NIDA (National Institute on Drug Abuse) CTN (Clinical Trials Network) Protocol 0068: Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for Methamphetamine Use Disorder
Phase: PHASE3
Conditions: Methamphetamine Use Disorder
Sponsor: University of Texas Southwestern Medical Center

 
 
NCT03078075 
 
PROTOCOL 
 
Title: NIDA CTN-0068 Accelerated Development of 
Additive Pharmacotherapy Treatment (ADAPT-2) for 
Methamphetamine Use Disorder 
Version 6.0 
Date: January 31, 2019 
 

 
 
NIDA CTN Protocol 0068 
Accelerated Development of Additive 
Pharmacotherapy Treatment (ADAPT-2) 
for Methamphetamine Use Disorder 
 
 
 
Lead Investigator (LI): Madhukar Trivedi, MD 
 
 
 
Version 6.0 
 
January 31, 2019 
 
 
Details regarding the timing of re-randomization and related statistical analysis (as it 
contains information about the timing of re-randomization) are omitted from the 
Protocol to protect the double blind. These details are contained in the confidential 
Statistical Analysis Plan. The Lead Team will provide the Statistical Analysis Plan 
directly to the site Institutional Review Board(s) or Independent Ethics Committee. 
 

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PROTOCOL DEVELOPMENT TEAM 
 
 
Lead Investigator: 
Madhukar Trivedi, MD  
 
Texas Node 
 
University of Texas Southwestern Medical Center 
 
Co-Lead Investigator & 
Robrina Walker, PhD 
Project Director: 
Texas Node 
 
University of Texas Southwestern Medical Center 
 
Co-Investigators: 
Walter Ling, MD 
 
Adriane de la Cruz, MD, PhD 
 
Protocol Development Team: 
Linda Chang, MD 
 
Mora Kim, MPH 
 
CCTN Project Coordinators: 
Udi Ghitza, PhD 
 
National Institute on Drug Abuse 
 
 
Petra Jacobs, MD 
 
National Institute on Drug Abuse 
 
Clinical Coordinating Center: 
Robert Lindblad, MD 
 
CCC Principal Investigator 
 
 
Eve Jelstrom, CRNA, MBA 
 
CCC Co-Principal Investigator 
 
 
Prashanth Parmar, MS 
 
Protocol Specialist 
 
Data Coordinating Center:  
Paul Van Veldhuisen, PhD 
 
DSC Principal Investigator 
 
 
 
Gaurav Sharma, PhD 
 
DSC Statistician 
 
 
Lauren Yesko 
 
DSC Project Manager 
 
 
Ashley Case 
 
DSC Data Manager 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 
LIST OF ABBREVIATIONS ............................................................................................ 7 
2.0 
SCHEMA ......................................................................................................................... 8 
3.0 
SYNOPSIS ...................................................................................................................... 9 
4.0 
BACKGROUND AND RATIONALE .............................................................................. 11 
4.1 
Background ............................................................................................................... 11 
4.1.1 
Treatment of Stimulant Use Disorder (Amphetamine-type) with Naltrexone ....... 11 
4.1.2 
Figure 1. Percentages of Urine Samples Negative for MA ................................. 12 
4.1.3 
Treatment of Stimulant Use Disorder (Amphetamine-type) with Bupropion ........ 13 
4.1.4 
Figure 2. Abstinence for the last two weeks among non-daily MA users ............ 15 
4.1.5 
Figure 3. Weekly Abstinence Rates for Light Users versus Heavy Users ........... 15 
4.2 
Study Rationale ......................................................................................................... 16 
4.3 
Significance of the Project to the Field ...................................................................... 17 
5.0 
OBJECTIVES ................................................................................................................ 18 
5.1 
Primary Objectives .................................................................................................... 18 
5.2 
Secondary Objectives ............................................................................................... 18 
6.0 
DESIGN ........................................................................................................................ 19 
6.1 
Overview of Study Design ......................................................................................... 19 
6.2 
Duration of Study and Clinic Visit Schedule............................................................... 19 
6.3 
Participant Selection ................................................................................................. 20 
6.3.1 
Inclusion Criteria ................................................................................................ 20 
6.3.2 
Exclusion Criteria ............................................................................................... 21 
6.4 
Site Selection ............................................................................................................ 22 
6.4.1 
Site Characteristics ............................................................................................ 22 
6.4.2 
Rationale for Site Selection ................................................................................ 23 
6.5 
Randomization Plan .................................................................................................. 23 
6.6 
Study Intervention ..................................................................................................... 23 
6.7 
Outcome Measures ................................................................................................... 24 
6.7.1 
Primary Efficacy Outcome Measure ................................................................... 24 
6.7.2 
Primary Safety Outcome Measure ..................................................................... 24 
6.7.3 
Secondary Outcome Measures .......................................................................... 24 
7.0 
PROCEDURES ............................................................................................................. 26 
7.1 
Screening and Baseline Phase ................................................................................. 26 
7.1.1 
Pre-screening Assessment ................................................................................ 26 
7.1.2 
Informed Consent .............................................................................................. 26 
7.1.3 
Screening and Baseline Assessments ............................................................... 26 
7.1.4 
Naltrexone Pre-Induction Strategy ..................................................................... 27 
7.1.5 
Final Confirmation of Eligibility ........................................................................... 28 
7.2 
Medication Phase...................................................................................................... 28 
7.2.1 
Randomization ................................................................................................... 28 

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7.2.2 
Pharmacotherapy............................................................................................... 28 
7.2.3 
Medical Management ......................................................................................... 29 
7.2.4 
Medication Adherence ....................................................................................... 29 
7.2.5 
Participant Medication Withdrawal ..................................................................... 29 
7.2.6 
Medication Phase Visits ..................................................................................... 31 
7.3 
Follow-up Phase ....................................................................................................... 31 
7.3.1 
Oral Study Medication Taper.............................................................................. 31 
7.3.2 
Post-Medication Phase Follow-up Visits ............................................................ 31 
7.4 
Study Medication Management/Drug Accountability .................................................. 31 
7.4.1 
Documentation ................................................................................................... 31 
7.4.2 
Storage .............................................................................................................. 31 
7.4.3 
Packaging .......................................................................................................... 32 
7.4.4 
Ordering and Dispensing ................................................................................... 33 
7.4.5 
Used/Unused Medication ................................................................................... 33 
7.4.6 
Lost Medication .................................................................................................. 33 
7.4.7 
Maintaining and Breaking Blind .......................................................................... 33 
7.5 
Participant Compensation ......................................................................................... 34 
7.5.1 
Table 1. Compensation Schedule ...................................................................... 34 
8.0 
ASSESSMENTS ........................................................................................................... 36 
8.1 
Table 2. Schedule of Assessments ........................................................................... 37 
8.2 
Screening Measures ................................................................................................. 38 
8.2.1 
Pre-Screening Interview Form............................................................................ 38 
8.2.2 
Informed Consent .............................................................................................. 38 
8.2.3 
Demographics Form .......................................................................................... 38 
8.2.4 
Alcohol and Substance Use History ................................................................... 38 
8.2.5 
DSM-5 Checklist ................................................................................................ 38 
8.2.6 
Psychiatric Diagnostic Screening Questionnaire ................................................ 38 
8.2.7 
Self-Report of HIV Testing ................................................................................. 38 
8.2.8 
Medical and Psychiatric History ......................................................................... 39 
8.3 
Safety Measures ....................................................................................................... 39 
8.3.1 
Physical Examination ......................................................................................... 39 
8.3.2 
Electrocardiogram (ECG) ................................................................................... 39 
8.3.3 
Injection Site Examination .................................................................................. 39 
8.3.4 
Injection Site Abnormality Log ............................................................................ 39 
8.3.5 
Clinical Laboratory Tests .................................................................................... 39 
8.3.6 
Concise Health Risk Tracking - Participant Rated Module ................................. 40 
8.3.7 
Pregnancy and Birth Control Assessment .......................................................... 40 
8.3.8 
Vital Signs .......................................................................................................... 40 
8.3.9 
Prior and Concomitant Medications ................................................................... 40 
8.3.10 
Adverse Events (AEs) and Serious Adverse Events (SAEs) .............................. 40 
8.3.11 
Naloxone Challenge Form ................................................................................. 41 

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8.4 
Efficacy Measures ..................................................................................................... 41 
8.4.1 
Urine Drug Screen ............................................................................................. 41 
8.4.2 
Timeline Followback .......................................................................................... 41 
8.4.3 
Visual Analog Craving Scale .............................................................................. 42 
8.4.4 
Patient Health Questionnaire-9 .......................................................................... 42 
8.4.5 
Treatment Effectiveness Assessment ................................................................ 42 
8.4.6 
Tobacco Use History .......................................................................................... 42 
8.4.7 
Quality of Life ..................................................................................................... 42 
8.4.8 
Sexual Risk Behaviors ....................................................................................... 42 
8.4.9 
Genetic Sampling............................................................................................... 42 
8.5 
Adherence Measures ................................................................................................ 43 
8.5.1 
Study Medication Dosing Logs ........................................................................... 43 
8.5.2 
Injection Administration Form ............................................................................. 43 
8.5.3 
Oral Medication Dispensation Form ................................................................... 43 
8.5.4 
Oral Study Medication Blood Levels................................................................... 43 
8.5.5 
Video Based Adherence to Oral Study Medication Database ............................. 43 
8.5.6 
End of Medication Form ..................................................................................... 43 
8.6 
Administrative and Other Forms ................................................................................ 44 
8.6.1 
Locator Form ..................................................................................................... 44 
8.6.2 
Eligibility - Randomization .................................................................................. 44 
8.6.3 
Missed Visit Form .............................................................................................. 44 
8.6.4 
Protocol Deviation Form ..................................................................................... 44 
8.6.5 
Protocol Satisfaction Surveys............................................................................. 44 
8.6.6 
Study Completion Form ..................................................................................... 44 
9.0 
TRAINING ..................................................................................................................... 45 
10.0 
STATISTICAL ANALYSES ........................................................................................... 46 
10.1 
General Design ......................................................................................................... 46 
10.1.1 
Study Hypothesis ............................................................................................... 46 
10.1.2 
Sample Size ....................................................................................................... 46 
10.1.3 
Primary Outcomes ............................................................................................. 46 
10.1.4 
Secondary Outcomes ........................................................................................ 46 
10.2 
Interim Analyses ....................................................................................................... 47 
10.2.1 
Sample Size Re-estimation ................................................................................ 47 
10.2.2 
Interim Monitoring of Primary Efficacy Endpoint ................................................. 48 
10.2.3 
Safety Interim Analyses ..................................................................................... 48 
10.2.4 
Conditional Power and Futility ............................................................................ 48 
10.3 
Demographic and Baseline Characteristics ............................................................... 49 
10.4 
Description of Plans to Conduct Analyses of Study Results by Sex and 
Race/Ethnicity ........................................................................................................... 49 
10.5 
Safety Analysis ......................................................................................................... 49 
11.0 
REGULATORY COMPLIANCE, REPORTING AND MONITORING ............................. 50 

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11.1 
Statement of Compliance .......................................................................................... 50 
11.2 
Institutional Review Board Approval .......................................................................... 50 
11.3 
Research Advisory Panel of California (California sites only) .................................... 50 
11.4 
Informed Consent...................................................................................................... 50 
11.5 
Health Insurance Portability Accountability Act (HIPAA) ............................................ 51 
11.6 
Investigator Assurances ............................................................................................ 51 
11.7 
Financial Disclosure .................................................................................................. 51 
11.8 
Confidentiality ........................................................................................................... 52 
11.9 
IND Requirements ..................................................................................................... 52 
11.10 Regulatory Files ........................................................................................................ 52 
11.11 Study Documentation ................................................................................................ 53 
11.12 Records Retention and Requirements ....................................................................... 53 
11.13 Reporting to Sponsor ................................................................................................ 53 
11.14 Safety Monitoring ...................................................................................................... 53 
11.14.1 
Adverse Events (AEs) ........................................................................................ 53 
11.14.2 
Definitions of Adverse Events and Serious Adverse Events ............................... 54 
11.14.3 
Reportable Adverse Events and Serious Adverse Events .................................. 54 
11.14.4 
Data and Safety Monitoring Board (DSMB) ........................................................ 54 
11.14.5 
Medical Monitor ................................................................................................. 54 
11.15 Protocol Deviations: Reporting and Management...................................................... 55 
11.16 Audits ........................................................................................................................ 55 
11.17 Quality Assurance Monitoring ................................................................................... 55 
12.0 
DATA MANAGEMENT AND PROCEDURES ............................................................... 57 
12.1 
Design and Development .......................................................................................... 57 
12.2 
Site Responsibilities .................................................................................................. 57 
12.3 
Data and Statistics Center Responsibilities ............................................................... 57 
12.4 
Data Collection and Entry .......................................................................................... 57 
12.5 
Data Monitoring, Cleaning, and Editing ..................................................................... 57 
12.6 
Database Transfer and Lock ..................................................................................... 58 
13.0 
PUBLICATIONS AND OTHER RIGHTS ....................................................................... 59 
14.0 
SIGNATURES ............................................................................................................... 60 
15.0 
REFERENCES .............................................................................................................. 61 
16.0 
APPENDIX A - Adverse Event Reporting Definitions and Procedures .................... 67 
17.0 
APPENDIX B - Data and Safety Monitoring Plan ....................................................... 71 
18.0 
APPENDIX C - Smartphone App-based Medication Adherence Procedures .......... 76 
 
 

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1.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AMC 
Active Medication Combination 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BL 
Blood levels of bupropion and/or metabolite 
BUP-XL 
Extended-release Bupropion  
CAP 
College of American Pathologists 
CCC 
Clinical Coordinating Center 
CCTN 
Center for the Clinical Trials Network 
CHRT 
Concise Health Risk Tracking 
CLIA 
Clinical Laboratory Improvement Amendment of 1988 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CTN 
Clinical Trials Network 
DSC 
Data and Statistics Center 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture system/Advantage eClinical 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
HIV 
Human Immunodeficiency Virus  
ICH 
International Council on Harmonisation 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IND 
Investigational New Drug 
iPLB 
Injectable Placebo 
LFT 
Liver Function Test 
LN 
Lead Node 
MA 
Methamphetamine 
Mg 
Milligrams 
NAL 
Naloxone 
NDA 
New Drug Application 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
oPLB 
Oral Placebo 
PCM 
Prior and Concomitant Medications 
PDSQ 
Psychiatric Diagnostic Screening Questionnaire 
PI 
Principal Investigator 
PLB 
Placebo Medication Combination 
RAP-C 
Research Advisory Panel of California 
SRB 
Sexual Risk Behaviors  
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
TEA 
Treatment Effectiveness Assessment 
TES 
Treatment Effectiveness Score 
TLFB 
Timeline Followback 
UDS 
Urine Drug Screen 
VAS 
Visual Analog Scale 
XR-NTX 
Extended-Release Naltrexone (as Vivitrol®) 

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2.0 
SCHEMA 
 

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3.0 
SYNOPSIS 
STUDY OBJECTIVE: The primary objective of this study is to evaluate the efficacy of extended-
release naltrexone plus bupropion as a combination pharmacotherapy for methamphetamine use 
disorder. Secondary objectives include assessing the safety of naltrexone plus bupropion and 
determining the efficacy of the combination pharmacotherapy on other substance use outcomes, 
on depression symptom scores, and on quality of life ratings. 
STUDY DESIGN: This is a double-blind, placebo-controlled, adaptive randomized clinical trial in 
which 400 individuals with moderate or severe methamphetamine use disorder will be randomly 
assigned to the 1) active medication combination (AMC) arm in which injections of extended-
release naltrexone (XR-NTX; as Vivitrol®) plus once daily oral extended-release bupropion (BUP-
XL) tablets will be provided or the 2) matching placebo (PLB) arm in which injections of placebo 
(iPLB) and once daily oral placebo (oPLB) tablets will be provided. During the course of the study, 
participants may or may not be switched to another arm, as determined by the a priori adaptive 
aspect of the study design. Participants appearing to respond well to their original treatment 
assignment will not be switched. Overall, approximately 50% of the participants will receive the 
AMC. After establishing eligibility during a maximum 21-day screening period, participants will 
begin the 12-week medication phase. Randomization will be stratified by site. At the end of the 
12-week medication phase, participants will complete a follow-up phase, including an oral 
medication taper. Post-medication phase follow-up visits will occur during Weeks 13 and 16.  
STUDY PARTICIPANTS: The study sample consists of 400 males and non-pregnant, non-
lactating females, ages 18 to 65 years old, who have met all eligibility criteria, including DSM-5 
criteria for moderate or severe stimulant use disorder (methamphetamine type), who report using 
methamphetamine 18 or more days during the 30 days prior to signing consent, and who provide 
at least 2 methamphetamine-positive urine specimens during screening. Potential participants 
have up to 3 weeks to meet eligibility criteria after signing consent.  
INTERVENTION: The study intervention consists of a 12-week medication phase. Participants 
randomized to the AMC arm will receive injections of extended-release naltrexone (Vivitrol®) plus 
450 mg of once-daily oral extended-release bupropion tablets while participants randomized to 
the PLB arm will receive placebo injections plus once-daily oral placebo tablets. Injectable study 
medication will be administered every three weeks (weeks 1, 4, 7, and 10). Take-home oral study 
medication will be dispensed once weekly for dosing on non-clinic days. Once weekly medical 
management sessions with the study medical clinician will be provided. Medication adherence 
procedures will include smartphone app-based videos of daily dosing. Participants will be asked 
to attend clinic twice weekly for observed oral study medication dosing, collection of urine drug 
screening samples, and self-report assessments. Compensation will be provided for visit 
attendance and dosing adherence.  
ASSESSMENTS: Screening/baseline assessments include safety and medical measures 
including a medical and psychiatric history, a physical examination, clinical lab tests (blood 
chemistry, hematology, and urinalysis), 12-lead electrocardiogram, vital signs, and pregnancy 
tests (for females). Screening/baseline assessments also include psychological and drug use 
measures. Methamphetamine use outcome assessments include Urine Drug Screens (UDS), 
self-reported use via the Timeline Followback (TLFB), and Visual Analog Scale (VAS) craving 
scores. Other outcome assessments include UDS and TLFB (i.e., alcohol, tobacco, and/or illicit 
drugs), depression (Patient Health Questionnaire-9), quality of life (QOL), functioning (Treatment 
Effectiveness Assessment), and clinic attendance. Safety measures include monitoring vital 
signs, adverse events (AEs), concomitant medications, clinical lab results, and assessments of 
suicidality. Oral study medication adherence will be assessed by self-report, quantitative blood 
levels of bupropion and its primary metabolite, and smartphone app-based dosing confirmation 
procedures. 

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A blood sample for genetic analysis will be collected from randomized participants who consent 
to this procedure and the de-identified sample will be sent to a cell and DNA repository. 
ANALYSES: The primary analysis will evaluate the impact of the AMC arm, relative to PLB, on 
methamphetamine use. The primary efficacy outcome is a measurement of treatment response 
based on MA-negative urine drug screen results obtained during weeks 5 to 6 and weeks 11 to 
12 of the medication phase. Outcome variables will be analyzed using appropriate statistical 
methods for the intention-to-treat (ITT) population and for the evaluable population.  

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4.0 
BACKGROUND AND RATIONALE 
4.1 
Background 
Many years of concerted efforts have produced no effective medication to help initiate and 
maintain abstinence from methamphetamine (MA). Several promising candidates have shown 
preliminary clinical utility, including bupropion and naltrexone (Elkashef et al., 2008; Jayaram-
Lindström et al., 2008b). Development of a safe and effective pharmacotherapy is an important 
objective with considerable public health significance.  
For many medical conditions, combinations of medications may be routine in clinical practice but 
are emerging only recently for methamphetamine pharmacotherapy. Well-publicized combination 
pharmacotherapy studies have tested combination medications for depression (CO-MED, Zisook 
et al., 2011; STAR-D, Trivedi et al., 2006) made possible by the availability of a number of 
medications approved for depression. Two notable attempts within the National Institute on Drug 
Abuse National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) include the Cocaine 
Use Reduction with Buprenorphine (CTN-0048 CURB) trial, a Vivitrol+Suboxone combination trial 
for cocaine dependence (Ling et al., 2016; Mooney et al., 2013), and the Accelerated 
Development of Additive Pharmacotherapy Treatment (CTN-0054 ADAPT) pilot trial completed 
in early 2015 that examined the combination pharmacotherapy naltrexone plus bupropion for MA 
use disorder in an open-label design (Mooney et al., 2016). Findings from the ADAPT pilot study 
provided a signal sufficient to advise the development of a fully powered, placebo-controlled study 
to test the efficacy of the combination in producing sustained abstinence from methamphetamine 
at the end of the study (see below). 
4.1.1 
Treatment of Stimulant Use Disorder (Amphetamine-type) with 
Naltrexone 
There is modest research to support the individual constituents of the combination 
pharmacotherapy of naltrexone and bupropion as a putative treatment for MA use disorder. 
Naltrexone mechanism of action: An early human laboratory study provided some evidence for 
modulation of the opioid system as the mechanism of action of naltrexone in its ability to reduce 
reinforcing effects of amphetamine (Jayaram-Lindström et al., 2005). Although not completely 
clear, the action of naltrexone that may work to reduce the reinforcing effects of alcohol and other 
drugs appears to derive from a blockade of effects of endogenous opioid peptides by occupation 
and binding of opioid receptors. A retrospective pooled data analysis of three studies examining 
alcohol dependent participants with single nucleotide polymorphism (SNP) A118G (heterozygous 
or homozygous) found that participants treated with naltrexone were substantially less likely to 
relapse (Oslin et al., 2003). However, one small randomized trial showed no difference in 
outcomes along this SNP (A118A vs. A118G) when prospectively assigning individuals to open-
label injectable naltrexone treatment for methamphetamine dependence (Pal et al., 2015). More 
recent controlled human laboratory data show that compared to placebo, steady state naltrexone 
at 50 mg per day significantly blunted cue-induced craving for methamphetamine and attenuated 
several of the hedonic subjective effects of methamphetamine, including craving, during 
administration of 30 mg IV methamphetamine challenge. Specifically, naltrexone decreased 
subjective ratings of "crave drug," "stimulated," and "would like drug access," decreased the post 
methamphetamine administration time course of "anxious," and increased ratings of "bad drug 
effects," as compared to placebo (Ray et al., 2015). There is no aversive response to 
administration of opioids or alcohol while naltrexone is present at clinical dosages. 
Efficacy of naltrexone in treating stimulant use disorders: A study conducted in Sweden 
(Jayaram-Lindström, 2008b) indicated that naltrexone reduced amphetamine use among human 

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subjects, though this efficacy was tested only for patients who could achieve two weeks of 
abstinence during the baseline screening period. Previously, efficacy of naltrexone for stimulant 
use disorder was found by Schmitz et al. (2001), reporting cocaine use decreased over time 
among cocaine-dependent patients taking 50 mg oral naltrexone compared to placebo. A 
question persists as to whether similar reductions can be expected among polydrug users, as the 
same authors subsequently found no effect on drug use among a sample of alcohol- and cocaine-
dependent individuals treated with 50 mg/day (Schmitz et al., 2004). In contrast, Comer et al. 
(2006), in a study of combination opioid and stimulant abusers, found that cocaine use was 
reduced among the portion of the sample randomized to 384 mg of sustained-release naltrexone, 
virtually the same dosage of the extended-release formulation to be used in this protocol.  
Efficacy of naltrexone in treating amphetamine dependent individuals: The clinical data 
emerging from research examining oral naltrexone in amphetamine dependent humans in 
Sweden provide convincing rationale for the exploration of naltrexone for MA dependence. 
Jayaram-Lindström and colleagues (2005) established tolerability and feasibility of naltrexone in 
an open-label trial, finding mild and transient side effects (nausea, headache, abdominal pains) 
and documenting reduced frequency and quantity of amphetamine use during treatment than 
before naltrexone treatment. Furthermore, in a double-blind trial, the same Swedish group 
(Jayaram-Lindström et al., 2008a) found that naltrexone reduced subjective effects of 
amphetamine. Subsequent work (Jayaram-Lindström et al., 2008b) found that oral naltrexone 
was effective in suppressing relapse to stimulant use among individuals meeting DSM-IV criteria 
for amphetamine dependence. While the current study protocol was being developed, a double-
blind, randomized, placebo-controlled trial (NCT01449565) of the injectable form of naltrexone 
was being conducted in San Francisco among methamphetamine dependent men who have sex 
with men (Coffin et al., 2017). Participants were assigned to extended-release injectable 
naltrexone (n=50) or matched placebo (n=50), administered every 4 weeks for a 12-week period. 
All participants reduced their methamphetamine use, as evidenced by urine drug screens, during 
the primary outcome evaluation period of intervention weeks 2 to 12; however, there were no 
significant differences by intervention arm. Therefore, this recent study does not provide support 
for the clinical benefit of the use of naltrexone alone as a treatment for methamphetamine 
dependence in men who have sex with men and who use methamphetamine during sex. Notably, 
study participants had excellent medication adherence, which lends support to the acceptability 
and tolerability of this medication in a methamphetamine dependent sample.  
Figure 1, from Jayaram-Lindström et al. (2008b), shows percentages of urine samples negative 
for MA, presented in the figure on the left in the intention-to-treat sample—for the naltrexone group 
(diamonds) versus the placebo group (circles)—and for the completer group in the right figure. 
4.1.2 
Figure 1. Percentages of Urine Samples Negative for MA 
 
The rationale for including extended-release injectable naltrexone (XR-NTX) in the original CTN-
0054 trial was based on preclinical and clinical pharmacology, as well as on results of clinical 

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trials using oral naltrexone in the treatment of amphetamine dependent individuals. Opiate 
antagonists, particularly naltrexone, have been shown to reduce amphetamine-induced dopamine 
release and amphetamine-induced locomotor activity in rats (Hitzemann et al., 1982), attenuate 
amphetamine-induced locomotor sensitization in rats (Haggkvist et al., 2011a), reduce cue-
induced reinstatement for MA in rats (Anggadiredja et al., 2004), block amphetamine-induced 
reinstatement of amphetamine self-administration in rats (Haggkvist et al., 2009), reduce the 
subjective effects of amphetamine in amphetamine-dependent patients (Jayaram-Lindström et 
al., 2008a), and prevent relapse to amphetamine in a double-blind, placebo-controlled trial 
(Jayaram-Lindström et al., 2008b). The progression of work logically extends from research on 
preclinical effects of opiate antagonists, to a clinical pharmacology demonstration of attenuation 
of amphetamine by naltrexone, to an outpatient efficacy study, then to the CTN-0054 combination 
medication trial on which the present trial is based.  
4.1.3 
Treatment of Stimulant Use Disorder (Amphetamine-type) with 
Bupropion 
Bupropion is an antidepressant with stimulant properties that has been proven effective for the 
treatment of nicotine dependence (Richmond & Zwar, 2003). The antidepressant effects of 
bupropion may be related to its noradrenergic and dopaminergic mechanisms of action. 
Bupropion has a favorable side effect profile: it causes fewer anticholinergic, cardiovascular, 
sedative or adverse sexual effects than tricyclics and does not cause weight gain (Bryant, 
Guernsy, & Ingram, 1983). Bupropion has been studied as an attractive candidate medication for 
the treatment of stimulant use disorder, which is associated with dopaminergic dysregulation that 
may contribute to craving and drug seeking. Restoration of dopamine deficit states, combined 
with bupropion’s ability to alleviate dysphoria observed in early abstinence from stimulants 
(Newton et al., 2004), may in turn reduce craving and help prevent relapse. 
Bupropion has been investigated as a treatment for cocaine use disorder. In a pilot study, Margolin 
et al. (1991) found that 300 mg/day bupropion substantially reduced cocaine use in four of the 
five cocaine-dependent, methadone-maintained patients, was well tolerated, and reduced self-
reported craving for cocaine. A multicenter placebo-controlled double-blind clinical trial of 
bupropion for cocaine dependence in methadone-maintained patients indicated efficacy of 
bupropion for the subgroup of patients with depression at study entry (Margolin et al., 1995). 
The results of preclinical studies designed to test the effectiveness of bupropion to block effects 
of MA support clinical use for the treatment of MA dependence (Kim et al., 2000). Bupropion 
provides complete protection against MA-induced decrease in dopamine uptake in the striatum in 
an in vitro model of MA-induced dopamine nerve terminal toxicity. The combination of bupropion’s 
dopaminergic activity and antidepressant properties may enhance its efficacy in the treatment 
and relief of the signs and symptoms of MA withdrawal and for reduction of relapse.  
In a Phase 1 double-blind inpatient clinical laboratory study, 26 subjects with a DSM-IV diagnosis 
of MA dependence or abuse were randomized to receive either twice-daily bupropion XL (150 mg 
twice daily) or placebo control and a series of 3 infusions of saline or MA. The first and second 
infusions were randomized to be either 0 mg or 15 mg of either saline or MA, and the last infusion 
was always 30 mg of saline or MA (Newton et al., 2006). Of the 26 subjects enrolled, 20 completed 
the entire study, with 10 subjects in each of the bupropion and placebo control groups. Bupropion 
treatment 
was 
associated 
with 
reduced 
ratings 
of 
“any 
drug 
effect”  
(p = 0.02), and “high” (p = 0.02) as assessed with visual analog scales following MA 
administration. Bupropion also significantly reduced cue-induced craving [General Craving Scale 
total score (p = 0.002); Behavioral Intention subscale (p = 0.001)] (Newton et al., 2006). Bupropion 
treatment was well tolerated, with the bupropion- and placebo-treated groups reporting similar 
rates of adverse events. MA administration was associated with expected stimulant 
cardiovascular effects, and these were not accentuated by bupropion treatment. Instead, there 

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was a trend for bupropion to reduce MA-associated blood pressure increases and a statistically 
significant reduction in MA-associated heart rate increases (Newton et al., 2005). 
Pharmacokinetic analysis revealed that bupropion treatment reduced the plasma clearance of MA 
and lowered plasma concentrations of the metabolite amphetamine in the plasma (Newton et al., 
2005). MA administration did not alter the peak and trough plasma concentrations of bupropion 
or its metabolites.  
A NIDA Phase 2 efficacy study showed that bupropion significantly decreased MA use in MA-
dependent participants who were using MA 18 days or less in the 30-day period prior to the start 
of screening (Elkashef et al., 2008). This study was a double-blind, placebo-controlled, 
randomized, two-arm, parallel-group design comparing 150 mg of bupropion to placebo 
administered twice daily to MA dependent outpatients. Of the 151 participants in the ITT sample, 
121 were considered evaluable. Conclusions regarding the efficacy of bupropion include: 
 
Results of analysis of the primary outcome measure (weekly proportion of participants 
with all urine specimens free of MA) showed a trend, albeit statistically non-significant, 
favoring bupropion over placebo for the entire population (GEE, p = 0.09). 
 
Bupropion showed a statistically significant effect for MA-free weeks in participants who 
used MA <18 days in the 30 days prior to the start of screening (GEE, p = 0.03). 
 
A higher percentage of participants in the bupropion group than the placebo group 
reduced their proportion of MA use days to 50% or less of their baseline rate based on 
self-report only (Chi-square test, p = 0.02).  
 
Bupropion showed a statistically significant effect for MA-free weeks in males  
(GEE, p = 0.04). 
 
Bupropion showed a trend toward significance favoring bupropion for MA-free weeks in 
non-depressed participants (GEE, p = 0.08). 
 
Bupropion showed a statistically significant effect for MA-free weeks in participants 
without attention-deficit disorder (GEE, p = 0.02). 
Participants were randomized to receive thrice-weekly CBT and either 150 mg twice daily 
bupropion SR or placebo. Randomization was balanced by frequency of self-reported MA use in 
the 30 days prior to the start of screening based on two rates of use: 1) low-rate users had 18 or 
fewer days of MA use; and 2) high-rate users had 19 or more days of MA use. Of the ITT sample, 
47% were low-rate users and 53% were high-rate users. A GEE analysis performed on the 
primary outcome measure for each of these two study subpopulations as well as for the entire 
ITT sample showed that the low-rate use group administered bupropion had a statistically 
significant increase (GEE, p<0.04) in the slope of weekly proportion of participants with MA-
negative urines compared to the low-rate use group administered placebo. The high rate of MA 
use appears to reduce the bupropion effect when examining the entire study population. 
Figure 2 illustrates the frequency of abstinence over the last two weeks in non-daily MA users in 
the bupropion study, in which 15 of 63 subjects (23.8%) achieved abstinence as compared to 3 
of 53 (5.7%) in the placebo group. This finding was shown to be statistically significant (Chi-
square, p=0.01). Although there was a fairly high dropout rate over the course of the study 
(approximately 50% of the participants completed the study), it is important to note that there were 
no significant differences in the rate of dropout between the two groups. 

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4.1.4 
Figure 2. Abstinence for the last two weeks among non-daily MA 
users 
 
Abstinence Last 2 Weeks 
Group 
Fail (%) 
Success (%) 
Total 
Bupropion 
48 (76.2%) 
15 (23.8%) 
63 
Placebo 
50 (94.3%) 
3 (5.7%) 
53 
 
98 
18 
116 
 
P = 0.01 (Chi-Square test) 
 
Bupropion was well tolerated in this study. The only significant treatment emergent adverse event 
was nausea. Participants receiving bupropion had a significant increase (Chi-square, p=0.019) in 
the incidence of nausea over the intervention period. One participant (a 31-year-old female) in 
the bupropion group temporarily discontinued taking bupropion during the study due to an adverse 
event four weeks after commencing study drug, but the investigator determined that the adverse 
event was not related to the study drug. 
 
Figure 3 is from Elkashef et al., 2008, showing the relative effects on MA use comparing 
participants who had reported 18 days or less of use per month at baseline (“light users”) against 
participants who had used more than 18 days per month (“heavy users”). 
4.1.5 
Figure 3. Weekly Abstinence Rates for Light Users versus 
Heavy Users 
 
To conclude, this study suggested efficacy of bupropion only in participants who had used 
methamphetamine relatively infrequently at baseline. However, in the Mooney et al. (2016) study, 
the medication combination of once-daily 450 mg bupropion XL and extended-release injectable 
naltrexone resulted in a clinically-meaningful outcome in terms of proportion of methamphetamine 
dependent participants who met “responder” criteria. Unlike in the Elkashef et al. (2008) study, 

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these “responders” were participants who had used methamphetamine frequently, having self-
reported at least 20 days of MA use in the 30 days prior to consent, and having submitted 3 MA-
positive urine drug screens out of 4 collected during screening. Thus, the 450 mg dose of 
bupropion XL used in the Mooney et al. (2016) trial merits further evaluation in a sufficiently 
powered, randomized, placebo-controlled trial. 
4.2 
Study Rationale 
Interest in the combination of naltrexone with other medications, especially with cognitive 
enhancers and anti-depressants (e.g., methylphenidate, bupropion, modafinil, mirtazepine), has 
increased. For example, “a formulation that combines naltrexone with methylphenidate could be 
a useful pharmaceutical approach to alleviate abuse potential of methylphenidate and other 
stimulants” (Zhu et al., 2011). The efficacy of naltrexone in reducing stimulant use has been 
empirically documented (Jayaram-Lindström et al., 2008b). Still, the medication is not wholly 
effective (e.g., Coffin et al., 2017), which is also true of another medication—bupropion—which 
has been extensively studied in trials for MA dependence. Bupropion has been found to be 
somewhat successful at reducing MA use in dependent patients but demonstrates an uneven 
response across patient types (e.g., many patients did not complete protocols, and participants 
assessed at baseline as high-frequency users did less well than low-frequency users).  
The rationale for combining bupropion and naltrexone, as examined in CTN-0054, is predicated 
on their potentially complementary effects as shown in clinical research and as postulated in 
mechanistic arguments for naltrexone (e.g., Hanson, 2004), for bupropion, which may involve 
noradrenergic and/or dopaminergic effects (e.g., Ascher et al., 1995; Newton et al., 2006), and 
for the combination, which could regulate the mesolimbic reward pathways (Ornellas & Chavez, 
2011). Anecdotal reports derived from research involving opioid addicts who also use stimulants 
(e.g., Comer et al., 2006) also substantiate the utility of naltrexone for reducing MA use. The 
combination of naltrexone and bupropion had also been studied in research on the efficacy of the 
combination pharmacotherapy for controlling obesity (e.g., Greenway et al., 2010; Wadden et al., 
2011) leading to the marketing of Contrave® for weight management. In a small (n = 7) clinical 
pharmacology trial, however, steady state naltrexone (50 mg per day), bupropion (300 mg per 
day), and their combination showed no statistically significant effect on behavioral responses or 
subjective effects following 0 mg, 10 mg or 30 mg intranasal methamphetamine (Stoops, Hays, 
Glaser, & Rush, 2015). 
Combination pharmacotherapy, whereby medications exerting effects on different mechanisms 
of action may complement each other to help reduce stimulant use and to prevent relapse to 
stimulant use once abstinence has been attained, can be conceived in three ways: (1) one 
medication may act to enable the effects of other medication(s) as in CTN-0048 where the effect 
of Vivitrol® allowed buprenorphine to exert the hypothesized therapeutic effect under 
investigation; (2) one medication may act to enhance therapeutic effects of another, including 
possibly reducing side effects, as in combining different opioids in clinical pain management; and 
(3) the two medications may synergistically exert their combined effects as a novel compound 
and be studied as a single test agent. In this protocol, bupropion may serve to ameliorate some 
of the anhedonia and dysphoria that characterize early-phase abstinence from MA, and it also 
may counteract some of the side effects associated with naltrexone.  
Some of the best evidence in support of this protocol is from the CTN-0054 pilot trial that was 
conducted as an open-label study of 49 participants at three sites in two CTN Nodes (Nexus 
Recovery Center, Inc., Texas Node; Integrated Substance Abuse Programs (ISAP) and University 
of Hawaii (UH), Pacific Region Node). Treatment-seeking, severe MA users (using an average of 
27 days out of the previous 30 prior to enrollment) were given bupropion XL (450 mg) daily and 
XR-NTX every 4 weeks for 8 weeks. Many procedures being proposed for this phase III RCT 

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were developed and evaluated in the initial pilot trial, including collection of data regarding the 
tolerability and titration procedures for the 450 mg bupropion in the AMC condition. The intent-to-
treat (ITT) analysis in the pilot trial defined the primary efficacy endpoint as the number of 
responders, with responders defined as participants who provide at least 6 MA-negative UDS 
tests during the last four weeks of the active medication phase (weeks 5 – 8), including a MA-
negative UDS test at the last clinic visit in week 8. Out of 49 participants, 9 responders were 
required to indicate that the medication combination has sufficient potential efficacy to warrant a 
fully-powered phase III, placebo-controlled trial. Findings from the 49 participants included in the 
analysis of the primary efficacy endpoint indicated that 11 were responders, which met the a priori 
specified criterion requiring 9 or more responders (p = 0.0075). The unbiased estimate of the 
responder rate was 24%, and the 95% lower confidence limit was 13%. There were no significant 
site, sex, race or ethnicity differences by responder status. The responder rate was highest at the 
ISAP site (27.8%) and lowest at the Nexus site (15.8%). Seven (26.9%) males and 4 females 
(17.4%) were responders. Four (16.7%) whites and 7 others (4 multiracial and 3 others) were 
responders. Seven responders were not Hispanic or Latino, and 4 were Hispanic or Latino.  
These data were used to support development of the current phase III randomized, double-blind, 
placebo-controlled trial of this combination pharmacotherapy to produce abstinence for 
participants with methamphetamine use disorder. It is intended that participants randomized to 
the active medication arm receive the maximum safe dose of both bupropion and naltrexone to 
maximally enable them to become abstinent within the treatment phase of this study. The 
recommended dosing regimen of Vivitrol® is every four weeks; however, plasma levels of 
naltrexone and its metabolite are at a plateau during the first three weeks after administration but 
fall off in the fourth week. Replenishment of the depot supply of naltrexone at the beginning of the 
fourth week by re-injecting Vivitrol® should prevent that decline and allow evaluation of the 
maximum safe dose of the combination medication.  
4.3 
Significance of the Project to the Field 
Identifying an effective medication, or combination of medications, to help achieve abstinence 
and to prevent relapse to MA use is an important objective with considerable public health 
significance. The proposed placebo-controlled trial, based on preliminary evidence established in 
the CTN-0054 ADAPT pilot trial, will advance medication research and potentially confirm the 
naltrexone plus bupropion combination as the first effective pharmacotherapy for the treatment of 
stimulant use disorder involving MA. 

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5.0 
OBJECTIVES 
The objective of this study is to evaluate an active medication combination (AMC) that comprises 
extended-release naltrexone (XR-NTX) plus bupropion (BUP-XL) as a potential pharmacotherapy 
for methamphetamine use disorder. 
5.1 
Primary Objectives 
The primary objective of this study is to evaluate the efficacy of the AMC arm, compared to a 
matched placebo (PLB) arm, in reducing methamphetamine use in individuals with moderate or 
severe methamphetamine use disorder seeking to stop or reduce methamphetamine use. It is 
hypothesized that the AMC arm will be associated with a greater number of “responders,” defined 
as participants who provide a pre-specified number of MA-negative UDS tests obtained during 
the evaluation period (i.e., weeks 5 to 6 and weeks 11 to 12) of the 12-week long medication 
phase, relative to the PLB arm.  
5.2 
Secondary Objectives 
Secondary objectives include evaluating the effect of the AMC arm, compared to the PLB arm, 
on safety, other substance use outcomes, depression scores, quality of life, overall functioning, 
clinic attendance, and medication adherence. 

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6.0 
DESIGN 
6.1 
Overview of Study Design 
The primary objective of this study is to assess the efficacy of extended-release naltrexone plus 
bupropion as a combination pharmacotherapy for methamphetamine use disorder. There will be 
400 individuals randomized into the study across 7 -10 clinical sites. Eligibility will be determined 
during a maximum 21-day screening period. To document an appropriate level of current 
methamphetamine use, prospective participants must submit at least 2 urine samples positive for 
methamphetamine of a possible 3 tests to occur within a 10-day period during which clinic visits 
occur with at least 2 days between visits. In addition, participants must self-report MA use on 18 
or more days in the 30-day period prior to consent using the Timeline Followback (TLFB) and 
meet diagnostic criteria for moderate or severe methamphetamine use disorder per DSM-5 (4 or 
more criteria) at screening. After screening is completed and eligibility is confirmed, participants 
will begin the 12-week medication phase of the trial. Participants will be randomized to either the 
1) AMC arm and receive injections of extended release naltrexone (XR-NTX; as Vivitrol®) plus 
once-daily oral extended-release bupropion tablets (BUP-XL) or the 2) matching placebo (PLB) 
arm and receive injections of placebo (iPLB) plus once-daily oral placebo (oPLB) tablets. This 
protocol will utilize a sequential parallel comparison design (SPCD), originally proposed by Fava 
et al. (2003), and later revised by Chen et al. (2011). A feature of this design is that it can reduce 
the overall placebo response rate. One advantage of the adaptive aspect of the design is that it 
requires a smaller sample size compared to a standard two group randomized trial design. During 
the course of the study, participants may or may not be switched to another arm, as determined 
by the a priori adaptive aspect of the study design. Participants appearing to respond well to their 
original treatment assignment will not be switched. Overall, approximately 50% of the participants 
will receive the AMC. Injections will be provided in weeks 1, 4, 7, and 10. Take-home oral study 
medication will be dispensed weekly for dosing on non-clinic days. Participants will be asked to 
attend the clinic twice weekly for observed oral medication dosing, assessments, collection of 
urine samples, and once-weekly medical management. On non-clinic days, participants will 
participate in smartphone app-based medication adherence activities. Participants will be asked 
to complete assessments as indicated on the schedule of assessments (see Section 8.0). 
Following the 12-week medication phase, participants will complete a follow-up phase, including 
a medication taper and post-medication phase follow-up visits during weeks 13 and 16. 
6.2 
Duration of Study and Clinic Visit Schedule 
Participants will be involved in the study for approximately 19 weeks, including a 
screening/baseline period of up to 3 weeks (i.e., 21 days), 12 weeks of medication, and a post-
medication follow-up phase. The screening phase may differ by participant in the length of time 
needed to complete preliminary eligibility assessments. Confirmation of opioid-free status (urine 
drug screen test(s) and optional naloxone challenge) before randomization and medication 
induction will take approximately 1.5 hours. Twice-weekly visits during the medication phase will 
range from about 20 to 90 minutes in length depending on scheduled assessments. Once-weekly 
medical management sessions will require an additional 20 minutes. Medication injection visits 
will take approximately 2 hours. The post-medication phase follow-up visits will take 
approximately 1 to 2 hours to complete. A 12-week medication period was selected based on 
expected time needed to observe clinical benefit and for pragmatic issues related to medication 
dosing.  
Enrollment is expected to take place over a period of approximately 18 months.  

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6.3 
Participant Selection 
A total of 400 males and females who meet eligibility criteria will be randomized. Study participants 
will be recruited using a variety of methods including word-of-mouth, referral, advertising, and 
study announcement flyers posted in local treatment programs. The study sites should attract a 
diverse study population. Efforts will be made to recruit a study sample that reflects, or exceeds, 
the proportion of minorities in the community where the site is located. Recruitment procedures 
aiming to enhance enrollment of women and/or minorities will be conducted, including linkages 
with medical sites and/or treatment programs that serve a large number of women and/or 
minorities, and advertising in media outlets with high female/minority audience. Participants will 
not receive other formal addiction treatment services while they are participating in the study. 
Thus, at the time of randomization participants must be willing to have the study intervention serve 
as their sole treatment during study participation. Mutual help support group attendance will be 
encouraged throughout the trial. Upon study completion, participants may enroll in behavioral or 
pharmacological addiction treatment services.  
6.3.1 
Inclusion Criteria 
Study participants must: 
1. Be 18 to 65 years of age; 
2. Be interested in reducing or stopping methamphetamine use; 
3. Be able to speak English sufficiently to understand the study procedures and provide 
written informed consent to participate in the study; 
4. Meet DSM-5 criteria for moderate or severe methamphetamine use disorder (4 or more 
criteria); 
5. Self-report methamphetamine use on 18 or more days in the 30-day period prior to 
consent using the Timeline Followback (TLFB); 
6. Provide at least 2 urine samples positive for methamphetamine out of a possible 3 tests 
to occur within a 10-day period during which clinic visits occur with at least 2 days 
between visits;  
7. If female, agree to use acceptable birth control methods and have periodic urine 
pregnancy testing done during participation in the study unless documentation of 
hysterectomy provided; 
8. Meet subjective and objective measures of being opioid-free prior to naltrexone induction 
per study medical clinician’s determination; 
9. Be willing to comply with all study procedures and medication instructions; 
10. Agree to use a smartphone app (downloaded for free to own device or on a study 
provided smartphone device) to take daily videos of medication dosing.  
 
 

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6.3.2 
Exclusion Criteria 
Study participants must not: 
1. Have an acute medical or psychiatric disorder that would, in the judgment of the study 
medical clinician, make participation difficult or unsafe;  
2. Have suicidal or homicidal ideation that requires immediate attention; 
3. Have a history of epilepsy, seizure disorder, or head trauma with neurological sequelae 
(e.g., loss of consciousness that required hospitalization); current anorexia nervosa or 
bulimia; or any other conditions that increase seizure risk in the opinion of the study 
medical clinician;  
4. Have evidence of second or third degree heart block, atrial fibrillation, atrial flutter, 
prolongation of the QTc, or any other finding on the screening ECG that, in the opinion of 
the study medical clinician, would preclude safe participation in the study; 
5. Have Stage 2 hypertension as determined by the study medical clinician (e.g., greater 
than or equal to 160/100 in 2 out of 3 readings during screening); 
6. Have any elevated bilirubin test value per laboratory criteria OR any other liver function 
test (LFT) value > 5 times the upper limit of normal per laboratory criteria;  
7. Have a platelet count <100 x 103/μL; 
8. Have a body habitus that precludes gluteal intramuscular injection of XR-NTX in 
accordance with the administration equipment (needle) and procedures;  
9. Have a known allergy or sensitivity to bupropion, naloxone, naltrexone, PLG (polyactide-
co-glycolide), carboxymethylcellulose or any other component of the XR-NTX diluents; 
10. Have been in a prior study of pharmacological or behavioral treatment for 
methamphetamine use disorder within 6 months of study consent; 
11. Have taken an investigational drug in another study within 30 days of study consent; 
12. Have been prescribed and taken naltrexone or bupropion within 30 days of study 
consent;  
13. Be concurrently enrolled in formal behavioral or pharmacological addiction treatment 
services;  
14. Be receiving ongoing treatment with tricyclic antidepressants, xanthines (i.e., 
theophylline and aminophylline), systemic corticosteroids, nelfinavir, efavirenz, 
chlorpromazine, MAOIs, central nervous system stimulants (e.g., Adderall, Ritalin, etc.), 
or any medication that, in the judgment of the study medical clinician, could interact 
adversely with study medications; 
15. Have a current pattern of alcohol, benzodiazepine, or other sedative hypnotic use which 
would preclude safe participation in the study as determined by the study medical 
clinician; 
16. Require treatment with opioid-containing medications (e.g., opioid analgesics) during the 
study period; 
17. Have a surgery planned or scheduled during the study period; 

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18. Are currently in jail, prison or any inpatient overnight facility as required by court of law or 
have pending legal action or other situation (e.g., unstable living arrangements) that 
could prevent participation in the study or in any study activities; 
19. If female, be currently pregnant, breastfeeding, or planning on conception. 
Although not targeted for recruitment, this study obtained authorization from the Office for Human 
Research Protections (OHRP) to follow-up with study participants who happen to become 
incarcerated during the trial, as needed and feasible at the individual study sites. Study staff may 
work with institutions to arrange research visits, and any needed assessments and procedures 
the institution will allow may be completed. Study medications will be discontinued during 
incarceration. 
6.4 
Site Selection 
The trial will include 7 -10 sites with each site randomizing approximately 30-70 participants.  
6.4.1 
Site Characteristics 
Participating sites must: 
1. Have a physician who can commit the time necessary to take a leadership role and 
oversee all medical aspects of the study, perform medical assessments, confirm 
participant eligibility, order and dispense or administer study medications, review 
adverse events, and appropriately evaluate and respond to adverse reactions that may 
occur during the course of the study. 
2. Have at least one other medical clinician (i.e., physician, physician’s assistant, or nurse 
practitioner) who can, in accordance with the regulations of the state where the site is 
located, make independent medical decisions and commit the time necessary to perform 
medical assessments, determine participant eligibility, order and dispense or administer 
study medications, review adverse events, and appropriately respond to adverse 
reactions that may occur during the course of the study. 
3. Have standard operating procedures in place for handling medical and psychiatric 
emergencies. 
4. Have a physician available to provide after-hours clinical back-up for study-related 
emergencies. 
5. Have access to a phlebotomist or other qualified personnel to complete blood draws. 
6. Have the ability to meet storage and dispensing requirements for all study medications, 
including access to adequate storage space, equipment, and appropriately qualified 
staff, as directed by the protocol and in accordance with local regulations and NIDA 
stipulations. 
7. Have access to, or the ability to contract with, a local laboratory to process biological 
specimens (e.g., blood and/or urine) in a timely manner during screening. 
8. Have adequate facility space available to conduct study procedures. 

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6.4.2 
Rationale for Site Selection 
The sites selected for participation in this trial will be selected, in part, based on the node’s interest 
in participating in the trial, the availability of a sufficient pool of potential study participants in the 
area, and the presence of an existing team of experienced personnel at the site knowledgeable 
in clinical trial operations and trained in core CTN assessments. Information on site readiness 
and capacity will be gathered via a site survey and a coordinated site/investigator selection 
process will confirm the following: 
1. An ability to recruit and randomize 3-4 eligible individuals with methamphetamine use 
disorder each month. 
2. Experienced regulatory personnel capable of the timely preparation of necessary 
regulatory documents and having the ability to facilitate an expeditious IRB submission, 
approval, modification, and continuing review processes. 
3. Medical staff who can commit the time necessary to oversee all medical aspects of the 
study, perform medical assessments, confirm participant eligibility, order and administer 
or dispense study medications, and appropriately respond to possible adverse reactions 
that may occur during the course of the study. 
4. Staff familiar with web-based Electronic Data Capture systems and who have the 
capacity and discipline to conform to protocol-required direct data entry procedures.  
5. Adequate and available space that is suitable for the performance of study procedures. 
6.5 
Randomization Plan 
Eligible participants will be randomized to the AMC and PLB treatment arms, stratifying by site. 
During the course of the medication phase, participants who provide sufficient UDS for evaluation 
of outcomes may or may not be switched to another arm. Switching, or re-randomization 
parameters, were determined a priori and are based on a combination of original treatment 
assignment, availability of data, and treatment response. Participants appearing to respond to 
their original treatment assignment will not be switched. Re-randomization will be implemented 
automatically by computer and will be stratified by site. Overall, approximately 50% of the 
participants will receive the AMC.  
 
The randomization process will be conducted centrally and electronically by the CTN Data and 
Statistics Center (DSC) via the Advantage eClinical Electronic Data Capture (EDC) system, and 
randomization assignments will not be conveyed to staff or participants to maintain the double 
blind. To ensure the lack of predictability while maintaining the designed randomization fraction, 
an urn scheme similar to one described in Wei and Lachin (1988) will be used. The DSC 
statistician will review randomization data on a regular basis to ensure that the scheme is being 
implemented according to plan. A randomization slot, once used, will not be re-allocated. 
6.6 
Study Intervention 
The study intervention consists of 12 weeks of pharmacotherapy, medical management, and 
medication adherence procedures. Participants randomized to the AMC treatment arm will 
receive an injection of extended-release naltrexone (XR-NTX; as Vivitrol®) plus 450 mg of once-
daily oral extended-release bupropion tablets (BUP-XL). Participants randomized to the PLB 
treatment arm will receive matched placebo in the form of injections of placebo (iPLB) plus once-

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daily oral placebo (oPLB) tablets. Injections of study medications (XR-NTX or iPLB) will be 
administered in weeks 1, 4, 7, and 10. All randomized participants will receive weekly medical 
management sessions with the study medical clinician and will utilize smartphone app-based 
medication adherence procedures.  
6.7 
Outcome Measures 
The primary outcome measure, as described below, is based on urine drug screen (UDS) test 
results and is considered a clinically significant improvement in methamphetamine use in this 
study population. The primary outcome (UDS) has been chosen because it is an objective 
measure of methamphetamine use. Secondary outcome variables are intended to explore various 
aspects of response to this medication combination and to identify factors that may be associated 
with treatment response or non-response. Some of the secondary outcome variables add a 
measure of clinical relevance to the reduction of use by assessing sustained abstinence, reduced 
frequency of methamphetamine use, reduction in craving that may be a prelude to relapse, and 
improvements in mood, quality of life, and overall functioning.  
6.7.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is a composite of MA-negative UDS test results obtained 
during weeks 5 to 6 and weeks 11 to 12 of the medication phase and will be compared by 
treatment group (AMC versus PLB).  
6.7.2 
Primary Safety Outcome Measure 
The safety and tolerability of the AMC arm, relative to the PLB arm, will be determined using 
participants’ reports of adverse events (serious and non-serious) collected at clinic visits or via 
other contact.  
6.7.3 
Secondary Outcome Measures 
Secondary outcome measures for the impact of the AMC, relative to the PLB arm, on other 
substance use outcomes, depression scores, quality of life, overall functioning, clinic attendance, 
and medication adherence will be evaluated as follows: 
1. Alternate measures and composites of methamphetamine use including: 
a) The Treatment Effectiveness Score (TES), as measured by UDS results, during the 
medication phase;  
b) Frequency of MA use, as measured by self-report, during the medication phase; 
c) Severity of MA craving, as measured by Visual Analog Craving Scales (VAS), during 
the medication phase; 
d) MA use, as measured by UDS and self-report, during the follow-up period. 
2. Quantity and frequency of alcohol, tobacco, and other drug use, as measured by self-
report, during the medication phase; 
3. Change in depressive symptoms, as measured by the PHQ-9, during the medication 
phase; 

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4. Changes in quality of life, as measured by the Quality of Life (QoL), during the 
medication phase; 
5. Changes in overall functioning, as measured by the Treatment Effectiveness 
Assessment (TEA), during the medication phase; 
6. Percentage of participants retained in treatment during the medication phase; 
7. Ratings of participant and staff satisfaction with study procedures, including use of the 
medication adherence app, compensation, and medication. 

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7.0 
PROCEDURES  
7.1 
Screening and Baseline Phase  
Assessments administered during screening will determine whether participants meet eligibility 
criteria and will provide baseline measures of drug use and other important domains. Screening 
and baseline assessments will be conducted as shown in Table 2 in section 8.0. Participants who 
do not complete all screening/baseline assessments within 21 days of signing consent, including 
the naltrexone pre-induction strategy, or who are otherwise found to be ineligible for participation 
in the study, will be considered screen fails. With Lead Node approval, screen fails may be allowed 
to return at a later date to repeat the screening process. 
7.1.1 
Pre-screening Assessment 
Individuals responding to recruitment materials or otherwise referred to the study will be pre-
screened on the phone or in person to ascertain preliminary eligibility status. A series of questions 
(e.g., MA use history, interest in participating in research to investigate medications that have 
potential to reduce MA use, ability and willingness to participate for the duration of the trial) will 
determine preliminary eligibility. Full screening appointments will be scheduled for those who 
meet preliminary eligibility criteria. 
7.1.2 
Informed Consent  
At the start of the screening appointment and before any assessments are administered, qualified 
study personnel will conduct the informed consent process with prospective participants. The 
informed consent process will begin with a description of the study, including study procedures 
and study medications. Potential study participants will be given a copy of the IRB-approved 
consent form to review either on site or at home, in accordance with IRB requirements. Potential 
study participants who remain interested after review of the consent form will answer written 
comprehension questions to ascertain their understanding of the study, including its purpose, 
procedures involved, and the voluntary nature of participation. For participants who do not 
correctly answer all comprehension items, research staff will re-explain the study, with a focus on 
aspects candidates did not understand. Participants may attempt the consent comprehension 
questions a maximum of three times before they are deemed unable to comprehend the study. 
Any participant who cannot demonstrate appropriate understanding of the study to research 
personnel will be ineligible to participate and will be assisted in finding other treatment resources 
if desired. Study participants who demonstrate understanding of the study and who voluntarily 
agree to participate will be asked to sign the IRB-approved consent form and, if the consent form 
is signed, will proceed with the screening assessments. As part of the informed consent process, 
participants also will be asked if they consent to (1) be contacted for future studies and (2) provide 
a blood sample for genetic testing. 
7.1.3 
Screening and Baseline Assessments 
Upon signing the IRB-approved consent form, participants enter a maximum 21-day screening 
phase to complete assessments to determine eligibility and to collect baseline data. 
Screening/baseline assessment procedures must be completed across at least two screening visits. 
During the screening phase, participants must submit at least 2 urine samples positive for 
methamphetamine out of a possible 3 tests to occur within a 10-day period during which clinic 
visits occur with at least 2 days between visits. Therefore, all screening visits will have at least 2 
days elapse between visits. In addition, participants must self-report MA use on 18 or more days 

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in the 30-day period prior to consent using the Timeline Followback. These criteria will be used to 
confirm current MA use and further substantiate a diagnosis of moderate or severe 
methamphetamine use disorder. 
Once the participant completes all screening and baseline assessments, submits 2 MA-positive 
UDS tests, and is found otherwise eligible for continued participation, the participant may begin 
the naltrexone pre-induction procedure (see below). All consented participants who do not 
complete all screening assessments within the 21-day screening period or who are otherwise 
found to be ineligible for study participation will be considered to be screen fails. Demographic 
data and the reasons for not meeting eligibility criteria must be documented for all screen fails. 
7.1.4 
Naltrexone Pre-Induction Strategy  
The screening/baseline phase includes a naltrexone pre-induction strategy to be conducted on 
the final screening visit after all other eligibility criteria have been met. The naltrexone pre-
induction strategy is designed to ensure participants meet subjective and objective measures of 
being opioid-free, per the study medical clinician’s determination, on the day of and prior to 
randomization and induction on the injectable study medication. Required and optional 
procedures are outlined below: 
1. Subjective measures of opioid-free status. Participants must self-report no clinically 
significant opioid use (i.e., at any level that could constitute a potential risk of 
precipitating opioid withdrawal upon naltrexone administration) in the 7-10 days prior to 
the day of randomization, as measured using the TLFB and the Prior and Concomitant 
Medications (PCM) assessment.  
2. Objective measures of opioid-free status. To objectively evaluate opioid-free status, a 
urine sample must be provided and tested on the day of anticipated randomization. 
Individuals must have negative results for opioids (on the OPI 2000 and the OPI 300 
tests) prior to randomization. Individuals with a positive opioid result on these tests may 
provide an additional urine sample on a subsequent day if the study medical clinician 
determines that a second screen is appropriate. The study medical clinician must 
determine suitability for continuing the pre-induction process for individuals positive for 
opioids on other opioid tests that may be conducted during Screening. 
3. Optional naloxone challenge. A naloxone challenge is not required but may be 
administered for definitive determination of opioid free status at the discretion of the 
medical clinician. If a naloxone challenge is administered, a minimum 0.8 mg bolus must 
be given before determining the outcome of the challenge. The study medical clinician 
will use clinical judgment to determine if the participant passes the naloxone challenge 
and is safe to continue on to randomization and subsequent XR-NTX or iPLB induction. 
Evidence of withdrawal signs or symptoms following naloxone administration will result 
in postponement of randomization until a negative naloxone challenge result is achieved. 
In other words, if a clinician opts to administer a naloxone challenge and withdrawal is 
precipitated, a second naloxone challenge must be administered, with no withdrawal 
observed immediately prior to randomization.  
Participants who experience withdrawal symptoms following a naloxone challenge may 
be treated with ancillary medications, observed until symptoms resolve, and given the 
opportunity to return another day and be re-challenged if clinically indicated. Participants 
who are not interested in continuing to participate, or who fail a repeat naloxone 
challenge, will not be eligible to participate in the study but will be given referrals to local 
treatment programs, as appropriate. 

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7.1.5 
Final Confirmation of Eligibility  
After completing all screening and baseline assessments, including the naltrexone pre-induction 
strategy, the study physician must review and approve safety and eligibility assessments in order 
to confirm participant eligibility prior to randomization. Randomization will occur on the day the 
naltrexone pre-induction strategy is completed (i.e., the participant is determined to be opioid-
free) after study eligibility has been confirmed and documented. 
7.2 
Medication Phase 
7.2.1 
Randomization 
Immediately following the naltrexone pre-induction strategy and final assessment and 
documentation of eligibility, eligible participants will be randomly assigned to the AMC arm or the 
matching PLB arm. The randomization procedure will be conducted electronically by the 
Advantage eClinical system. The switching or re-randomization procedure described previously 
will occur seamlessly by the electronic system, based on data routinely collected and entered. 
7.2.2 
Pharmacotherapy 
Participants will receive the first intramuscular gluteal injection of study medication (XR-NTX or 
iPLB) on the day of randomization (Day 1), following confirmation of opioid-free status and final 
confirmation of study eligibility by the study physician. Subsequent intramuscular gluteal injections 
(XR-NTX or iPLB) will be administered at the beginning of Weeks 4, 7, and 10 and shall be 
administered following guidelines in the XR-NTX package insert. Study medical clinicians will 
evaluate participants to ensure continued suitability for injectable study medication administration. 
Urine drug screening procedures will help clinicians evaluate participant opioid-free status at the 
time of study medication injection. A naloxone challenge may be administered prior to any study 
medication injection at the discretion of the study medical clinician. 
Take-home oral study medication will be dispensed weekly. The first dose of oral study medication 
(BUP-XL or oPLB) will be taken on the day of randomization (Day 1) immediately following 
administration of the injectable study medication. For each clinic visit, participants will be asked 
to refrain from taking their dose at home and to bring their oral study medication for in-clinic 
dosing. On the days in which injectable study medication is administered, oral study medication 
self-administration will occur immediately following the injection. All in-clinic self-administration of 
oral study medication will be observed by study staff. Participants will take a dosing video using 
the study app for all in-clinic and non-clinic self-administrations of oral study medication. 
If a participant reports intolerable symptoms or side effects at the full 450 mg dose, ancillary 
medications may be used and/or a dose reduction may occur if deemed appropriate by the study 
medical clinician. The study medical clinician, in collaboration with the study physician and site 
principal investigator, is encouraged to consult with the Lead Investigator(s) in making the 
decision to reduce a participant’s dose. The dose may be reduced to 300 mg daily. Medication 
packaging will allow for dose reductions without re-dispensing; participants will be instructed to 
take only the tablets in the first two wells for each day they are on a reduced dose. If intolerable 
adverse effects continue, the participant may be withdrawn from further medication 
administration. If intolerable adverse effects resolve after an initial dose reduction or are 
appropriately addressed with the use of ancillary medications, and if deemed appropriate by the 
study medical clinician, titration to the full 450 mg target dose may be attempted (i.e., participants 
will be instructed to take all three tablets for each day) on any visit except visits in which injectable 
study medication is administered. 

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7.2.3 
Medical Management 
Medical management procedures will be conducted as follows. Participants will meet with a study 
medical clinician once weekly for an individual medical management session that utilizes a 
structured adherence enhancement manual designed for pharmacotherapy trials with subjects 
with substance use disorder (adapted from Carroll et al., 1996). The goal of medical management 
sessions is to achieve high quality supportive treatment that reinforces adherence to study 
procedures and the study medication regimen. A session will be approximately 20 minutes and 
focus on: 
1. Setting abstinence from methamphetamine as a goal,  
2. Participant adherence with study medications and procedures,  
and  
3. Current functioning.  
Medical clinicians will also review adverse events, consider potential medication side effects, and 
discuss other pertinent issues in keeping with sound medical practice. Ancillary medications may 
be provided for study medication-related adverse events as clinically indicated. A range of 
prescription and over-the-counter ancillary medications may be used for symptoms such as 
anxiety, nausea, vomiting, diarrhea, muscle pain, and insomnia. At all medical management 
sessions, the medical clinician will remind participants about the importance of adhering to the 
study procedures, including attending scheduled clinic visits and complying with smartphone app-
based dosing confirmation procedures. Mutual help support group attendance will be encouraged. 
7.2.4 
Medication Adherence 
Medication adherence procedures will be conducted as follows. To encourage and monitor 
adherence to oral study medication, procedures include discussing adherence during medical 
management sessions and twice-weekly observed dosing in the clinic as described previously. 
Procedures also include the use of a smartphone app to take dosing videos to document oral 
study medication self-administration on non-clinic days and during clinic visits (while staff 
observe), including on the taper days in the post-medication follow-up phase. Participants will 
access the app on either a study provided smartphone device or by downloading the app to their 
personal device. Further details are outlined in Appendix C. Dosing will be assessed by 
automated visual recognition software during the video capture to ensure the videos clearly show 
dosing adherence based on assessment criteria. Participants will be compensated for dosing 
videos (see section 7.5). 
7.2.5 
Participant Medication Withdrawal 
Participants will be withdrawn from further study medication administration if it is clinically 
determined that continuation may be unsafe. For example, participants who develop uncontrolled 
hypertension (160/100 or higher on three consecutive visits) will be withdrawn from further study 
medication administration. Likewise, women who become pregnant during the medication period 
will be immediately withdrawn from study medication administration. Participants reporting use of 
medications that may interact with naltrexone or bupropion will be withdrawn based on clinical 
judgment. Participants who experience intolerable adverse effects or other physical or psychiatric 
conditions, regardless of relationship to the study medication, may also be withdrawn from further 
study medication administration. 

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The medical clinician may determine that a participant’s clinical condition has deteriorated during 
the course of the study to the extent that now taking study medication may be possibly unsafe or 
unwise. Examples of clinical deterioration that might trigger a decision to withdraw the participant 
from study medication include the following: 
 
New onset of psychiatric or medical conditions that would require intervention and 
preclude continued participation in the study (e.g., emergence of psychosis, suicide risk, 
severe cognitive impairment, or dangerous criminal behaviors); 
 
Worsening of a pre-existing psychiatric or medical condition that would preclude 
continued safe participation in the study; 
 
Worsening of substance use disorder or overdose such that a higher level of care is 
indicated; 
 
Increase in LFT or decrease in platelet test results at week 6 that may increase 
participant health risks. This includes any of the following: AST/ALT results > 5 times 
ULN, total bilirubin > 2 times ULN, or platelets below 75 x 103/μL.  
The study medical clinician, in collaboration with the study physician and site principal 
investigator, should consult with the Lead Investigator(s) and Study Medical Monitor in making 
the decision to withdraw a participant from study medications. Also, participants may decide at 
any time that they no longer wish to continue to receive medication or participate in the study. 
In most cases, a taper is not indicated if the study medical clinician determines medication 
discontinuation is warranted for medical or psychiatric reasons. Generally, a taper of bupropion 
is not medically necessary as there is no evidence of a physiological dependence or increased 
incidence of adverse events when this medication is discontinued. However, as down titration is 
common in clinical practice, clinicians are guided to follow this convention for the majority of study 
participants. If a taper is believed to be necessary based on clinical judgment, the study medical 
clinician, in collaboration with the study physician and site principal investigator, should consult 
with the Lead Investigator(s) and Study Medical Monitor on how to best proceed. 
In the event a participant becomes pregnant during the medication period, a taper is not indicated 
as bupropion is a pregnancy category C medication and the risks of taper outweigh the benefits 
in pregnant women. The pregnant participant will be immediately discontinued from further study 
medication administration, referred for medical care, and the pregnancy followed until an outcome 
is known. 
A taper is also not indicated for participants who become incarcerated or for participants who lose 
study medication during the medication phase of the study. Participants who lose study 
medication will resume their dosing schedule at the appropriate next study visit; no medication 
should be dispensed earlier than scheduled. 
As the primary aim of this study is to evaluate the efficacy of XR-NTX plus BUP-XL as a 
combination pharmacotherapy, withdrawal from either study medication will typically lead to 
discontinuation of the other medication. With Lead Node and Study Medical Monitor approval, 
participants may be allowed to continue on one medication if discontinued from the other. In the 
event a participant is withdrawn from further study medication administration, referrals to 
treatment programs or recommendations for medical care will be provided. Unless consent is 
officially withdrawn, study staff will encourage participants who are withdrawn from study 
medications or who opt out of study medications to continue attending twice weekly clinic visits 
and complete study assessments throughout the duration of the medication phase (weeks 1 – 12) 
and the follow up phase (weeks 13 and 16).  

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7.2.6 
Medication Phase Visits 
Given the requirements across study visits (e.g., meeting with medical clinician, blood draws, 
injections, assignment of oral medication only after the participant arrives, physical exam, ECG, 
etc.), the study was designed with the expectation that all visits occur at the study site. However, 
there may be cases in which off-site visits may be possible with Lead Team approval.  
7.3 
Follow-up Phase 
7.3.1 
Oral Study Medication Taper 
A taper will occur during the first four days of Week 13 (Days 85 – 88) for participants continuing 
on oral study medication (BUP-XL or oPLB) through the end of the medication phase. The daily 
dose will be 300 mg for Days 85 and 86 and 150 mg for Days 87 and 88. This taper schedule will 
apply to all participants, including any participants already taking a reduced dose. 
7.3.2 
Post-Medication Phase Follow-up Visits 
All enrolled participants will be asked to complete post-medication phase follow-up visits in weeks 
13 and 16 according to the schedule of assessments (see Table 2, section 8.0). There may be 
cases in which off-site visits may be possible with Lead Team approval. Tracking and locating 
strategies will be used to ensure the highest possible follow-up rates.  
7.4 
Study Medication Management/Drug Accountability 
As set forth in the protocol agreement signed by each site principal investigator (see Section 14, 
Signatures), study sites are required to observe local, state, and federal regulations regarding 
receipt, custody, dispensing, administration, and associated documentation of all medications 
used in this study. Medications used in the study include extended-release bupropion, extended-
release injectable naltrexone, oral placebo, and injectable placebo provided by the NIDA 
contractor as well as naloxone purchased and maintained by each site.  
7.4.1 
Documentation 
Upon receipt, the investigator, pharmacist, or authorized designee at each site is responsible for 
maintaining written inventory of the investigational agents and naloxone obtained for the study. 
Appropriately trained and qualified personnel will maintain an accurate and real-time accounting 
of all medications, which will be available for verification by study monitors. Medication 
accountability records, including perpetual inventory, will document the amount of study 
medication ordered, received, transferred between areas of the study site (e.g., from pharmacy 
to clinic), and medications administered to or dispensed to and returned by an individual 
participant. Documentation will also record unused medications destroyed on site or returned to 
the NIDA contractor for destruction. As with all study documentation, medication accountability 
records must be maintained in accordance with Good Documentation Practices and must be 
attributable, legible, contemporaneous, original, accurate, and complete. 
7.4.2 
Storage 
All medication used in this study will be stored in compliance with federal, state, and local laws 
and institutional policy. Study medications will be stored in a locked, secure, limited-access 
location under the conditions specified by the package insert; XR-NTX and iPLB injectable kits 

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will be stored in a secure, limited access refrigerator. Temperature logs will show a daily record 
of medication storage temperature for all medications. 
7.4.3 
Packaging 
Intramuscular gluteal injections (XR-NTX and iPLB) will be supplied in single use kits marked with 
medication kit numbers which will be used for tracking and inventory purposes. Each active 
injectable medication kit will contain one 380 mg vial of Vivitrol® microspheres, one vial containing 
4 mL (to deliver 3.4 mL) diluent for the suspension of Vivitrol®, one 5 mL prepackaged syringe, one 
1-inch 20-gauge needle, two 1.5-inch 20 gauge needles, and two 2-inch 20 gauge needles with 
needle protection devices. Each injectable placebo medication kit will be prepared to look identical 
and will contain the same contents as the active medication kits but with no active medication. 
Participants will receive once-daily oral study medication (BUP-XL or oPLB). BUP-XL blister cards 
will contain a daily dose of 300 mg for the up titration days and a daily dose of 450 mg for all other 
days in the medication phase. BUP-XL blister cards for the taper days (Days 85-88) will contain 
a daily dose of 300 mg (Days 85 and 86) and 150 mg (Days 87 and 88). 
Oral study medication (BUP-XL and oPLB) will be pre-packaged in weekly blister cards that 
contain 3 tablet wells for each day. The packaging will be designed such that participants will take 
all 3 tablets each day, including during the up titration and taper periods. 
There will be five types of blister cards manufactured to appear identical for both treatment arms. 
There will be three types of 7 day cards for use in weeks 1 to 12—one for up titration (for AMC 
only) and two for target dosing (AMC and PLB). Two types of cards will contain a 4-day supply 
for the week 13 taper period (AMC and PLB). 
The up titration AMC card will be dispensed twice during the study: in week 1 for participants 
randomized to AMC and again when some participants may be re-randomized and assigned to 
receive AMC. Therefore, the up titration card will be manufactured to contain 3 tablets for each 
day of the titration in order to appear identical to the target dosing card. The up titration card will 
contain two active and one placebo tablet each day for days 1 - 3, and it will contain three active 
tablets each day for days 4 - 7. Packaging the up titration card in this way will help protect the 
double-blind throughout the trial.  
The target dosing cards will contain either active medication or placebo. The AMC taper card will 
contain two active and one placebo tablet for the first two days and one active and two placebo 
tablets for the last two days. The PLB taper card will contain three placebo tablets for each of the 
four days.  
Weekly blister cards dispensed to participants will be labeled to include protocol number, study 
drug information, and blister card number. The label will also include blister card contents, 
“Caution: New Drug - Limited by Federal Law to Investigational Use. Store at Controlled Room 
Temperature (20-25°C or 68-77°F)” as well as the manufacturer and distributor information. 
Below, the medication packaging plan is summarized visually, whereby P indicates placebo tablet 
and A indicates active tablet. Weekly blister cards for each treatment arm by the dosing period 
(up titration, target dosing, and taper) will be dispensed as follows: 
 
 

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Dosing Period during Medication Phase 
 
 
Day 
Up titration 
Target 
Taper 
  Treatment Arm 
 
 
 
PLB 
1 
2 
3 
4 
5 
6 
7 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
P P P 
 
P P P 
P P P 
P P P 
P P P 
 
 
 
 
 
 
 
 
AMC 
1 
2 
3 
4 
5 
6 
7 
 
A A P 
A A P 
A A P 
A A A 
A A A 
A A A 
A A A 
A A A 
A A A 
A A A 
A A A 
A A A 
A A A 
A A A 
 
A A P 
A A P 
A P P 
A P P 
 
 
 
 
 
 
Key: A - Active medication tablet 
P - Placebo tablet 
7.4.4 
Ordering and Dispensing 
All study medications shall be ordered only by delegated licensed medical staff and dispensed by 
research staff appropriately trained to do so. Injectable medications will be administered by 
qualified staff during Weeks 1, 4, 7, and 10. Oral medications will be dispensed to the participant 
weekly in labeled blister cards that will include both in-clinic observed doses and self-administered 
doses for non-clinic days. 
7.4.5 
Used/Unused Medication 
Unused study medication will be returned and logged into a perpetual inventory. Returned, 
damaged, expired or otherwise unused study medications will be accurately labeled, securely 
stored, kept separately, and shall be accounted for prior to disposition. Any unused or expired 
investigational agent shall be accounted for at all times. Expired naloxone and other ancillary 
medications obtained for this study will be destroyed on site or sent for destruction per local 
institutional policies.  
7.4.6 
Lost Medication 
There will be no replacement of any dispensed study medications. 
7.4.7 
Maintaining and Breaking Blind 
This is a double-blind, placebo-controlled trial. With the exception of the data management group 
overseeing the random assignment schedule and the NIDA-contracted research pharmacist 
preparing study medications, all other study personnel and participants will remain blinded to 
medication status until nationwide completion of the trial. A Data and Safety Monitoring Board 
(DSMB) will review study data throughout the course of the trial. In rare cases, it may be 

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necessary to break the blind for a particular study participant before completion of the trial (e.g., 
pregnancy or other medical necessity). A request to break the study blind for an individual 
participant must be made by the study physician after consultation with the Lead Investigator. 
Unblinding the participant should only be done in cases of medical emergency when knowledge 
of the treatment group assignment may be necessary for clinical management and decision 
making. The decision to break the blind for a participant will be made jointly by the CCC Medical 
Monitor and at least one of the Lead Investigators. Any requests for unblinding will be responded 
to within one business day or less. 
7.5 
Participant Compensation 
Study participants will be provided with study medications, medical management, and a study 
medication adherence app for use on his/her own device at no cost. Alternatively, a study 
smartphone device pre-loaded with the medication adherence app will be provided if needed. In 
addition, participants will receive gift cards or cash (based on local requirements) as 
compensation for time, travel, parking, and other costs borne by the participant. A total of up to 
$50 will be provided for completion of screening/baseline assessments (divided among at least 
two screening visits). Ten dollars ($10) will be provided for each additional eligibility phase clinic 
visit to provide a urine sample. During the medication phase, $10 will be provided for completion 
of assessments including a urine sample ($5 will be provided for assessments without a urine 
sample); $5 for bringing the study medication on clinic days and taking a self-dosing video via the 
smartphone app while staff observe; and $25 for each injection visit. Participants will be 
compensated an additional $40 per visit for completion of the mid-treatment visit (visit 602) and 
the end of treatment visit (visit 1202), and $30 for each follow-up visit in weeks 13 and 16. In 
addition, participants will be compensated $5 for each dosing video taken on non-clinic days, 
including the taper in week 13 (see Appendix C for details). Participants may earn a visit 
attendance bonus of $20 (received up to 6 times) when they attend each visit expected to occur 
within each 2-week block of the medication phase. For example, a participant could earn $20 for 
attending four visits in weeks 1-2, $20 for weeks 3-4, and so on until weeks 11-12. Participants 
may also receive up to $40 to offset the cost of additional data service needed for the dosing app 
on their personal device or for return of the study smartphone device (see Appendix C for details). 
Total compensation possible is $1,160 as outlined below.  
7.5.1 
Table 1. Compensation Schedule 
Visit/Assessment 
Amount 
# of Payments 
Total 
Screening Assessments 
$50 
1 
$50 
Eligibility Phase Clinic Visits 
$10 
4 
$40 
Injection Visits 
$25 
4 
$100 
Clinic Visits (12-week Medication Phase) 
$10 
23 
$230 
In-clinic dosing/med return (2x/wk) 
$5 
24 
$120 
Mid-Treatment Visit (visit 602) and End-of-
Treatment Visit (visit 1202)  
$40 
2 
$80 
Dosing video (5x/wk+4 taper days)  
$5 
64 
$320 
Attendance Bonus (attending all expected visits in 
each 2-week block) 
$20 
6 
$120 
Follow-up Visits (Weeks 13 and 16) 
$30 
2 
$60 

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Visit/Assessment 
Amount 
# of Payments 
Total 
Additional data service for dosing app on personal 
device OR smartphone device return  
$40 
1 
$40 
 Maximum Compensation Possible 
$ 1,160 

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8.0 
ASSESSMENTS 
Study measures were chosen to minimize the research burden on participants yet collect 
adequate data to support analyses and ensure safety. Importantly, many of the study measures 
were selected to record vital health information and are similar to other recent and ongoing studies 
of bupropion and extended-release naltrexone. Additional measures were also selected to obtain 
information typically assessed in medication studies, including assessments of drug abuse and 
dependence diagnoses, psychological status, and measures of craving. Safety is assessed at 
each visit. Additional forms will be used to collect and document information such as dosing and 
protocol satisfaction. The NIDA endorsed Substance Abuse and Addiction (SAA) common data 
elements from Core Tier 1 of the PhenX Toolkit (http://www.phenxtoolkit.org), which include 
demographic and other baseline information, will be captured directly or will be populated from 
the answers to questions from other assessments. Table 2 provides the schedule of study 
assessments. On average, screening and eligibility assessments will be completed in 6-8 hours. 
Twice-weekly assessments during the medication phase will be completed in approximately 30 
to 90 minutes. Once-weekly medical management sessions will require an additional 20 minutes. 
The post-medication phase follow-up visits will take approximately 1 to 2 hours. 

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8.1 
Table 2. Schedule of Assessments 
 
 
 
 
 
Study Phase
Screening/ 
Baseline
Study Week
0
1
2
3
4
5
6
7
8
9
10
11
12
13
16
Screening Measures
Pre-Screening Interview Form
X*
Informed Consent
X*
Demographics Form
X*
Alcohol and Substance Use History
X*
DSM-5 Checklist
X*
Psychiatric Diagnostic Screening Questionnaire
X*
Sexual Risk Behaviors
X*
X2
X2
Self-Report of HIV Testing
X*
Medical and Psychiatric History
X*
Safety Measures
Physical Examination
X*
X2
Electrocardiogram
X*
X
Injection Site Examination
X2
X2
X2
X2
Injection Site Abnormality LogA
Clinical Laboratory Tests
X*
X
     Liver function tests & platelet lab tests
X
Concise Health Risk Tracking
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy Test 
XE
Pregnancy and Birth Control Assessment
X*
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
XC
X
X
X
XC
X
X
XC
X
X
XC
X
X
Prior and Concomitant Medications
X+
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
Adverse Events and Serious Adverse Events
XD
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
Naloxone Challenge Form
XE
XE
XE
XE
Efficacy Measures
Urine Drug Screen
X+
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
     OPI 300 
X**
X**
X**
X**
Timeline Followback
X+
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
Visual Analog Craving Scale
X+
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Health Questionnaire-9
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Effectiveness Assessment
X*
X2
X2
Tobacco Use History
X*
 
X2
X2
Quality of Life
X*
X2
X2
Blood draw for genetic testing
XF
Adherence Measures
Study Medication Dosing Logs
XE
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
Injection Administration Form
X
X
X
X
Oral Medication Dispensation Form
X
X
X
X
X
X
X
X
X
X
X
2X
XE
Bupropion Blood Levels
XB
XB
XB
X2
End of Medication FormE  
X
Administrative and Other Forms
Locator Form
X*
X
X
X
X
Eligibility - Randomization
X*
Missed Visit FormE
Protocol Deviation FormE
Protocol Satisfaction Surveys
X
Study Completion Form
X
 X2 = collected at the second visit of the week.
A Completed in the event an injection site reaction is reported by a participant or an abnormality is identified during an injection site examination.
B Collected according to schedule of assessments, but must be prior to administration of ANY medications (e.g., naloxone; injectable or oral study medication) in a given visit. 
D Collected at each visit after consent (i.e. SV02 through the final follow-up visit)
E Completed as applicable
F If consent is provided, collect genetic sample at the end of the day of randomization if possible. Otherwise, collect during any future visit in which a blood draw occurs.
NOTES:  X* = once during screening/baseline    
Follow-up
Medication Phase
C Collected according to schedule of assessments, including  BEFORE and AFTER administration of naloxone challenge(s) as well as BEFORE and AFTER administration of the 
study medication combination. 
X** = required prior to randomization and injectable study medication administration, may be collected at other times per Medical Clinician discretion.
X+ = at each screening/baseline visit
X= a procedure or assessment performed once per week and on the first visit of the week, unless otherwise noted.
2X= a procedure or assessment performed twice per week.

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8.2 
Screening Measures 
8.2.1 
Pre-Screening Interview Form  
Individuals responding to recruitment materials or otherwise referred to the study will be pre-
screened on the phone or in person to ascertain preliminary eligibility status. Prior to administering 
the IRB-approved Pre-Screening Interview, staff will provide a brief overview of the study and will 
obtain and document verbal consent. The Pre-Screening Interview consists of questions to 
assess essential information in determining potential eligibility.  
8.2.2 
Informed Consent 
Prior to beginning any study assessments, all participants will review and sign an IRB-approved 
consent form and any other related documents in accordance with IRB requirements. The date the 
IRB-approved consent form was signed will be entered into the electronic data capture system. 
8.2.3 
Demographics Form 
The Demographics Form will collect information about demographic characteristics of the 
participant at screening including sex, date of birth, ethnicity, race, education, employment 
pattern, and marital status.  
8.2.4 
Alcohol and Substance Use History 
The Alcohol and Substance Use History will be completed at screening to incorporate PhenX 
Core Tier 1 items. The participant will be asked whether he/she has ever used alcohol and/or 
various substances as well as his/her age when the substance was first used. The intent of this 
measure is to document any alcohol use, illicit drug use (e.g., illegal, more than prescribed, not 
prescribed), and any marijuana use. 
8.2.5 
DSM-5 Checklist 
The DSM-5 Checklist has been designed as a semi-structured interviewer-administered 
instrument that provides current diagnoses for substance use disorders based on DSM-5 
diagnostic criteria. The DSM-5 Checklist will be completed at screening. 
8.2.6 
 Psychiatric Diagnostic Screening Questionnaire  
The Psychiatric Diagnostic Screening Questionnaire (Zimmerman, 2002) is a self-report 
questionnaire used primarily as a psychiatric disorder screener administered in primary care. The 
Psychiatric Diagnostic Screening Questionnaire will evaluate symptoms of common psychiatric 
disorders and will be administered during the screening phase. 
8.2.7 
 Self-Report of HIV Testing 
HIV testing status will be assessed via self-report questionnaire using PhenX Core Tier 1 items. 
Items will assess whether the participant has ever had an HIV test, when the most recent test 
occurred, the test result, and, if the participant was not tested in the past 12 months, and the most 
important reason the participant was not tested. This will be administered during the screening 
phase.  

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8.2.8 
Medical and Psychiatric History 
The medical and psychiatric history, collected at screening, will document participants’ past and 
present health conditions to help determine eligibility and to provide baseline information. 
8.3 
Safety Measures 
8.3.1 
Physical Examination 
A physical examination will be completed at screening to ensure there are no exclusionary 
medical conditions and to gather baseline information. The physical at screening will also include 
an examination of the participant’s body habitus and the planned injection site(s) to assess 
appropriateness for intramuscular gluteal injections. The physical examination will be repeated at 
the end of the medication phase (week 12 visit 2).  
8.3.2 
Electrocardiogram (ECG) 
A 12-lead ECG will be administered at screening to assist in determination of participant eligibility 
and again at study exit (i.e., week 12 visit 1) to assess safety at termination. The ECG tracings 
will be reviewed by a qualified medical clinician for accuracy and transmitted to be read by a 
central cardiologist. Results from the central cardiologist’s interpretation will be assessed by a 
qualified medical clinician at the site. 
8.3.3 
Injection Site Examination 
Appropriate medical personnel will examine the injection site on the visit following each 
intramuscular gluteal injection. These examinations will usually occur at visits 0102, 0402, 0702, 
and 1002 but should occur at the next attended visit if any of the aforementioned visits are missed. 
Additional monitoring may also be required. Well-developed precautionary procedures will be 
followed to avoid adverse events associated with injectable study medication administration. For 
example, body habitus will be assessed during the physical exam at screening to assure that 
intramuscular administration is feasible as an inadvertent subcutaneous injection may increase 
the likelihood of injection site reactions. Individuals whose body habitus precludes a gluteal 
intramuscular injection using the needles provided will be excluded from the study. 
8.3.4 
Injection Site Abnormality Log 
Participants will be asked to immediately report any injection site reactions to allow evaluation, 
monitoring, and possible referral, as needed. A log entry is completed in the event an injection 
site reaction is reported by a participant or an abnormality is identified during an injection site 
examination. All injection site reactions should be documented on the Injection Site Abnormality 
Log. If the abnormality results in a Serious Adverse Event (SAE), the Adverse Event forms must 
also be completed. 
8.3.5 
Clinical Laboratory Tests  
A comprehensive blood chemistry including liver function tests (LFTs: including AST, ALT, ALP, 
and bilirubin), hematology panel, and a standard urinalysis will be performed to help determine 
eligibility at screening. At week 6 visit 1, clinical lab tests to assess LFTs and platelet counts will 
be repeated for safety monitoring. Clinical labs completed at screening (chemistry, LFTs, 
hematology, and standard urinalysis) will be repeated during the final week of the medication 
phase (week 12 visit 1). An accredited local laboratory (College of American Pathologists or 

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equivalent) that meets CLIA guidelines will perform testing, provide normal values, and provide 
proof of lab certifications.  
8.3.6 
Concise Health Risk Tracking - Participant Rated Module 
The Concise Health Risk Tracking measure will assess aspects of suicidal ideation and behavior 
using 16 questions scored on a 5-item Likert scale, including ideation frequency, duration and 
severity; identifiable deterrents to an attempt; reasons for living/dying; degree of specificity/planning; 
method availability/opportunity; expectancy of actual attempt; and actual preparation. The Concise 
Health Risk Tracking measure will be used at screening, every week during the medication phase, 
and at the week 13 and 16 follow-up visits. Participants who report a significant suicidal/homicidal 
risk will be assessed by a qualified clinician before leaving the clinic.  
8.3.7 
Pregnancy and Birth Control Assessment 
For females, urine pregnancy test administration, test results, and self-reports of birth control 
method(s) will be documented during screening unless documentation of hysterectomy is 
provided. A urine pregnancy test will be performed prior to the naltrexone pre-induction strategy 
in the screening/baseline phase and may be performed at any other time if clinically indicated or 
if a woman suspects she is pregnant. If a woman is found to be pregnant at any point during the 
study, she will be allowed to continue in the study but will be withdrawn from study medications, 
given an appropriate referral, and followed until resolution of the pregnancy. Self-reports of birth 
control method(s) will be documented every week during the medication phase.  
8.3.8 
Vital Signs 
Vital signs (e.g., body temperature, blood pressure, pulse, respiration rate) will be collected at 
least once during screening, as well as before and after any naloxone challenge conducted during 
the study. During study medication injection clinic visits, vitals will be collected before and after 
participants receive the combination of the study medications. On non-injection clinic visits, vitals 
will be collected weekly before oral medication self-dosing. Vital signs can be repeated to confirm 
the reading or on more frequent intervals, as clinically indicated. 
8.3.9 
Prior and Concomitant Medications 
At screening, the Prior and Concomitant Medications form will collect information about 
prescription and over-the-counter medications used by participants in the prior 30-day period. At 
other visits, the form will document medications taken since the previous data collection visit. 
Participants may be excluded based on medications reported during screening. Participants will 
be instructed to contact the study medical clinician before taking any non-study medications, 
including prescription medications, over-the-counter preparations, and herbal supplements, 
during the course of the study. 
8.3.10 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Medical or psychiatric adverse events (AEs) will be collected by inquiring of participants: “How 
have you been feeling since your last visit?” AEs will be recorded at each visit after consent 
according to the adverse event reporting definitions and procedures. If an AE or abnormality 
suggests medical or psychological deterioration, it will be brought to the attention of the study 
medical clinician for further evaluation. All AEs and SAEs will be medically managed, reported, 
and followed in accordance with applicable regulatory requirements. Seizures will be reported to 
the DSMB. 

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8.3.11 
Naloxone Challenge Form  
The Naloxone Challenge Form will document the time of administration, total dose, route of 
administration, and result of each naloxone challenge administered during the study. A naloxone 
challenge may be conducted at the discretion of the medical clinician prior to any injection of study 
medication; the Naloxone Challenge Form will be completed for each naloxone challenge.  
8.4 
Efficacy Measures 
8.4.1 
Urine Drug Screen  
Urine samples will be collected at every clinic visit. Urine drug screen (UDS) testing will be 
performed on site using an FDA-cleared for use one-step urine drug dip card and/or dipstick 
following all the manufacturer's recommended procedures. 
The UDS will test for the presence of opiates, oxycodone, barbiturates, benzodiazepines, cocaine, 
amphetamines, methamphetamine, marijuana (THC), methadone, and ecstasy (MDMA). Prior to 
drug screening, a temperature and validity assessment will be performed on all urine samples 
collected. The validity assessment will be performed using a commercially available adulterant 
test strip that indicates normal ranges for creatinine, pH (at minimum), nitrate, glutaraldehyde, 
specific gravity, bleach and pyridinium chlorochromate. If the temperature or adulterant test falls 
outside the normal range, the first urine specimen will be considered adulterated and will not be 
screened. In this case, the first urine sample will be discarded, and the participant will be asked 
to provide another sample following oral hydration. If the only out of range value from the second 
sample is a high specific gravity on the adulterant test strip and there are no visible precipitants, 
this sample may be considered not adulterated and can be drug tested. Any other out of range 
value on either the temperature strip or adulterant test indicates adulteration and the second 
sample should not be tested. Study teams at each site may opt to observe the urine collection 
process either at each collection or as deemed necessary (e.g., recommend observing urine 
collection if specimen tampering is suspected) according to clinic standard operating procedures. 
Throughout the study, urine will be tested to evaluate urine opiate levels at 2000 ng/mL. At 
Screening/Baseline and prior to each injection of XR-NTX or iPLB, urine will be tested to evaluate 
urine opiate levels at 300 ng/mL. Additional onsite urine drug testing may occur at 
Screening/Baseline and during the medication phase to detect urine metabolites of other drugs 
that are not detected by the previously described tests. Results from any urine drug test intended 
for forensic use only, or otherwise not cleared by the FDA for use in clinical settings, may not be 
used in any clinical evaluation and is collected for data purposes only. 
8.4.2 
Timeline Followback  
The Timeline Followback (TLFB) procedure (Sobell & Sobell, 1992; Fals-Stewart, 2000) will be 
used to elicit the quantity and frequency of the participant’s self-reported use of cigarettes, e-
cigarettes, alcohol and illicit drug use. At screening, substance use reported by the participant in 
the 30-day period prior to consent will be assessed. The TLFB will be administered at each study 
visit throughout the screening phase, the medication phase and the post medication phase follow-
up visits to document the participant’s self-reported use of substances for each day since the 
previous TLFB assessment. Adherence to this procedure will ensure that self-reported substance 
use for the entire study period is documented without gaps. 

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8.4.3 
Visual Analog Craving Scale  
Participants’ craving for methamphetamine will be documented on a visual analog scale (VAS) 
that ranges from 0 (no craving) to 100 (most intense craving possible). The VAS will be completed 
at each screening visit, once weekly throughout the medication phase, and at the week 13 and 
16 follow-up visits.  
8.4.4 
Patient Health Questionnaire-9 
The Patient Health Questionniare-9 (Kroenke et al., 2001) is a well validated self-report tool that 
measures diagnostic criteria for major depression, severity and frequency of depressive 
symptoms, presence of suicidal ideation, and functional impairment related to depression. The 
Patient Health Questionniare-9 will be collected during screening, weekly during the medication 
phase, and at the week 13 and 16 follow-up visits. 
8.4.5 
Treatment Effectiveness Assessment 
The Treatment Effectiveness Assessment (Ling, 2012) is a 4-item self-administered assessment 
that uses a Likert scale (1-10) to document changes in four life domains: substance use, personal 
responsibilities, health, and community. The Treatment Effectiveness Assessment will be 
collected at screening, mid-treatment (week 6 visit 2) and end-of-treatment (week 12 visit 2). 
8.4.6 
Tobacco Use History 
The Tobacco Use History assessment will be administered at screening, mid-treatment (week 6 
visit 2), and end-of-treatment (week 12 visit 2) to incorporate PhenX Core Tier 1 items. Tobacco 
use items assessed include lifetime use, 30-day quantity and frequency, and age of first tobacco 
use. 
8.4.7 
Quality of Life 
Quality of Life will be assessed using items from the PhenX Core Tier 1. Participants will be asked 
to provide ratings of general health, physical health, and mental health during the past 30 days at 
screening, mid-treatment (week 6 visit 2), and end-of-treatment (week 12 visit 2). 
8.4.8 
Sexual Risk Behaviors  
The Sexual Risk Behaviors assessment will be administered at screening, mid-treatment (week 
6 visit 2), and end-of-treatment (week 12 visit 2) to assess engagement in risky sexual related 
behaviors in the 30 days prior to each assessment. Participants will answer questions about the 
number and sex of sexual partners, HIV status of partners, and use of condoms as well as the 
use of drugs and alcohol during sex.  
8.4.9 
Genetic Sampling 
The NIDA CCTN has requested that blood samples for genetic analysis be obtained for all new 
CTN pharmacotherapy trials. Randomized participants who consented to the optional genetic 
testing will have approximately 30 mL (2 tablespoons) of blood drawn at the end of the day of 
randomization, after all medication administration and monitoring has been completed. However, 
if the sample cannot be collected on the day of randomization, the sample may be collected at 
any subsequent visit, ideally at a visit in which a blood draw is scheduled to occur. The blood 
samples will be coded and only the local investigators will know the identity of the participant 

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providing the sample. The blood sample will be sent to the Rutgers University Cell and DNA 
Repository for storage and future analysis. 
8.5 
Adherence Measures 
8.5.1 
Study Medication Dosing Logs 
Dosing logs will document medication administered in-clinic and dispensed for take-home dosing. 
Medications to be recorded on dosing logs include naloxone, injectable study medication, and 
oral study medication. A dosing log will also document return of oral medication blister cards and 
the participant’s self-report of doses taken. Logs will be completed at each visit when medications 
are dispensed or administered throughout the study. 
8.5.2 
Injection Administration Form 
The Injection Administration Form(s) will document whether injectable study medication is to be 
administered, it will automatically assign (in real time) an injection kit number for administration, 
and it will document information related to the administration of the medication (e.g., time of 
injection). The form is to be completed only after the participant appears in clinic. This form will 
be completed at each visit in which injectable study medication is administered (i.e., weeks 1, 4, 
7, and 10). 
8.5.3 
Oral Medication Dispensation Form 
The Oral Medication Dispensation Form(s) will document whether oral study medication is to be 
dispensed and it will automatically assign (in real time) a blister card number for dispensation. 
The first question on this form is to be completed only after the participant appears in clinic, even 
if oral study medication is not being dispensed.  
8.5.4 
Oral Study Medication Blood Levels 
One of the methods used to evaluate medication adherence requires collecting blood to test for 
bupropion and hydroxybupropion levels at a central bioanalytical laboratory. Blood will be 
collected for this purpose prior to study medication administration at visits 0401, 0701, and 1001 
and again at the final medication phase visit (week 12 visit 2).  
8.5.5 
Video Based Adherence to Oral Study Medication Database 
Dosing adherence will be assessed in part by automated visual recognition software during the 
video capture within the AiCure app. The software converts adherence information into data that 
is automatically entered and stored in the database maintained by AiCure for this study. This 
database will contain data indicating whether a video was submitted, whether the dosing was 
deemed valid (i.e., the study participant is clearly ingesting study medication), and whether the 
dosing was self-reported as opposed to documented via video. Study staff will help ensure 
information in the AiCure dashboard (the visual representation of the database) is accurate. No 
additional logs or forms are required for documenting video based adherence.  
8.5.6 
End of Medication Form 
An End of Medication Form will be completed any time a decision is made to discontinue a 
participant from further medication administration or at the post-medication phase follow-up 
assessment in Week 13. 

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8.6 
Administrative and Other Forms 
8.6.1 
Locator Form 
A locator form will be used to obtain information to assist in tracking participants during treatment 
and at follow-up. The locator form will collect information such as participants’ current address, 
email address, social media accounts, and phone numbers, as well as names, addresses, and 
phone numbers of family/friends who may know how to reach the participants if direct contact 
efforts are unsuccessful. This information will be collected at screening and updated in weeks 3, 
6, 9, and 12 and whenever the participant reports a change in locator information. No identifying 
information from this form will be used in data analyses. 
8.6.2 
Eligibility - Randomization 
The Enrollment form lists all the study inclusion and exclusion criteria and must be completed for 
every participant who has signed consent and entered the screening/baseline phase. Eligibility is 
assessed on an ongoing basis during the screening phase. Only participants who continue to 
meet study eligibility criteria will be allowed to continue in the screening phase, including the 
naltrexone pre-induction procedures (e.g., naloxone challenge). The Enrollment form is to be 
completed in the electronic data capture system after all screening and baseline procedures are 
complete. Eligible participants will be randomized; ineligible participants will be excluded and 
deemed screen failures. 
8.6.3 
Missed Visit Form 
This form is designed to capture the reason any study visit was missed. Once the visit window 
closes without completion of the visit, this Missed Visit Form will be completed directly in the 
electronic data capture system. Completing this form will remove the requirement for most 
assessments scheduled for that missed visit. Active tracking and follow-up should be performed 
for all missed visits.  
8.6.4 
Protocol Deviation Form 
This form should be entered into the electronic data capture system whenever a protocol deviation 
occurs. This form will document a description of the deviation, how it occurred, the corrective 
action taken to resolve the specific deviation, as well as a description of the plan implemented to 
prevent future occurrences of similar deviations.  
8.6.5 
Protocol Satisfaction Surveys 
Satisfaction with medication components, smartphone app, and other study procedures will be 
recorded on the Protocol Satisfaction Survey completed at the week 13 visit. A survey will be 
completed by both the participant and a study team member. These forms will be used in data 
analyses to evaluate secondary objectives including the acceptability of the combination 
medication and the usefulness of smartphone app-based technology for improving and monitoring 
medication adherence. 
8.6.6 
Study Completion Form 
Information regarding when and why study visits were stopped for each participant, including 
whether a participant completed the final follow-up visit in week 16, will be recorded on this form. 

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9.0 
TRAINING 
The study staff will be trained as specified in the Training Plan. Required training will include 
Human Subjects Protection (HSP) and Good Clinical Practice (GCP), as well as protocol-specific 
training as needed (e.g., assessments, study interventions, safety procedures, data management 
and collection). Support mechanisms will also be identified as part of the training (e.g., who to 
contact for aid, questions, resources). All study staff will also complete any additional training per 
their study site and IRB requirements. An Operations Manual will be provided for this study that 
will outline study procedures in more detail as necessary for the day-to-day conduct of the trial. 
The Operations Manual will be used to train study staff, to provide reference for study procedures, 
and to support quality management activities. 
 

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10.0 STATISTICAL ANALYSES 
10.1 General Design 
10.1.1 
Study Hypothesis 
The primary hypothesis is that the combination of extended-release depot naltrexone plus 
extended-release bupropion medication (AMC), relative to the PLB, will be associated with greater 
MA non-use. Participants will be randomized to one of two conditions, PLB or AMC. 
Randomization will be stratified by site. 
10.1.2 
Sample Size 
A sample size of 400 is chosen for this study to detect the difference between the two treatment 
arms. A total of 7 - 10 sites will participate in the trial. It is anticipated that each site will randomize 
approximately 30 - 70 participants over the recruitment period.  
10.1.3 
Primary Outcomes  
The primary efficacy outcome measure is MA-negative urine drug screen (UDS) test results 
obtained during weeks 5 to 6 and weeks 11 to 12, which will be compared by treatment group 
(AMC versus PLB). Participants will be defined as a “responder” if there are at least 75% MA-
negative UDS tests during the pre-specified evaluation period. The treatment groups will be 
compared as to the proportion of responders using a Z test. All treatment comparisons will be 
performed under the Intent-to-Treat (ITT) criteria. 
10.1.4 
Secondary Outcomes 
Secondary outcomes include methamphetamine and other substance use outcomes in the pre-
evaluation period, in the evaluation period, at the follow-up assessment, and any combination of 
these periods, for responders, non-responders, and other sub-groups. Secondary outcomes also 
include depression scores, quality of life, overall functioning, clinic attendance, and ratings of 
participant and staff satisfaction with study procedures, including use of the smartphone app, 
compensation, and study medication. Secondary safety outcomes will be participants’ reports of 
treatment emergent adverse events including serious adverse events collected at scheduled clinic 
visits or via other contact.  
Drug use will be measured by several outcomes including but not limited to the Treatment 
Effectiveness Score (TES; Ling et al., 1997), days of self-reported drug use, number of 
consecutive negative UDS, and UDS as a binary outcome (positive or negative) across time. The 
TES is the percentage of the scheduled urine drug screens that were negative for each drug. 
Mixed-model analysis of repeated measures will be used to explore the presence of time-related 
medication effects, including severity of cravings. In the models, we will control for baseline MA 
use and other key demographic and participant variables. Additional analyses will include 
assessment of drug use in the pre-evaluation period, over the entire medication period and at the 
follow-up assessment. Changes occurring over the medication period in severity and type of drug-
related problems and in quality of life will be analyzed with parametric and nonparametric 
measures. Participant and staff satisfaction ratings will be summarized. A two-sided test of 
significance will be used with a p-value less than 0.05 indicating significance. 
Analyses of secondary outcomes will be primarily performed on all individuals who are 
randomized and inducted onto study medications. Secondary analyses will also be performed by 

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examining responses in subgroups with varying characteristics. Adherence with oral study 
medication dosing will be measured by participant self-report, smartphone device app dosing 
videos, and in-clinic observation. A dosing adherent per-protocol analysis will be performed by 
evaluating response rates in the medication-adherent group. Because per-protocol analyses may 
be biased (Sheiner and Rubin, 1995) an unbiased complier-adjusted-causal-effects analysis (Jo 
and Stuart, 2009) may also be used to adjust for adherence. Multiple testing will not be adjusted 
for in the secondary analyses, since these are not part of the study’s primary objective. When 
multiple tests are conducted, the chance of finding a significant difference in one of the tests, 
when in fact no difference exists, is greater than the stated Type I error rate. The investigators 
are aware of the issues associated with multiple testing and will interpret results with caution. 
All the above mentioned secondary analyses (except staff satisfaction ratings) will be performed 
in a similar way as the primary analysis. For continuous outcomes, ordinary least squares and 
mixed effects model for repeated measures (MMRM) will be used and for binary outcomes, a 
logistic regression will be used. These will be described in the protocol Statistical Analysis Plan 
(SAP). 
10.2 Interim Analyses 
In coordination with the centralized Data and Statistics Center, a DSMB will monitor the progress 
of the trial. As requested by the DSMB, interim analyses of sample size re-estimation and 
monitoring of the efficacy and safety data will be performed. However, if ADAPT-2 has a rapid 
recruitment such that the proportion of Week 12 outcomes realized is small when recruitment is 
completed or nearly completed, discussion with the DSMB will take place about whether sample 
size re-estimation and interim analysis of efficacy data is warranted. 
10.2.1 
Sample Size Re-estimation 
Sample size re-estimation analysis will be conducted when approximately half of the participants 
have been enrolled. This analysis will not reveal the treatment effect observed in the trial at the 
time of this interim analysis. A sample size re-estimation will be performed to assess the adequacy 
of the projected study sample size and whether a sample size increase is warranted.  
The timing of the sample size re-estimation is based on a number of factors: recruitment rate, 
timing of the primary outcome, amount of loss to follow-up, and time to perform the sample size 
re-estimation. The sample size re-estimation will be done only once, and done before any interim 
analysis of the primary outcome is performed. The results of the sample size re-estimation 
analysis would be presented in a closed session of the DSMB, who will then provide a 
recommendation to the NIDA CCTN regarding whether the target sample size should be modified. 
A decision regarding any such modification would be made subsequently by the CCTN, taking 
into consideration the recommendation of the DSMB. 
Update to the sample size: 
The NIDA CTN DSMB reviewed the sample size re-estimation report dated July 23, 2018, 
prepared by the DSC. Based on the results, the DSMB and NIDA CCTN recommended increasing 
the originally planned sample size of 370 by 30 additional participants to maintain the targeted 
90% power. The CCTN approved the increase in sample size to 400 participants in a letter to the 
Lead Investigator dated August 13, 2018. 
 

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10.2.2 
Interim Monitoring of Primary Efficacy Endpoint 
Interim monitoring for efficacy will be performed. There will be no interim efficacy monitoring 
before a sample size re-estimation is performed (or a determination that re-estimation is not 
needed) because sample size re-estimation could change the target sample size, affecting the 
alpha spending function used in the interim efficacy monitoring. After sample size re-estimation, 
interim efficacy monitoring will be performed only once during the recruitment period.  
All interim monitoring will use an O’Brien-Fleming-type boundary with information fraction equal 
to the proportion of the target sample size with primary outcome. This approach spends very little 
alpha at the interim look, therefore the impact of an interim monitoring on the sample size is 
negligible. The only criterion for early stopping for efficacy will be based on Z-scores and its 
relation to O’Brien-Fleming-type boundary. 
Before recommending early termination, the DSMB will consider: 
 
Internal consistency of primary and secondary results. 
 
Internal consistency of primary and secondary results by subgroups defined by baseline 
characteristics (e.g., severity of MA use, tobacco use history, treatment effectiveness 
assessment and visual analog craving scale). 
 
Distribution of baseline prognostic factors among the two groups. 
 
Consistency of primary and secondary results across clinical sites and among clinical 
sites enrolling larger numbers of participants. 
 
Possible impact of missing data from missed participant visits for assessment of the 
primary and secondary response variables. 
 
Possible differences in concomitant interventions or medications. 
10.2.3 
Safety Interim Analyses 
Safety interim looks will be performed for the regular DSMB meetings or at unscheduled times 
per the DSMB’s request. These will include analysis of adverse events and narrative reports on 
serious adverse events. 
Simultaneous with primary interim efficacy monitoring analysis, a “poor efficacy” statistic will be 
calculated to assess whether the combination of extended-release depot naltrexone plus 
extended-release bupropion medication (AMC), relative to the PLB, is associated with greater MA 
use. This analysis will be conducted after the sample size re-estimation. If the “poor efficacy of 
AMC” statistic crosses its boundary, defined as the response rate for PLB minus AMC being 
greater than 10%, the DSMB will consider whether to stop the trial early because of poor efficacy 
of AMC relative to PLB.  
10.2.4 
Conditional Power and Futility 
Unless otherwise requested, a futility/conditional power calculation will be performed every time 
interim monitoring is performed. If at any DSMB meeting the conditional power falls below 0.3, 
this will stimulate a discussion among the DSMB members about whether we should stop for 
futility. 

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10.3 Demographic and Baseline Characteristics 
Baseline demographic and clinical variables will be summarized for participants randomized and 
inducted on study medications. 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.  
10.4 Description of Plans to Conduct Analyses of Study Results by Sex 
and Race/Ethnicity 
The association between specific demographic characteristics and outcome will be studied. The 
demographic characteristics of potential importance include: age, sex, race, and ethnicity. In 
accordance with NIH guidelines, analyses will be completed to determine whether treatment 
response was significantly affected by participant minority/sex status using an interaction term for 
treatment, time and minority/sex as appropriate. 
10.5 Safety Analysis 
AEs, including SAEs, will be summarized by body system and preferred term using MedDRA 
codes (per The Medical Dictionary for Regulatory Activities). AEs 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 
body system, and preferred term. Detail in these listings will include severity, relationship to study 
drug(s), and action taken, as available. 

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11.0 REGULATORY COMPLIANCE, REPORTING AND MONITORING 
11.1 Statement of Compliance 
This study will be conducted in compliance with the current version of the study protocol, in 
accordance with the ethical principles outlined in the Declaration of Helsinki, consistent with 
current International Conference on Harmonization Good Clinical Practice (GCP) Guidelines, and 
all other applicable regulatory requirements.  
11.2 Institutional Review Board Approval 
Participating sites must obtain written approval of the study protocol, consent form(s), other 
supporting documents, any materials given to the participant, and any advertising for participant 
recruitment from their Institutional Review Board (IRB) of record or Independent Ethics Committee 
(IEC) to participate in the study. Prior to initiating the study, site investigators will obtain written 
IRB approval to conduct the study at their respective site. Any amendments to the protocol or 
consent must be approved by the Lead Investigator and IRB before implementation. Progress 
reports, and any required post-approval reports will be submitted to the IRBs either annually or at 
a frequency requested by each IRB so that continuous study approval is maintained without lapse. 
The Lead Investigator is responsible for maintaining copies of all performance site(s)’ current IRB 
approval notice(s) and IRB-approved consent document(s), including approvals for all protocol 
and consent modifications. These materials must be received by the Lead Investigator prior to 
the initiation of research activities at a given site, must be maintained by the Lead Investigator 
throughout the course of the trial, and must be available at any time for audit. 
11.3 Research Advisory Panel of California (California sites only) 
Prior to initiating the study, the sponsor or designee will obtain written approval from the Research 
Advisory Panel of California (RAP-C). Any planned research project to be conducted in California 
requiring the use of a Schedule I or Schedule II Controlled Substance as its main study drug as 
well as research for the treatment of controlled substance addiction or abuse utilizing any drug, 
scheduled or not, must be submitted to RAP-C for review and approval prior to study start-up. 
Study approval is based on review of the study protocol, consent form, and other pertinent study 
documents. Yearly reports will be provided to the RAP-C by the sponsor or designee to maintain 
continuing study approval. Protocol amendments must also be submitted, and it is required that 
the Panel be notified of any significant study drug related adverse events that may emerge during 
conduct of the study at the California sites only. 
11.4 Informed Consent 
All potential candidates for the study will be given a current IRB-approved consent form in English 
to read. In accordance with IRB policies, appropriately trained and qualified study personnel will 
explain all aspects of the study in lay language and answer all the study candidates’ questions. 
Participants who remain interested after receiving an explanation of the study will be given a short 
quiz to test their understanding of the project including the purpose, procedures involved, and the 
voluntary nature of participation. Those who cannot successfully answer all quiz items will have 
the study re-explained by research staff with a focus on aspects they did not understand. Anyone 
who cannot demonstrate appropriate understanding of the study will be ineligible to participate 
and will be assisted in finding other treatment resources. Those who demonstrate understanding 
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form. Participants will not be administered any assessments or participate in study procedures in 
any way prior to signing and dating the IRB-approved consent form. 
Informed consent is a process and not just a document. The informed consent process is a means 
of providing study information to each prospective participant in understandable language and 
taking all the time needed to answer all questions to allow for an informed decision about study 
participation. The IRB-approved consent form must be revised whenever important new 
information becomes available including whenever the protocol is amended in any way that may 
affect a study participant’s willingness to continue participating in the trial. All study sites must 
have the study consent forms approved by their IRB(s). Sites must maintain the original signed 
IRB-approved consent forms for all study participants in a locked, secure location that is in 
compliance with IRB and institutional policies. Signed/dated IRB-approved consent forms must 
be accessible for quality assurance review and regulatory compliance at all times. Every study 
participant will be provided with a copy of the signed/dated consent form that can be used as 
continual reference for study information including procedures, possible risks and/or side effects, 
and contact information for questions and/or emergencies. California site participants will also be 
provided with a California Research Subjects’ Bill of Rights. Individuals who refuse to participate 
or who withdraw from the study will be treated without prejudice.  
11.5 Health Insurance Portability Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. 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 laws and regulations, are prohibited. Sites will be responsible for 
communicating with their IRBs or Privacy Boards and obtaining the appropriate approvals or 
waivers to be in regulatory compliance. 
11.6 Investigator Assurances 
Each participating site must file (or have previously filed) a Federalwide Assurance (FWA) with 
the HHS Office for Human Research Protections setting forth the commitment of the organization 
to adhere to appropriate policies and procedures for the protection of human research subjects. 
The site’s FWA must be current at trial initiation and must be maintained throughout the duration 
of the study with documentation sent to NIDA or its designee, as requested. 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 OHRP-registered IRB designated in the 
assurance (45 CFR 46.103(b) and (f)). Prior to initiating the study, the principal investigator and 
sub-investigators at each study site will sign a protocol signature page, providing assurances that 
the study will be performed according to the standards stipulated therein. 
11.7 Financial Disclosure 
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. All study personnel with decision-making responsibilities regarding the protocol must 
comply with their institution’s policy regarding conflict of interest. 

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11.8 Confidentiality 
Confidentiality will be maintained in accordance with all applicable federal regulations and/or state 
law and regulations. Particular attention is drawn to the regulations promulgated by the Food and 
Drug Administration (FDA) under the Freedom of Information Act providing, in part, that 
proprietary information furnished to investigators and Institutional Review Boards will be kept 
confidential by the FDA only if maintained in confidence by the clinical investigator and 
Institutional Review Board (IRB). By signing 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, Ethical Review Committee, or similar expert committee; 
affiliated institution; and employees only under an appropriate understanding of confidentiality 
with such board or committee, affiliated institution and employees.  
The Lead Investigator obtained a federal Certificate of Confidentiality (CoC) and distributed it to 
all sites when it was received. A CoC helps researchers protect the privacy of human research 
participants enrolled in biomedical, behavioral, clinical and other forms of sensitive health-
related research (e.g., drug use). Certificates protect against compulsory legal demands, such as 
court orders and subpoenas, for identifying information or identifying characteristics of a research 
participant. The department that issues the CoC will be advised of any changes in the CoC 
application information that may occur during the study, as required. Participating sites will be 
notified if CoC revision is necessary.  
Participant records will be kept confidential by using study codes for identifying participants on 
CRFs, secure separate storage of any documents that have participant identifiers, and secure 
computing procedures for entering and transferring electronic data. All laboratory specimens, 
eCRFs, reports, and other data records will be identified by the participant identification study 
code that includes the site number, node number, and participant number. Research records will 
be stored in a locked cabinet. Only authorized individuals will have access to the study records. 
Participant information will not be released without written permission, except as necessary for 
monitoring by the FDA, NIDA-contracted monitors, local node monitors, lead node staff, or NIDA. 
By signing the protocol signature page, the investigator agrees that within local regulatory 
restrictions and ethical considerations, NIDA or any regulatory agency may consult and/or copy 
study documents in order to verify eCRF data. 
11.9 IND Requirements 
A request for IND exemption was submitted to FDA for this protocol, as described in title 21 of the 
Code of Federal Regulations, part 312 (21 CFR 312) and the Agency determined that the ADAPT-
2 study was exempt from FDA IND regulations, as per Title 21 of the Code of Federal Regulations, 
Part 312.2. 
Though exempt from IND regulation, this study will be conducted in accordance with International 
Council on Harmonisation Good Clinical Practices (ICH GCPs), all applicable FDA and OHRP 
Guidance documents, and any state and institutional requirements applicable at the clinical site 
level. 
11.10 Regulatory Files 
Essential documents are those documents which individually and collectively permit evaluation of 
the conduct of a trial and the quality of the data produced. These documents serve to demonstrate 
the compliance of the investigator, sponsor and monitor with the standards of Good Clinical 
Practice and with all applicable regulatory requirements. Regulatory files should be maintained 
throughout the lifecycle of the trial and should contain all required regulatory documents, study-

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specific documents, and all important study-related communications. Regulatory files will be 
checked at each participating site for regulatory document compliance prior to study initiation, 
throughout the study, as well as at study closure.  
11.11 Study Documentation 
Study documentation includes, but is not limited to, all data-related forms, workbooks, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence, 
signed protocols including amendments, Ethics Review Committee or Institutional Review 
Board/Committee correspondence, approved current and previous consent forms, and signed 
participant consent forms. Source documents include all recordings of observations or notations 
of clinical activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. All clinical trial information should be recorded, handled, and stored in 
a way that allows its accurate reporting, interpretation, and verification. The original recording of 
an observation should be retained as the source document.  
11.12 Records Retention and Requirements 
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, and regulatory files) are to be maintained by the investigator in a secure location 
for a minimum of 3 years after the study is completed and closed. These records are also to be 
maintained in compliance with IRB, state and federal requirements, whichever is longest. The 
sponsor and Lead Investigator must be notified in writing and acknowledgment must be received 
by the site prior to the destruction or relocation of research records. 
11.13 Reporting to Sponsor 
The site principal investigator agrees to submit accurate, complete, legible and timely reports to 
the sponsor, as required. These include, but are not limited to, reports of any changes that 
significantly affect the conduct or outcome of the trial or increase risk to study participants. 
Adverse Event reporting and Serious Adverse Event reporting will occur as described herein. At 
the completion of the trial, the Lead Investigator will provide a final report to the sponsor. 
11.14 Safety Monitoring 
11.14.1 
Adverse Events (AEs) 
All adverse events (medical and/or psychiatric) occurring during the course of the study will be 
assessed, documented, and reported. AEs occurring during the course of the clinical trial will be 
collected, documented, and reported by the principal investigator or sub-investigators according 
to the specific instructions detailed in this section of the protocol and Appendix A. Appropriately 
qualified and trained medical personnel will elicit participant reporting of AEs and SAEs at each 
study visit designated to collect AEs (i.e., the first visit following informed consent and at every 
visit thereafter). Study staff will follow-up on the status of any AEs that remain at the post-
medication phase follow-up visit assessment for up to 30 days post last study visit.  
An AE is defined as any reaction, side effect, or untoward event that occurs during the course of 
the clinical trial, whether or not the event is considered investigational product-related or clinically 
significant. For this study, AEs will include events reported by the participant, as well as clinically 
significant abnormal findings on physical examinations or laboratory evaluations. A new illness, 
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condition or abnormality is considered an AE. Stable chronic conditions, such as arthritis, which 
are present prior to clinical trial entry and do not worsen are not considered AEs. All AEs must be 
recorded on the AE log and CRF. The AE log and CRF are also used to record follow-up 
information for unresolved events reported on previous visits. 
Each week, appropriately qualified and trained medical personnel must review the AE log and 
CRF completed for the previous week for any events that were reported as continuing. All AEs, 
including clinically significant abnormal findings on laboratory evaluations, regardless of severity, 
will be followed until satisfactory resolution.  
A study medical clinician (MD, DO, PA, or NP) will review or provide consultation for each adverse 
event. These reviews will include an assessment of the severity and causality to the study drug 
or study procedures. The study medical clinician, in collaboration with the study physician and 
site principal investigator, will also make decisions to exclude, refer, or withdraw participants as 
required. The study staff will be trained to monitor for and report adverse events and serious 
adverse events. 
Each participating site has established practices for managing medical and psychiatric 
emergencies, and the study staff will continue to utilize these procedures. Study medical clinicians 
at each site will be responsible for monitoring participants for possible clinical deterioration or 
other problems, and for implementing appropriate courses of action. 
11.14.2 
 Definitions of Adverse Events and Serious Adverse Events 
Full definitions of adverse events and serious adverse events, their identification, and 
characterization regarding severity and relationship to therapy and processing are described in 
Appendix A. 
11.14.3 
 Reportable Adverse Events and Serious Adverse Events 
For the purpose of this study, all AEs and SAEs will require reporting in the electronic data system. 
Reporting of AEs and SAEs is described in Appendix A. The local site is responsible for reporting 
all their local AEs and SAEs to their IRBs per IRB guidelines. 
11.14.4 
Data and Safety Monitoring Board (DSMB) 
This study will utilize the CTN DSMB to oversee ongoing trial progress. The purpose of this board 
is to determine whether risks emerge during the conduct of the trial that make continuation 
unethical. This process is intended to assure the IRBs, the sponsor, and investigators that 
participants are provided with an accurate and ongoing risk evaluation when participating in CTN 
research trials. Safety monitoring begins with the initial review of the protocol during the study 
development process. Reports of participant seizures will be provided to the DSMB as they occur. 
The DSMB will meet as necessary over the study duration. 
11.14.5 
Medical Monitor 
Under the supervision of the NIDA-assigned Medical Monitor, the study Safety Monitor will be 
responsible for overseeing safety and for evaluating all Adverse Events (AEs). The Safety Monitor 
will review all Serious Adverse Events (SAEs) within one business day of their reporting in 
eClinical and all other Adverse Events on a regular basis. The Medical Monitor will review events 
regularly and will be available at all times for consultation. It is the responsibility of the site principal 
investigator to provide this information to the Safety Monitor. It is also the site principal 
investigators’ responsibility to inform the IRBs per IRB guidelines. 
 

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In addition, the Medical Monitor will independently review the safety data, present it to the DSMB 
for periodic review, and provide site principal investigators a “Safety Letter” when necessary. The 
Medical Monitor will determine which safety events require expedited reporting to NIDA, the 
DSMB, study drug manufacturers, and regulatory authorities. This will include all suspected 
adverse reactions that are serious and unexpected. Furthermore, in the event of participant 
seizures, reports will be submitted to the DSMB using the AE form with additional information 
about the event as deemed appropriate. 
11.15 Protocol Deviations: Reporting and Management 
Any divergence from procedures and requirements outlined in the protocol will be classified a 
protocol deviation. A protocol deviation is an action (or inaction) that alone may or may not affect 
the scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a 
study participant. In some cases, a protocol deviation may compromise participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and is cause for 
corrective action to resolve the departure and to prevent re-occurrence. Protocol deviations will 
be monitored at each site for (1) significance, (2) frequency, and (3) impact on the study 
objectives, to ensure that site performance does not compromise the integrity of the trial. The 
decision about whether a deviation from the protocol will be designated as minor or major will be 
made by the protocol’s Lead Investigator(s) in conjunction with the Clinical Coordinating Center 
(CCC). The consequences will be specified and participating sites will be informed. 
All protocol deviations will be recorded in the Electronic Data Capture (EDC) system via the 
Protocol Deviation CRF. Additionally, each site is responsible for tracking and reporting protocol 
deviations to their IRB, as required. The CCC and the Data and Statistics Center (DSC) and the 
Lead Investigator must be contacted immediately if an unqualified/ineligible participant is entered 
into the study. 
11.16 Audits 
The Sponsor has an obligation to ensure that this trial is conducted according to good research 
practice guidelines and may perform quality assurance audits for protocol compliance. The Lead 
Investigator and authorized staff from the Texas Node; the National Institute on Drug Abuse 
Center for the Clinical Trials Network (NIDA CCTN, the study sponsor); NIDA’s contracted agents, 
monitors or auditors; and other agencies, such as the Department of Health and Human Services 
(HHS), the Food and Drug Administration (FDA), the Office for Human Research Protections 
(OHRP), and the sites’ Institutional Review Boards may inspect research records for verification 
of data, compliance with federal guidelines on human participant research, and to assess 
participant safety. 
11.17 Quality Assurance Monitoring 
Protection of the rights and welfare of study participants will be a vigilant process conducted by 
the research teams at all sites and at the Lead Node and by the sponsors of the research. 
Monitoring of the study sites will be conducted on a regular basis using a combination of NIDA- 
contracted monitors, local node monitors, and lead node staff.  
Site investigators will host periodic visits by monitors who will ensure all study procedures are 
appropriately conducted, 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), and corresponding 
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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 signed/dated consents, eligibility for study 
participation, protocol adherence, safety monitoring, IRB reviews and approvals, regulatory 
documents, participant records, study drug accountability, and principal investigator supervision 
and involvement in the trial. Reports will be prepared following the visits and forwarded to the site 
principal investigator, the Lead Investigator and NIDA CCTN. 
Qualified node personnel (Node Protocol Managers and/or QA monitors) will provide site 
management for each site during the trial to encourage and assess compliance with the study 
protocol, Good Clinical Practice guidelines, and to ensure the integrity of the trial progress. These 
visits will take place as specified by the local protocol team, Node PI or Lead Team, and visits will 
occur as often as needed to help prevent, detect, and correct problems at the study sites. Node 
staff will ensure that study procedures are properly followed and that site staff are trained and 
able to conduct the protocol appropriately. If the node staff’s review of study documentation 
indicates that additional training of study personnel is needed, node staff will undertake or arrange 
for that training.  

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12.0 DATA MANAGEMENT AND PROCEDURES 
12.1 Design and Development 
This protocol will utilize a centralized Data and Statistics Center (DSC). The DSC will be 
responsible for the development of the Case Report Forms (CRFs) and Participant Reported 
Outcome (PRO) forms, development and validation of the clinical study database, ensuring data 
integrity, and training site and participating node staff on applicable data management 
procedures. 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 used in clinical trials are upheld. The remainder of 
this section provides an overview of the data management plan associated with this protocol. 
12.2 Site Responsibilities 
The data management responsibilities of each site will be specified by the Lead Node and the 
DSC. 
12.3 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 Case Report Forms in electronic (eCRF) and paper 
(CRF) format, and Participant Reported Outcome forms in electronic (ePRO) and paper (PRO) 
format for the collection of all data required by the study, 3) develop data dictionaries for each 
CRF and PRO form that will comprehensively define each data element, 4) prepare instructions 
for the use of Advantage eClinical and for the completion of forms, 5) conduct ongoing data 
validation and cleaning activities on study data collected from all participating sites, and 6) perform 
data validation and cleaning activities prior to any interim analyses and prior to the final study 
database lock.  
12.4 Data Collection and Entry 
Data will be collected at the study sites on source documents and entered by the site on the form 
in Advantage eClinical, or will be collected via direct entry into the eCRF by the site or direct entry 
into the ePRO by the participant. In the event that Advantage eClinical is not available, the DSC 
will provide the sites with paper source documents and completion instructions. Data will be 
entered into Advantage eClinical in accordance with the instructions provided during protocol-
specific training and guidelines established by the DSC. Data entry into the forms shall be 
performed by authorized individuals. Selected eCRFs may also require the investigator’s 
electronic signature. 
The principal investigator at the site is responsible for maintaining accurate, complete and up-to-
date research records. In addition, the investigator is responsible for ensuring the timely 
completion of forms for each research participant.  
12.5 Data Monitoring, Cleaning, and Editing 
Data will be entered into the DSC automated data acquisition and management system 
(Advantage eClinical). Forms will be monitored for completeness and accuracy throughout the 
study. Dynamic reports listing missing values and forms are available to sites at all times in 

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Advantage eClinical. These reports will be monitored regularly by the DSC. In addition, the DSC 
will identify inconsistencies within forms and between forms and post data clarification requests 
or queries in Advantage eClinical on a scheduled basis. Sites will resolve data inconsistencies 
and errors by entering all corrections and changes directly into Advantage eClinical. 
The CCC will conduct regular visits to sites, during which audits comparing source documents to 
the data entered will be performed. Any discrepancies identified between the source document 
and the eCRF or ePRO will be corrected by the site. 
Trial progress and data status reports, which provide information on recruitment, availability of 
primary outcome, treatment exposure, attendance at follow-up visits, regulatory status, and data 
quality, will be generated routinely and posted to a secure website. These reports will be available 
to the site, the corresponding Local Node, the Lead Investigator, the coordinating centers, and 
NIDA, to monitor the sites’ progress on the study. 
12.6 Database Transfer and Lock 
At the conclusion of data collection for the study, the DSC will perform final data cleaning activities 
and will “lock” the study database from further modification. The final analysis dataset will be 
returned to the Lead Investigator and to NIDA, as requested, for storage and archive. 

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13.0 PUBLICATIONS AND OTHER RIGHTS 
Protocol development and implementation in the NIDA CTN is a collaborative process. The 
planning, preparation, and submission of publications will follow the policies of the CTN 
Publications Committee. Individuals making substantive contributions to the protocol 
development and implementation will have opportunities to participate in publications. Other 
contributors will also be acknowledged. Per NIH policy, the results of the trial are to be made 
available to the research community and to the public at large. The project will adhere to 
stipulations in accord with the NIH Public Access Policy (for any articles based on work supported 
by NIH funding) required for Applications, Proposals, or Reports Submitted After July 1, 2013, as 
set forth in: 
http://publicaccess.nih.gov/ 
http://publicaccess.nih.gov/FAQ.htm#792 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-119.html  
 

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14.0 SIGNATURES 
 
SPONSOR’S REPRESENTATIVE (CCTN DESIGNEE) 
 
 
 
 
 
Udi Ghitza, PhD 
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
 
 
I am in receipt of version 6.0 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 
 
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15.0 REFERENCES 
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Haggkvist, J., Lindholm, S., & Franck, J. (2009). The opioid receptor antagonist naltrexone 
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Jayaram-Lindstrom, N., Wennberg, P., Beck, O., & Franck, J. (2005). An open clinical trial of 
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Kim, S., Westphalen, R., Callahan, B., Hatzidimitriou, G., Yuan, J., & Ricaurte, G. A. (2000). 
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Koffarnus, M. N., & Bickel, W. K. (2014). A 5-trial adjusting delay discounting task: accurate 
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Margolin, A., Kosten, T. R., Avants, S. K., Wilkins, J., Ling, W., Beckson, M., . . . et al. (1995). A 
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1332. doi:10.4088/JCP.10m06724 

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

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pregnant during the medication period will be discontinued from further medication administration, 
referred for medical care, and the pregnancy followed until an outcome is known. 
Medical and Psychiatric History 
A thorough medical and psychiatric history during the screening/baseline phase should record 
any chronic, acute, or intermittent preexisting or current illnesses, diseases, symptoms, or 
laboratory signs of the participant, to avoid reporting pre-existing conditions as new AEs and to 
assist in the assessment of worsening in intensity or severity of these conditions that would 
indicate an AE. Stable chronic conditions, such as arthritis, which are present prior to clinical trial 
entry and do not worsen are not considered AEs. 
Site Staff’s Role in Eliciting and Reporting Adverse Events  
All adverse events (medical and/or psychiatric) occurring during the course of the study will be 
assessed, documented, and reported. Appropriately qualified and trained medical personnel will 
elicit participant reporting of AEs and SAEs at each study visit designated to collect AEs (i.e., the 
first visit following informed consent and at every visit thereafter). Study staff will follow-up on the 
status of any AEs that remain at the post-medication phase follow-up visit assessment for up to 
30 days post last study visit. Study personnel will obtain as much information as possible about 
the reported AE/SAE in order to complete AE/SAE documentation (i.e., log and CRFs) and will 
consult with medical clinicians and the Study Medical Monitor as necessary.  
Standard reporting, within 7 days of the site staff becoming aware of the event, is required for 
AEs. Expedited reporting, within 24 hours of their occurrence and/or site staff's knowledge of the 
event, is required for SAEs (including death and life-threatening events). Site staff is responsible 
for reporting SAEs to the IRB, per IRB’s guidelines. 
Site staff is required to enter AEs and SAEs in the eClinical system as soon as they become 
aware of the event. The AE log and CRF are used to capture AEs (as defined in the protocol). 
Additional information may need to be gathered to evaluate serious adverse events and to 
complete the appropriate CRFs and the summary. This process may include obtaining hospital 
discharge reports, medical records, autopsy records or any other type of records or information 
necessary to provide a complete and clear picture of the 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. 
Adverse events will be followed until resolution, stabilization or study end. Any serious adverse 
reactions will be followed until resolution or stabilization even beyond the end of the study.  
Site Staff’s Role in Assessing Severity and Causality of Adverse Events 
Appropriately qualified and trained medical personnel will conduct an initial assessment of 
seriousness, severity, and causality when eliciting participant reporting of adverse events. A study 
medical clinician will review AEs for seriousness, severity, and causality on at least a weekly 
basis. 
 
 

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Guidelines for Assessing Severity  
The severity of an adverse event refers to the intensity of the event. 
Grade 1 
Mild 
Transient or mild discomfort (< 48 hours), no or minimal medical 
intervention/therapy 
required, 
hospitalization 
not 
necessary 
(non-prescription or single-use prescription therapy may be 
employed to relieve symptoms, e.g., aspirin for simple headache, 
acetaminophen for post-surgical pain) 
Grade 2 
Moderate 
Mild to moderate limitation in activity, some assistance may be 
needed; no or minimal intervention/therapy required, hospitalization 
possible. 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/ therapy required, hospitalization possible. 
 
Guidelines for Determining Causality 
The study medical clinician will use the following question when assessing causality of an adverse 
event to study drug/intervention where an affirmative answer designates the event as a suspected 
adverse reaction: 
Is there a reasonable possibility that the study drug/intervention caused the event?  
Quality Assurance Staff’s Role in Monitoring Adverse Events 
Quality assurance monitors (from the node staff and the CRO contract monitor staff) will review 
safety documentation on a regular basis and will promptly advise site staff to report any previously 
unreported safety issues and ensure that the reportable safety-related events are being followed 
to resolution and reported appropriately. Staff education, re-training or appropriate corrective 
action plan will be implemented at the participating site when unreported or unidentified reportable 
AEs or serious events are discovered, to help ensure future identification and timely reporting. 
Sponsor’s Role in Safety Management Procedures of AEs/SAEs 
A NIDA-assigned Medical Monitor is responsible for reviewing all serious adverse event reports. 
All reported SAEs will generate an e-mail notification to the Medical Monitor, Lead Investigator, 
and designees. All SAEs will be reviewed by the Medical Monitor and, if needed, additional 
information will be requested. The Medical Monitor will also report events to the sponsor, the Data 
and Safety Monitoring Board (DSMB), study drug manufacturers, and regulatory authorities. The 
DSMB will receive summary reports of all adverse events annually, at a minimum. The DSMB or 
the NIDA assigned Medical Monitor may also request additional and updated information. Details 
regarding specific adverse events, their treatment and resolution, will be summarized by the 
Medical Monitor in writing for review by the sponsor and DSMB. Subsequent review by the 
Medical Monitor, DSMB, and ethics review committee or IRB, the sponsor, or relevant local 
regulatory authorities may also suspend further trial treatment at a site. The study sponsor and 
the DSMB retain the authority to suspend additional enrollment and treatments for the entire study 
as applicable. 
Reporting to the Data and Safety Monitoring Board 
The DSMB will receive a listing of AEs and summary reports of all SAEs at a frequency requested 
by the DSMB, but at least annually. Furthermore, the DSMB will be informed of expedited reports 
of SAEs. 
 
 

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Participant Withdrawal 
The study medical clinician must apply his/her clinical judgment to determine whether or not an 
adverse event is of sufficient severity to require that the participant is withdrawn from further study 
medication administration. The study medical clinician should consult with the study physician, 
site principal investigator, the Lead Investigator and/or Medical Monitor as needed. If necessary, 
a study medical clinician may suspend any trial treatments and institute the necessary medical 
therapy to protect a participant from any immediate danger. A participant may also voluntarily 
withdraw from treatment due to what he/she perceives as an intolerable adverse event or for any 
other reason. If voluntary withdrawal is requested, 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. Other 
reasons for the investigator or sponsor terminating a participant from the study may include, but 
are not limited to, the participant becoming a threat to self or others, lack of funding, or DSMB 
early termination of the study for safety or effectiveness reasons.  
 
AE Chart 
 
AEs Identified
Research staff documents AE 
information on AE Log. A Study 
Medical Clinician will review AEs for 
seriousness, severity, and causality.
Is the event a 
Serious AE?
(SAE)
Continue follow-up and reporting until 
event is resolved, stabilized or 
participant is lost to follow-up and/or 
terminated from the study.
Safety monitor reports event to 
sponsor and DSMB at the frequency 
requested by the DSMB.
Continue follow-up and reporting until 
event is resolved, stabilized or 
participant is lost to follow-up and/or 
terminated from the study.
No
Yes
Research staff completes AE eCRF.
Standard reporting within 7 days of 
knowledge of the event.
Site PI or designee submits AE & SAE 
eCRF with as much info as is available. 
Expedited initial reporting within 24 
hours of knowledge of the event. 
EDC system will automatically notify 
Safety Monitor, Lead Investigator(s). 
 
 

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17.0 APPENDIX B - DATA AND SAFETY MONITORING PLAN 
BRIEF STUDY OVERVIEW 
This double-blind, placebo-controlled, randomized clinical trial will investigate a combination 
medication, extended-release injectable naltrexone plus extended-release bupropion, compared 
to placebo as a potential pharmacotherapy for MA dependence. Screening will occur over a 
maximum of 21 days. Study medications will be provided during a 12-week medication phase. 
Participants will be randomized to either the active medication combination (AMC) arm in which 
injections of extended-release naltrexone (XR-NTX; as Vivitrol®) plus 450 mg / day oral extended-
release bupropion (BUP-XL) tablets will be provided or the matching placebo (PLB) arm in which 
injections of placebo (iPLB) and once daily oral placebo (oPLB) tablets will be provided. Injections 
will be provided in weeks 1, 4, 7, and 10. Participants will be asked to attend clinic twice weekly 
for observed oral medication dosing and provision of take-home oral medication, collection of 
urine samples, assessments, and medical management. Following the 12-week medication 
phase, participants will complete a follow-up phase, including a medication taper and post-
medication phase follow-up visits during Weeks 13 and 16. 
Details for the definitions and reporting of safety events are found in Appendix A of the protocol. 
OVERSIGHT OF CLINICAL RESPONSIBILITIES 
A. Site Principal Investigator 
Each participating site’s PI is responsible for study oversight, including ensuring human research 
subject protection by designating appropriately qualified, trained research staff and medical 
clinicians to assess, report, and monitor adverse events.  
Regarding safety, all Adverse Events (AEs) occurring during the course of the clinical trial will be 
collected, documented, and reported by the investigator or sub-investigators according to the 
protocol. The assessment of Adverse Events (medical and/or psychiatric) will commence the visit 
after consent and will continue through all study visits. Study staff will follow-up on the status of 
any AEs that remain for up to 30 days after the last planned study visit in week 16. 
The occurrence of AEs and Serious Adverse Events (SAEs) will be assessed at each clinic visit 
after consent. All adverse events will be followed until resolution, stabilization or study end. 
Serious adverse events will be followed until resolved or considered stable, with reporting to the 
CCC Safety Monitor/Medical Monitor through the follow-up period. 
Standard reporting, within 7 days of the site becoming aware of the event, is required for AEs. 
Expedited reporting (within 24 hours of their occurrence and/or site's knowledge of the event) is 
required for reportable SAEs (including death and life-threatening events).  
B. Medical Monitor/Safety Monitor 
The NIDA Clinical Coordinating Center (CCC) Safety Monitor/Medical Monitor is responsible for 
reviewing all adverse events and serious adverse events reported. All SAEs will be reviewed at 
the time they are reported in eClinical. The 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 
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in the Advantage eClinical data system and will be a part of the safety database. All AEs will be 
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, study drug 
manufacturers, and regulatory authorities if the event meets the definition of an expedited event. 
All SAEs that meet expedited reporting based on federal regulations will be reported to the DSMB 
in writing within 15 calendar days of notification of the CCC. If the SAE meets the criteria for death 
or is immediately life-threatening, the CCC will notify the DSMB electronically, by phone or by fax 
as soon as possible but no later than 7 calendar days of notification of the CCC, with a follow-up 
written report within 15 calendar days of notification of the CCC. The CCC will prepare an 
expedited report and copies will be distributed to site investigators. 
Reports will be generated and presented for Data and Safety Monitoring Board (DSMB) meetings. 
The DSMB will receive listings of AEs and summary reports of all SAEs at a frequency requested 
by the DSMB, but at least annually. Furthermore, the DSMB will be informed of expedited reports 
of SAEs. 
C. Data and Safety Monitoring Board (DSMB) 
The NIDA CTN DSMB affiliated with this trial will be responsible for conducting periodic reviews 
of accumulating safety, trial performance, and outcome data. The DSMB will make 
recommendations to NIDA as to whether there is sufficient support for continuation of the trial, 
that study procedures should be changed, or 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, 
including DSMB recommendations, in writing to the study Lead Investigator. Study safety 
information will be submitted to participating IRBs. 
D. Quality Assurance (QA) Monitoring 
Monitoring of study sites will be conducted on a regular basis using a combination of NIDA CCC 
contract monitors, the local node site managers, and lead node staff. The purpose of these visits 
is to assess compliance with GCP requirements and to document the integrity of the trial progress. 
Areas of particular concern will be the review of inclusion/exclusion criteria, participant informed 
consent forms, protocol adherence, safety monitoring, IRB reviews and approvals, regulatory 
documents, participant records, study drug accountability, and Principal Investigator supervision 
and involvement in the trial. The Monitors will interact with the site staff to identify issues and re-
train the site staff as needed to enhance research quality. 
QA Site Visit Reports will be prepared by the NIDA CCC contract monitors following each site 
visit. These reports will be forwarded to the site Principal Investigator, the study Lead Investigator 
and NIDA. 
E. Management of Risks to Participants 
Confidentiality 
Confidentiality of participant records will be secured by using 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. All study data will be 
stored in a secure location with limited access. Only research staff will have access to the study 
records. Other parties with access to study data, such as local or central IRBs, will be specified 

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to the participants per HIPAA regulations. No identifying information will be disclosed in reports, 
publications or presentations. 
Participants’ information will not be released without their written permission, except as necessary 
for monitoring or suspected abuse or violence. The Lead Investigator (LI) will apply for a Certificate 
of Confidentiality that will cover all sites participating in the study. By participating in this protocol, 
the local site investigator agrees that within local regulatory restrictions and ethical considerations, 
any regulatory agency may consult and/or copy study documents to verify study data. 
By participating in this protocol, the local site investigator affirms that information furnished to the 
investigator by the Lead Investigator will be maintained in confidence and such information will 
be divulged to the IRB, Ethical Review Committee, or similar expert committees, affiliated 
institutions, and employees only under an appropriate understanding of confidentiality with such 
boards or committees, affiliated institutions, and employees. 
Information Meeting Reporting Requirements 
The consent form will specifically state the types of information that are required to be reported 
and the fact that the information will be reported as required. These include suspected or known 
sexual or physical abuse of a child or elders, or threatened violence to self and/or others. 
Participant Protection 
The study physician will evaluate all pertinent screening and baseline assessments prior to 
participant randomization to ensure that the participant is eligible and safe to enter the study. 
Adverse events (AEs) and concomitant medications will be assessed and documented at each 
clinic visit. Individuals who experience an AE that compromises safe participation will be 
discontinued from further medication administration and provided referrals for other treatment or 
to specialized care. Study personnel will request that the participant complete an end-of-
medication visit to assure safety and to document end-of-medication outcomes. 
Pregnancy 
Pregnancy is an exclusion criterion for study participation. A positive pregnancy test post-
enrollment will result in the cessation of study medication. Participants who discontinue 
medications will be expected to continue with study visits. Pregnancy test results and related 
outcome information will be collected on a Pregnancy and Outcome CRF. The site staff will follow 
the participant until an outcome of the pregnancy is known. 
Expected Risks of the Study Medication 
For anyone who has opioids in their system, naloxone and naltrexone may cause opioid 
withdrawal symptoms. As with any study drug, there is also the possibility of an allergic reaction. 
Participants will be monitored for at least 30 minutes following the naloxone challenge, and at 
least 15 minutes following each medication induction (co-administration of injectable and oral 
study medications). 
BUPROPION Extended Release: Possible side effects include elevated blood pressure, agitation, 
irritability, restlessness, sleeplessness, dry mouth, headache/migraine, nausea, vomiting, 
constipation, and shakiness. At doses of 450 mg daily, there is 1 chance in 1000 that a participant 
taking bupropion will experience a seizure. Individuals with a history of epilepsy or seizure 
disorder, current eating disorder, or who are taking certain medications will not be allowed to 
participate. Although bupropion is used to treat depression, a small percentage of people who 
take antidepressants have increased thoughts of suicide, particularly during the early weeks of 
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NALTREXONE for Extended Release (Vivitrol®): Possible side effects include nausea, vomiting, 
headaches, dizziness, insomnia, dry mouth, and depressed mood. In rare cases people who 
received naltrexone developed suicidal thoughts, or a type of pneumonia (lung inflammation) 
caused by an excess of a certain type of white blood cells in the lungs. The most serious side 
effect of naltrexone is liver (hepatocellular) injury, which has almost always occurred with oral 
doses of 1400 to 2100 mg per week. Recent study findings show that no evidence of liver injury 
was found in people receiving once-monthly Vivitrol® injections. For safety, participants with acute 
symptomatic hepatitis or liver failure will not be allowed to participate. 
Vivitrol® injections may cause pain, tenderness, hardening or damage of body tissues, swelling, 
redness, bruising, itching, or infection at the injection site. Such injection site reactions have been 
the most common side effects associated with Vivitrol®. The injection site will be monitored after 
each injection. Participants will be instructed to report any injection site reactions immediately to 
the study team. Any participants showing signs of injection site reactions such as a localized 
infection (abscess), skin infection (cellulitis), body tissue damage, or extensive swelling will be 
monitored by the study medical staff and treated accordingly. 
Data Management Procedures 
This protocol will utilize a centralized Data and Statistics Center (DSC). A web-based distributed 
data entry model will be implemented. This electronic data capture system (Advantage eClinical) 
will be developed to ensure that guidelines and regulations surrounding the use of computerized 
systems in clinical trials are upheld. 
Data and Statistics Center Responsibilities 
The DSC will: 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide Case Report Forms in electronic (eCRF) and paper 
(CRF) format, and Participant Reported Outcome forms in electronic (ePRO) and paper (PRO) 
format for the collection of all data required by the study, 3) develop data dictionaries for each 
CRF and PRO form that will comprehensively define each data element, 4) prepare instructions 
for the use of Advantage eClinical and for the completion of forms, 5) conduct ongoing data 
validation and cleaning activities on study data collected from all participating sites, and 6) perform 
data validation and cleaning activities prior to any interim analyses and prior to the final study 
database lock. 
Data Collection and Entry 
Data will be collected at the study sites on source documents and entered by the site on the form 
in Advantage eClinical, or will be collected via direct entry into the eCRF by the site or direct entry 
into the ePRO by the participant. In the event that Advantage eClinical is not available, the DSC 
will provide the sites with paper source documents and completion instructions. Data will be 
entered into Advantage eClinical in accordance with the instructions provided during project-
specific training and guidelines established by the DSC. Data entry into the forms shall be 
performed by authorized individuals. Selected eCRFs may also require the site investigator’s 
electronic signature. 
The principal investigator at the site is responsible for maintaining accurate, complete and up-to-
date research records. In addition, the site investigator is responsible for ensuring the timely 
completion of forms for each research participant. 
 
 

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Data Monitoring, Cleaning and Editing 
Data will be entered into the DSC automated data acquisition and management system 
(Advantage eClinical). Forms will be monitored for completeness and accuracy throughout the 
study. Dynamic reports listing missing values and forms will be 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 forms and between forms and post data clarification requests 
or queries in Advantage eClinical on a scheduled basis. Sites will resolve data inconsistencies 
and errors by entering all corrections and changes directly into Advantage eClinical. 
The CCC will conduct regular visits to sites, during which audits comparing source documents to 
the data entered will be performed. Any discrepancies identified between the source document 
and the eCRF or ePRO will be corrected by the site. 
Trial progress and data status reports, which provide information on recruitment, availability of 
primary outcome, treatment exposure, attendance at follow-up visits, regulatory status, and data 
quality, will be generated routinely and posted to a secure website. These reports will be available 
to the site, the corresponding Local Node, the Lead Investigator, the coordinating centers, and 
NIDA, to monitor the sites’ progress on the study. 
Data Lock and Transfer 
At the conclusion of data collection for the study, the DSC will perform final data cleaning activities 
and will “lock” the study database from further modification. The final analysis dataset will be 
returned to the Lead Investigator and NIDA, as requested, for storage and archive. 
 
 

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18.0 APPENDIX C - SMARTPHONE APP-BASED MEDICATION 
ADHERENCE PROCEDURES 
The smartphone app will be provided by AiCure and will be referred to as the “app” or 
“study app.” 
Technology Training 
After eligibility has been established and the participant has been randomized, staff will provide 
training on the use of the medication adherence app that will monitor and encourage adherence. 
The AiCure app will be downloaded onto the participant’s personal smartphone or, if unable to be 
downloaded, a study provided smartphone device will be provided with the app pre-loaded on it. 
Training will include using the app features and capabilities, security features (e.g., encryption), 
and taking practice dosing videos.  
Medication Adherence App on Participant Personal Smartphone 
Participants who choose to use their own smartphone must own a device that is camera-equipped 
and capable of SMS text messaging and taking videos. Participants who download the app on 
their personal smartphone devices will be provided an additional $10 at the beginning of each 
study month to offset the costs for additional data services needed due to use of the app. 
Participants who require a study provided smartphone device at any point during the study may 
be provided one. However, to ensure that participants are compensated equitably, no participant 
will receive more than $10 per study month for using either the app or a study provided 
smartphone device.  
Study Provided Smartphone Device 
Participants who do not have a personal device or are unable to download the AiCure app will be 
provided with a smartphone device (and battery charger). Service plans will be included to allow 
participants to receive text messages and reminders from study staff through the study app and to 
take dosing videos. The smartphone device equipment will be retained by participants through the 
end of their participation in the study. A replacement device may be available in the event of 
unintentional damage or loss. Sites are encouraged to consult with the Lead Team when 
considering providing replacement study devices for participants who are withdrawn from study 
medications. If the participant does not require a replacement smartphone device during the course 
of the study, the participant will be provided up to $40 payment (i.e., $10 for each study month) for 
the safe return of the smartphone device and, ideally, all accompanying accessories (e.g., charger, 
carrying case). Replacement smartphone devices will be returned at the end of study participation, 
but no payment will be provided to those participants requiring a replacement device.  
Set-up and Maintenance of App (and Smartphone Device, if applicable) 
Study staff will activate the AiCure app on participant smartphones or prepare the study provided 
smartphone for the participant. If a participant is using a study provided smartphone device, study 
staff will provide appropriate training on how to use the device.  
Smartphone Device-Based Procedures and Compensation 
Prior to randomization, study personnel will request a signed agreement from participants 
regarding the use of the smartphone app or study provided device for the purposes of the study. 
Participants will be informed of the medication adherence procedures, including the requirement 
to take daily videos of oral study medication ingestion. If a participant fails to bring his/her oral 
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can be taken, the participant will be asked to take a video of him/herself taking the dose for that 
day at home (if the dose has not already been taken). Participants will be compensated $5 for 
each dosing video taken on non-clinic days, including the taper in week 13. “Red Alerts” are 
triggered by AiCure when there is a pattern of problematic behaviors observed during video 
dosing. AiCure staff will guide site staff in how to re-train participants to appropriately use the app. 
If a pattern of recurring Red Alerts are triggered by AiCure, this indicates repeated problematic 
dosing behaviors are occurring, indicating non-adherence to oral study medication. Recurring 
Red Alerts may result in a participant not being compensated for dosing videos; sites should 
consult with the Lead Team when repeated Red Alerts occur.  
Lost/Stolen/Inoperable Smartphone Devices 
The purpose of providing a study smartphone device (to participants unable to use their own) is 
to monitor and improve medication adherence on non-clinic days as well as provide a means of 
study staff contacting participants. Participants will be notified that study provided devices will 
have a tracking tag on the back which allows for lost or stolen devices to be retrieved via a 
nationwide network and that removal of the tracking tag reveals a “stolen property” embossing on 
the device. Study provided smartphone devices are operational for study purposes only and are 
locked down to any other use. A one-time replacement of a lost, stolen, or inoperable study 
provided smartphone device may be permitted. Study staff should consult with the Lead Team 
should a second loss/theft of a study smartphone device occur. 
Protection of Participant Privacy 
Participants will be advised on how to secure their devices with passwords and how the software 
application will be used to transmit dosing videos to the secure server as an encrypted file. 
Research staff will only access smartphone device settings as needed to help troubleshoot a 
problem with the AiCure app and when requested by the participant.  
Staff-to-Participant Contact 
Staff will send texts from a list of pre-determined messages to participants through the app 
regarding reminders for clinic visits or dosing requirements. If a participant has not taken the 
dosing video by an agreed upon time on a take-home dosing day, study staff will contact the 
participant to ask the participant to take his/her study medication dose via the app as soon as 
possible.