring role. 
After each stepped wedge, the study team with expertise in implementation will meet to review 
identified barriers and facilitators to implementing the RP intervention and modify or adapt the RP 
IF package accordingly. Barriers and facilitators mapped across the CFIR framework will be 
captured using various qualitative data including structured notes from Site Mapping meetings 
and coaching sessions, internal implementation team meeting notes, and staff structured 
interviews at the end of each stepped wedge. Review of other implementation-level data at the 
end of the study will inform final adaptations or modifications to the RP IF package. This IF 
package will form the basis of technical assistance and support widespread dissemination of rapid 
XR-NTX initiation. 
The Standard Procedure follows treatment as usual for induction onto XR-NTX and it is expected 
that site-level processes are already established for implementing SP (preconditions to be 
selected for study participation). Given these preconditions, SP sites do not require systematic 
implementation facilitation support. A brief overview and training of SP (primarily based on the 
XR-NTX prescribing information) will be provided at the start of the trial. Throughout the trial, the 
study team will meet with sites implementing SP for monitoring and engaging treatment teams in 
study participation. 
6.2.1 
Initial Elements Included in Implementation Facilitation 
The following elements will be included in the initial implementation of the Rapid Procedure and 
facilitation package; 
Pre-Implementation/Planning Phase 
Identifying a local 
Implementation Team 
and Champion 
A local implementation team and champion will be identified at each site to help 
guide and motivate change in the local context. This team may include executive 
leadership, key clinical staff, site PI, or other relevant stakeholders essential to the 
success of implementing the Rapid Procedure. 
Site Mapping 
We will meet with the identified local implementation team weekly (for 
approximately 4 to 5 weeks depending on each site’s needs) and conduct an 
implementation needs assessment that identifies relevant staff and procedures on 
the detoxification unit, facilitates site-level buy-in and engagement, maps inner 
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implementation, and identifies potential barriers and facilitators to implementing the 
intervention. 
Facilitate Buy-in and 
Engagement  
Site Mapping meetings will begin process of facilitating buy-in and we will 
encourage engagement of staff (not involved in these meetings) by internal 
facilitators and local champions. 
Training Needs 
Assessment 
We will identify specific training needs at each site and customize delivery of 
training and procedural support. 
General Staff Training 
and Orientation 
We will provide a brief intensive training program for unit staff outlining the clinical 
procedures in the Rapid Induction Procedures, commonly encountered clinical 
issues, and provide guidance on communicating with patients throughout the 
procedure. 
Customization of 
Clinical Tools 
Clinical tools developed by the study team will be reviewed with the site staff and 
customized accordingly to their needs. Clinical tools and handouts include a structured 
progress note, clinical algorithms for the procedure, flow charts, checklists, order sets, 
shared decision-making handout on medications for opioid use disorder, etc.  
Logistics Planning and 
Procedural Support 
Any necessary modifications to internal procedures will be addressed prior to 
implementation of RP when feasible. All providers and staff will receive a manual 
describing in detail the steps involved in the RP with detailed guidelines on prescribing 
and monitoring. Clinical tools will be reviewed and customized as per local staff needs.   
Implementation Phase 
Coaching and 
Procedural Support 
Sessions 
We will act as external facilitators to implementation of the RP intervention and 
meet with the site weekly, or more frequently if needed, to provide coaching and 
procedural support. Site staff will include key clinical staff and other relevant 
stakeholders (i.e., members of local implementation team).  
Expert clinician 
consultation as needed 
Expert clinicians on the study team will be readily available and on call to 
clinical staff during the initial implementation phase for acute clinical concerns 
or questions. 
Individual-level 
feedback from local 
champion(s) and 
stakeholders  
We will interview individual staff from each site at the end of the 14-week stepped 
wedge to gather feedback about their experience implementing the procedure, other 
key issues not identified in group meetings, and any other barriers or facilitators to 
implementation and the maintenance of the RP. 
Maintenance Phase 
Collaborative Coaching 
Sessions 
All sites randomized to RP will meet routinely (weekly or less frequently depending on 
sites’ needs) for collaborative coaching sessions. The study team will attend these 
sessions for monitoring, and will be available if additional coaching is needed but 
collaboration and coaching between site staff will be encouraged with a longer term 
goal of these sessions continuing after study completion. 
Individual Site-Level 
Coaching Support as 
needed 
Individual site coaching sessions with the study team will be available as needed. 
6.2.2 
Iterative Development of the Implementation Facilitation 
Package 
After each step of the study and RP implementation, a subset of the study team with 
implementation expertise will meet to review barriers and facilitators mapped across the 
Consolidated Framework for Implementation Research (CFIR). The CFIR identifies elements for 
determining successful implementation of an evidence-based practice into clinical care, including: 

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1. Characteristics of the intervention, 
2. Individual recipients of the facilitation, including people affected by and who influence 
implementation of the innovation, 
3. Qualities of the inner and outer (i.e., social, policy, regulatory and political 
infrastructures) context in which the evidence is being introduced and enacted upon, 
and 
4. Facilitation (i.e., the implementation intervention), the active process of promoting 
implementation by assessing and responding to the recipients and associated context. 
The CFIR domains contain various constructs that are determinants or measures related to 
implementation of the intervention. These measures will be assessed after each stepped wedge 
across various qualitative data including structured notes from Site Mapping meetings and 
coaching sessions, internal implementation team meeting notes, and staff structured interviews 
at the end of each stepped wedge. Staff will include medical prescribers, nursing staff, 
rehabilitation clinicians, social workers, and unit administrators.  Identified barriers and facilitators 
(mapped across the CFIR framework) will inform modifications and adaptations to implementation 
strategies and the IF package. Modifications and adaptations to implementation strategies will be 
categorized using the FRAME-IS model, the ERIC taxonomy for naming of implementation 
strategies, and Proctor and colleagues’ guidance on specifying implementation strategies (REF). 
Review of other implementation-level data at the end of the study will inform final adaptations or 
modifications to the RP IF package. These data include the qualitative listed above as well as 
patient satisfaction survey and quantitative data (Organizational Readiness to Change 
Assessment (ORCA) and readiness/preparedness rulers administered to individual staff, fidelity 
to the implementation facilitation components (fidelity to implementation assessments), fidelity to 
the intervention (critical action checklists and daily medication administration log), and proportion 
of participants successfully inducted onto XR-NTX. This strategic approach will facilitate 
refinement and production of a high-quality IF manual for widespread dissemination. 
6.3 Duration of Study and Visit Schedule 
Each participant is engaged in the overall study for approximately 13 weeks as follows: 
• Up to 11 days: consent, screening (up to 7 days prior to inpatient admission; up to 
4 days from admission, including admission day). 
• Up to 30-day induction phase: starting with day of admission up to day of 1st XR-NTX (or 
day of detox failure): Daily research assessment. 
• 8 weeks (56 days) of post-induction treatment. Weekly research assessment. 
• Post-study transition to community-based treatment. 

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6.4 Study Timeline 
 
6.4.1 
Table 2: Study Timeline 
The first step of trial preparation includes obtaining IRB approval of the protocol for all study sites; 
this is expected to last up to 6 weeks. 
After receiving CCTN approval of the full/final protocol, approximately 13 weeks of trial 
preparation activities will elapse prior to commencing enrollment of participants. This will include 
developing the data collection forms, developing the manual of operating procedures (MOP), 
developing the study and SP training plan and implementation guidelines for the RP, hiring staff 
and conducting all staff training, sites’ securing CLIA Certificates of Waiver (as needed), 
completing Site Initiation Visits and action items required for endorsement, and endorsing sites. 
If feasible, the initial study initiation may be implemented in a single wave; Recruitment is 
expected to take approximately 70 weeks, with follow-up continuing for approximately 10 weeks 
post completion of the recruitment phase. Following completion of the induction phase at week 
96 (when data collection for the primary outcome has been completed), approximately three 
months of data cleaning will elapse. Data lock will take place at approximately Week 100, or at 
minimum 2 months following last participant’s last visit; at the same time work will continue on 
developing a training package. 
Therefore, data lock is projected to occur at approximately 25 months after IRB approval of the 
initial protocol. The preliminary analyses and a draft of the final implementation package will be 
developed within four months of the data lock. 

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7.0 OUTCOME MEASURES 
7.1 Primary Outcome Measure 
The primary goal of the study is to show RP is non-inferior to SP XR-NTX induction method. 
The primary outcome measure is the proportion of patients who receive the first XR-NTX injection 
(dichotomous: did or did not receive first dose of XR-NTX). 
We hypothesize that a Rapid Induction Procedure will be non-inferior to a Standard Induction 
Procedure in terms of proportion of patients with successful inductions while inpatient. 
7.2 Secondary Outcome Measure(s) 
7.2.1 
Table 3: Secondary Clinical Outcomes, Outcome Measures and 
Hypotheses 
Outcome 
Outcome Measure 
Hypothesis 
Time from admission 
to first XR-NTX 
injection 
Days to first XR-NTX 
injection 
Participants in the RP will receive their first injection 
significantly faster than those in the SP. 
Significance/Rationale: The RP decreases the time to 
the first injection (which has a potential to decrease 
costs and staff burden). 
Opioid Craving (VAS) 
over time 
Mean for opioid craving 
measured by VAS daily 
during days leading to the 
first XR-NTX injection, and 
during post-induction Weeks 
1-8 
Participants in RP and SP will have comparable 
intensity of craving during 1) the inpatient treatment 
period, and 2) during the first week after the first XR-
NTX injection. 
Significance/Rationale: Earlier trial showed 
comparable craving severity in both procedures 
(Sullivan et al., 2017). 
Opioid withdrawal 
(SOWS and COWS) 
over time 
Mean for opioid withdrawal 
measured by SOWS and 
COWS score, daily (starting 
with day of admission) during 
days leading to the first XR-
NTX injection and during 
post-induction Weeks 1-8 
Participants in RP and SP will have comparable 
severity of opioid withdrawal during: 1) the inpatient 
treatment period, and 2) during the first four weeks 
after the first XR-NTX injection. 
Significance/Rationale: Earlier trial showed 
comparable withdrawal severity in both procedures 
(Sullivan et al., 2017). 
Receive second and 
third injections (binary: 
did or did not receive 
second and third dose 
of XR-NTX) 
Proportion of participants 
that receive second and third 
injection of XR-NTX (at 4 
weeks and 8 weeks, from 
first injection) 
Participants in RP and SP will have comparable rates 
of treatment retention. 
Significance/Rationale: Because there is no 
difference in tolerability of the first and second XR-
NTX injections in both study arms, we do not expect 
differential treatment dropout. 
Targeted safety 
events, overdoses and 
SAEs, related to study 
medications 
Frequency of targeted safety 
events, overdose episodes 
and SAEs by relationship to 
study medication during the 
induction period and during 
eight weeks of post-induction 
RP and SP will produce equivalent rates of targeted 
safety events and SAEs during the induction and 
during the first eight weeks of treatment with XR-
NTX. 
Significance/Rationale: Careful documentation of 
SAEs, targeted safety events, and  overdose 

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Outcome 
Outcome Measure 
Hypothesis 
treatment 
episodes, 
would be considered essential safety data, 
and 
important component of a comparative 
effectiveness trial. 
Use of opioids over 
time during the 8-week 
of post-induction 
treatment while on 
study medication 
(Weekly TLFB, 
confirmed by urine 
drug screens when 
available) 
Percent of participants 
positive for opioids using 
weekly TLFB during eight 
weeks of post-induction, and 
urine drug screens at week 4 
and 8.  
RP and SP will produce comparable levels of opioid 
use. 
Significance/Rationale: XR-NTX produces complete 
blockade of opioid effects, so that during treatment 
with monthly injections, opioid use can be expected 
to be minimal and no different between study arms. 
7.3 Implementation Process and Outcome Measures 
7.3.1 
Identifying Facilitators and Barriers to Implementation Success 
Both quantitative and qualitative measures will be collected on factors hypothesized to be related 
to implementation success. Measures of implementation process capturing elements organized 
by the domains in the Consolidated Framework for Implementation Research (CFIR; 
(Damschroder and Hagedorn, 2011)) were used to guide measurement selection. This framework 
identifies the domains of intervention characteristics (e.g., complexity, relative advantage), inner 
setting (e.g., readiness, clinical leadership), individual characteristics (e.g., provider beliefs, self- 
efficacy), and implementation process (e.g., fidelity and feasibility) as necessary to understand 
the factors contributing to and barriers preventing implementation success. Table 4 summarizes 
these domains and the associated measures applicable to this trial. 
7.3.2 
Table 4: Implementation Measures Organized by the 
Consolidated Framework for Implementation Research 
Constructs 
 
Construct 
Measure 
Data Sources (Timeline) 
Intervention 
Characteristics 
Intervention Source  
Evidence Strength & Quality 
Relative Advantage 
Adaptability 
Complexity 
Design Quality and Packaging 
Cost 
ORCA (Before and after each wedge 
intervention) 
Staff Structured Interviews (After each wedge 
intervention and study conclusion) 
Coaching Session Progress Notes 
Internal Implementation Team Meeting Notes 
NMS Assessments and Staff Structured 
Interviews 
Outer Setting 
Patient Needs & Resources 
Peer Pressure 
External Policy & Incentives 
Site Mapping Needs Assessment and 
Progress Notes (Pre-implementation phase 
before each wedge intervention) 
Coaching Session Progress Notes 
Staff Structured Interviews (After each wedge 

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Construct 
Measure 
Data Sources (Timeline) 
intervention and study conclusion) 
Inner Setting 
Structural Characteristics 
Culture 
Implementation Climate 
(Tension for Change, 
Compatibility, Relative 
Priority) 
Learning Climate 
Readiness for Implementation 
(Leadership Engagement, 
Available Resources) 
Site Mapping Needs Assessment and 
Progress Notes (Pre-implementation phase 
before each wedge intervention) 
Coaching Session Progress Notes 
Internal Implementation Team Meeting Notes 
ORCA (Before and after each wedge 
intervention) 
Readiness/preparedness rulers (Before and 
after each wedge intervention) 
Staff Structured Interviews (After each wedge 
intervention and study conclusion) 
Individuals 
Knowledge and Beliefs about 
the Intervention 
Self-efficacy 
Individual Stage of Change 
Individual Identification with 
Organization 
Other Personal Attributes 
ORCA (Before and after each wedge 
intervention) 
Readiness/preparedness rulers (Before and 
after each wedge intervention) 
Staff Structured Interviews (After each wedge 
intervention and study conclusion) 
Process 
Planning 
Engaging  
Executing 
Reflecting & Evaluating 
Critical Action Checklists (Throughout trial, 
weekly) 
Implementation Process Fidelity Checklist 
(Throughout trial, monthly) 
Daily Medication Administration Log 
(Throughout trial, daily) 
Coaching Session Progress Notes 
(Throughout trial, weekly or more frequently 
based on site needs) 
Internal Implementation Team Meeting Notes 
(Throughout trial as needed) 
Staff Structured Interviews (After each wedge 
intervention and study conclusion) 
Patient End of Induction Survey (At end of 
detox admission) 
Patient Treatment Satisfaction Survey (At trial 
completion) 
Organization Level Clinical Implementation 
Data Form (Before and after each wedge 
intervention) 
 

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7.3.3 
Implementation Related Outcome Measures 
In addition to the above measures considering factors impacting successful implementation, 
implementation-related outcome measures will also be collected. These will be organized 
according to the RE-AIM framework, designed to enhance the public health impact of research 
evidence through coherent organization of outcomes related to implementation (Glasgow et al., 
1999). 
This framework includes the domains of: Reach to the intended target population, Effectiveness, 
Adoption by target staff and institutions, Implementation consistency (including fidelity to the 
Intervention), and 
Maintenance 
of the 
intervention over time 
by 
the 
target providers. The 
following
table describes study related measures organized according to this framework: 
7.3.4 
Table 5: Implementation Outcome Domain 
Implementation 
Outcome Domain 
Specific Study Measures 
Reach 
Clinic level data on percent of individuals with OUD screened for trial 
participation, percentage of individuals with OUD who receive XR-NTX during 
inpatient detox or residential rehab. 
Effectiveness 
Secondary clinical outcomes related to effectiveness will be gathered as 
described above (Table 3). 
Adoption 
An implementation checklist will capture all planned implementation 
processes, including the number of providers participating in each 
implementation activity. 
Implementation 
Fidelity to suggested clinical guidelines for trial participants will be gathered 
for each patient throughout the detoxification and rehabilitation stay via a 
critical action checklist. 
Maintenance 
Qualitative data (structured progress notes and staff interviews with key 
personnel) will capture barriers and facilitators that inform modifications and 
adaptations to implementation strategies to support long term adoption of the 
study procedures. 
 
7.3.5 
Integration Process for Iterative Improvement of Implementation 
Facilitation 
All implementation measures will be analyzed by categorizing individual facilitators and barriers 
within the framework of the CFIR model. These measures will be assessed after each stepped 
wedge across various qualitative data including structured notes from Site Mapping meetings and 
coaching sessions, internal implementation team meeting notes, and staff structured interviews 
at the end of each stepped wedge.  
Structured progress notes will contain sections for identified barriers and facilitators captured 
through site meetings and internal implementation team discussions. In addition, any 
modifications or adaptations made throughout the step wedge will be documented using these 
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recorded, transcribed, and coded based on the CFIR framework using Atlas.ti software (i.e., 
intervention characteristics, patient/provider characteristics, internal setting factors, and external 
setting factors). Qualitative data analysis will involve conceptual mapping of identified barriers 
and facilitators across the CFIR framework), and will inform modifications and adaptations to 
implementation strategies and the IF package. Modifications and adaptations to implementation 
strategies will be categorized using the FRAME-IS model, the ERIC taxonomy for naming of 
implementation strategies, and Proctor et al.’s guidance on specifying implementation strategies. 
This systematic approach will be used to make improvements on implementation procedures and 
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8.0 STUDY POPULATION 
Study participants are treatment-seeking heroin- and/or prescription opioid-dependent volunteers, 
without chronic pain requiring opioid therapy, who are willing to undergo opioid withdrawal and 
accept relapse prevention treatment with XR-NTX. The target recruitment is approximately 75 
participants per site or approximately 450 participants in total across 6 sites, with approximately 
225 participants treated using SP and approximately 225 participants treated using the RP. 
8.1 Participant Inclusion Criteria 
Study participants must meet all of the following inclusion criteria in order to be eligible to 
participate in the study: 
1. 18 years of age or older. 
2. Meets current DSM-5 criteria for opioid use disorder. 
3. Seeking treatment for opioid use disorder, willing to accept treatment with XR-
NTX and, in the judgment of the treating physician, is a good candidate for 
naltrexone- based treatment. 
4. Willing and able to provide written informed consent. 
5. Able to speak English sufficiently to understand the study procedures and 
provide written informed consent to participate in the study. 
6. If female of childbearing potential, willing to practice an effective method of 
birth control for the duration of participation in the study. 
8.2 Participant Exclusion Criteria 
All individuals meeting any of the following exclusion criteria will be excluded from study 
participation: 
1. Serious medical, psychiatric or substance use disorder that, in the opinion of the study 
physician, would make a detoxification and naltrexone initiation, or maintenance 
treatment with XR-NTX, hazardous (relative contra-indications) or requires a different 
level of care. Examples include: 
a) Disabling or terminal medical illness (e.g., uncompensated heart failure, severe 
acute hepatitis, cirrhosis or end-stage liver disease) as assessed by medical 
history and/or review of systems. 
b) Severe, untreated or inadequately treated mental disorder (e.g., active 
psychosis, uncontrolled manic-depressive illness) as assessed by history and/or 
clinical interview. 
c) Current severe alcohol, benzodiazepine, or other depressant or sedative 
hypnotic use likely to require a complicated medical detoxification (routine 
alcohol and sedative detoxifications may be included). 
d) Suicidal or homicidal ideation that requires immediate attention. 

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2. Known allergy or sensitivity to buprenorphine, naloxone, naltrexone, polylactide-co-
glycolide, carboxymethylcellulose, or other components of the Vivitrol® diluent. 
3. Maintenance treatment with methadone within 14 days of consent. 
4. Maintenance treatment with buprenorphine unless the patient is determined to have a 
poor treatment response (in the form of buprenorphine non-adherence with or without 
the use of illicit opioids), warranting change to XR-NTX treatment. 
5. Presence of pain of sufficient severity as to require ongoing pain management with 
opioids. 
6. Circumstances (legal, personal, occupational) that would threaten the feasibility of XR-
NTX treatment or make another treatment (e.g., buprenorphine or methadone) a better 
choice. 
7. Are currently in jail, prison or other overnight facility as required by court of law or have 
pending legal action that could prevent participation in study activities. 
8. If female, currently pregnant or breastfeeding, or planning on conception. 
9. Body habitus that, in the judgment of the study physician, precludes safe intramuscular 
injection of XR-NTX (e.g., BMI>40, excess fat tissue over the buttocks, emaciation). 
10. Admitted to the inpatient detoxification or residential rehabilitation unit more than 4 
calendar days prior to enrollment into to SP or RP. 
8.3 Special Populations to Consider 
This study is likely to enroll persons involved in the criminal justice system, many of whom are 
expected to be in treatment at the clinical sites participating in this study. The study will exclude 
persons incarcerated/detained in a correctional facility, but will not exclude parolees, 
probationers, or persons in sentencing diversion or drug court programs who are enrolled at 
participating sites. Some of these subjects may be classified as prisoners per 45 CFR 46 Subpart 
C. 
8.4 Strategies for Recruitment and Retention 
Recruitment efforts will vary per site and may broadly include site staff education and distribution 
of study materials, community or participant-level outreach and advertisements, and the 
encouragement of word-of-mouth referrals among site patient populations. During (or prior to) the 
first four
 ca
lendar days of an inpatient admission, clinical and/or research staff will evaluate all 
admitted patients for XR-NTX and provide information about the study to all patient-participants 
that express interest in treatment with XR-NTX. 

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9.0 SITE SELECTION 
9.1 Number of Sites 
The study is conducted at six sites that will be recruited from the NIDA National Drug Abuse 
Treatment Clinical Trials Network (CTN). Each of the sites will be expected to enroll approximately 
1-2 eligible participant(s) per week over the 70 weeks recruitment period for the total N=450 
enrolled. 
9.2 Site Eligibility 
To be included in the study, the selected sites must have the following characteristics: 
1. Provide opioid detoxification services (inpatient/residential) where participants can be 
maintained opioid-free. 
2. Able to provide treatment in hospital or residential treatment for at least the 14 days 
needed to carry out the SP initiation regimen. 
3. Have the capacity to provide ongoing treatment with XR-NTX on an outpatient basis for 
at least 2 months after the induction and administer subsequent XR-NTX injections. 
4. Have the capacity to provide outpatient care including medical management and 
counselling (at least one group and/or individual counseling session per 
week). 
5. Have the capacity to provide psychiatric evaluation and either offer treatment for co-
occurring psychiatric disorders or provide linkage to psychiatric 
care. 
6. Currently offering XR-NTX induction using buprenorphine taper and a wait period for 
individuals entering treatment with active substance use and requesting XR-NTX. 
7. Have no experience initiating patients onto XR-NTX using a RP. 
8. Agree to implement the suggested RP as the induction method for patients attempting to 
transition from active opioid use to XR-NTX using the implementation regimen included 
in the study. 
9. Have an adequate flow of patients entering treatment as to provide a sufficient 
population of potential participants to achieve study enrollment goals. We predict that 
with 3-5 patients admitted each week for “detoxification,” at least 1 participant per week 
should be interested in XR-NTX induction and be eligible to enroll into the study (other 
will initiate agonist maintenance). 
10. Have leadership desiring to adopt XR-NTX initiation (SP and RP) as routine 
clinical 
practice for patients requesting detoxification. 
11. Have the ability to provide deidentified information on individuals who were admitted to 
the unit during the study period but were not enrolled in the 
study. 
12. Can provide space and resources for up to 6 study-supported staff. 
13. With support from the study budget, able to enroll participants who do not 
have 
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9.3 Rationale for Site Selection 
The volume of patients admitted to the unit must be adequate to ensure a steady stream of eligible 
patients for recruitment. A diverse, representative sample of patients and unit characteristics is 
desirable to enhance the external validity of the study. Geographical diversity of settings is 
desirable and research experience and successful participation in prior studies is essential as it 
provides evidence of the feasibility of study implementation. 
Clinical experience using the standard method of XR-NTX induction with buprenorphine taper 
followed by a waiting period before XR-NTX induction is the standard of care in many treatment 
programs. Including only programs with experience with this method will allow for an appropriate 
comparison between the RP and SP methods of induction without the need for significant 
implementation or training to provide the SP. At the same time, we will not include sites 
experienced with the RP. Reduction of site variance in this research study will improve the power 
in statistical analysis to detect an effect for the primary outcome. 
The research staff will preferably have experience working in the addiction treatment setting and 
therefore can be quickly integrated into the team.
 

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10.0 STUDY PROCEDURES 
Schematic of study phases is presented in Figure 1. 
10.1 Pre-screening, Consent and Screening (Phase 1) 
Participants will be recruited from the population of individuals presenting for treatment of opioid 
use disorder at the participating study sites. 
Pre-screening will be completed before participants are approached for informed consent. All 
patients admitted to the unit with an OUD diagnosis should be pre-screened for the study and 
entered on the Participant Pre-Screening Log as well as on the pre-screening enrollment form in 
Advantage eClinical. The following will be assessed at pre-screening: current and active OUD, 
demographics, eligibility to receive XR-NTX and willingness to participate in the study. 
All participants who are interested may begin the  informed consent procedures up to 7 calendar 
days prior to the inpatient admission or during the first four calendar days of admission. All 
participants must sign the informed consent and complete screening procedures prior to the fourth 
calendar day of admission to be eligible to enroll in the Rapid Procedure or Standard Procedure. 
The timing of consent and screening procedures is flexible, and allows sites to customize 
recruitment, consent, and screening procedures to accommodate local conditions. Obtaining 
consent and screening/baseline data early in the admission will allow a full accounting of persons 
interested in study enrollment. For individuals consenting after admission, data will be collected 
about medication administration starting from admission using medication flowsheets and EMR 
abstraction (performed and confirmed by study staff).  
10.1.1 Informed Consent Procedures for Participants 
Candidates for the study are given a current IRB-approved copy of the Informed Consent Form 
to read. Appropriately qualified and trained study personnel explain all aspects of the study in lay 
language and answer all the study candidate’s questions. Study procedures and the potential 
risks and benefits of participating in the trial will be explained. Staff will be available to answer 
questions about the consent form while participants are reviewing it. 
Prior to signing the consent form, the participant must pass a brief consent quiz to illustrate 
comprehension of the study activities - understanding of the project, the purpose and procedures 
involved, and the voluntary nature of his/her participation. Those who cannot successfully answer 
quiz items have the study re-explained by research staff with a focus on aspects they did not 
understand. Those who demonstrate understanding of the study and voluntarily agree to 
participate are asked to sign the Informed Consent Form. After passing the quiz and signing the 
consent form, participants will be offered a copy of the forms to keep for their records. The 
informed consent process and quiz will take approximately 30-45 and 5 minutes to complete, 
respectively. 
Given the multi-site nature of the trial, it is possible that ancillary studies, or long term follow up 
studies, will be proposed before or after the study begins recruitment. For this reason, during the 
informed consent process, we also will seek permission to contact the participant in the future 

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about other study opportunities. 
Participants are not administered any study assessments or procedures prior to signing informed 
consent. The informed consent includes a HIPAA Authorization to permit study staff to access the 
participant’s medical records at the study site relating to the inpatient admission; the purpose of 
this is to capture study related clinical information that is collected during routine treatment (daily 
vitals, daily COWS, medication administration log, 
etc.). 
10.1.2 HIPAA Authorization and Medical Record Release Forms 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information (PHI). Sites will be responsible for communicating with the IRB of 
Record or any local Privacy Boards and obtaining the appropriate approvals or waivers to be in 
regulatory compliance. 
10.1.3 Screening/Baseline Visit 
Screening and baseline assessments are detailed in Section 12 and capture participant 
demographics; medical, psychiatric, drug use, and treatment history; quality of life; and current 
health status. Urine testing will also be performed. Following obtainment of consent and the final 
confirmation of eligibility, participants are considered enrolled into  SP or RP and begin completing 
baseline assessments. 
10.2 Treatment Initiation 
To maximize generalizability, this study is designed to permit consent of participants before and 
during the first four calendar days of inpatient treatment (Day 1 is day of admission). Patients 
judged clinically to be good candidates for detoxification and XR-NTX induction will, upon 
admission to the unit, begin treatment with non- opioid medications (mainly clonidine) and 
buprenorphine will be administered to address withdrawal symptoms as they emerge. Sites will 
agree to this regimen as their standard practice for the first four calendar days of inpatient-
residential treatment. During the first four calendar days of admission, patients will have the 
opportunity to consent to the study, and concurrent treatment will follow the SP or RP, depending 
on which procedure the site is offering at that time per the study design. 
10.3 Randomization 
Randomization will be performed at the site level. Six sites that have the required characteristics 
to be included in this study will be randomized to the order in which they begin to implement the 
RP. Patient-participants will be treated with the SP or RP according to which procedure is being 
used at the site at the time the patient is admitted. 
The randomization of each site will follow the stepped-wedge design (Table 1). At the selected 
time points as described in the Study Timeline section , one randomly selected site will make a 
“step” and will cross-over from the standard to the Rapid XR-NTX induction. Note that the first 
randomized site will be in the Rapid Procedure arm for the entire duration of the study whereas 
the 6th site (after 5 sites have been randomized to the Rapid Procedure) will be in the Standard 
Procedure arm for the entire duration of the study and will never switch to the Rapid Procedure. 

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The DSC statistician will conduct the randomization and inform the sites eight weeks before the 
selected site is scheduled to transition. 
10.4 Inpatient Treatment/Intervention (Phase 2) 
Participants are inducted onto their assigned XR-NTX induction regimen: Standard (Table 6A) or 
Rapid (Table 6B). These regimens are guidelines to be applied by the clinical teams with coaching 
from the lead team and may be modified by the site clinician based on the clinical status of each 
patient. 
10.4.1 Standard Induction Procedure (SP) 
SP includes stabilization on buprenorphine (6-8 mg) on Day 1 followed by a taper over the 
subsequent 4 days (Table 6A), however this schedule may be modified by the site clinician to suit 
the clinical status of each patient.  Depending on the level of physical dependence, time from the 
last dose of an opioid, type of an opioid (prescription opioid, heroin, or fentanyl), and the severity 
of withdrawal, participants may be required to wait additional time and receive symptomatic 
treatment until it is safe for them to start taking buprenorphine. 
After the completion of buprenorphine taper, participants will enter a washout period of at least 8 
days. Adjunctive (non-opioid) medications will be administered during the washout period, as 
needed, to alleviate significant withdrawal symptoms, with choice of medications and doses as 
routinely used at the site. On the last day of the taper, participants will be evaluated for eligibility 
to receive XR-NTX injection, as it is routinely used at the site. This may include a naloxone 
challenge (e.g., 0.8-1.2 mg IM), a naltrexone titration (e.g., 25 mg PO), and/or a urine toxicology 
negative for buprenorphine and other opioids (as in CTN-0051). Once found eligible, an XR-NTX 
injection will be given.  
10.4.2 Table 6A. Standard Induction Procedures 
Day 1 
Participants will receive buprenorphine 6 mg. If continue to experience 
significant withdrawal (COWS >6) they can receive additional 2-4 mg. 
Day 2 
Buprenorphine 6 mg in AM 
Day 3 
Buprenorphine 4 mg in AM 
Day 4 
Buprenorphine 2 mg in AM 
Day 5 
Buprenorphine 1 mg in AM 
Days 6-13 
Adjunctive medications as needed (i.e., clonidine and clonazepam) 
Day 13 or 14 
XR-NTX eligibility determination followed by the XR-NTX injection 
 
10.4.3 Rapid Induction Procedures (RP) 
RP includes 1 day of buprenorphine 6-8 mg, followed by a day of washout and 4 days of oral 
naltrexone titration, however this schedule may be modified by the site clinician to suit the clinical 
status of each patient. Implementation facilitation will train sites to provide detoxification based on 
the following procedures: 

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Conditions for initiating buprenorphine and dosing schedule in RP on Day 1 are similar to the Day 
1 in the SP guidelines.  Naltrexone should be administered starting with Day 3, according to the 
schedule outlined in Table 6B. On Day 3 naltrexone will be administered starting with 0.5 mg 
dose, 1 hour after pretreatment with adjunctive medication. COWS will be administered 2 hours 
after naltrexone and, if there is no increase in withdrawal (change in COWS score is less than 3) 
the next dose scheduled for this day (e.g., another 0.5 mg on Day 3) will be administered. The 
same procedure will be repeated on Days 4-6. Table 6B provides a guided timeline for RP, 
however, induction procedures should be modified to suit the clinical status of each patient and 
determine eligibility to administer XR-NTX. 
10.4.4 Table 6B. Rapid Induction Procedure Guidelines 
Day 1 
Participants will receive buprenorphine 6 mg. If continue to experience significant 
withdrawal (COWS >6) they can receive additional 2-4 mg. Adjunctive medications 
will be initiated if necessary, to alleviate residual withdrawal persisting after 
administration of buprenorphine 10 mg. 
Day 2 
Standing doses of clonidine and clonazepam, with additional adjunctive medications 
as needed*. 
Day 3 
Standing doses of clonidine and clonazepam, with additional adjunctive medications 
as needed*. 
Following the first morning dose of adjunctive medication, participants will receive 
naltrexone 0.5 mg. If there is no significant increase in withdrawal over the 
subsequent 120 minutes (COWS increase < 3) they will receive additional 
naltrexone 0.5 mg. 
Day 4 
Standing doses of clonidine and clonazepam, with additional adjunctive medications 
as needed*. 
Following the first morning dose of adjunctive medication naltrexone 1 mg. If there is 
no significant increase in withdrawal over the subsequent 120 minutes (COWS 
increase < 3) they will receive additional naltrexone 1 mg. 
Day 5 
Standing doses of clonidine and clonazepam, with additional adjunctive medications 
as needed*. 
Following the first morning dose of adjunctive medication they will receive 
naltrexone 3 mg. If there is no significant increase in withdrawal over the 
subsequent 120 minutes (COWS increase < 3) they will receive additional 
naltrexone 3 mg. 
Day 6 
Standing doses of clonidine and clonazepam, with additional adjunctive medications 
as needed*. 
Following the first morning dose of adjunctive medication they will receive 
naltrexone 6 mg. If there is no significant increase in withdrawal over the 
subsequent 4 hours (COWS increase < 3) participant will receive an injection of XR-
NTX 380 mg IM. For those who were not able to tolerate naltrexone 6mg, please 
refer to Day 7 procedure. 
Day 7 
Standing doses of clonidine and clonazepam, with additional adjunctive medications 
as needed*. 
Participants that were not able to tolerate naltrexone 6 mg during Day 6 will have 
procedures from Day 6 repeated. 
*Adjunctive 
medication to be 
administered 
during days 1-7 
• clonidine 0.2 mg every 4 hours (lower or withhold the dose if SBP<90 or HR<50), 
MDD=1.2 mg/d 
• clonazepam 1 mg every 6 hours (withhold the dose if the patient is difficult to 

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arouse), MDD=4 mg/d 
• trazodone 100 mg at night as needed for insomnia 
• prochloperazine 10 mg every 8 hours as needed for 
nausea 
• zolpidem 10 mg at night as needed for insomnia 
• ibuprofen 600 mg po every 8 hours as needed for muscle 
pain 
 
The XR-NTX injection is administered on Day 6 after naltrexone dose of 6 mg is received and 
tolerated over the 4 hours post-dose monitoring period (change in COWS score is less than 3). 
In the RP Order Set, adjunctive medication will be written to be administered as standing doses 
and withheld only in case of intolerance, excessive sedation or patient’s request. Adjunctive 
medications will include clonazepam, up to 4 mg/day, and clonidine, up to 1.2 mg/day. 
Staff on units providing rapid induction will be trained to offer psychoeducational counseling, 
conducted by clinical staff, on a daily basis. The goals of these counseling sessions are as follows: 
(1) To educate and support the participant as they transition to XR-NTX to improve tolerability of 
the induction; (2) Provide education on opioid withdrawal signs and symptoms and discuss 
pharmacological and nonpharmacological strategies for the management of opioid withdrawal;(3) 
Provide education regarding any medication side effects with a goal to increase adherence and 
correct use of medications, and (4) Increase participant’s motivation to adhere to the regimen and 
to complete the transition to XR-NTX. 
10.5 Post-Induction Treatment (Phase 3) 
Following the administration of the 
first XR-NTX dose or induction failure, participants will be 
encouraged to continue follow-up treatment per standard clinical practice. The sites should 
provide outpatient care as clinically appropriate and are recommended to provide participants 
with at least weekly clinic visits during the first month of treatment then biweekly visits during the 
second month. 
Participants 
will 
also complete research ratings, including self-report of withdrawal, 
mood, and drug use as noted in Section 12. The participant provides a urine sample at each 
injection visit for an onsite toxicology testing. 
10.5.1 Psychosocial Counseling 
Psychosocial counseling consists of outpatient counseling provided at the CTP. Selected sites 
agree to provide outpatient care that consists of at least one group and/or individual counseling 
session. Data is collected from the clinic record or from the participant on counseling sessions 
attended. Participation in counseling sessions is voluntary. Failure to attend counseling sessions 
will not be considered a reason to be excluded or withdrawn from the trial. 
10.5.2 
 Medical Management 
During 
the 
8-week 
course 
of 
post-induction 
treatment, 
participants 
receive 
two 
additional 
injections 
of XR-NTX (Vivitrol
®) 380 mg, at 4 and 8 weeks after the first injection.  All sites will be provided 
with training in providing Medical Management (MM) clinical support to be provided by the same 
study clinicians (e.g., MD, DO, PA, NP, RN/LPN; working within the scope of their local licensure, 
clinical privileges and/or scope of practice) in unblinded fashion.  

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Briefly, MM sessions focus on establishing and maintaining patient-clinician rapport and 
partnership, education surrounding opioid addiction and treatment, establishing and maintaining 
a plan for XR-NTX adherence, advice and encouragement to maintain abstinence, monitoring 
medication side effects and dose adjustments, and support for ancillary treatment, including 
psychosocial counseling, 12-step involvement, and further community-based treatment. MM also 
provides guidelines for assessment and management of relapse in both arms. 
In keeping with a pragmatic, community-based comparative effectiveness trial, MM is broadly 
guided by provider training prior to study start and regular MM provider calls. Suggested guidance 
for providing post-induction follow up can be found in Module 6 – Treatment & Follow-Up of the 
MOP, but is not subject to rigorous quality assurance procedures (i.e., audiotaping, manualization 
and QA audits). Suggested MM frequency is weekly until week 4 then biweekly until week 8. XR-
NTX is injected at the MM visit at Week 4 and at Week 8. 
10.5.3 Rapid Procedure: Adjunctive Medication Taper 
On the day of discharge, following the XR-NTX injection, participants in RP arm will receive a 
prescription for tapering doses of adjunctive medications for 7 days. The study guidance for this 
taper is Day 1-2: clonidine 0.1 
mg 4xday, clonazepam 0.5 mg 2xday; Day 3-4: clonidine 0.1 mg 
3xday, clonazepam 0.25 mg 3xday; Day 5-6: clonidine 0.1 mg 2xday, clonazepam 0.25 mg 
2xday; Day 7-8: clonidine 0.1 mg 1xday, clonazepam 0.25 mg 1xday). Participants will also 
receive zolpidem 10 mg at night as needed for insomnia during the first week. Flexibility and 
clinical judgment should be used in providing this taper based on the needs of the individual 
patient. 
10.5.4 XR-NTX Injections 
XR-NTX (4cc, ~380mg of naltrexone base) is administered approximately every four weeks, in 
the form of Vivitrol®. XR-NTX injections may take place more often than 4 weeks apart if there is 
clinical concern about non-adherence (participant is inconsistent in attending scheduled visits) or 
if clinical observation is that opioid craving and/or use re-emerge during the 4th week after the last 
injection; however, time between injections must always be at least 21 days. XR-NTX is 
administered by a deep intramuscular injection to the buttocks (alternating sides) 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. XR-NTX is 
provided by the study at no cost to the participant. 
10.5.5 Handling of XR-NTX Induction Procedure Intolerance 
Participants who are unable to tolerate the study-specific procedures will have the option to 
remain in the study with modification to the regimen based on the clinical judgment of the 
treatment providers. For example, a buprenorphine taper duration in a SP can be extended or a 
naltrexone titration in RP can be held. If adjustment is not sufficient, induction is not achieved 
within 30 days of admission or at any point when participants 
are no 
longer 
willing 
to 
continue 
with 
XR-NTX induction, participants 
will be considered an induction failure and should be managed as 
clinically appropriate by the unit with encouragement of continuation of medication for opioid use 
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medication maintenance treatment. The goal is to minimize the chance that participants leave the 
hospital without medication to prevent relapse. Participants who fail to induct XR-NTX while 
inpatient will remain in the study and be asked to return only for week 4 and week 8 study visits. 
Induction failures will still be allowed to receive study supplied XR-NTX until study completion at 
week 8. 
10.5.6 Handling of Missed XR-NTX Doses, Lapses, and Relapses 
Use of illicit opioids may be of a concern in patients receiving XR-NTX. Because of the long 
duration of action of XR-NTX (full blockade out to 5 weeks after the last injection), a grace period 
of 7-21 days can be expected during which the injection can be rescheduled, provided the 
participant has not relapsed and become re-dependent. Relapse is defined as daily use of illicit 
opioid for 7 or more days that starts after 35 or more days after the XR-NTX injection. If the 
participant misses a scheduled injection and does not otherwise meet the relapse criteria, XR-
NTX should  be administered as soon as possible, following a negative naloxone challenge (if 
clinically indicated). The participant is eligible to receive the 2nd and 3rd XR-NTX injection from 
study supply up to 21 days from the target Week 8 visit (i.e. up to 77 days from 1st XR-NTX). 
10.5.7 XR-NTX Discontinuation Post-Induction 
XR-NTX may be discontinued in the event of intolerable side effects or safety concerns preventing 
further medication treatment (e.g., pregnancy), relapse where restarting XR-NTX is not possible, 
or the end of the active treatment phase. Participants discontinuing medication prior to Week 8 
continue within the same study assessment schedule. All participants who end treatment early 
(prior to Week 8) are encouraged to complete an End of Medication Treatment visit.  In all cases 
of treatment discontinuation, the research and clinical team will make an effort to arrange for 
continued community treatment, as appropriate and available, including further XR-NTX and 
Buprenorphine-Naloxone (Suboxone®) (BUP-NX), or methadone maintenance and intensive 
outpatient psychosocial aftercare. For participants who do not wish to continue with XR-NTX, or 
for whom community resources to continue with XR-NTX are not available, the study will make 
alternative arrangements to make sure there is no gap in providing medication-based treatment 
(e.g., buprenorphine or methadone) as clinically appropriate to minimize the risk of relapse and 
related adverse outcomes such as an overdose. 
10.5.8 Ancillary Medications 
Participants who experience protracted withdrawal symptoms, sleeplessness, and/or depressive 
symptoms may be treated with ancillary medications. Depression is common in opioid-dependent 
patients and may adversely affect prognosis of naltrexone treatment. Participants who show 
depressive symptoms may be treated with antidepressants and/or referred for psychiatric 
evaluation and treatment. In general, psychiatric or medical problems emerging during the study 
treatment period are handled by the CTP according to their usual practices for treatment and 
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10.5.9 Criminal Justice Involvement 
This study includes subjects who may be classified as prisoners per 45 CFR 46 Subpart C. If a 
subject becomes incarcerated during the study, treatment and follow-up procedures may be 
continued in accordance with local IRB approvals. Procedures must be compliant with 45 CFR 46 
Subpart C. Data may be collected either in person, by phone, in writing, and/or by electronic 
means, provided that data collection follows the procedures approved by OHRP, the IRB of 
record, and any local regulatory authorities. Details of the nature of the research will not be shared 
with staff at the jail/prison, and visits, whether in person or by phone, will only be conducted if the 
participant’s confidentiality can be maintained and no audio-taping occurs. 
10.6 End of Study 
Participants will have their last study visit at the end of post-induction Week 8. An effort will be 
made to assess all participants at Week 8 post-induction or induction failure. P55 assessments 
will be completed at that time. 
Aggressive outreach procedures will be implemented to locate and assess all study participants 
to minimize missing data. 
10.7 Disposition and Referral (Phase 4) 
During the last month of study, as part of standard clinical care, arrangements will be made by 
the clinical team for participants to either continue treatment at the same program or be referred 
to another program in the community for follow-up care, which should ideally include continuation 
of XR-NTX. The third XR-NTX injection will be administered as a part of the study in order to 
objectively assess the retention in treatment 8-weeks after the induction and to assure the 
continuation of treatment with XR-NTX during the post-study transition period. However, 
participants will not be followed with study assessments after third injection as at this point, they 
will be engaged with and 
followed 
in 
the 
community-based 
clinical 
care 
where 
they 
will 
be 
assessed 
medically following standard procedures. The disposition plan may include continuing treatment 
with XR-NTX or another medication in the study clinic or in a different clinic in the community. 
Participant may also be referred to another CTN study where long-term outcome of treatment with 
XR-NTX is evaluated (e.g., CTN-0100). 
10.8 Study Intervention Adherence 
As part of the implementation assessment noted below adherence to study procedures on the 
inpatient units will be monitored via review of nursing flowsheets and order sets. Once participants 
begin the post-induction phase, participant adherence (i.e. retention in treatment during post-
induction phase) to XR-NTX injections will be tracked as part of a secondary outcome measure. 
10.9 Premature Withdrawal of Participants 
All participants will be followed for the duration of the study unless they withdraw consent, die, or 
the investigator or sponsor decides to discontinue their enrollment for any reason. The participant 
may be discontinued from the study if the participant, the investigator, or the sponsor determines 
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achieve induction will continue to be followed as part of the study for all secondary outcomes until 
discharge and will be assessed at Week 4 and Week 8 for the end of study visit. Reasons for 
study discontinuation may include, but are not limited to: 
• Withdrawal by participant 
• Lack of efficacy 
• Relapse 
• Participant becoming a threat to self or others in the opinion of the investigator 
• Lost to follow-up 
• Non-adherence to study medications or procedures in the opinion of the investigator 
• DSMB early termination of the study for safety or effectiveness reasons 
• Lack of funding 
In the event that a participant chooses to withdraw from the study, the investigator will make an 
effort to ascertain the reason for withdrawal and be encouraged to continue with medication 
assisted treatment. Enrolled participants will be asked to return to the clinic for an Early Medication 
Termination visit. If the participant fails or refuses to return to the clinic an attempt must be made 
to contact the subject by phone or mail, and attempts must be documented. Participants who 
withdraw from the trial will be offered treatment referrals as clinically appropriate. The reason for 
study discontinuation will be documented on the appropriate case report form.  
10.10 Study Termination 
The sponsor may close the investigational sites or terminate the study at any time. The 
Investigator may initiate site closure at any time, provided there is reasonable cause and sufficient 
notice is given in advance of the intended termination. Reasons for the early closure of an 
investigational site by the Sponsor or Investigator, or termination of a study by the sponsor, may 
include but are not limited to: 
• failure of the Investigator to comply with the protocol 
• safety concerns 
• ethical issues 
• inadequate recruitment of participants by the Investigator. 
Study termination will be promptly reported to IRB, DSMB and 
NIDA. 
10.11 Blinding 
This study is a pragmatic, open-label clinical trial. Treatment assignment and active medication 
assignment is known to all staff and all participants. 

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10.12 Participant Reimbursement 
Study participants who cannot access treatment or specific study medications at participating 
programs due to reimbursement restrictions will be provided with pharmacotherapy, medication, 
and medical management at no cost. However, the study will not cover the cost of detoxification 
or residential treatment stay. 
In addition, participants are reimbursed with cash, or vouchers of equivalent value, to offset costs 
of time and travel and to provide modest incentives for attending study visits. This study does not 
employ contingency management targeting abstinence or specifically targeting medication 
adherence (in other words, reimbursement is earned for presenting to scheduled visits and 
completing assessments and medication management visits if applicable). 
Participants will be reimbursed for participation in this study. Reimbursement will be in accordance 
with the IRB of record’s policies and procedures, and subject to IRB approval. If a participant is 
found to be incarcerated at time of follow-up, the participant is reimbursed the agreed upon 
amount as approved by the IRB of record and/or collaborating prison facilities. 
10.13 Retention Plan 
Retention in treatment during the induction phase and receipt of XR-NTX is a central focus of the 
intervention used in the present study and the primary outcome of the randomized study. All 
participants, regardless of induction success or failure status, will be strongly encouraged to 
remain in treatment even if they choose to leave the study. 

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11.0 MEDICATION PACKAGING/HANDLING/STORAGE / 
ACCOUNTABILITY 
11.1 Study Medication Sources 
Study will provide XR-NTX (Vivitrol
®) to all sites to avoid the issue of inability to fund treatment, 
which is an issue independent of the study objectives (how to induct onto XR-NTX). It is expected 
that all units will be able to provide all other medications, including low-dose oral naltrexone and 
buprenorphine. 
11.2 Study Medication Management 
Each research site is required to observe local, state, and federal regulations regarding receipt, 
custody, dispensing, and disposition of all study medications. Each site will maintain an adequate 
supply of unexpired study medications on site. Medications will be supplied to sites by the NIDA 
contractor. 
11.3 Medication Accountability Records 
Appropriately qualified and trained study personnel maintain accurate and current accounting of 
all study medication by utilizing drug accountability records which are made available for review 
by study monitors and other appropriate research personnel. 
Accurate drug accountability records: 
• Demonstrate that the study medication was dispensed according to the protocol. 
• Document receipt of the study medication, date, lot #, expiration date, quantity and 
dosage. 
• Account for unopened, un-dispensed, unused, returned, wasted or broken 
medication. 
• Dosing logs should record participant ID #, date dispensed, drug name, lot # and amount 
dispensed. 
• Indicate who dispensed or handled the study medication. 
• Temperature logs should show a daily record of medication storage 
temperature. 
11.4 Dispensing of Study Medication 
All study medications shall be prepared and dispensed by a pharmacist or licensed medical 
practitioner appropriately trained and authorized to dispense study medications per local 
regulations. 
11.5 Study Medication Storage 
Study medication should be stored in compliance with federal, state, and local laws and 
institutional policy. Study medication is stored in a secured location under the conditions specified 
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11.6 Used/Unused Medication 
Study medication returned by a participant may not be re-issued for use. Unused study medication 
is  returned  and  logged  into  a  perpetual  inventory  of  study  medication  returned.  Damaged, 
returned, expired, or unused study medication is accounted for by the NIDA contract monitor and 
may be sent to the central distributor or a reverse distributor for destruction. Expired XR-NTX may 
be destroyed on-site per local institutional policies following a complete accounting by the NIDA 
contract monitor. 
11.7 Lost Medication 
At the discretion of the site study treatment team, very limited replacement of study medications 
is permitted as clinically indicated. 
11.8 Medication Packaging 
All study medications shall be prepared and dispensed by a pharmacist or licensed medical 
practitioner appropriately trained and authorized to dispense study medications per local 
regulations. 
XR-NTX is supplied in single use kits. Each kit will contain one 380 mg vial of Vivitrol® 
microspheres and one vial containing 4 mL (to deliver 3.4 mL) diluent for the suspension of 
Vivitrol®, one 5-mL prepackaged syringe, one 1-inch 20-gauge needle, two 1.5-inch 20-gauge 
needles and two 2-inch 20-gauge needles with needle protection devices. Lot number is included 
on the kit labels as supplied by the manufacturer. 

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12.0 STUDY ASSESSMENTS 
Study assessments are intended to capture the outcomes of interest as efficiently as possible, 
minimizing the time and expense of research visits. Table 7 and 7a is a schedule of procedures 
and assessments. 
12.1 General 
12.1.1 Locator Form 
A locator form is used to obtain information to assist in contacting participants during treatment 
and at follow-up. This form collects the participant’s current address, email address, and phone 
numbers. In order to facilitate locating participants if direct contact efforts are unsuccessful, 
addresses and phone numbers of family/friends who may know how to reach the participant are 
collected, as well as information such as social security number, driver’s license number and other 
information to aid in searches of public records. This information is collected at screening and is 
updated at least every month during the active treatment phase. No information from this form is 
used in data analyses. 
12.1.2 Prisoner Status Assessment 
The Prisoner Status Assessment will collect information on the participant’s incarceration status. 
Candidates will complete a Prisoner Status Assessment to determine that they do not meet the 
OHRP definition of prisoner. If they do meet the definition, they will not be able to enter the study 
and considered a screen fail. They will be referred to clinical staff on site for their treatment needs. 
If the potential participant does not meet the definition of prisoner, they will be invited to learn 
more about the study and complete the informed consent process. 
12.1.3 PhenX Tier 1 and Demographics 
The Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org) 
includes measures that are being adopted across NIDA-funded research. The Core Tier 1 
collection includes measures for demographics (age, ethnicity, gender, race, educational 
attainment, employment status, marital status), quality of life, and HIV risk and status; substance 
use measures include age of onset, past 30-day quantity and frequency, lifetime use for alcohol, 
tobacco and other substances. Substance use and other data that will be captured via other forms 
(e.g., Timeline Followback) will not be re-assessed via Core Tier 1 PhenX measures. However, 
PhenX assessments will be used to supplement this data in order to maintain compliance with 
NIDA recommendations, (e.g., Quality of Life (QLP) and Tobacco Use History (TUH)). Core Tier 
1 assessments are completed at Baseline only. 
12.1.4 Motivation Scale 
A Likert scale asking about motivation to complete detoxification will be administered at baseline.  
This will be used to assess patient reported level of motivation as a mediator of successful 
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12.1.5 Patient-Reported Outcomes Measurement Information System 
(PROMIS) 
Health-Related Quality of Life (HRQoL) is measured using the Patient-Reported Outcomes 
Measurement Information System (PROMIS) (Cella et al., 2010; HealthMeasures). PROMIS was 
developed using item response theory (IRT), with support from the NIH. Because of its IRT 
foundation, PROMIS is able to improve upon common deficiencies of existing, widely-used, 
HRQoL instruments capable of generating a single health utility index value for the calculation of 
Quality-Adjusted Life Year estimates (QALYs), such as the Euro-QoL, Health Utilities Index (HUI), 
SF-6D, and Quality of Well-being Index, including: floor and ceiling effects among participants 
who are especially ill or healthy, respectively, and imprecise questions that blend concepts. The 
PROMIS-Preference (PROPr) scoring system uses the respondent’s scores for each of the 
following PROMIS domains to calculate a health utility index value that represents the general 
US population’s preference for the respondent’s current health state: Cognitive Function–Abilities, 
Depression, Anxiety, Fatigue, Pain Interference, Pain Intensity, Physical Function, Sleep 
Disturbance, and Ability to Participate in Social Roles and Activities (Hanmer et al., 2015). 
PROMIS has 5 levels for each domain: no problems, slight problems, moderate problems, severe 
problems, and extreme problems. The health-utility value produced by PROPr can range from  
-0.022 to 1, where 0 represents death, 1 represents perfect health, and values below 0 represent 
states perceived to be worse than death. Construct validity for PROPr has been demonstrated 
using the EQ-5D-5L, the HUI, and two large datasets from the general US population (Hanmer et 
al., 2018). The health-utility value is then used to calculate QALYs. PROMIS is completed at the 
time points specified in Table 7. 
12.1.6 End of Medication Treatment Form  
If a participant withdraws from XR-NTX treatment before Week 8, the reason for discontinuation 
of treatment should be documented on the EMT assessment form. 
12.1.7 Study Completion Form 
This form tracks the participant’s status in the study. It is completed at the Week 8 visit, after the 
third XR-NTX injection is administered. This form is used in data analyses to address variables 
such as treatment retention and completion. This form also provides a location for the site PI 
attestation of review of all study data. At the conclusion of study treatment, participants are 
discharged to treatment in the community. This form documents the treatment plan identified for 
the participant at the timepoints specified in Table 7 if an individual leaves the study early. 
12.1.8 Treatment Satisfaction Survey 
Satisfaction with treatment is recorded on the Treatment Satisfaction Survey completed at the 
timepoints specified in Table 7. 
12.1.8 COVID-19 Impact 
This form was developed for the NIDA CTN and documents the effect that COVID-19 has had on 
the participant’s life in the following domains: A) Personal exposure and illness related to COVID-
19; B) Mental health symptoms and functioning and health care accessibility (Hefner et al., 2021). 

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12.2 Measures of Primary and Secondary Outcomes 
12.2.1 End of Induction Form 
This form tracks the participant’s status with regards to the completed inpatient XR-NTX induction 
and receipt of the first XR-NTX dose (primary outcome measure). It will be completed by all 
enrolled patients in both arms of the trial at the end of the inpatient induction phase. 
12.2.2 The Subjective Opioid Withdrawal Scale (SOWS) 
The SOWS is a 16-item questionnaire designed to measure the severity of opioid withdrawal 
symptoms. The participant rates the intensity of symptoms using a 5-point scale; with 0 
representing “not at all” and 4 representing “extremely”. SOWS is administered at the time points 
specified in Table 7. Assessments captured during inpatient admission but prior to study 
enrollment will be retrospectively abstracted from the participant’s chart. 
12.2.3 Clinical Opiate Withdrawal Scale (COWS) 
The COWS is a questionnaire designed to measure 11 common opioid withdrawal signs and 
symptoms (Wesson and Ling, 2003). 
The summed score provides information about the severity 
of opioid withdrawal and the level of physical dependence on opioids. The COWS will be 
administered by a clinician at the time points specified in Table 7. Assessments captured during 
inpatient admission but prior to study enrollment will be retrospectively abstracted from the 
participant’s chart. 
12.2.4 Visual Analogue Scales (VAS) 
The craving for opioids will be measured using a horizontal VAS, that ranges from 0 (no craving) 
to 100 (most intense craving possible). Participants will be instructed to indicate the overall 
intensity of craving experienced. These scales are completed for opioid craving at the time points 
specified in Table 7. 
A separate VAS will be used to document responses to opioid use, in the event that participants 
self-reports use of opioids during the study and will range from 0 (no opioid effect) to 100 (most 
intense opioid effect possible). 
12.2.5 Timeline Followback (TLFB) 
The Timeline Followback (Robinson et al., 2014, Sobell and Sobell, 1992) procedure is used to 
elicit the participant’s self-reported use of substances before and throughout the entire study 
period. The study TLFB also captures participant self-reported use of MOUD. At baseline, this 
form is used to assess substance use reported by the participant for 31 days, ranging from 30days 
prior to inpatient admission and including any use on admission day. After baseline, the TLFB is 
administered at every study visit to document the participant’s self-reported use of substances 
and MOUD for each day since the previous TLFB assessment. The TLFB is administered at the 
time points specified in Table 7. Note that TLFB assessments during post-induction phase should 
capture any XR-NTX study injection given to participants who leave the unit and return to receive 
their first XR-NTX injection. If available in the EMR, research staff should capture any MOUD 

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received by participants that do not complete follow up assessments during the post-induction 
phase. 
12.2.6 Urine Drug Screen (UDS) 
Urine samples for drug toxicology testing are collected at the time points specified in Table 7. 
Urine toxicology tests administered during inpatient admission but prior to study enrollment will 
be retrospectively abstracted from the participant’s chart. In most cases the UDS should be 
completed before assessing self-reported drug use or administering/dispensing medications. All 
urine specimens are collected using FDA-approved one-step temperature-controlled urine drug 
test cups following all of the manufacturer
's recommended procedures. The UDS tests for the 
presence of the following drugs: opioids (morphine, oxycodone, methadone, buprenorphine, 
fentanyl), benzodiazepines, barbiturates, cocaine, amphetamine, methamphetamine, 
phencyclidine (PCP), ecstasy (MDMA), and marijuana. In the event urine specimen tampering is 
suspected, either based on the observation of specimen collection or identified by the adulterant 
tests, study staff will request a second urine sample and may observe the urine collection process 
according to clinic standard operating procedures. A further validity check will be performed using 
a commercially available adulterant test strip. 
12.2.7 Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a 9-item screening, diagnosing, monitoring, and measurement tool of depression 
severity with comparable diagnostic validity across multiple studies to longer screening tools 
(Kroenke et al., 2001). This assessment is completed at the time points specified in Table 7. 
12.2.8 Low Dose Naltrexone Titration 
The Low Dose Naltrexone Titration form records whether or not a low dose naltrexone titration 
occurred at each study day. If a titration did not occur for a visit, this form records the reason. 
12.2.9 XR-NTX Administration  
The XR-NTX Administration form is used to collect information about the participant’s prior XR-
NTX injection and the current XR-NTX injection performed at the follow-up study visit. Induction 
success participant’s injections are documented on the EOI (1st injection) and the INN and M97 
(2nd and 3rd injections). Induction failure injections are documented only on the M97 (all 3 
injections). 
12.3 Safety and Medical 
The study physician must review and approve all safety and eligibility assessments in order to 
confirm participant eligibility prior to enrollment. However, the baseline medical and psychiatric 
evaluation (including history, physical and mental status exams) and laboratory tests are part of 
standard admission procedures at sites and may be conducted prior to study consent. 
12.3.1 Medical and Psychiatric History 
The site medical 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. 

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This will be collected during screening. This will include screening for suicidal thoughts and risk 
factors as well as severe psychiatric illness that are exclusionary for study participation. 
12.3.2 PTSD Checklist for DSM-5 (PCL-5) 
This is a 20-item self-report measure that assess symptoms of PTSD at baseline. The PCL-5 
assesses trauma exposure (Criterion A), allows for a total symptom severity score (0-80), DSM-
5 symptom cluster severity scores (Clusters B, C, D, and E), provisional PTSD diagnosis, and a 
preliminary diagnostic cut-point (i.e., 33). (Weathers et al., 2013b). 
12.3.3 
 Adult ADHD Self-Report Screening Scale for DSM-5 (ASRS-5) 
This 6-item screening scale (Ustun et al., 2017) is used to assess Attention Deficit-Hyperactivity 
Disorder based on DSM-5 criteria at baseline. 
12.3.4 Overdose Questionnaire 
An 8-item overdose questionnaire has been developed and used in research at McLean Hospital 
(unpublished questionnaire). The questionnaire examines participants’ lifetime and recent history 
of opioid overdose, and the degree to which it is related to suicidal ideation vs. accident 
(responses indicating suicidal ideation trigger an evaluation and completion of the MHA). All 
overdoses that occur during an individual’s participation in the study and meet SAE criteria will 
also be reported as an SAE.  
12.3.5 Concomitant Medications 
The Concomitant Medications form captures any medications that have been taken in the past 
week, other than those taken for treatment of opioid use disorder. 
12.3.6 Death 
The Death Form is used to report any participant deaths that occurred during the duration of the 
study.  
12.3.7 HIV and Hepatitis Self-Report Assessments 
At baseline, self-report forms will be collected regarding the participant’s HIV, hepatitis C virus 
(HCV) and hepatitis B status. These forms will not be used to determine eligibility and will only be 
collected from participants who enroll into the study. 
12.3.8 DSM-5 Criteria 
The site medical clinician, or designee, conducting initial evaluation at screening will complete the 
DSM-5 checklist that includes all 11 DSM-5 criteria to determine a current diagnosis for all 
substances (opioids, cannabis, alcohol, stimulants, etc.) use categories, with opioid use disorder 
diagnosis being used to determine eligibility. 
12.3.9 General Anxiety Disorder-7 
The GAD-7 is a 7-item screen used to assess anxiety. It has been validated as a screening tool 
providing diagnostic and severity information in the general and substance use disorder 

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populations. This assessment is completed at the time points specified in Table 7. 
12.3.10 PHQ-Panic Disorder  
The PHQ-PD is a two-part screening battery including a single screening question with follow up 
questions.  It has been found to have moderate sensitivity and good specificity for panic disorder 
in high risk populations. It will be administered at baseline. 
12.3.11 Pregnancy, Birth Control, and Breastfeeding Assessment 
Urine pregnancy test (for biologically female participants) will be performed to help determine 
eligibility at screening. Receipt and review of pregnancy test result is necessary before confirming 
eligibility, finalizing enrollment, and starting study medication for biological females of childbearing 
potential. Pregnancy tests administered during inpatient admission but prior to study enrollment 
will be retrospectively abstracted from the participant’s chart. 
This form documents that pregnancy tests were administered, pregnancy test results, and self- 
reported birth control and breastfeeding status. The pregnancy and birth control assessment, 
including on-site urine pregnancy tests, is conducted at screening and may be repeated prior to 
enrollment and/or induction. Birth control assessment and urine pregnancy tests are performed 
before each XR-NTX injection. 
12.3.12 Mental Health Assessment 
This assessment must be completed if the participant endorses suicidality on item 9 of the PHQ-
9. The completion of the Mental Health Follow-Up Assessment form requires notification of the 
site clinician and evaluation of the participant for suicide/homicide risk according to the site’s 
specific SOP. This evaluation will take place prior to the participant’s leaving the study site. 
12.3.13 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
At each medical management visit the study clinician assess for AEs and SAEs by asking the 
study participant, “How have you been feeling since your last visit?” AEs and SAEs may also be 
spontaneously reported to study staff at any visit following consent. A trained clinician will examine 
the XR-NTX injection site and participants will be asked to immediately report any injection site 
reactions to study staff for evaluation. Medication injection site reactions should be documented 
on the Medication Injection Site Abnormality Log and will not be duplicate-reported as an adverse 
event unless meeting the SAE definition. 
AEs and SAEs suggesting medical or psychiatric deterioration will be brought to the attention of 
a study clinician for further evaluation and management. Medical management visits will 
emphasize overdose risk and risk-management; reported overdoses will be captured on the 
overdose questionnaire and if they meet SAE criteria will also be reported as SAEs on AE/SAE 
form sets. All volunteered, elicited, and observed SAEs will be recorded on the AE/SAE form set. 
AE and SAE reporting is according to the reporting definitions and procedures outlined in the 
protocol and in accordance with applicable regulatory requirements. 

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For the purpose of this study, AEs included in the following list of targeted safety events should 
be recorded on the Targeted Safety Events form and reported in the data system: 
• Fall event (related to medical/psychiatric condition such as dizziness, confusion with 
head injury) 
• Acute change in mental status (i.e. disorientation, amnesia, cerebrovascular accident, 
coma)  
• Acute medical complication likely exacerbated by the stress of withdrawal (i.e. 
hypertensive crisis, hypotensive event with medical sequelae such as fall and/or 
requiring urgent fluid resuscitation, severe chest pain, acute respiratory 
decompensation, asthma attack, diabetic ketoacidosis, severe hypoglycemia, severe 
electrolyte abnormalities (hyper-/hyponatremia, hyper-/hypokalemia), precipitated 
withdrawal  
• Acute psychiatric symptoms (i.e., psychosis, hypomania, severe agitation, violence)  
Targeted safety events will also be captured on study specific forms (for example, COWS, SOWS, 
PHQ-9, Medication Injection Site Abnormality Log and Overdose Questionnaire). 
Spontaneous reporting of withdrawal symptoms (including any withdrawal precipitated by the 
study medication) by the participant will be captured on scheduled specific structured 
questionnaires. Targeted safety events will not be duplicate-reported as an adverse event unless 
meeting the SAE definition. 
12.4 Implementation Related Outcomes 
12.4.1 Quantitative Data Collection and Analysis 
12.4.1.1 Unit Organizational Readiness 
The Organizational Readiness to Change Assessment (ORCA) (Helfrich et al., 2009) instrument 
evaluates factors impacting implementation. The ORCA has been applied to the evaluation of 
interventions intended to promote evidence-based practices, including addiction treatment, and 
predicts implementation efforts. 
We will use a modified version of the ORCA with wording to reflect 
XR-NTX initiation readiness. This 5-minute survey asks the respondent to rate local factors 
related to beliefs regarding the evidence behind the intervention, internal and external 
organizational level factors as well as facilitation process related factors on a 5-point Likert scale 
from strongly disagree to strongly agree. Facilitation questions will be omitted from the baseline 
assessment since this part of the intervention will not have taken place. 
12.4.1.2 Medical Provider Readiness and Preparedness 
We will use change rulers, among appropriate providers, to assess readiness and preparedness 
on XR-NTX initiation (LaBrie et al., 2005). Stage of change assessments have been validated 
and have been used in the field of addiction and mental health to assess readiness to adopt 
evidence-based treatments (Aarons, 2004, Amodei and Lamb, 2004, Haug et al., 2008). 

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The change rulers will independently assess, on a 0-10 scale each provider’s: 
1. Readiness to provide the intervention 
2. Preparedness to provide the intervention 
The readiness rulers will be completed at the beginning of the study and before and after each 
stepped-wedge intervention. 
12.5 Qualitative Data Collection and Analysis 
At each of the six study sites, we will conduct interviews with a purposeful sample of key 
stakeholders at distinct stages of our project: at each site after the brief XR-NTX implementation 
intervention and at the study conclusion. However, this information is part of an iterative process, 
and therefore additional structured interviews, one-on-one phone interviews and email 
correspondence will take place as needed. Purposeful sampling is a well-established method in 
qualitative studies and is designed to identify study participants who have direct experience with 
or knowledge of the phenomenon of interest, in this case OUDs and XR-NTX initiation (Palinkas 
et al., 2015). We will interview a variety of participants including detox/rehab patients, nurses, 
social workers, physicians, NPs, PAs, pharmacists and nursing directors at each detoxification/ 
residential rehab site and office-based XR-NTX providers and representatives from outpatient 
treatment programs to allow for evaluation of processes from multiple perspectives (triangulation). 
Interviews will be conducted with study participants chosen at random and representation from 
each of the stakeholder categories. The interview guides will be informed by the CFIR framework 
and include questions designed to establish rapport and elicit open-ended responses. For 
example, participants will be asked open ended questions regarding their attitudes towards the 
overall experience of implementing XR-NTX. Probes will be used to understand specific details 
of those experiences and allow for clarification of ideas. We will design and pilot test these guides 
with study participants and key informants from the participating NIDA CTN nodes and refine as 
indicated. 
12.5.1 Verbal Consent for Structured Participant Interviews 
Key stakeholders comprised of detoxification/residential rehab staff and participants undergoing 
induction procedures will each be provided with an IRB-approved verbal consent including all 
significant elements of the study. We will work with the detox and rehab units to provide staff 
assurances that their participation in the research will in no way affect their employment status 
either positively or negatively. Interviews will be voluntary, and information collected for research 
purposes will not become part of staff participants’ personnel records. The verbal consent for the 
detoxification/residential rehab staff participants will outline these assurances. For the recording 
of the interviews, all participants will be made aware during the verbal consent process that the 
sessions will be digitally recorded and, for induction participants, that the nature of these sessions 
will involve participants speaking about information regarding their health status and opioid use. 
All structured interview participants will also be made aware that they will complete a brief 
demographic survey. 

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12.5.2 Conduct of Structured Interviews 
Trained and qualified personnel will conduct structured interviews with each detoxification/ 
residential rehab site. The structured interviews will be recorded by the lead team and 
professionally transcribed for qualitative analysis. Participants will also complete a brief 
demographic survey. Using directed content analysis, we will analyze the data with a multi- 
disciplinary group with experience in qualitative methods, which will include Addiction 
Medicine/Psychiatry physicians. Consistent with prior studies, we will plan to generate a summary 
of the findings to share with participants via email and conference calls for their feedback. We will 
use data reduction strategies to sharpen, sort, focus, discard and organize data in order to draw 
inferences regarding the implementation interventions in place at each detoxification/residential 
rehab site. These data will directly inform the implementation facilitation package and be used to 
evaluate the facilitation process and outcomes. This will be an iterative process. We will develop 
a template summary of data at each detoxification/residential rehab organized by evidence, 
context and facilitation-related factors. At the completion of all detoxification/residential rehab 
sites implementation periods, we will create a matrix across all sites and respondents to 
understand the major issues regarding implementation across sites that can be disseminated to 
the wider addiction treatment community. 
12.6 Implementation Process Outcomes Measures 
12.6.1 Fidelity to Clinical Procedures 
12.6.1.1 Critical Action Checklist and Medical Procedures Data 
Capture Form 
Study personnel will assess fidelity to clinical procedures and guidelines (adherence) for each 
participant using a critical action checklist throughout the detoxification and rehab stay. The 
checklist will include confirmation of: urine toxicology obtained, urine pregnancy test completed 
for females; patient-participant meets criteria for DSM-5 moderate-severe opioid use disorder; 
urine positive for opioid; daily formal assessment of Clinical Opioid Withdrawal Scale (COWS); 
buprenorphine and comfort medication orders written and administered according to the 
recommended study procedures, including standing and as needed additional administrations; 
detox/rehab-initiated XR-NTX provided; XR-NTX education and induction instructions provided; 
education regarding XR-NTX and continued treatment is provided; comfort medication 
prescriptions provided upon discharge for potential protracted opioid withdrawal symptoms and 
appropriate tapered dosing plans for clonidine and benzodiazepines; and an appointment for 
ongoing XR-NTX is provided. 
In addition to the critical action checklist, all medical assessments (vital signs, COWS, lab tests 
etc.) and administered medications will be captured using a medical procedures data capture 
form. In cases where programs are showing poor fidelity to study related procedures, this will be 
raised with the local team during coaching calls to explore barriers and create an action plan to 
improve fidelity going forward. 

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12.6.1.2 Organization Level Clinical Implementation Data Collection 
Form 
In addition, the following organization level implementation related clinical and clinical process 
outcomes will be captured: The proportion of eligible patients screened for XR-NTX, proportion of 
patients who begin XR-NTX on the detox or residential units, proportion of those who are 
successfully linked to office-based XR-NTX providers and/or OTPs. EHRs will be queried for each 
month to determine potential ICD (International Classification of Diseases) 10 codes identifying 
patients that were potentially eligible for XR-NTX. 
12.6.2 Coaching Progress Notes 
Clinical staff and other key stakeholders from each site will participate in routine meetings to 
discuss study and clinical issues that arise during the RP implementation phase. Individual site-
level coaching sessions will occur once weekly at a minimum during the initial RP implementation 
phase with flexibility for additional support sessions as per each site’s needs (tota
l number of 
coach
ing sess
ions de
l
ivered to each s
ite w
i
l
l be captured). After ind
iv
idua
l
 s
ite-leve
l
 coach
ing support 
sess
ions, a
l
l s
ites random
ized to RP w
i
l
l part
ic
ipate in
 co
l
laborat
ive coach
ing sess
ions beg
inn
ing 
week
ly and the frequency mov
ing forward w
i
l
l be determ
ined by the s
ites
’ needs. A structured 
progress note will be developed (informed by the CFIR framework) and completed by the study 
team that will include barriers/facilitators to implementing the RP intervention, pertinent action 
items, and any modifications or adaptations to implementation strategies or clinical processes. 
This information will be integrated with other implementation data to guide iterative improvements 
in the implementation facilitation package. 
12.6.3 Site Needs Assessment and Site Mapping Progress Notes 
Study personnel at each site will complete an implementation needs assessment during the pre-
implementation phase that will provide preliminary information to the study team about 
organizational processes, clinical procedures and workflow, and other factors potentially 
influencing the uptake and success of implementing the Rapid Procedure. The study team will 
meet with the site to review the Site Needs Assessment and gather additional details through a 
process of Site Mapping. Weekly meetings will be held in the pre-implementation phase to review 
a structured Site Mapping guide that facilitates discussions around inner structure and 
organizational processes related to the implementation of the Rapid Procedure. A structured 
progress note will be used to capture meeting minutes, identified barriers and facilitators, and 
potential modifications or adaptations needed on-site and to implementation strategies in order to 
facilitate future implementation of the intervention. 
12.6.4 Internal Implementation Team Meeting Notes 
A subset of the research team with expertise in implementation will meet routinely to review the 
implementation facilitation process, identified barriers and facilitators, and evaluate if 
modifications or adaptations to the implementation strategies are needed in order for the site to 
successfully implement the Rapid Procedure. A structured note will be used to capture meeting 
minutes, pertinent barriers and facilitators, and final decisions on any modifications or adaptations 
to the implementation strategies. 

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12.6.5 Fidelity to Implementation Procedures Checklist 
Study personnel at each site will track implementation activities using an implementation activity 
checklist. This will include fidelity to suggested training programs and other implementation 
procedures. The checklist will be completed after the initial training activities at the start of the 
study, after each wedge implementation and each month to capture follow up implementation 
support (weekly clinical case conferences etc.). To capture engagement with implementation 
processes, the number of providers attending the initial educational session and follow up 
coaching session will be tracked. 
12.6.6 Treatment Utilization Measures 
12.6.6.1 Medical Management Log 
A Medical Management attendance log will be completed at the end of the induction phase and 
at every post-induction visit to document attendance or non- attendance at each Medical 
Management session during the active treatment phase.  
12.6.6.2 Psychosocial and Medical Treatment Participation Log 
At each visit, participants will complete a psychosocial and medical treatment utilization log 
(“psychosocial log”) to report on their participation in any medical and/or psychosocial treatment 
since the last visit. 
12.7 Other Assessments 
12.7.1 Fagerström Test for Nicotine Dependence (FTND) 
The Fagerström Test for Nicotine Dependence (FTND) is used for assessing nicotine dependence 
and is administered at the time points specified in Table 7 (Fagerstrom, 1978). 
12.7.2 NIDA Cannabis Assessment 
The NIDA cannabis assessment is a recently developed measure of medical and recreational 
cannabis use, and perceived benefit and/or harm associated with its use over the previous 12 
months. It will be assessed at the time points specified in Table 7. 
12.7.3 Daily Medication Administration Log 
Data on detoxification, including number of days on the unit and medications received since 
admission, will be collected. The Daily Medication Administration Log will be completed as 
described in Table 7. 
12.7.4 Non-Study Medical and Other Services (NMS) 
Medical services that are not part of the treatment intervention will be recorded on the NMS form. 
The NMS form captures services received outside the study and CTP, including therapy visits, 
physician visits, subsequent residential or hospital detoxification, hospital visits and emergency 
room visits, medication use, and participation in mutual-support group meetings through 
participant self-report. The assessment also captures health insurance status, housing status, 
employment, criminal activities, and contact with the criminal justice system. Homelessness is of 

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particular interest and concern with this population. Thus, a question to determine whether the 
participant is currently homeless or living in a shelter is asked at baseline in conjunction with the 
PhenX Quality of Life assessment and during each monthly visit where follow-up XR-NTX 
injections are administered. The NMS will be completed as described in Table 7. 
12.7.5 
 Oral Fluid Collection for Genetic Sample and Family Origin 
NIDA CCTN has requested that oral fluid samples for genetic analyses be collected for all 
pharmacotherapy trials. Enrolled participants who provide consent for genetic analyses will have 
an oral fluid sample collected for genetic analyses and will complete a Family Origin form. The 
family origin form is designed to be interviewer administered. It collects information about the 
participant and her/his biological family members’ race/ethnicity, place of birth, and ancestry. If a 
participant does not know the information requested, the participant may answer “unknown.”   This 
sample will ideally be collected during the baseline visit. If this is not possible, this sample can be 
collected at any other future visit. The oral fluid samples will be coded, thus only the local 
investigators will know the true identity of the participant providing the sample.  This sample will 
be sent to a common repository. 
 

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12.7.6 Table 7: Study Assessments 
 
Consent 
Screening Baseline 
Inpatient Induction Phase 
Post-Induction Phase 
End of Medication 
Treatment 
Visit # 
 
 
 
Rapid 
Procedure 
Standard 
Procedure 
1 
2 
3 
4 
5 
6 
EMT 
Week 
 
 
 
1 
2 
3 
4 
6 
8 
 
Time 
 
 
 
IND-RP 
IND-SP 
P6 
P13 
P20 
P27 
P41 
P55 
Varies 
Discussion of XR-
NTX for relapse 
prevention to opioid 
dependence 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical Release 
Form 
X 
 
 
 
 
 
 
 
 
 
 
 
GENERAL 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Checklist 
 
X 
 
 
 
 
 
 
 
 
 
 
Locator form 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Prisoner Status 
Assessment 
 
X 
 
 
 
 
 
X 
 
 
 
 
Demographics  
X 
 
X 
 
 
 
 
 
 
 
 
 
PhenX Tier 1 
Assessments 
1 
 
 
X 
 
 
 
 
 
 
 
 
 
Fagerstrom 
 
 
X 
 
 
 
 
 
 
 
 
 
Cannabis Use 
Assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
Motivation Scale 
 
 
X 
 
 
 
 
 
 
 
 
 
End of Induction 
Form 
 
 
 
X 
X 
 
 
 
 
 
 
 
End of Medication 
Treatment Form 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment 
Satisfaction Survey 
 
 
 
 
 
 
 
 
 
 
X 
 
Study Completion 
Form 
 
 
 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
X 
 
COVID Impact 
Assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
SAFETY & 
MEDICAL 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Psychiatric 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
DSM-5 criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
ASRS-5  
 
 
X 
 
 
 
 
 
 
 
 
 
PHQ-Panic Disorder  
 
 
X 
 
 
 
 
 
 
 
 
 
PCL-5  
 
 
X 
 
 
 
 
 
 
 
 
 

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Consent 
Screening Baseline 
Inpatient Induction Phase 
Post-Induction Phase 
End of Medication 
Treatment 
Visit # 
 
 
 
Rapid 
Procedure 
Standard 
Procedure 
1 
2 
3 
4 
5 
6 
EMT 
Week 
 
 
 
1 
2 
3 
4 
6 
8 
 
Time 
 
 
 
IND-RP 
IND-SP 
P6 
P13 
P20 
P27 
P41 
P55 
Varies 
General Anxiety 
Disorder-7  
 
 
X 
X2 
X2 
X 
X 
X 
X 
X 
X 
 
HIV and Hepatitis 
Assessments 
 
 
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy and 
Birth Control 
Assessment 
 
X 
 
X3 
X3 
 
 
 
X3 
 
X3 
 
Daily Medication 
Administration Log 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
AEs & SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opioid Overdose 
Questionnaire 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Medication Injection 
Site Abnormality Log 
 
 
 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
Death Form  
 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
Saliva Sample 
(Genetic Sample) 
 
 
X 
 
 
 
 
 
 
 
 
 
Family Origin 
Assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
TREATMENT 
SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
Induction 
Buprenorphine 
 
 
 
X 
X 
 
 
 
 
 
 
 
Naltrexone Titration 
 
 
 
X 
 
 
 
 
 
 
 
 
XR-NTX 
Administration  
 
 
 
X 
X 
 
 
 
X 
 
X 
 

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Consent 
Screening Baseline 
Inpatient Induction Phase 
Post-Induction Phase 
End of Medication 
Treatment 
Visit # 
 
 
 
Rapid 
Procedure 
Standard 
Procedure 
1 
2 
3 
4 
5 
6 
EMT 
Week 
 
 
 
1 
2 
3 
4 
6 
8 
 
Time 
 
 
 
IND-RP 
IND-SP 
P6 
P13 
P20 
P27 
P41 
P55 
Varies 
ADHERENCE 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Management 
Log 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychosocial Log 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
OUTCOME 
 
 
 
 
 
 
 
 
 
 
 
 
Timeline Followback 
– Substance Use 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Timeline Followback 
– MOUD 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Urine Drug Screen 
 
X 
 
X3 
X3 
 
 
 
X3 
 
X3 
 
PROMIS 
 
 
X 
 
 
 
 
 
X 
 
X 
 
VAS Opioid Craving 
 
 
X 
X4 
X4 
X 
X 
X 
X 
X 
X 
 
VAS Opioid Effect 
 
 
 
 
 
^ 
^ 
^ 
^ 
^ 
^ 
 
Patient Health 
Questionnaire-9 
 
 
X 
X2 
X2 
X 
X 
X 
X 
X 
X 
 
Mental Health 
Assessment 
 
 
^ 
 
 
^ 
^ 
^ 
^ 
^ 
^ 
 
Subjective Opioid 
Withdrawal Scale 
 
 
X 
X4 
X4 
X 
X 
X 
X 
X 
X 
 
Clinical Opioid 
Withdrawal Scale 
 
 
X 
X5 
X5 
 
 
 
 
 
 
 
Non-Medical and 
Other Services 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X1 = Includes ASU, TUH, QLP assessments 
X2 = 
repeat weekly during inpatient induction phase 
X3  
= 
 
before 
each 
XR-NTX 
injection 
X4= repeat 
each 
inpatient 
study 
day 
 
X5= repeat 
daily, as many times as clinically appropriate 
^ 
= 
As 
Needed 
 

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12.7.7 Table 7a: Implementation Assessments 
 
Pre-Implementation 
Training  
(8 weeks prior to 
Step Start) 
Beginning of Site 
Implementation 
(Step Start) 
Weekly during 
Site 
Implementation 
Monthly during 
Site 
Implementation 
Post Site 
Implementation 
(End of Step) 
Study 
Conclusion 
Critical Action 
Checklist 
 
 
X1,2 
 
 
 
Medical Procedures 
Form 
 
 
X1,2 
 
 
 
Coaching Progress 
Notes 
 
 
X3 
 
 
 
Staff Structured 
Interviews 
 
 
 
 
X 
X 
Site Needs 
Assessment 
X 
 
 
 
 
 
Site Mapping 
Progress Notes 
X 
 
 
 
 
 
Internal 
Implementation 
Team Notes 
X 
 
X3 
 
X 
X 
ORCA 
X 
 
 
 
X 
 
Readiness and 
Preparedness 
Rulers 
X 
 
 
 
X 
 
Organization Level 
Clinical 
Implementation Data 
Collection Form 
 
X 
 
 
 
 
Fidelity to 
Implementation 
Procedures 
Checklist 
 
X 
 
 
X 
 
 
1 = Patient level assessment 
2 = During inpatient induction phase only 
3 = May occur more frequently depending on site needs

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13.0 GENETIC SAMPLING 
The NIDA CCTN has requested that blood or saliva samples for genetic analysis be obtained for 
all new CTN pharmacotherapy trials. All participants will be asked to provide a saliva sample for 
genetic testing. As part of the study ICF, participants will be asked to consent to providing a 
genetics sample. This will consist of having a single saliva cheek swab. Saliva will be collected 
during the baseline visit but may occur thereafter. The saliva sample will be sent to Infinity 
BiologiX, LLC (previously called the Rutgers University Cell and DNA Repository) for storage and 
future analysis. The saliva samples will be coded and only the local investigators will know the 
identity of the participant providing the sample. 
The Family Origin CRF will be collected from participants at baseline. 

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14.0 TRAINING REQUIREMENTS 
14.1 Overall 
A Training Plan will be developed that will be independent from the implementation facilitation 
procedures for clinical team. The Plan will incorporate study-specific training for research 
procedures and assessments, mechanisms for competency assessment as well as a detailed 
description of training, supervision, and fidelity monitoring procedures. The Investigative Team is 
responsible for the development of a comprehensive Training Plan, instructional materials, and 
delivery of the training, with the team comprised of the Lead Node, CCC, DSC, as well as other 
participating nodes and subject matter experts, as applicable. 
The CTN-0097 study staff will be trained as specified in the study Training Plan. Training will 
include Human Subjects Protection (HSP) and Good Clinical Practice (GCP) as well as protocol- 
specific training on assessments, medication management, study interventions, safety and safety 
event reporting, study visits and procedures, data management, quality assurance, laboratory 
procedures, etc. The Lead Node is primarily responsible for development and delivery of study- 
specific training related to the study intervention(s) and procedures. The CCC is responsible for 
the development and delivery of non-intervention training, including regulatory and laboratory 
procedures, safety and safety event reporting, quality assurance and monitoring, etc. The DSC is 
responsible for training related to data management (DM), the electronic data capture system, and 
good DM practices. Other parties will contribute as needed based on the subject matter and 
material to be covered. The various sub-teams will collaborate to deliver quality instructional 
material designed to prepare research staff to fully perform study procedures based on the 
assigned research roles and responsibilities. 
In addition to general and study-specific training, the Training Plan will include a description of the 
delivery methods to be used for each training module (e.g., via self-study, online, webcast, or 
teleconference). Study staff is required to complete institutionally required training per their 
research site, Institutional Review Board(s), and authorities with regulatory oversight. Tracking of 
training completion for individual staff as prescribed for assigned study role(s) will be documented, 
endorsed by the site Principal Investigator and the Lead Node, and audited by the CCC. As 
changes occur in the prescribed training, the Training Plan and training documentation tracking 
forms will be amended to reflect these adjustments. 

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15.0 CONCOMITANT THERAPY/INTERVENTION 
15.1 General 
Prescribed psychoactive medications, including anxiolytics and antidepressants, will be allowed 
for the duration of the study per the judgement of the local clinical team. At the  screening visit, 
participants will be asked about the medications they taken one week prior to inpatient admission, 
including 
prescription 
and 
nonprescription 
medications, 
vitamins, 
and 
supplements. 
At 
subsequent 
post-induction visits, participants will be asked about medication use over the last week. 
15.2 Medications Prohibited/Allowed During Trial 
Opioid agonist that are not prescribed as part of the trial (e.g., buprenorphine) will not be allowed 
for the duration of the trial. Though, participants will not be withdrawn if they use illicit 
 
opioids 
including non-prescribed buprenorphine or methadone. 

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16.0 STATISTICAL DESIGN AND ANALYSES 
16.1 General Design 
16.1.1 Study Hypothesis 
We hypothesize that the Rapid method will be non-inferior to the Standard method in terms of 
proportion of participants that receive the first XR-NTX injection. The primary goal of this hybrid 
effectiveness-implementation study is to determine whether the Rapid Procedure of initiating 
treatment with XR-NTX is non-inferior to a Standard Procedure on the primary effectiveness 
outcome of successful initiation of XR-NTX (receiving the first injection) when implemented at 
community- based inpatient or residential programs. 
16.1.2 Primary and Secondary Outcomes (Endpoints) 
Primary Endpoint: The primary outcome measure is a dichotomous indicator of whether each 
participant receives the first XR-NTX injection while inpatient or not at the end of the induction 
period, which is approximately Day 6 in the Rapid Induction Procedure and Day 13 in the 
Standard Induction Procedure. 
Secondary Endpoints: Secondary endpoints include time to first injection or time to failure to 
receive first injection, receiving 2nd and 3rd monthly injections of naltrexone, opioid withdrawal 
symptoms, selected opioid and other drug use, adherence to any type of MOUD and adverse 
events during the induction period and in the month after XR-NTX initiation as discussed in 
Section 7.2. A set of additional implementation outcome measures, including acceptability and 
barriers, are detailed in Section 7.3. A preliminary economic analysis that compares cost of both 
interventions will also be included. 
16.1.3 Study Design 
The therapeutic strategies defined above are evaluated and compared in a multi-center, optimized 
stepped-wedge cluster randomized trial. 
16.1.4 Recruitment 
Patients with OUD planning admission or admitted to inpatient/short-term residential treatment 
sites will participate in a shared decision-making process regarding choice of maintenance 
medication (methadone, buprenorphine, XR-NTX). All those choosing XR-NTX and meeting 
clinical criteria for appropriateness for XR-NTX will be offered participation in the study and asked 
to provide informed consent. Further recruitment will vary based on individual site level factors 
(see Section 8.4 for further recruitment details). Note that the step length corresponding to the 
stepped-wedge design will remain fixed and will not be extended if recruitment rates are found to 
be slower than anticipated. 
16.1.5 Randomization and Factors for Stratification 
For this stepped-wedge cluster randomized trial, the randomization will be performed at site level. 
A total of six sites will be enrolled, five sites to initiate treatment using the Standard Procedure 

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first, and one site to initiate the Rapid Procedure (randomly chosen). The Rapid regimen will be 
introduced 1 site at a time, with one site chosen randomly every 14 weeks. The 6th site (the site 
remaining after the other 5 sites have been chosen to transition to RP) will only offer SP for the 
entire duration of the study). 
16.2 Rationale for Sample Size and Statistical Power 
16.2.1 Introduction 
CTN-0097 SWIFT is a six-center, optimized stepped-wedge cluster randomized trial comparing 
effectiveness and safety of Rapid (5-7-day) versus the Standard (14-day) XR-NTX induction 
procedure (SP vs. RP). In this optimized stepped-wedge design (Thompson et al., 2017), one 
randomly 
selected 
site 
will initiate treatment using 
a RP regimen, while 5 sites will initiate treatment 
using SP regimen first. After 14 weeks, one of the 5 sites will be randomly selected to stop offering 
SP and will begin offering a RP to participants interested in the study. After another 14 weeks, 
another randomly selected site will switch from SP to RP and 14 weeks later another randomly 
selected site will switch from SP to RP, and finally after another 14 weeks another randomly 
selected site will switch from SP to RP. The remaining (6
th) site will continue offering SP for the 
reminder of the study and will never switch to RP. This design is represented schematically as the 
Design Pattern matrix of Table 8. This optimized stepped-wedge design provides more power to 
detect a treatment effect than a standard stepped-wedge design (Thompson et al., 
2017). 
16.2.2 Table 8: Design Pattern Matrix 
Table 8: Design pattern matrix giving schematic representation of the optimized stepped- wedge 
design compared with a standard stepped-wedge design feasible for CTN0097 
Rows are sites, columns are blocks of time (steps), and cells contain 0 for Standard 
Induction Procedure or 1 for Rapid Induction Procedure. 
Optimized Stepped-Wedge Design 
Standard Stepped-Wedge Design 
 
 
The primary outcome measure is the proportion of patients who receive the first XR-NTX injection 
at the end of the induction period, which is approximately Day 6 in the Rapid Induction Procedure 
Time Block 
 
1 2 3 4 5 
1 1 1 1 1 1 
2 0 1 1 1 1 
3 0 0 1 1 1 
Site 
 
 
 
 
 
4 0 0 0 1 1 
5 0 0 0 0 1 
6 0 0 0 0 0 
 
Time Block 
 
1 
2 3 4 
1 0 1 1 1 
2 0 1 1 1 
3 0 0 1 1 
Site 
 
 
 
 
4 0 0 1 1 
5 0 0 0 1 
6 0 0 0 1 
 

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and Day 13 in the in the Standard Induction Procedure (binary: did or did not receive first injection 
of XR-NTX). It is hypothesized that the Rapid Induction Procedure will be non-inferior to the 
Standard Induction Procedure. 
16.2.3 Values of Parameters Underlying Power Simulations 
Probability of Success in 
the SP 
arm: 
We 
base 
the assumed success probability in the SP initiation 
regimen on the mean success rate in the NTX arm of CTN-0051, which is 55% for sites 02011, 
02017, and 02052 pooled together. These are sites that are similar to the types of sites that would 
be eligible for this study. These sites were chosen because they used the standard induction 
method (agonist taper followed by the wait). Other sites, with much higher success rates, (75%- 
95%) were excluded because these were already using a version of the Rapid method (no agonist 
taper, using only alpha-2 agonist and other non-opioid medications) or were highly experienced 
with XR-NTX induction. 
Probability of Success in the RP arm: We assume a difference in the proportion of successes of 
15% based on the results of our prior controlled study, which compared Standard and Rapid XR-
NTX procedures and found a 23.4% difference (56.1% vs 32.7%) (Sullivan et al., 2017). We are 
assuming a smaller true treatment difference (15%) between SP and RP arm, which we believe to 
be more realistic in the inpatient/short-term residential setting. As the proposed trial will be 
conducted on the inpatient unit, reducing the risk of illicit opioid use, and because sites will use 
regimen-driven, aggressive dosing of adjunctive medications, we believe that overall success will 
be 55% in the Standard Procedure arm (as in study CTN051) with the 15% difference for the 
Rapid Procedure arm leading to an assumed probability of success of 70% in the RP arm. 
Margin of non-inferiority: To show non-inferiority of RP to SP, we assume a 10% margin of non- 
inferiority, which corresponds to an odds ratio of 0.67 (proportion of success in RP = 0.45, 
proportion of successes in SP = 0.55). To show RP is non-inferior to SP, we need to show that the 
lower bound of the two-sided 95% CI for the odds ratio for RP and SP is higher than 
0.67. 
Under the above assumptions, the null and alternative hypotheses can be stated as follows: In 
terms of proportions (p): 
Null (inferiority of RP to SP): p(RP) - p(SP) <=-10% 
Alternative (non-inferiority of RP to SP under which power was calculated): p(RP) - p(SP) 
>15% 
In terms of odds ratios (OR): 
Null (inferiority of RP to SP): OR [odds(RP)/odds(SP)] <= 0.67 
Alternative (non-inferiority of RP to SP under which power was calculated): OR 
[odds(RP)/odds(SP)] > 1.91 
Intraclass Correlation Coefficient: We base the ICC estimate on a logistic regression of induction 
success/failure 
in 
CTN-0051 
on 
treatment 
arm, with 
a 
random site 
effect 
whose 
variance 
is 
allowed 
to depend on arm. The adjusted analysis model for this study may have extra covariates (chosen 

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before data analysis), but we do not include them in the power analysis. We assume that extra 
covariates will improve analysis accuracy, implying that our current power estimates may be 
conservative. The estimated site standard deviation in the NTX arm from the regression model 
using data from CTN-0051 is 0.86, leading to an estimated ICC in the Standard induction arm of 
0.14 under the generalized mixed model. As mentioned above, this ICC may be thought of as 
the 
induction status correlation between two individuals chosen randomly without replacement from 
the NTX arm of CTN-0051, given that they come from the same site. 
In summary, the assumptions used for the power calculations for this non-inferiority optimized 
stepped-wedge cluster randomized trial are as follows: 
• The projected number of clusters is 6 (sites), that will enroll participants across 5 periods 
of time, each period 14 weeks long 
• The projected total number of participants enrolled is 450, with 15 participants enrolled 
per cluster per time period (equal allocation to sites per time 
period) 
• The outcome of interest is a binomial outcome (the patient received or did not receive 
the first XR-NTX injection) 
• The probability of success in the Standard induction arm is 0.55 
• The probability of success in the Rapid induction arm is 0.70 (i.e. an effect size of 
0.15) 
• The margin of non-inferiority is 10%, which corresponds to an odds ratio of 0.67 (based 
on proportion of success in RP = 0.45 and proportion of successes in SP = 0.55). Refer 
to Figure 5 for the relationship between non-inferiority margin as a difference in 
proportions versus non-inferiority margin as an odds ratio. 
• Observations are equally correlated within cluster, regardless of time or induction 
method with a site standard deviation of 0.86. The corresponding ICC in the Standard 
induction arm based on a logistic regression with random effects is 0.14. 
In our power calculations, we vary the above assumptions to evaluate the sensitivity of the power 
calculations to different parameter values such as different ICCs, effect sizes, or number of sites. 
For the power calculations, correlated binary data were simulated using the Parzen algorithm 
[Parzen, M., 2009] and power analyses were performed using the logistic model below. 
Logistic model used for power calculations: 
!!!!!!!!!!(##!!!!!! ) = ''
!!!!  ∗ )) + ++!!  + ,,!! 
,,!!~..(0, 112)  
where: 
• j indexes the site 
• s indexes the 4-month block of time 
• i indexes the individual within site j at time s. 
• ++!! is 
the 
fixed 
effect 
of 
time 

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• ,,!! is 
the 
random 
site 
effect 
• ##!!!!!! is the probability of success for individual i within site j at time s. 
• ''
!!!! is the treatment indicator for site j at time s 
• )) is the treatment 
effect 
For all simulations, we used 10,000 iterations. 
A SAS snippet capable of estimating the above model follows: proc glimmix data = simul 
method = quad; 
class site trt time; 
model success = trt time / dist = binary link = logit solution oddsratio;  
 
random intercept / subject = site group = trt; 
run; 
16.2.4 Power Curve 
Two-tailed power to show non-inferiority of RP to SP at alpha level 0.05 is shown in Figure 2 as 
a function of ICC. For the sake of clarity, the vertical power scale runs from 0.6 to 1 instead of the 
conventional 0 to 1. Horizontal and vertical reference lines denote power = 80% and ICC = 0.14, 
respectively. Figure 2 depicts two power curves (explained below), but the 
uppermost curve (black 
line) shows power for the optimized stepped-wedge design. For the optimized stepped-wedge 
design, the expected power exceeds 88% for all possible values of the ICC. As the ICC increases, 
power first declines, then increases. This reflects that the source of power in a stepped-wedge 
design shifts from across-site comparisons to within-site comparisons as ICC increases. Note that 
the power for a similar standard stepped-wedge design was 3% to 8% lower compared to the 
optimized stepped-wedge design, across different ICC values. 
16.2.4.1 Figure 2: Two Power Curves as Functions of ICC 
Figure 2: Two power curves as functions of ICC corresponding to the optimized and standard 
stepped-wedge (SW) design to show non-inferiority of RP to SP, assuming a 
15% treatment effect 
(d = 0.15). The non-inferiority margin is 10%, operationalized here as an odds ratio of 0.67. In 
other words, we reject the null of inferiority of RP to SP if the lower 95% confidence limit of the 
treatment success odds ratio [odds(RP)/odds(SP)] exceeds 0.67. 

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16.2.4.2 Table 9: Power for ICC to show non-inferiority of RP to SP 
Table 9: Power for ICC = 0.14 corresponding to the optimized and standard stepped- wedge 
(SW) design to show non-inferiority of RP to SP, assuming a 15% treatment effect (d = 0.15) 
and a margin of 10% 
 
Non- 
inferiority 
SW Design 
Sites Steps SP 
Success 
RP 
Success 
Effect 
Size 
ICC Power 
Participants per 
Site per Time 
Period 
Total 
Sample 
Size 
Optimized 6 
5 
0.55 
0.70 
0.15 
0.14 0.887 
15 
450 
Standard 
6 
4 
0.55 
0.70 
0.15 
0.14 0.836 
19 
456 
SP = Standard Procedure; RP = Rapid Procedure; SW – Stepped – wedge; ICC – intra class correlation 
coefficient. 
16.2.5 Power in Unforeseen Circumstances 
As remarked above, for the parameters chosen, we expect power to be at least 88%, irrespective 
of the true ICC. However, there might be unforeseen circumstances, such as sites failing to enroll 
or rates of enrollment to be lower than anticipated. Figure 3 explores the impact upon power if a 
site drops or if enrollment is 10% lower than expected. Figure 3 suggests that for this study design, 
losing site 3 costs more than losing site 1 or 5, or having a 10% less enrollment, in terms of power 
loss. However, there is still reasonable power (79% or more) to show non-inferiority of RP to SP 
regardless of which site drops or if enrollment is 10% lower, and irrespective of the true ICC. For 
ICC = 0.14, the power to show RP non-inferior to SP is 80% or more regardless of which site drops 
or if the enrollment is 10% lower. 
In addition, we explored loss of power when the true treatment effect is smaller than anticipated. 
Figure 4 suggests that even for a smaller treatment effect of 13% we still have 80% power or 
more to show RP is non-inferior to SP, irrespective of the ICC values; for a treatment effect of 
12% we have 78% power or more, irrespective of the ICC values; however, for a treatment effect 

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smaller than 11% we will not have enough power to show non-inferiority of RP to SP, for larger 
values of ICC. If the treatment effect is 11% or 10%, the power drops to 75% and 71%, 
respectively, for ICC=0.14 (or even lower for higher ICC values). 
16.2.5.1 Figure 3: Power curves as functions of ICC when a site 
drops or when enrollment rates are lower than anticipated 
Figure 3: Power curves as functions of ICC corresponding to the optimized stepped-wedge (SW) 
design to show non-inferiority of RP to SP, assuming a 15% treatment effect (d 
= 0.15) and a 10% 
margin when a site drops or when enrollment rates are lower than 
anticipated. 
 
 
16.2.5.2 Table 10: Power for ICC when a site drops or when 
enrollment rates are lower than anticipated 
Table 10: Power for ICC = 0.14 for the optimized stepped-wedge (SW) design to show non- 
inferiority of RP to SP, assuming a 15% treatment effect (d = 0.15) and a 10% margin when a site 
drops or when enrollment rates are lower than anticipated. 
Non-inferiority 
Optimized SW Design Sites Steps 
Participants per 
Site per Step 
Total 
Sample Size ICC 
SP 
Success 
RP 
Success 
Effect 
Size Power 
No Drop-out 
6 
5 
15 
450 
0.14 0.55 
0.7 
0.15 
0.887 
Site 1 Drops 
5 
5 
15 
375 
0.14 0.55 
0.7 
0.15 
0.824 
Site 3 Drops 
5 
5 
15 
375 
0.14 0.55 
0.7 
0.15 
0.799 
 
 
Non-inferiority 
Optimized SW Design Sites Steps 
Participants per 
Site per Step 
Total 
Sample Size ICC 
SP 
Success 
RP 
Success 
Effect 
Size Power 
Site 5 Drops 
5 
5 
15 
375 
0.14 0.55 
0.7 
0.15 
0.810 
~10% Less 
Enrollment 
6 
5 
13 
390 
0.14 0.55 
0.7 
0.15 
0.844 
SP = Standard Procedure; RP = Rapid Procedure; SW – Stepped – wedge; ICC – intra class correlation coefficient. 

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16.2.5.3 Figure 4: Power curves as functions of ICC to show non-
inferiority of RP to SP with a 10% margin, assuming 
different treatment effects  
Figure 4: Power curves as functions of ICC corresponding to the optimized stepped-wedge (SW) 
design to show non-inferiority of RP to SP with a 10% margin, assuming different treatment effects 
between 15% and 10% 
 
 
16.2.5.4 Table 11: Power for ICC to show non-inferiority of RP to SP 
with a 10% margin 
Table 11: Power for ICC = 0.14 corresponding to the optimized stepped-wedge (SW) design to 
show non-inferiority of RP to SP with a 10% margin, assuming different treatment effects 
between 15% and 10% 
Non-inferiority 
Optimized SW 
Design 
Sites Steps 
Participants 
per Site per 
Step 
Total 
Sample 
Size 
ICC 
SP 
Success 
RP 
Success 
Effect 
Size 
Power 
Optimized SW 
6 
5 
15 
450 
0.14 0.55 
0.70 
0.15 
0.887 
Optimized SW 
6 
5 
15 
450 
0.14 0.55 
0.69 
0.14 
0.858 
Optimized SW 
6 
5 
15 
450 
0.14 0.55 
0.68 
0.13 
0.824 
Optimized SW 
6 
5 
15 
450 
0.14 0.55 
0.67 
0.12 
0.789 
Optimized SW 
6 
5 
15 
450 
0.14 0.55 
0.66 
0.11 
0.750 
Optimized SW 
6 
5 
15 
450 
0.14 0.55 
0.65 
0.10 
0.713 
SP = Standard Procedure; RP = Rapid Procedure; SW – Stepped – wedge; ICC – intra class correlation coefficient. 
 
 
 

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16.2.5.5 Figure 5: Non-inferiority margin as a difference in 
proportions versus non-inferiority margin as an odds ratio 
 
 
In Figure 5, the vertical and horizontal reference lines represent the proportion of successes in 
the Rapid Procedure (p[RP] = 0.45) and proportion of successes in the Standard Procedure (p[SP] 
= 0.55) used to calculate the margin of non-inferiority in terms of odds ratios [OR=0.67]. The 
straight line represents the margin of non-inferiority as a difference in proportions i.e., the line 
p[RP]-p[SP] = -10%. The curved line represents the margin of non-inferiority as an odds ratio i.e. 
odds[RP]/odds[SP] = 0.67. The graph suggests that the margin of non-inferiority as a difference 
in proportions versus odds ratio, in general, corresponds to similar probabilities of success except 
for extreme values of p[SP] and p[RP] (i.e. less than 0.3 or greater than 0.7). 
16.2.6 Conclusion 
The 
optimized 
stepped-wedge 
design, 
with 
6 
sites 
(clusters) 
and 
5 
periods 
of 
time 
(steps), 
enrolling 
a total of 450 participants (15 participants per cluster per time period), assuming 0.55 probability 
of success in the SP and 0.70 in the RP and a non-inferiority margin of 10%, will provide 88% or 
more power to show non-inferiority of RP to SP. For the sample size, and probabilities of success 
hypothesized for CTN0097, power to show RP is non-inferior to SP is at least 88%, irrespective of 
the value of the ICC. In addition, the study is adequately powered to account for simulated site 
drop-out, lower rates of enrollment or for slightly smaller true treatment effects. 
16.3 Statistical Methods for Primary and Secondary Outcomes 
16.3.1 Primary Outcome Analysis 
As 
is standard 
for 
the 
analysis of stepped-wedge 
designs 
(Barker 
et 
al., 
2016) 
the 
primary 
outcome 
analysis for non-inferiority will be performed using a generalized linear mixed effects model with a 
logistic link, similar to the model used for the power calculations. The log odds of a participant 
receiving the first XR-NTX injection (yes/no) will be modeled as a function of which treatment they 
received (RP vs SP), which study month it is (to control for secular trends), and a random effect 
for site to control for nesting of participants within site. We will reject the null of inferiority of RP to 

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SP if the lower 95% confidence limit of the odds ratio of success [odds(RP)/odds(SP)] exceeds 
0.67. Supplemental analyses related to the primary objective will test for a treatment*study month 
interaction, which, if significant, would indicate differential impact of treatment after a longer period 
of experience. Sensitivity analyses of the primary outcome may be performed to account for 
different correlation structures. 
16.3.2 Secondary Outcome Analysis: 
Secondary outcomes will include receiving 2nd and 3rd monthly injections of naltrexone, and 
opioid withdrawal symptoms and adverse events during and in the month after XR-NTX initiation. 
These outcomes will be modeled using similar mixed effects logistics regression methods as 
above. Note that the analysis of secondary outcomes before first XR-NTX injection will be 
performed using all enrolled participants using an intent-to-treat population (ITT) whereas the 
analyses of secondary outcomes after receipt of first XR-NTX injection will be performed for all 
enrolled participants as well as for a subset of the ITT population i.e., all enrolled participants who 
successfully received the scheduled XR-NTX injections (inducted population). 
16.4 Implementation Outcome Analysis 
Implementation 
outcomes, 
such 
as 
patients’ 
ratings 
of 
acceptability 
and 
satisfaction 
with 
treatment, 
and clinicians’ ratings of knowledge and attitudes toward XR-NTX and XR-NTX induction methods 
before and after sites’ protocol participation, will be modelled as continuous outcomes using mixed 
effects linear regression models, again with random intercepts for site. Additional implementation 
outcome measures including acceptability and barriers measured qualitatively are detailed in 
Section 7.3. 
16.5 Significance Testing 
The primary analysis focuses on estimation of the treatment difference and uses and α=5% 
criterion for significance. There are several secondary outcomes; however, multiple comparisons 
will not be adjusted for since these are not part of the study’s primary objective. 
16.6 Interim Analysis 
Interim analysis for futility is not planned, as a secondary aim is to place confidence limits on the 
difference in XR-NTX initiation success rates between Standard vs. Rapid methods, and greater 
precision of this estimate is desirable, regardless of whether the null hypothesis can be rejected. 
Also, a stepped-wedge requires all steps to be completed to estimate the treatment effect. The 
Investigators and DSMB will monitor SAEs. 
16.7 Exploratory Analysis 
Participant-level factors will be examined with moderator analysis to identify factors predicting 
success vs. failure to initiate XR-NTX. Site-level factors as measured with the implementation 
measures will also be explored as moderators of successful initiation. A nested prediction model 
will be created with participant-level factors nested within sites, and site level factors as gathered 
from implementation assessments (like staff knowledge and attitudes). 

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16.8 Prediction Models 
Several factors are predicted to be associated with successful XR-NTX induction including 
severity of opioid use disorder based on route of use (IV vs. non-IV) with IV users having a more 
severe disorder, type of opioid (fentanyl vs. heroin vs. prescription opioid) with fentanyl users 
being most severe and prescription opioid users least severe, as well as psychiatric and 
substance use disorder comorbidity. 
We will explore prediction in terms of patient level factors that predict success vs. failure to initiate 
XR-NTX. We are also interested in site level factors, measured with the implementation 
measures. Though with 6 sites power for that would be limited. It could be a nested prediction 
model with patients nested within sites, and site level factors (like staff knowledge and attitudes) 
in the model. 
16.9 Missing Data and Dropouts 
The primary outcome, whether or not a participant receives the XR-NTX while inpatient, is not 
expected to have missing data. Other outcome variables (opioid and other substance use over 
time, craving, mood, etc.) will have missing data due to missed visits and dropout from treatment 
and from study participation. The generalized linear model, or mixed effects model framework 
that will be used for analyses, works with what data are gathered, and assumes missing data are 
missing at random. For selected secondary outcome analyses, sensitivity analyses will be 
considered to examine the stability of estimated treatment effects in the face of departures from 
the assumption of missing at 
random. 
16.10 Demographic and Baseline Characteristics 
Baseline demographic and clinical variables will be summarized for participants enrolled in the 
active medication phase of the trial. Descriptive summaries of the distribution of continuous 
baseline variables will be presented with percentiles (median, 25th and 75th percentiles), and with 
mean and standard deviation. Categorical variables will be summarized in terms of frequencies 
and percentages. 
Demographic variables will include: gender, age, race, ethnicity, educational level, employment 
status, marital status. 
Baseline clinical characteristics will include: opioid dependence severity, severity of other 
substance use, severity of mood/anxiety symptoms, severity of opioid withdrawal symptoms, 
current/past co-occurring psychiatric disorders, current medical disorders, history of legal 
problems, currently under legal supervision (parole, probation, or mandated). 
16.11 Safety Analysis 
SAEs will be summarized by body system and preferred term using MedDRA codes (per The 
Medical Dictionary for Regulatory Activities). Targeted Safety Events (TSEs) will be coded if 
feasible. For a list of TSEs refer to Section 12.3.10. TSEs and SAEs will be presented as: (1) the 
number and proportion of participants experiencing at least one incidence of each event overall; 
and (2) the total number of each event overall in tabular form. Listings of SAEs will be sorted by 

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system organ class (SOC), and preferred term (PT). Detail in these listings will include severity, 
relationship to study medication(s), and action taken, as available. 

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17.0 REGULATORY COMPLIANCE, REPORTING AND MONITORING 
17.1 Statement of Compliance 
This trial will be conducted in compliance with the current version of the protocol, in full conformity 
with the ethical principles outlined in the Declaration of Helsinki, the Protection of Human Subjects 
described in the International Council for Harmonisation Good Clinical Practice (GCP) guidelines, 
applicable United States (US) Code of Federal Regulations (CFR), and NIDA Terms and 
Conditions of Award, and 
all other applicable state, local, and 
federal regulatory 
requirements. 
The 
Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the Sponsor and documented approval from the Institutional Review 
Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. 
An Operations Manual will be provided as a reference guide and study quality assurance 
tool. 
17.2 Institutional Review Board Approval 
Prior to initiating the study, participating site investigators will obtain written approval from the 
Ethics Review Committee (ERC) or Institutional Review Board (IRB) to conduct the study at their 
respective site, which will include approval of the study protocol. If changes to the study protocol 
become necessary, protocol amendments will be submitted in writing by the investigators for IRB 
approval prior to implementation. In addition, IRBs will approve all consent forms, recruitment 
materials, and any materials given to the participant, and any changes made to these documents 
throughout study implementation. Approval of both the protocol and the consent form(s) must be 
obtained before any participant is consented. For changes to the consent form, a decision will be 
made regarding whether previously consented participants need to be re-consented. IRB 
continuing review will be performed annually, or at a greater frequency contingent upon the 
complexity and risk of the study. Each site principal investigator is responsible for maintaining 
copies of all current IRB approval notices, IRB-approved consent documents, and approval for all 
protocol modifications. These materials must be received by the investigator prior to the initiation 
of research 
activities at 
the 
site 
and 
must 
be 
available 
at 
any 
time 
for 
audit. 
Unanticipated 
problems 
involving risk to study participants will be promptly reported to and reviewed by the IRB of record, 
according to its usual procedures. 
This study will utilize a single IRB as the IRB of record for the protocol and will provide study 
oversight in accordance with 45 CFR 46. Participating institutions will agree to rely on the single 
IRB of Record and will enter into reliance/authorization agreements for Protocol CTN-0097. The 
single 
IRB 
will 
follow 
written 
procedures 
for 
reporting its 
findings 
and 
actions 
to 
appropriate 
officials 
at each participating institution. 
17.3 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. Informed consent 
continues throughout the individual’s study participation. The informed consent form(s) will include 
all of the required elements of informed consent and may contain additional relevant consent 
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informed consent(s) approved by the IRB of record. Prior to initial submission to the IRB and with 
each subsequent consent revision, the consent form(s) must be sent to the Clinical Coordinating 
Center (CCC) and the Lead Node (LN) to confirm that each consent form contains the required 
elements of informed consent as delineated in 21 CFR 50.25(a) and CFR 46.116(b), as well as 
pertinent additional elements detailed in 21 CFR 50.25(b) and 45 CFR 46.116(c) and any 
applicable CCTN requirements. Every study participant is required to sign a valid, IRB-approved 
current version of the study informed consent form prior to the initiation of any study related 
procedures. The site must maintain the original signed informed consent for every participant in 
a locked, secure location that is in compliance with all applicable IRB and institutional policies and 
that is accessible to the study monitors. Every study participant should be given a copy of the 
signed consent form. 
During the informed consent process, research staff will explain the study to the potential 
participant and provide the potential participant with a copy of the consent form to read and keep 
for reference. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and their rights as 
research participants. Extensive discussion of risks and possible benefits will be provided to the 
participants. Participants will have the opportunity to carefully review the written consent form and 
ask questions prior to signing. The participants should have the opportunity to discuss the study 
with their family and close friends or think about it prior to agreeing to participate. If the participant 
is interested in participating in the study, a qualified staff member will review each section of the 
IRB-approved informed consent form in detail and 
answer any 
questions the participant may pose. 
The participant, or participant’s legally authorized representative, will consent by signing and 
dating the consent document. The person obtaining consent and a witness, if required by the IRB 
of record, will also sign and date the consent document. It is strongly recommended that another 
research staff member review the consent after it is signed to ensure that the consent is properly 
executed and complete. Staff members delegated by the PI to obtain informed consent must be 
listed on the Delegation of Responsibility and Staff Signature Log and must be approved by the 
IRB, if required. All persons obtaining consent must have completed appropriate GCP and Human 
Subjects Protection training, as mandated by NIDA standard operating procedures. 
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 participants’ 
participation in the trial. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. The participant will be informed that their participation is voluntary, and 
they may withdraw from the study at any time, for any reason, without penalty. Individuals who 
refuse to participate or who withdraw from the study will be treated without prejudice. Study sites 
will be responsible for maintaining signed consent forms as source documents for quality 
assurance review and regulatory compliance. 
The study does not preempt any applicable federal, state, or local laws which require additional 
information 
to 
be disclosed 
in 
order 
for informed 
consent 
to 
be legally 
effective. It is in 
conformance 
with 42 CFR 2.52, which allows for research-related provisions with regard to the disclosure of 
substance use disorder patient identifying information in the absence of the informed consent 

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process and HIPAA authorization. 
17.4 Quality Assurance Monitoring 
In accordance with federal regulations, the study sponsor is responsible for ensuring proper 
monitoring of an investigation and ensuring that the investigation is conducted in accordance with 
the 
protocol. 
Qualified 
monitors will oversee aspects of site 
conformity to 
make certain 
the 
site staff 
is operating within the confines of the protocol, and in accordance with GCP. This includes but is 
not limited to protocol compliance, documentation auditing, monitoring of drug disposition, and 
ensuring the informed consent process is being correctly followed and documented. Non-
conformity with protocol and federal regulations will be reported as a protocol deviation and 
submitted to the study sponsor and study IRB of record, as applicable, for further 
review. 
17.5 Participant and Data Confidentiality 
Participant confidentiality and privacy are strictly held in trust by the participating investigators, 
their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency, and will be 
maintained in accordance with all applicable federal regulations and/or state/Commonwealth law 
and regulations. This confidentiality is extended to the data being collected as part of this study. 
Data 
that could be used to identify a specific study 
participant will be held in strict confidence within 
the research team. No personally-identifiable information from the study will be released to any 
unauthorized third party without prior written approval of the sponsor/funding agency and the 
participant.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or representatives 
from companies or organizations supplying the product, may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site 
will permit access to such records. 
Participant records will be held confidential 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. 
The 
study 
participant’s 
contact 
information 
will be securely stored at each clinical site and on the e
lectron
ic data capture system for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as denoted in 
Section 17.12 Records Retention and Requirements. 
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/Privacy Board, Ethical Review Committee, or similar expert committee; affiliated institution; 
and employees only under an appropriate understanding of confidentiality with such board or 
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17.5.1 Certificate of Confidentiality 
To further protect the privacy of study participants, the Secretary, Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, 
behavioral, clinical or other human subjects research funded wholly or in part by the federal 
government. Recipients of NIH funding for human subjects research are required to protect 
identifiable research information from forced disclosure per the terms of the NIH Policy (see 
https://humansubjects.nih.gov/coc/index). This protects participants from disclosure of sensitive 
information (e.g., drug use). It is the NIH policy that investigators and others who have access to 
research records will not disclose identifying information except when the participant consents or 
in certain instances when federal, state, or local law or regulation requires disclosure. NIH expects 
investigators 
to 
inform 
research 
participants 
of 
the 
protections 
and 
the 
limits 
to 
protections 
provided 
by a Certificate issued by this Policy. 
17.5.2 Health Insurance Portability and Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use of 
protected health information (PHI). Sites will be responsible for communicating with the IRBs or 
Privacy Boards of record and obtaining the appropriate approvals or waivers to be in regulatory 
compliance. Releases of participant identifying information that are permitted by the HIPAA 
regulations, but which are prohibited by other applicable federal regulations and/or 
state/Commonwealth law and regulation, are prohibited. 
17.6 Investigator Assurances 
Each site must have on file an active Federalwide Assurance (FWA) with the HHS Office for 
Human Research Protection setting forth the commitment of the organization to establish 
appropriate policies and procedures for the protection of human research subjects in alignment 
with 45 CFR 46, Subpart A, with documentation sent to NIDA or its designee. Research covered 
by these regulations cannot proceed in any manner prior to NIDA receipt of certification that the 
research has been reviewed and approved by the IRB provided for in the assurance (45 CFR 
46.103). Prior to initiating the study, the Principal Investigator at each study site will sign a protocol 
signature page and investigator agreement, providing assurances that the study will be performed 
according to the standards stipulated therein. 
17.6.1 Financial Disclosure/Conflict of Interest 
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. Everyone with decision-making responsibilities regarding the protocol will confirm to the 
sponsor annually that they have met their institutional financial disclosure 
requirements. 
17.7 Clinical Monitoring 
Investigators will host periodic visits by NIDA contract monitors who will examine whether study 
procedures are conducted appropriately, and that study data are generated, documented and 
reported in compliance with the protocol, GCP, and applicable regulations. These monitors will 
audit, at mutually agreed upon times, regulatory documents, case report forms (CRFs), informed 

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consent forms and corresponding source documents for each 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, 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 (Node QA monitors) or other designated party(ies) will provide site 
management for each site during the trial. Node QA staff or other designated party(ies) will audit 
source documentation, including informed consent forms and HIPAA forms. This will take place 
as specified by the local protocol team, node PI or lead team and will occur as often as needed 
to help prevent, detect, and correct problems at the study sites. Node QA personnel will verify 
that study procedures are properly followed and that site personnel are trained and able to 
conduct the protocol appropriately. If the node personnel’s review of study documentation 
indicates that additional training of site study personnel is needed, node QA personnel will 
undertake or arrange for that training. Details of the contract, node QA and data monitoring are 
found in the study QA monitoring plan. 
17.8 Inclusion of Women and Minorities 
The study sites should aim and take steps to enroll a diverse study population. If difficulty is 
encountered in recruiting an adequate number of women and/or minorities, the difficulties involved 
in recruitment will be discussed in national conference calls and/or face-to-face meetings, 
encouraging such strategies as linkages with medical sites and/or treatment programs that serve 
large numbers of women and/or minorities, advertising in newspapers or radio stations with a high 
female/minority readership/listening audience, etc. 
17.9 Prisoner Certification 
As per 45 CFR 46 Subpart C, there are additional protections pertaining to prisoners as study 
participants. A prisoner is defined as any individual involuntarily confined or detained in a penal 
institution. The term is intended to encompass individuals sentenced to such an institution under 
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment 
procedures 
which 
provide 
alternatives 
to 
criminal 
prosecution 
or 
incarceration 
in 
a 
penal 
institution, 
and 
individuals 
detained 
pending 
arraignment, 
trial, 
or 
sentencing. 
In 
order 
to 
meet 
these 
additional 
protections, 
the 
study 
team 
will 
obtain 
certification 
from 
the 
Office 
for 
Human 
Research 
Protections 
(OHRP) 
to 
enroll 
prisoners 
(see 
Section 
8.3) and 
follow-up 
with 
participants 
who 
become 
prisoners 
during the course of the study, as necessary. 
17.10 Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be checked at each participating site for 
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closure. 
17.11 Records Retention and Requirements 
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, audio and video recordings, and regulatory files) will be maintained by the 
investigator in a secure location for a minimum of 3 years after the study is completed and closed. 
These records are also to be maintained in compliance with IRB, state and federal requirements, 
whichever is longest. The Sponsor and Lead Investigator must be notified in writing and 
acknowledgment from these parties must be received by the site prior to the destruction or 
relocation of research records. 
17.12 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. Safety 
reporting will occur as previously described. At the completion of the trial, the Lead Investigator 
will provide a final report to the Sponsor. 
17.13 Audits 
The Sponsor has an obligation to ensure that this trial is conducted according to good clinical 
research practice guidelines and may perform quality assurance audits for protocol compliance. 
The Lead Investigator and authorized staff from the Greater New York Node; 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 Institutional Review Board of 
record may inspect research records for verification of data, compliance with federal guidelines on 
human participant research, and to assess participant safety. 
17.14 Study Documentation 
Each participating site will maintain appropriate study documentation (including medical and 
research records) for this trial, in compliance with ICH E6 R2 and regulatory and institutional 
requirements for the protection of confidentiality of participants. Study documentation includes all 
case report forms, workbooks, source documents, monitoring logs and appointment schedules, 
sponsor-investigator correspondence, and signed protocol and amendments, Ethics Review 
Committee or Institutional Review Board correspondence and approved consent form and signed 
participant consent forms. As part of participating in a NIDA-sponsored study, each site will permit 
authorized representatives from NIDA and regulatory agencies to examine (and when permitted 
by law, to copy) clinical records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety, progress, and data validity. 
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. 
Whenever possible, the original recording of an observation should be retained as the source 

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document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
17.15 Protocol Deviations 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
As a result of deviations, corrective actions will be developed by the site and implemented 
promptly. 
These practices are consistent with ICH GCP: 
• Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3 
• Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1 
• Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2. 
Any 
departure 
from 
procedures 
and 
requirements 
outlined 
in 
the 
protocol 
will 
be 
classified 
as 
either 
a major or minor protocol deviation. Variations in clinical procedures are not specifically mandated 
by the protocol and are part of the implementation outcome and therefore will not be considered 
protocol deviations. The difference between a major and minor protocol deviation has to do with 
the seriousness of the event and the corrective action required. A minor protocol deviation is 
considered an action (or inaction) that by itself is not likely to affect the scientific soundness 
of the investigation or seriously affect the safety, rights, or welfare of a study participant. Major 
protocol deviations are departures that may compromise the participant safety, participant rights, 
inclusion/exclusion criteria or the integrity of study data and could be cause for corrective actions 
if not rectified or prevented from re-occurrence. Sites will be responsible for developing corrective 
action 
plans 
for 
both 
major 
and 
minor 
deviations 
as 
appropriate. 
Those 
corrective 
action plans may 
be reviewed/approved by the Lead Node and the CCC with overall approval by the IRB of record 
as needed. All 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. 
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 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. 
17.16 Safety Monitoring 
The Lead Investigator (LI) may appoint a Site Medical Clinician (MD, DO, NP, or PA) for this study, 
who will review or provide consultation for each Targeted Safety Event (TSE) and Serious 
Adverse Event (SAE) as needed. These reviews will include an assessment of the possible 

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relatedness of the event to the study intervention or other study procedures. The Site Medical 
Clinician will also provide advice for decisions to exclude, refer, or withdraw participants as 
required. In addition, NIDA will assign a Safety Monitor/Medical Monitor to this protocol to 
independently review the safety data and present it to the DSMB for periodic review. The Safety 
Monitor/Medical Monitor will determine which safety events require expedited reporting to NIDA 
and the DSMB. This will include events that are serious, related and unexpected. The study staff 
will be trained to monitor for and report TSEs and SAEs. 
Each of the sites has established practices for managing medical and psychiatric emergencies, 
and the study staff will continue to utilize these procedures. Treatment providers at each site will 
be responsible for monitoring participants for possible clinical deterioration or other problems, and 
for implementing appropriate courses of action. 
17.16.1 Data and Safety Monitoring Board (DSMB) 
An independent CTN DSMB will examine accumulating data to assure protection of participants’ 
safety while 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, or evidence that study procedures should be changed, 
or 
if 
the 
trial 
should 
be 
halted, 
for 
reasons 
relating 
to 
the 
safety 
of 
the 
study 
participants, 
the 
efficacy 
of the treatment under study, or inadequate trial performance (e.g., poor recruitment). 
17.16.2 Safety Monitor/Medical Monitor 
The CCC Safety Monitor/Medical Monitor is responsible for reviewing all targeted safety events 
(TSEs) and serious adverse events (SAEs) reported. All SAEs will be reviewed within one 
business day of being reported in Advantage eClinical. The Safety Monitor/Medical Monitor will 
also indicate concurrence or not with the details of the report provided by the site. Where further 
information is needed the Safety Monitor/Medical 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 TSEs are reviewed on a regular basis to observe trends or unusual 
events. 
The CCC Safety Monitor/Medical Monitor will in turn report events to the sponsor if the event 
meets the definition of an expedited event. Reports will be generated and presented for Data 
Safety Monitoring Board (DSMB) meetings. 
17.16.3 Safety Events 
Standard definitions for adverse events and serious adverse events, their identification, 
characterization regarding severity and relationship to therapy and processing are described in 
Appendix A. 
For the purpose of this study, events included in the following list of targeted safety events should 
be recorded on the Targeted Safety Events form and reported in the data system: 

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• Fall event (related to medical/psychiatric condition such as dizziness, confusion with 
head injury) 
• Acute change in mental status (i.e. disorientation, amnesia, cerebrovascular accident, 
coma) 
• Acute medical complication likely exacerbated by the stress of withdrawal (i.e. 
hypertensive crisis, hypotensive event with medical sequelae such as fall and/or 
requiring urgent fluid resuscitation, severe chest pain, acute respiratory 
decompensation, asthma attack, diabetic ketoacidosis, severe hypoglycemia, severe 
electrolyte abnormalities (hyper-/hyponatremia, hyper-/hypokalemia), precipitated 
withdrawal 
• Acute psychiatric symptoms (i.e. psychosis, hypomania, severe agitation, violence)  
Targeted safety events will also be captured on the appropriate, related study specific forms (for 
example, COWS, SOWS, PHQ-9, Medication Injection Site Abnormality Log and Overdose 
Questionnaire).  
Spontaneous reporting of withdrawal symptoms (including any withdrawal precipitated by the 
study medication) by the participant will be captured on scheduled specific structured 
questionnaires.  
Targeted safety events will not be duplicate-reported as an adverse event unless meeting the 
SAE definition. 
17.16.4 Serious Adverse Events (SAEs) 
All safety events will be evaluated to determine if they meet the criteria for an SAE (see Appendix 
A). For the purpose of this study, the following events will not be reported as an SAE. Detox 
admissions will be recorded on study specific forms in the data system. These events will be 
reported to the single IRB (and any local IRB(s), if applicable) per IRB guidelines: 
• Admissions for detoxification 
• Admission for labor and delivery 
• Admission for elective or pre-planned surgery 
17.16.5 Known Potential Toxicities of Study Medication/Intervention 
All medications used in the proposed study are FDA-approved and widely used 
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18.0 DATA MANAGEMENT 
18.1 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 good clinical data management procedures. Advantage eClinical, a web- 
based distributed data entry system, will be implemented to collect eCRFs. This system will be 
developed to ensure 
that 
guidelines and regulations surrounding the use of computerized systems 
used in clinical trials are upheld. In addition, quantitative implementation assessments will be 
collected in QualtricsXM, a commercial off-the-shelf data collection system. Of note, the DSC will not 
be responsible for providing support for data collection and analysis of qualitative interviews or 
coaching progress notes. The remainder of this section provides an overview of the data 
management plan associated with this 
protocol. 
18.2 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. 
18.3 Data Center Responsibilities 
The DSC will 1) develop a data management plan and will conduct data system development and 
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 
and 
quality 
assurance 
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 for 
all data collected in eClinical. 
18.4 Data Collection 
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical or QualtricsXM, or will be collected via direct entry into the eCRF. In the 
event that Advantage eClinical or QualtricsXM are not available, the DSC will provide the sites with 
a final set of guided source documents and completion instructions. Data entry into Advantage 
eClinical should be completed according to the instructions provided and project specific training. 
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. 
18.5 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 who have 
adequately completed required training shall have access to eCRFs. 

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18.6 Data Editing 
Completed data will be entered into Advantage eClinical. If incomplete or inaccurate data are 
found, a query will be generated to the appropriate site for their response. Sites will resolve 
data inconsistencies and errors and enter all corrections and changes into Advantage eClinical. 
18.7 Data Transfer/Lock 
Study 
participant 
research 
data, 
which 
is 
for 
purposes 
of 
statistical 
analysis 
and 
scientific 
reporting, 
will be transmitted to and stored at the DSC. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by 
a unique study identification number. The study data entry and study management systems used 
by clinical sites and by DSC staff will be secured and password protected. 
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. 
18.8 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. 
18.9 Data Quality Assurance 
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 
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19.0 PUBLIC ACCESS AND DATA SHARING PLAN 
This study will comply with the NIH Data Sharing Policy and Implementation Guidance 
(https://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm) and (for HEAL- 
funded studies) the HEAL Public Access and Data Sharing Policy 
(https://heal.nih.gov/about/public-access-data). Investigators will also register and report results 
of 
the 
trial 
in 
ClinicalTrials.gov, 
consistent with the requirements of the Policy on the Dissemination 
of NIH-Funded Clinical Trial Information and the Clinical Trials Registration 
(https://grants.nih.gov/policy/clinical-trials/reporting/understanding/nih-policy.htm). 
Primary data for this study will be available to the public in the NIDA data repository, per NIDA 
CTN policy. For more details on data sharing please visit https://datashare.nida.nih.gov/. 
The primary outcome(s) publication will be included along with study underlying primary data in 
the data share repository, and it will also be deposited in PubMed Central 
http://www.pubmedcentral.nih.gov/ per NIH Policy (http://publicaccess.nih.gov/). 
The 
planning, 
preparation, 
and 
submission 
of 
publications 
will 
follow 
the 
policies 
of 
the 
Publications 
Committee of the CTN. Considerations for ensuring confidentiality of any shared data are 
described in Section 17.6. 

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20.0 PROTOCOL SIGNATURE PAGE 
SPONSOR’S REPRESENTATIVE (CCTN SCIENTIFIC OFFICER OR DESIGNEE) 
 
 
Printed Name 
 
Signature 
 Date 
 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
 
● I am in receipt of version 3.0 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 (DHHS), the state, and the IRB. 
 
 
SITE’S PRINCIPAL INVESTIGATOR 
 
 
Printed Name 
 
Signature 
 Date 
 
 
 
 
Clinical Site Name 
 
 
 
Node Affiliation 
 

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Lee, J. D., Friedmann, P. D., Kinlock, T. W., Nunes, E. V., Boney, T. Y., Hoskinson, R. A., Jr., 
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Löwe, B., Decker, O., Müller, S., Brähler, E., Schellberg, D., Herzog, W. and Herzberg, P.Y., 2008. 
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PD) in high-risk groups in primary care. Journal of affective disorders, 130(1-2), pp.260-267. 

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22.0 APPENDIX A: ADVERSE EVENT REPORTING 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. 
22.1 Definition of Adverse Events and Serious Adverse Events 
An 
adverse 
event (AE) 
is any 
untoward 
medical 
occurrence 
in 
humans, 
whether 
or not 
considered 
study 
medication/intervention 
related 
which 
occurs 
during 
the 
conduct 
of 
a 
clinical 
trial. 
Any 
change 
from baseline in clinical status, ECGs, lab results, x-rays, physical examinations, etc., that is 
considered clinically significant by the site medical clinician are considered AEs. 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the study medication/intervention caused the adverse event. A reasonable possibility implies that 
there is evidence that the study medication/intervention caused the event. 
Adverse reaction is any adverse event caused by the study medication/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 site 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 medication/intervention, must be reported. 
2) Is life-threatening: Life-threatening means that the study participant was, in the opinion 
of 
the medical clinician or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention. 
3) Requires inpatient hospitalization or prolongation of existing hospitalization. 
4) Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) Is a congenital abnormality or birth defect. 
6) Is an 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. 
22.2 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. 

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22.3 Pregnancy 
Pregnancy will be followed within the context of this study. 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. Pregnant women should be engaged by their site medical provider 
in a shared decision-making process to determine whether they remain on medication for OUD 
and which medication to use. The pregnancy followed until an outcome is known. 
22.4 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 events and to assist in the 
assessment of worsening in intensity or severity of these conditions that would indicate a TSE or 
SAE.  
Stable chronic conditions, such as arthritis, which are present prior to clinical trial entry and do not 
worsen are not considered TSEs. 
22.5 Site’s Role in Eliciting and Reporting Safety Events 
Appropriately qualified and trained personnel will elicit participant reporting of TSEs and SAEs at 
each study visit designated to collect these events. TSEs (medical and/or psychiatric) assessment 
will initiate with participant consent and follow-up of ongoing events will continue through 
resolution or 30 days post last study visit. Study personnel will obtain as much information as 
possible about the reported TSE/SAE to complete the TSE/SAE forms and will consult with the 
Safety Monitor/Medical Monitor as warranted. 
Standard 
reporting, within 
7 days 
of the 
site 
becoming 
aware 
of the 
event, 
is required 
for 
reportable 
TSEs. 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). Sites are 
responsible for reporting SAEs to the IRB of record, per the IRB or record’s guidelines. 
Sites are required to enter reportable TSEs and SAEs in the Advantage eClinical system. The 
TSE form is used to capture reportable TSEs. The AE/SAE form set is used to capture SAEs (as 
defined in the protocol). In this protocol, only SAEs are being reported on the AE/SAE form set.  
Additional information may need to be gathered to evaluate SAEs and to complete the appropriate 
CRFs and the summary. This process may include obtaining hospital discharge reports, medical 
records, autopsy records or any other type records or information necessary to provide a complete 
and clear picture of the serious event and events preceding and following the event. If the SAE is 
not resolved or stable at the time of the initial report or if new information becomes available after 
the initial report, follow-up information must be submitted as soon as possible. 
Any serious adverse reactions will be followed until resolution or stabilization for as long as 
possible beyond the end of the study. If the study team is unable to follow up with individuals with 
reportable safety  events, every effort will be made to connect these individuals with the 
appropriate community-based 
treatment. 

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22.6 Site’s Role in Assessing Severity and Causality of Adverse Events 
Appropriately qualified and trained study 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 safety events for seriousness, severity, and causality on 
at least a weekly basis. 
22.7 Guidelines for Assessing Severity 
The severity of an adverse event refers to the intensity of the event. 
 
Grade 1 
Mild 
Transient or mild discomfort (typically <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 but unlikely. 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/ therapy required, 
hospitalization possible. 
 
22.8 Guidelines for Determining Causality 
The site medical clinician will use the following question when assessing causality of an adverse 
event to study medication/intervention where an affirmative answer designates the event as a 
suspected adverse reaction: 
Is there a reasonable possibility that the study medication/intervention caused the event? 
22.9 Site’s Role in Monitoring Safety Events 
Local quality assurance monitors will review study sites and respective study data on a regular 
basis and will promptly advise sites to report any previously unreported safety issues and ensure 
that the reportable safety-related events are being followed to resolution and reported 
appropriately. Staff education, re-training or appropriate 
corrective action plan will be implemented 
at the participating site when unreported or unidentified reportable TSEs or serious events are 
discovered, to ensure future identification and timely reporting by the site. 
22.10 Sponsor’s Role in Safety Management Procedures of AEs/SAEs 
A NIDA-assigned Safety Monitor/Medical Monitor is responsible for reviewing all serious adverse 
event reports. All reported SAEs will generate an e-mail notification to the Safety Monitor/Medical 

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Monitor, 
Lead 
Investigator, 
and 
designees. 
All 
SAEs 
will 
be 
reviewed 
by 
the 
Safety 
Monitor/Medical 
Monitor in Advantage eClinical and, if needed, additional information will be requested. The Safety 
Monitor/Medical Monitor will also report events to the sponsor and the DSMB as required. The 
DSMB will receive summary reports of all targeted safety events and SAEs annually, at a 
minimum. The DSMB or the NIDA assigned Safety Monitor/Medical Monitor may also request 
additional and updated information. Details regarding specific targeted safety events or SAEs, 
their treatment and resolution, will be summarized by the Safety Monitor/Medical Monitor in writing 
for review by the sponsor and DSMB. Subsequent review by the Safety Monitor/Medical Monitor, 
DSMB, FDA and ethics review committee or IRB, the sponsor, or relevant local regulatory 
authorities may also suspend further trial treatment at a site. The study sponsor, DSMB and FDA 
retain the authority to suspend additional enrollment and treatments for the entire study as 
applicable. 
22.11 Regulatory Reporting for a non-IND study 
If an SAE meets the expedited reporting criteria (serious and unexpected suspected adverse 
reactions), the Safety Monitor/Medical Monitor on behalf of the sponsor will provide an SAE 
narrative summary. 
22.11.1 Reporting to the Data and Safety Monitoring Board 
The DSMB will receive listing of TSEs 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. 
22.12 Participant Withdrawal 
The site 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 be 
withdrawn from 
further study 
medication 
administration/study 
intervention. 
The 
site 
medical 
clinician 
should 
consult 
with 
the 
site. 
Principal Investigator, the Lead Investigator and/or Safety Monitor/Medical Monitor as needed. If 
necessary, a site 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, the participant will be asked to 
complete 
an 
end-of-medication 
visit 
to 
assure 
safety 
and 
to 
document 
end-of-medication 
outcomes 
and will be given recommendations for medical care and/or referrals to treatment, as 
necessary. 
 
 

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22.13 Adverse Event Reporting (Chart) 
 
 
Notify IRB(s) per IRB 
Requirements 
Record per site 
requirements 
report per IRB 
requirements 
Serious? 
Targeted 
Safety 
Event (TSE) 
Expedited initial 
reporting within 24 
hours via AE/SAE 
eCRFs in EDC 
EDC system will 
automatically notify 
Medical/ Safety 
Monitor, Lead 
Investigator, and 
designees 
Reportable 
SAE 
Standard 
Reporting 
Record per 
site 
requirements 
report per 
IRB 
requirements 
TSE 
reviewed by 
designated 
staff 
Complete 
TSE eCRF 
within 7 
days 
Study medical 
clinician reviews all 
relevant records and 
completes SAE 
report and 
documentation 
Complete AE and 
SAE forms in EDC 
system within 7 days 
Continue follow-up 
and reporting until 
event is resolved or 
stabilized 
AE Identified 

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23.0 APPENDIX B: DATA AND SAFETY MONITORING PLAN 
1.0 BRIEF STUDY OVERVIEW 
This is an open-label, multi-center, stepped-wedge cluster randomized trial. It will be conducted 
in 6 CTN-affiliated Community Treatment Programs (CTPs) that provide inpatient/residential 
detoxification services and have the capacity to provide ongoing outpatient treatment with 
extended-release naltrexone (XR-NTX). All sites will first implement the control procedure 
(Standard, 14-day procedure; SP), to establish the within-site comparison condition, and then at 
selected staggered time-points (steps) will switch to implementing only the experimental 
procedure (Rapid, 5-7-day procedure: RP). Implementation of RP at study sites will be staggered 
by 4 months and the order in which sites will cross-over to RP will be randomly chosen. The 
primary goal of the study is to determine whether the Rapid method 
of initiating treatment with XR-
NTX is non-inferior to the standard method. Secondary objectives include comparing RP and SP 
for craving, withdrawal, retention, abstinence, depression and anxiety, and safety measures. 
Other exploratory outcomes include predictors of induction success, economic analyses, and 
barriers to implementation. 
2.0 OVERSIGHT OF CLINICAL RESPONSIBILITIES 
A. Site Principal Investigator 
Each participating site’s Principal Investigator (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. 
All safety events (TSEs and SAEs) 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 occurrence of TSAEs and serious adverse events (SAEs) will be assessed at each clinic visit 
during the study. Serious adverse events will be followed until considered resolved or stable. 
Reportable TSAEs are required to be entered into the data system within 7 days of the site staff 
becoming aware of the event. Reportable SAEs (including death and life-threatening events) are 
required to be entered into the data system within 24 hours of site
's knowledge of the event. 
B. CCC Safety Monitor/Medical Monitor 
The NIDA CTN Clinical Coordinating Center’s (CCC) Safety Monitor/Medical Monitor or designee 
is responsible for reviewing all targeted safety events and serious adverse events reported. The 
CCC Safety Monitor/Medical Monitor is alerted via email each time an SAE is reported in 
the EDC. 
All SAEs will be reviewed at the time they are reported in the EDC. The Safety Monitor/Medical 
Monitor or designee will also indicate concurrence or not with the details of the report provided by 
the site PI. Where further information is needed, the Safety Monitor/Medical Monitor or designee 
will discuss the event with the site staff. Reviews of SAEs by the CCC Safety Monitor/Medical 
Monitor or designee will be documented in the Advantage eClinical data system and will be a part 
of the safety database. All TSEs are reviewed on a weekly basis to observe trends or unusual 
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C. Voluntary Regulatory Reporting in non-IND Trials: 
For non-IND trials, if an event meets expedited reporting criteria (serious, related and unexpected) 
the CCC Safety Monitor/Medical Monitor will provide an SAE narrative summary. 
D. 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. Reports will be generated and 
presented for Data and Safety Monitoring Board (DSMB) meetings. The DSMB will receive listings 
of targeted safety events and narratives 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. The 
DSMB will make recommendations to NIDA CCTN 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) 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 
summarizing study safety information will be submitted to participating IRBs. 
E. Quality Assurance (QA) Monitoring 
The monitoring of the study site(s) will be conducted on a regular basis using a combination of 
NIDA CCTN CCC monitors (if applicable) and the local Node QA Monitors (if applicable). 
Investigators will host periodic visits for the monitors. The purpose of these visits is to assess 
compliance with the protocol, GCP requirements, and other applicable regulatory requirements, 
as well as to document the integrity of the trial progress. The investigative site will provide direct 
access to all trial related sites (e.g., pharmacy, research office), source data/documentation, and 
reports for the purpose of monitoring and auditing by the monitors, as well as inspection by local 
and regulatory authorities. 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 site staff 
to identify issues and re-train the site as needed to enhance research quality. 
Site Visit Reports will be prepared by the NIDA CCC monitors following each site visit. These 
reports will be sent to the site Principal Investigator, the study Lead Investigator and NIDA CCTN. 
Local Node QA site visit reports will be prepared following each site visit, as applicable. These 
reports are sent to those entities required of them by the Lead Investigative team, generally 
including the Lead Investigator, site Principal Investigator, Node PI and a CCC representative, 
usually the protocol specialist for the study. 
F. Management of Risks to Participants Confidentiality 
Confidentiality of participant records will be secured by the use of study codes for identifying 
participants on CRFs, and secure storage of any documents that have participant identifiers  on 

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site, as well as secure computing procedures for entering and transferring electronic data. The 
documents or logs linking the study codes with the study participant on site will be kept 
locked/securely stored separately from the study files and the medical records. No identifying 
information will be disclosed in reports, publications or presentations. 
3.0 Information That Meets Reporting Requirements 
The consent form will specifically state the types of information that are required for reporting and 
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. 
4.0 Participant Protection 
The site’s study clinician or other designated and qualified individual will evaluate all pertinent 
screening assessments prior to participant enrollment to ensure that the participant is eligible and 
safe to enter the study. Safety events and concomitant medications will be assessed and 
documented at each study visit. Individuals who experience an safety event that compromises 
safe 
participation 
in 
a 
study 
will 
be 
discontinued 
from further 
medication 
administration/intervention 
and provided referrals for other treatment or to specialized care. Study personnel will request that 
the participant complete an end-of medication visit to assure safety and to document end-of-
medication outcomes. 
5.0 Pregnancy 
Participants who are found to be pregnant during the screening will not be enrolled in the study. 
Pregnant women should be engaged by their site medical provider in a shared decision-making 
process to determine whether they remain on medication for OUD and which medication to use. 
The site staff will follow the participant until an outcome of the pregnancy is known and reported. 
6.0 Study Specific Risks 
Risk of Overdose 
Opioid detoxification carries a moderately high risk of relapse and a risk of opioid overdose if one 
uses a significant amount of opioids after losing tolerance. Self-administration of large doses of 
opiates may override the blockade produced by naltrexone resulting in an opiate overdose with 
its attendant risks, including respiratory depression and death. Participants will be warned of the 
severe danger of using opiates, including trying to override the blockade. Also, participants who 
have stopped naltrexone and resume opiates will not be tolerant initially, so that the quantities of 
opiates self-administered prior to treatment, when they were tolerant, may be quite dangerous in 
the non-tolerant state. Participants will be warned of this. Participants who self-administer opiates 
to the point of somnolence or stupor will be removed from the trial and referred to inpatient 
detoxification or agonist maintenance treatment. Until such individuals are accepted for treatment 
elsewhere, they will remain at the site where they will be offered therapy and treated in the open 
label manner for the duration of trial. 
Risks of Naltrexone 
The 
possible 
side 
effects 
of naltrexone 
in 
individuals with 
opioid 
dependence 
may 
include: a period 

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of more severe withdrawal symptoms due to precipitated withdrawal, difficulty sleeping, anxiety, 
nervousness, 
abdominal 
pain/cramps, 
nausea 
and/or 
vomiting, low energy, joint muscle pain, and 
headaches. Less common side effects include loss of appetite, diarrhea, constipation, increased 
thirst, increased energy, feeling down, irritability, dizziness, skin rash, delayed ejaculation and 
chills. 
Naltrexone has been associated with reversible hepatocellular injury indicated by elevated liver 
enzymes when administered at doses substantially greater than the 50mg per day dose 
recommended for maintenance treatment of OUD and proposed for the present study. 
When 
used 
in the recommended dose range in opiate-dependent patients, this risk is remote (Brahen et al., 
1988). Naltrexone is therefore contraindicated in patients with acute hepatitis or liver failure, and 
such patients are excluded from the study. Patients with hepatic enzyme levels greater than 5 
times the upper limit of normal are therefore excluded. 
In the event of a medical emergency requiring opiate analgesia, an individual on naltrexone will 
require higher doses of opiates than normally administered. Participants will be informed of this 
and will be given a naltrexone medication card to carry in their wallet. 
Naltrexone does not block intoxicating effects of other drugs such as cocaine, sedatives, or 
alcohol and it does not reduce the risk of using these substances. 
Risks of Opioid Withdrawal 
During 
XR-NTX 
induction 
procedure, 
participants 
are 
likely 
to 
experience 
mild 
to 
moderate severity 
opioid withdrawal, and it is possible that the withdrawal will be more severe in the group receiving 
Rapid XR-NTX induction. Opioid withdrawal may cause agitation, bone and joint aches, 
restlessness, runny nose and tearing, nausea, vomiting, diarrhea, anxiety or irritability, elevated 
pulse and blood pressure and other signs of sympathetic arousal, and sometimes confusion. 
Adjunctive medications will be used to alleviate the severity of withdrawal. 
Risks of Ancillary Medications 
Opioid withdrawal symptoms are treated with clonidine, an alpha-2-adrenergic receptor agonist 
which reduces sympathetic nervous system output produced 
by 
opiate withdrawal; clonazepam, a 
benzodiazepine which reduces the anxiety and dysphoria and permits sleep; and zolpidem or 
trazodone for insomnia. Clonidine may produce somnolence, dry mouth, drowsiness, dizziness, 
constipation, hypotension, syncope, bradycardia and QT prolongation. Clonazepam commonly 
may 
produce 
somnolence, 
poor 
muscle 
control, 
loss of inhibition, constipation, respiratory infection 
and infection. Trazodone may produce drowsiness, sedation, dizziness, constipation, and blurred 
vision. Zolpidem may produce drowsiness, sedation, and headache. The procedure is conducted 
in an inpatient setting with a medical professional present at all times, to permit close monitoring 
of vital signs and mental status. 
Risks of XR-NTX injection 
Risk of XR-NTX injection involves possible irritation at the injection site.  XR-NTX injections may 
be followed by a period of, suicidal thoughts, pain, 
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abscess, sterile abscess, and pruritus. Cases of serious injection site reactions, some of which 
involved surgical intervention, have been reported. 
3.0 
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. 
4.0 
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 and quality 
assurance activities on study data collected from all participating sites, and 6) perform data 
cleaning activities prior to the final study database lock for assessments collected in Advantage 
eClinical. 
A. 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 a final set of guided 
source 
documents with instructions for completion. Data will be entered into Advantage eClinical in 
accordance with the instructions provided during protocol-specific training and guidelines 
established by the DSC. Data entry into the eCRFs will be performed by authorized individuals 
who have satisfactorily completed the relevant training. Selected source documents and eCRFs 
may also require the investigator’s signature (wet or electronic). In some situations, data collected 
on source documents will not be entered into Advantage eClinical, but when it is entered, it will 
follow the guidelines stated above. 
The Principal Investigator at the site is responsible for maintaining accurate, complete and up-to-
date research records. In addition, the Principal Investigator is responsible for ensuring the timely 
completion of eCRFs for each research participant. 
B. DATA MONITORING, CLEANING AND EDITING 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and missing 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 queries by entering all corrections and changes directly 
into Advantage eClinical or by verifying the data are correct as is. 
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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. 
Trial progress and data status reports, which provide information on items such as recruitment, 
availability of primary outcome data, 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 staff, local Node staff, the Lead Investigator, the coordinating 
centers, and NIDA CCTN, to monitor each site’s progress on the study. 
C. DATABASE LOCK AND TRANSFER 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DSC. Individual participants and their research 
data will be identified by a unique study identification number; further, some identifiable data may 
be collected in eClinical. The study data entry and study management systems used by clinical 
sites and by DSC staff will be secured and password protected in compliance with regulatory 
standards. 
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 raw datasets will be 
transferred to the Lead Investigator or designee. De-identified versions of these datasets will also 
be provided to the NIDA CCTN-designated party for storage and archiving. These datasets may 
be posted on the NIDA Data Share 
website. 
Reference: http://grants.nih.gov/grants/guide/notice-files/not98-084.html