Clinical trial NCT05283304
Conditions: Methamphetamine-dependence
Sponsor: Madhukar H. Trivedi, MD
Start date: 2023-03-24; Completion date: 2023-11-19
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a 12-week randomized, double-blind, placebo-controlled trial that will investigate the use of injectable buprenorphine (BUP-Inj) compared to injectable placebo (PBO-Inj) for the treatment of methamphetamine use disorder (MUD) among individuals with mild co-use of opioids.

Detailed description:
Primary Objective: To evaluate whether assignment to 12 weeks of outpatient BUP-Inj compared to 12 weeks of outpatient PBO-Inj reduces MA use (as measured by twice-weekly urine drug screens (UDS)) during Weeks 9-12 in participants with moderate to severe MUD with co-occurring mild opioid use disorder (OUD) or opioid misuse not warranting medication for opioid use disorder (MOUD).

Secondary Objectives: To evaluate whether assignment to 12 weeks of outpatient BUP-Inj compared to 12 weeks of outpatient PBO-Inj among participants with moderate to severe MUD with co-occurring mild OUD or opioid misuse not warranting MOUD improves: 1) outcomes related to alternate measures of MA use including total number of MA negative urine drug screens (UDS) during study and self-reported days of MA use; 2) measures of opioid use and self-reported frequency of opioid use; and 3) measures of MA and opioid co-use and self-reported days of MA and opioid co-use.

Arms: arm 1: Following successful titration to 16 mg of daily sublingual buprenorphine, the participants will then transition to injectable buprenorphine (300 mg dose) every 4 weeks arm 2: Following successful titration to 16 mg of daily sublingual buprenorphine, the participants will then transition to injectable placebo (300 mg dose) every 4 weeks.
Interventions: intervention 1: Buprenorphine injection (BUP-Inj) intervention 2: Placebo injection
Intervention descriptions: intervention 1: Sublingual Buprenorphine induction, then SublocadeTM, Indivior injectable (300mg) intervention 2: Sublingual buprenorphine induction, then Placebo injectable (300 mg)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
NCT05283304 
 
Protocol and Statistical Analysis Plan
 
Title: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of 
monthly injectable buprenorphine for methamphetamine use disorder (MURB) 
IRB# STU2021-0118 
Date: November 8, 2023 
 


STU2021-0118, Trivedi, FormA3-Protocol_v7.0_to_v8.0_RLSO_01Nov2023, Mod_17, 11-08-23 (2) (1) 
RESTRICTED 
 
 
 
 
NIDA CTN Protocol 0110 
 
Randomized, double-blind, placebo-
controlled trial of monthly injectable 
buprenorphine for methamphetamine 
use disorder (MURB) 
 
 
 
Lead Investigator: Steven Shoptaw PhD, UCLA 
Co-Lead Investigator: Madhukar H. Trivedi, MD, UT Southwestern 
 
 
Sponsor: Madhukar H. Trivedi, MD, UT Southwestern 
Funded by: National Institute on Drug Abuse (NIDA) 
 
November 01, 2023 
Version 8.0


NIDA CTN-0110 Protocol 
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Lead Investigator (LI): 
Steven Shoptaw, PhD 
 
Big South/West Node 
 
UCLA 
 
 
Sponsor/Co-LI: 
Madhukar H. Trivedi, MD 
 
Big South/West Node 
 
UT Southwestern Medical Center 
 
 
Protocol Development Team: 
Andrew Herring, MD 
Alameda Health System 
 
Mariah M. Kalmin, PhD 
UCLA 
 
Steven Nieto, PhD 
 
UCLA 
 
Thomas Carmody, PhD 
UT Southwestern Medical Center 
 
Angela Casey-Willingham 
UT Southwestern Medical Center 
 
 
CCTN Scientific Officer: 
Udi Ghitza, PhD 
 
National Institute on Drug Abuse 
 
 
Data and Statistics Center (DSC): 
Jennifer McCormack, MS 
DSC Principal Investigator 
Emmes 
 
 
Clinical Coordinating Center (CCC): 
Eve Jelstrom MBA, CRNA 
 
CCC Principal Investigator 
 
Emmes  
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the recipient 
that no unpublished information contained herein will be published or disclosed without prior approval of the Lead 
Investigator or other participating study leadership and as consistent with the NIDA terms of aw


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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS .............................................................................................................. 8 
2.0 
PROTOCOL SUMMARY ................................................................................................................ 10 
2.1 
SYNOPSIS ..................................................................................................................................... 10 
3.0 
STUDY SCHEMA ........................................................................................................................... 14 
3.1 
KEY RESEARCH SITE ROLES .......................................................................................................... 14 
4.0 
INTRODUCTION ............................................................................................................................. 15 
4.1 
STUDY RATIONALE ........................................................................................................................ 15 
4.2 
BACKGROUND AND SIGNIFICANCE TO THE FIELD.............................................................................. 16 
4.2.1 Buprenorphine mechanism of action....................................................................................... 16 
4.2.2 Efficacy of buprenorphine in stimulant-dependent individuals ................................................ 16 
4.2.3 Support for buprenorphine in treating individuals with methamphetamine use disorder ........ 17 
4.2.4 Ethical considerations of placebo for mild OUD or opioid misuse .......................................... 19 
4.2.5 Significance of the project to the field ..................................................................................... 20 
4.3 
RISK/BENEFIT ASSESSMENT .......................................................................................................... 21 
5.0 
OBJECTIVES.................................................................................................................................. 23 
5.1 
PRIMARY OBJECTIVE ..................................................................................................................... 23 
5.2 
SECONDARY OBJECTIVES .............................................................................................................. 23 
5.3 
EXPLORATORY OBJECTIVE(S) ........................................................................................................ 23 
6.0 
STUDY DESIGN ............................................................................................................................. 26 
6.1 
OVERVIEW OF STUDY DESIGN ........................................................................................................ 26 
6.1.1 Sublingual Buprenorphine Induction ....................................................................................... 26 
6.1.2 Injectable Formulations ........................................................................................................... 27 
6.2 
DURATION OF STUDY AND VISIT SCHEDULE .................................................................................... 27 
7.0 
OUTCOME MEASURES ................................................................................................................ 28 
7.1 
PRIMARY OUTCOME MEASURE ....................................................................................................... 28 
7.2 
SECONDARY OUTCOME MEASURES ................................................................................................ 28 
7.3 
OTHER EXPLORATORY MEASURES ................................................................................................. 28 
7.4 
STUDY TIMELINE ............................................................................................................................ 30 
8.0 
STUDY POPULATION ................................................................................................................... 31 
8.1 
PARTICIPANT INCLUSION CRITERIA ................................................................................................. 31 
8.2 
PARTICIPANT EXCLUSION CRITERIA ................................................................................................ 32 
8.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ........................................................................... 33 
9.0 
SITE SELECTION ........................................................................................................................... 34 
9.1 
NUMBER OF SITES ......................................................................................................................... 34 
9.2 
SITE CHARACTERISTICS ................................................................................................................. 34 
9.3 
RATIONALE FOR SITE SELECTION ................................................................................................... 35 
10.0 
STUDY PROCEDURES .................................................................................................................. 36 
10.1 
PRESCREENING ASSESSMENT ....................................................................................................... 36 
10.2 
SCREENING VISIT .......................................................................................................................... 36 
10.2.1 
Informed Consent Procedures for Participants ................................................................... 36 


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10.2.2 
HIPAA Authorization and Medical Record Release Forms ................................................. 37 
10.2.3 
Screening Assessments ...................................................................................................... 37 
10.3 
RANDOMIZATION ............................................................................................................................ 38 
10.4 
STUDY INTERVENTION(S) ADMINISTRATION ..................................................................................... 38 
10.4.1 
Induction Phase................................................................................................................... 38 
10.4.2 
Injections ............................................................................................................................. 38 
10.5 
STUDY INTERVENTION ADHERENCE ................................................................................................ 39 
10.6 
PREMATURE WITHDRAWAL OF PARTICIPANTS ................................................................................. 39 
10.7 
CONSIDERATIONS REGARDING ONGOING OPIOID USE ..................................................................... 39 
10.8 
RULES FOR IMMEDIATE STUDY REVIEW .......................................................................................... 40 
10.9 
FOLLOW-UP .................................................................................................................................. 40 
10.10 
DISCONTINUATION OF STUDY INTERVENTION ............................................................................... 40 
10.11 
BLINDING .................................................................................................................................. 42 
10.11.1 Type of Blinding................................................................................................................... 42 
10.11.2 Maintenance of the Blind ..................................................................................................... 42 
10.11.3 Breaking the Blind ............................................................................................................... 42 
10.12 
PARTICIPANT REIMBURSEMENT .................................................................................................. 42 
11.0 
STUDY ASSESSMENTS ................................................................................................................ 43 
11.1 
TABLE OF ASSESSMENTS ............................................................................................................... 43 
11.2 
GENERAL MEASURES .................................................................................................................... 46 
11.2.1 
Prescreening Interview ........................................................................................................ 46 
11.2.2 
Informed Consent ................................................................................................................ 46 
11.2.3 
Demographics ..................................................................................................................... 46 
11.2.4 
Mini International Neuropsychiatric Interview (MINI) Modules ............................................ 46 
11.2.5 
Sexual Risk Behaviors ........................................................................................................ 46 
11.2.6 
PhenX Tier 1 ....................................................................................................................... 46 
11.2.7 
Alcohol and Substance Use ................................................................................................ 47 
11.2.8 
Medical and Psychiatric History .......................................................................................... 47 
11.3 
SAFETY MEASURES ....................................................................................................................... 47 
11.3.1 
Physical Examination .......................................................................................................... 47 
11.3.2 
Electrocardiogram (ECG) .................................................................................................... 47 
11.3.3 
Medication Side Effects ....................................................................................................... 47 
11.3.4 
Buprenorphine-XR/Placebo Injection Site Evaluation ......................................................... 47 
11.3.5 
Concise Health Risk Tracking (CHRT) —Participant (CHRT-SR) ...................................... 48 
11.3.6 
Concise Health Risk Tracking (CHRT) —Clinician Rated Module (CHRT-CR) .................. 48 
11.3.7 
Urine Pregnancy Test, Pregnancy and Birth Control Assessment ..................................... 48 
11.3.8 
Vital Signs ........................................................................................................................... 48 
11.3.9 
Prior and Concomitant Medications .................................................................................... 49 
11.3.10 Adverse Events, Serious Adverse Events, and Medical Review ........................................ 49 
11.4 
CLINICAL AND EFFICACY ASSESSMENTS ......................................................................................... 49 
11.4.1 
Urine Drug Screen (UDS) ................................................................................................... 49 
11.4.2 
Timeline Followback (TLFB) ............................................................................................... 50 
11.4.3 
Visual Analog Scales for Methamphetamine and Opioid Craving ...................................... 50 
11.4.4 
Clinical Opiate Withdrawal Scale (COWS) ......................................................................... 50 
11.4.5 
Subjective Opiate Withdrawal Scale (SOWS) ..................................................................... 51 
11.4.6 
Inventory of Depressive Symptomology - Self-Report (IDS-SR) ........................................ 51 
11.4.7 
Generalized Anxiety Disorder Scale (GAD-7) ..................................................................... 51 
11.4.8 
Concise Associated Symptoms Tracking Irritability Scale (CAST-IRR) .............................. 51 
11.4.9 
Dimensional Anhedonia Rating Scale (DARS) ................................................................... 51 


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11.4.10 Amphetamine Cessation Symptom Assessment (ACSA) ................................................... 51 
11.4.11 Perceived Stress Scale (PSS) ............................................................................................ 51 
11.4.12 Pain Frequency, Intensity, and Burden Scale (P-FIBS) ...................................................... 51 
11.4.13 Cognitive Behavioral Therapy Documentation .................................................................... 52 
11.4.14 Iowa Gambling Task (IGT) and Documentation .................................................................. 52 
11.4.15 Treatment Effectiveness Assessment ................................................................................. 52 
11.4.16 Cannabis Use Assessment ................................................................................................. 52 
11.4.17 Tobacco Use History ........................................................................................................... 52 
11.4.18 Quality of Life ...................................................................................................................... 52 
11.4.19 Semi-Structured Qualitative Interview ................................................................................. 52 
11.5 
ADHERENCE MEASURES ................................................................................................................ 53 
11.5.1 
Buprenorphine-XR/Placebo Injection .................................................................................. 53 
11.5.2 
BUP-SL Dispensing ............................................................................................................ 53 
11.6 
LABORATORY EVALUATIONS ........................................................................................................... 53 
11.6.1 
Urine Screening for Disease ............................................................................................... 53 
11.6.2 
Complete Blood Count, Blood Chemistry, and Liver Function Tests .................................. 53 
11.6.3 
Disease Serology ................................................................................................................ 53 
11.6.4 
Blood Sample for UTSW Repository ................................................................................... 53 
11.6.5 
Blood Sample for NIDA Genetic Testing and Family Origin ............................................... 54 
11.6.6 
Buprenorphine Blood Levels ............................................................................................... 54 
11.7 
ADMINISTRATIVE AND OTHER FORMS.............................................................................................. 55 
11.7.1 
Locator Form ....................................................................................................................... 55 
11.7.2 
Eligibility-Randomization (Enrollment Form) ....................................................................... 55 
11.7.3 
Visit Documentation ............................................................................................................ 55 
11.7.4 
Mental Health Follow-up Assessment ................................................................................. 55 
11.7.5 
End of Medication................................................................................................................ 56 
11.7.6 
Protocol Deviation and Review ........................................................................................... 56 
11.7.7 
Treatment Satisfaction ........................................................................................................ 56 
11.7.8 
Study Completion ................................................................................................................ 56 
12.0 
MEDICATION PACKAGING / HANDLING / STORAGE / ACCOUNTABILITY ............................ 57 
12.1.1 
Study Medication Management ........................................................................................... 57 
12.1.2 
Dispensing of Study Medication .......................................................................................... 57 
12.1.3 
Study Medication Storage ................................................................................................... 57 
12.1.4 
Used/Unused Medication .................................................................................................... 57 
12.1.5 
Lost Medication ................................................................................................................... 58 
12.1.6 
Medication Packaging ......................................................................................................... 58 
13.0 
GENETIC SAMPLING .................................................................................................................... 59 
14.0 
TRAINING REQUIREMENTS ......................................................................................................... 60 
14.1 
OVERALL....................................................................................................................................... 60 
15.0 
CONCOMITANT THERAPIES OR INTERVENTIONS ................................................................... 61 
15.1 
GENERAL ...................................................................................................................................... 61 
15.1.1 
Medications and Interventions Allowed During Trial ........................................................... 61 
16.0 
STATISTICAL DESIGN AND ANALYSES .................................................................................... 62 
16.1 
GENERAL DESIGN .......................................................................................................................... 62 
16.1.1 
Study Hypothesis ................................................................................................................ 62 


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16.1.2 
Primary and Secondary Outcomes (Endpoints) .................................................................. 62 
16.1.3 
Randomization and Factors for Stratification ...................................................................... 62 
16.2 
RATIONALE FOR SAMPLE SIZE AND STATISTICAL POWER ................................................................. 62 
16.2.1 
Projected Number of Sites .................................................................................................. 64 
16.2.2 
Projected Number of Participants per Site .......................................................................... 64 
16.3 
STATISTICAL METHODS FOR PRIMARY AND SECONDARY OUTCOMES ................................................ 64 
16.3.1 
Primary Outcome ................................................................................................................ 64 
16.3.2 
Secondary Outcomes (medication phase, Weeks 1-12):.................................................... 64 
16.4 
SIGNIFICANCE TESTING .................................................................................................................. 66 
16.5 
INTERIM ANALYSIS ......................................................................................................................... 66 
16.6 
EXPLORATORY ANALYSIS ............................................................................................................... 67 
16.7 
MISSING DATA AND DROPOUTS ...................................................................................................... 69 
16.8 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................................................... 70 
16.8.1 
Subgroup Analyses ............................................................................................................. 70 
16.9 
SAFETY ANALYSIS ......................................................................................................................... 70 
17.0 
REGULATORY COMPLIANCE, REPORTING AND MONITORING ............................................. 72 
17.1 
STATEMENT OF COMPLIANCE ......................................................................................................... 72 
17.2 
INSTITUTIONAL REVIEW BOARD APPROVAL ..................................................................................... 72 
17.3 
RESEARCH ADVISORY PANEL OF CALIFORNIA (CALIFORNIA SITES ONLY) .......................................... 72 
17.4 
INFORMED CONSENT ..................................................................................................................... 73 
17.5 
QUALITY ASSURANCE MONITORING ................................................................................................ 74 
17.6 
PARTICIPANT AND DATA CONFIDENTIALITY ...................................................................................... 74 
17.6.1 
Certificate of Confidentiality ................................................................................................ 75 
17.6.2 
Health Insurance Portability and Accountability Act (HIPAA) ............................................. 75 
17.7 
INVESTIGATOR ASSURANCES ......................................................................................................... 75 
17.7.1 
Financial Disclosure/Conflict of Interest .............................................................................. 75 
17.7.2 
DEA Registration ................................................................................................................. 76 
17.7.3 
IND Requirements ............................................................................................................... 76 
17.8 
CLINICAL MONITORING ................................................................................................................... 76 
17.9 
INCLUSION OF WOMEN AND MINORITIES.......................................................................................... 77 
17.10 
PRISONER CERTIFICATION ......................................................................................................... 77 
17.11 
REGULATORY FILES ................................................................................................................... 77 
17.12 
RECORDS RETENTION AND REQUIREMENTS ................................................................................ 77 
17.13 
REPORTING TO SPONSOR .......................................................................................................... 77 
17.14 
AUDITS ..................................................................................................................................... 78 
17.15 
STUDY DOCUMENTATION ........................................................................................................... 78 
17.16 
PROTOCOL DEVIATIONS ............................................................................................................. 78 
17.17 
SAFETY MONITORING................................................................................................................. 79 
17.17.1 Data and Safety Monitoring Board (DSMB) ........................................................................ 79 
17.17.2 Safety Monitor / Medical Monitor ......................................................................................... 80 
17.17.3 Adverse Events (AEs) ......................................................................................................... 80 
17.17.4 Serious Adverse Events ...................................................................................................... 80 
17.17.5 Known Potential Toxicities of Study Medication ................................................................. 81 
18.0 
DATA MANAGEMENT ................................................................................................................... 82 
18.1 
DESIGN AND DEVELOPMENT ........................................................................................................... 82 
18.2 
QUALITATIVE DATA MANAGEMENT .................................................................................................. 82 
18.3 
SITE RESPONSIBILITIES .................................................................................................................. 82 
18.4 
DATA CENTER RESPONSIBILITIES ................................................................................................... 82 


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18.5 
DATA COLLECTION AND ENTRY ...................................................................................................... 82 
18.6 
DATA EDITING ............................................................................................................................... 83 
18.7 
DATA TRANSFER/LOCK .................................................................................................................. 83 
18.8 
DATA TRAINING ............................................................................................................................. 83 
18.9 
DATA QUALITY ASSURANCE ........................................................................................................... 83 
19.0 
DATA SHARING, PUBLIC ACCESS AND PUBLICATIONS ........................................................ 84 
20.0 
PROTOCOL SIGNATURE PAGE .................................................................................................. 85 
21.0 
PROTOCOL AMENDMENT HISTORY .......................................................................................... 86 
22.0 
REFERENCES ................................................................................................................................ 87 
23.0 
APPENDIX A: ADVERSE EVENT REPORTING AND PROCEDURES ........................................ 91 
23.1 
ADVERSE EVENT REPORTING (CHART) ........................................................................................... 95 
24.0 
APPENDIX B: DATA AND SAFETY MONITORING PLAN (DSMP) ............................................. 96 
24.1 
BRIEF STUDY OVERVIEW ........................................................................................................ 96 
24.2 
OVERSIGHT OF CLINICAL RESPONSIBILITIES ...................................................................... 96 
24.3 
DATA MANAGEMENT PROCEDURES .................................................................................... 100 
24.3.1 
Data and Statistics Center Responsibilities ...................................................................... 100 
24.3.2 
Data Collection and Entry ................................................................................................. 100 
24.3.3 
Data Monitoring, Cleaning and Editing ............................................................................. 100 
24.3.4 
Database Lock and Transfer ............................................................................................. 101 
 
 


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1.0 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
Adverse Event 
AST 
Aspartate Transaminase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
BUP 
Buprenorphine 
BUP-Inj 
Extended-Release Injectable Buprenorphine, XR-BUP, BUP-XR, 
SublocadeTM 
CAST 
Concise Associated Symptom Tracking Scale 
CBT 
Cognitive Behavioral Therapy 
CCC 
Clinical Coordinating Center 
CCTN 
Center for the Clinical Trials Network 
CFR 
Code of Federal Regulations 
CHRT-SR 
Concise Health Risk Tracking – Self-Report 
CLIA 
Clinical Laboratory Improvement Amendments  
CoC 
Certificate of Confidentiality 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Forms 
CRA 
Clinical Research Associate 
CTN 
Clinical Trials Network 
CURB 
Cocaine Use Reduction with Buprenorphine 
DARS 
Dimensional Anhedonia Rating Scale 
DEA 
Drug Enforcement Administration 
DM 
Data Management 
DSC 
Data and Statistics Center 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – 5th Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GAD-7 
Generalized Anxiety Disorder Scale-7 
GCP 
Good Clinical Practice 
HCV 
Hepatitis C Virus 
HHS 
Department of Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
IGT 
Iowa Gambling Task 
IDS-SR 
Inventory of Depressive Symptomology - Self-Report 
IND 
Investigational New Drug 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
LFT 
Liver Function Tests 
LI 
Lead Investigator 
LN 
Lead Node 
MA 
Methamphetamine 
MINI 
Mini International Neuropsychiatric Interview 
MOP 
Manual of Procedures 
MOUD 
Medication for Opioid Use Disorder 
MUD 
Methamphetamine Use Disorder 
MURB 
Methamphetamine Use Reduction with Buprenorphine 
MSM 
Men who Have Sex with Men 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OUD 
Opioid Use Disorder 
PBO-Inj 
Injectable Placebo 
PEBL 
Psychology Experiment Building Language 
P-FIBS 
Pain Frequency, Intensity, and Burden Scale 
PI 
Principal Investigator 
PSS 
Perceived Stress Scale 
PT 
Preferred Term 
RAP-C 
Research Advisory Panel of California 
RCT 
Randomized Controlled Trial 
REMS 
Risk Evaluation and Mitigation Strategy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sIRB 
Single Institutional Review Board 
SOC 
System Organ Class 
SOP 
Site Operating Procedures 
SOWS 
Subjective Opiate Withdrawal Scale 
STI 
Sexually Transmitted Infection 
SUSAR 
Serious Unexpected and Suspected Adverse Reaction 
TEA 
Treatment Effectiveness Assessment 
TES 
Treatment Effectiveness Score 
TLFB 
Timeline Followback 
UDS 
Urine Drug Screen 
UPT 
Urine Pregnancy Test 
UP 
Unanticipated Problem 
US 
United States 
VAS 
Visual Analog Craving Scales 
XR-BUP 
Extended-Release Injectable Buprenorphine, BUP-Inj, BUP-XR, 
SublocadeTM 
XR-NTX 
Extended-release Naltrexone 


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2.0 
PROTOCOL SUMMARY 
2.1 
Synopsis 
Title 
Randomized, double-blind, placebo-controlled trial of monthly injectable 
buprenorphine (BUP) for methamphetamine (MA) use disorder (MURB) 
Study Number 
CTN-0110 
IND Number 
161851 
Study 
Description 
This study is a 12-week randomized, double-blind, placebo-controlled trial 
that will investigate the use of injectable buprenorphine (BUP-Inj) 
compared to injectable placebo (PBO-Inj) for the treatment of 
methamphetamine use disorder (MUD) among individuals with mild co-
use of opioids. 
Objectives 
Primary Objective: To evaluate whether assignment to 12 weeks of 
outpatient BUP-Inj compared to 12 weeks of outpatient PBO-Inj reduces 
MA use (as measured by twice-weekly urine drug screens (UDS)) during 
Weeks 9-12 in participants with moderate to severe MUD with co-
occurring mild opioid use disorder (OUD) or opioid misuse not warranting 
medication for opioid use disorder (MOUD). 
Secondary Objectives: To evaluate whether assignment to 12 weeks of 
outpatient BUP-Inj compared to 12 weeks of outpatient PBO-Inj among 
participants with moderate to severe MUD with co-occurring mild OUD or 
opioid misuse not warranting MOUD improves: 1) outcomes related to 
alternate measures of MA use including total number of MA negative urine 
drug screens (UDS) and self-reported days of MA use; 2) measures of 
opioid use and self-reported frequency of opioid use; and 3) measures of 
MA and opioid co-use and self-reported days of MA and opioid co-use.  
Exploratory Objectives: Include exploring whether assignment to BUP-Inj 
compared to PBO-Inj during the medication phase corresponds with 
changes in measures of subjective effects of MA including MA withdrawal 
symptoms and self-reported MA craving; measures of subjective effects of 
opioids including opioid withdrawal symptoms and self-reported opioid 
craving; measures of self-reported craving for MA and opioid co-use; 
measures of mood, stress and pain including self-reported symptoms of 
depression, anxiety, mood, anhedonia, stress, and pain; retention in the 
protocol; infectious disease markers, incidence, and Human 
Immunodeficiency Virus (HIV) transmission risk behaviors; measures of 
overall functioning; measures of adverse events and fatal and non-fatal 
overdose events; changes in other substance use or new sexually 
transmitted infections (STIs) and whether a neurocognitive measure of 
impulse inhibition predicts treatment outcomes.  


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Outcome 
Measures 
Primary Outcome Measure: The number of MA-negative UDS obtained 
during Weeks 9 through 12 of the medication phase as measured for the 
BUP-Inj and PBO-Inj conditions. 
 
Secondary Outcome Measures:  
1) Alternate measures of MA use during Weeks 1-12: total number of 
MA negative UDS (Treatment Effectiveness Score) and self-
reported days of MA use (Timeline Followback, TLFB);  
2) Opioid use during Weeks 1-12: Opioid Treatment Effectiveness 
Score (TES); self-reported frequency of opioid use (TLFB);  
3) MA and opioid co-use during Weeks 1-12: total number of MA and 
opioid negative UDS (TES) and self-reported days of MA and 
opioid co-use on the TLFB. 
 
Exploratory Measures: 
1) MA subjective effects during Weeks 1-12: Withdrawal symptoms 
(Amphetamine Cessation Symptom Assessment, ACSA); Self-
reported MA craving (Visual Analog Craving Scales, VAS);  
2) Opioid subjective effects: Withdrawal symptoms (Clinical Opiate 
Withdrawal Scale, COWS and Subjective Opiate Withdrawal 
Scale, SOWS) at Weeks 1, 5, 9, and 12; Self-reported opioid 
craving (VAS) during Weeks 1-12;  
3) Self-reported craving (VAS) for MA and opioid co-use during 
Weeks 1-12 
4) Mood, stress, and pain : Self-reported depressive symptoms 
(Inventory of Depressive Symptomology - Self-Report, IDS-SR) 
during Weeks 1-12; Self-reported anxiety symptoms (Generalized 
Anxiety Disorder Scale-7, GAD-7) during Weeks 1-12; Self-
reported anhedonia (Dimensional Anhedonia Rating Scale, DARS) 
at Weeks 1, 5, 9, and 12; Self-reported mood (Concise Associate 
Symptom Tracker, CAST-IRR) during Weeks 1-12; Self-reported 
stress (Perceived Stress Scale, PSS) at Weeks 1, 5, 9, and 12; 
Self-reported pain (Pain Frequency, Intensity, and Burden Scale, 
P-FIBS) during Weeks 1-12; 
5) Retention in treatment, defined as present and providing urine 
drug samples during Weeks 1-12;  
6) Infectious disease: Biomarkers at Week 12 (remaining HIV 
negative for participants HIV-negative at screening; remaining 
Hepatitis C Virus (HCV) negative for participants HCV negative at 
screening); Self-reported HIV transmission risk behaviors at 
Weeks 1, 6, and 12 (Sexual Risk Behaviors - number of new 
sexual partners, number of sexual partners with condomless sex 
who are serodiscordant or unknown serostatus and whether illicit 


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substances were used during sex (chemsex), number of male 
sexual partners (for men), number of episodes sharing needles, 
injection equipment or paraphernalia);  
7) Measures of functioning: Quality of Life (QoL) at Weeks 1 and 12 
and Treatment Effectiveness Assessments (TEA) at Week 12;  
8) Measures of adverse events during Weeks 1-12: number and 
severity of adverse events reported; number and outcomes (fatal, 
non-fatal) of overdose events reported; 
9) Self-reported measures of alcohol, tobacco and other drug use 
during Weeks 1-12 (TLFB) and UDS results of other substance 
use not quantified for primary or secondary outcomes; 
10) Urinalysis results indicating a new chlamydia or gonorrhea 
diagnosis at Week 12;  
11) Iowa Gambling Task (IGT) performance at screening.  
Study 
Population 
The study will consist of approximately 246 males and females who meet 
eligibility criteria, including Diagnostic and Statistical Manual of Mental 
Disorders-5 (DSM-5) criteria for moderate to severe MUD and co-
occurring mild OUD or opioid misuse not warranting MOUD, supported by 
urine samples positive for MA and negative for opioids during screening.  
Phase or Stage 
This is a Phase IIb double-blind, randomized, placebo-controlled trial. 
Description of 
Sites Enrolling 
Participants 
The trial will include 4-8 sites with appropriate staffing and facilities to 
conduct all study procedures and will not include sites outside of the 
United States.  
Description of 
Study 
Intervention  
The study intervention is 3 doses of 300mg BUP-Inj delivered by 
abdominal subcutaneous injection every 4 weeks. 
Safety 
Reporting 
Appropriately qualified and trained personnel will elicit participant reporting 
of Adverse Events (AEs) and Serious Adverse Events (SAEs) at each 
study visit. Study personnel will obtain as much information as possible 
about the reported AE/SAE to complete the AE/SAE forms and will consult 
with the Safety Monitor/Medical Monitor as warranted. Standard reporting, 
within seven days of the study site becoming aware of the event, will be 
required for reportable AEs. Expedited reporting, within 24 hours of the 
site's becoming aware of the event, will be required for reportable SAEs 
(including death and life-threatening events). 
Analyses 
Primary Statistical Analysis: Generalized estimating equations will be used 
to model the log-odds of a MA-negative UDS during Weeks 9-12, 
assuming an autoregressive lag-1 working correlation matrix. The robust 
(sandwich) estimator will be used to adjust the covariances for the 
correlation of UDS from the same participant. Missing UDS are imputed 
as MA-positive.  
Study Duration 
The study will be conducted over a period of approximately 20-24 months.  


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Participant 
Duration 
Participants will complete all study-related tasks over a period of 19 weeks 
(up to 3 weeks for screening, 12 weeks for the medication phase, and a 
follow-up safety visit at Week 16; about five months total). 


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3.0 
STUDY SCHEMA 
 
3.1 
Key Research Site Roles 
Site Principal Investigator (MD; DO; PhD) 
Medical Clinician #1 (NP; PA; MD; DO) [May be a shared role with Site PI] 
Medical Clinician #2 (NP; PA; MD; DO) 
Research Coordinator 
Research Assistant 
Unblinded Medical Personnel (RN, LVN, MA, or other healthcare provider able to administer 
Sublocade™ injections per local licensure requirements) 
Suggested Additional Roles (not required) 
Recruiter/Pre-screener/Retention Specialist 


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4.0 
INTRODUCTION 
4.1 
Study Rationale 
Stimulants are the drivers of the fourth wave of the United States drug overdose epidemic1. 
Although most national attention and resources have been targeted at combating opioid use due 
to the surge of overdose deaths related to fentanyl, recent reports suggest populations that use 
opioids are also using methamphetamine (MA) at high rates2,3. Indeed, current data show that as 
many opioid overdose deaths involved psychostimulants as did not4-6. These stark 
epidemiological data underscore the significance of developing one or more broadly efficacious 
treatments for methamphetamine use disorder (MUD) – especially in the setting of ongoing opioid 
use. 
Most therapeutic trials for MUD have failed, with one notable exception: one small randomized 
controlled trial (RCT) of mirtazapine tested in San Francisco among men who have sex with men 
(MSM)7; and a larger replication RCT in a larger sample of MSM with MUD that showed that 30 
mg mirtazapine reduced MA use by 27% at week 368. A recent RCT completed by the CTN (CTN-
0068; ADAPT-2; Trivedi Lead Investigator) tested injectable naltrexone plus high-dose oral 
bupropion 450 mg/day compared to placebo and reported statistically significant reductions in 
methamphetamine use in a broad sample of people with MUD (in review). This combination 
pharmacotherapy is impossible to use among those with MUD who use opioids as the opioid 
antagonist naltrexone precipitates immediate opioid withdrawal, further underscoring the impact 
of evaluating a broad pharmacotherapy strategy that does not include an opioid antagonist. 
As a monotherapy, buprenorphine (BUP) has sufficient rationale for evaluation as a medication 
for MUD in the setting of opioid co-use. Findings from the CTN-0048 Cocaine Use Reduction with 
Buprenorphine (CURB) study showed that extended-release Naltrexone (XR-NTX) plus oral BUP 
(4mg and 16 mg), produced modest, though statistically significant, reductions in cocaine use 
(urine-verified) among those adherent to oral BUP (verified with BUP blood levels) compared to 
placebo9. These findings provide initial support for a kappa antagonist approach to treating 
stimulant use disorder, in this case MUD, as the combination pharmacotherapy used in the CURB 
study left only a kappa antagonist working at the opioid receptor10. Kappa antagonists are potent 
antidepressants, elevating mood while also producing an overall sense of “well-being”11. While 
there are no placebo-controlled RCTs of buprenorphine for MA addiction, a recent clinical report 
showed patients treated for OUD using buprenorphine showed a 15% reduction in MA use from 
baseline to follow-up12. 
The recent approval of Sublocade™ and the pending final approval of BrixadiTM, both BUP 
extended-release injection formulations for subcutaneous use, provide renewed interest in using 
BUP to treat stimulant-use disorders. The availability of injectable formulations of BUP eliminates 
problems regarding medication adherence that plague MA medication trials. With medication 
adherence virtually assured (all study products after induction are injectable), the confidence in a 
definitive test of the pharmacotherapy is greatly increased. 
This rationale is the foundation for this protocol, which will investigate the use of BUP-Inj 
compared to placebo for treatment of MUD among individuals with co-use of opioids. This study 


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will apply findings learned from prior studies to a population that has been understudied to date, 
but who are at risk for overdose due to both MA and opioids. Elimination of medication adherence 
problems allows evaluation of safety and efficacy of BUP-Inj compared to placebo for reducing 
MA use and of subjective reports of dysphoria and stress. Positive findings would support 
additional evaluation of BUP-Inj as a treatment for those with mild OUD or opioid misuse. 
4.2 
Background and Significance to the Field  
Current levels of MA use in the United States (US) are at historic levels with endemic levels in the 
Southwestern US, including California13. In 2017, the Drug Enforcement Administration reported 
that MA was the greatest drug threat in the Pacific, Southwest, West Central, and Southeast 
regions of the United States14. MA use is a leading cause of drug overdose in the US, particularly 
in the West, South, and Midwest15,16. The use of MA provides a number of positive attributes for 
the user, including focused attention, enhanced body states, diminished appetite, increased 
attention and mood and euphoria at high doses. With repeated use, addiction develops. Negative 
effects of continued frequent use of MA include cardiovascular problems (including myocardial 
infarction and stroke)17, psychiatric problems (depression, hypomania, anxiety, panic)18, criminal 
justice involvement19, problems with friends and family members, and employment difficulties. 
MA use also is associated with increased risk for HIV and other STIs, especially among men who 
have sex with men (MSM). Increasing rates of STIs also are reported among women and 
heterosexual men linked to increased MA use20,21. For people living with HIV, MA use challenges 
sustained viral suppression, creating opportunities for onward HIV transmission and related 
morbidity and mortality22. 
4.2.1 
Buprenorphine mechanism of action 
BUP is an opioid partial agonist originally approved for the treatment of cancer pain and approved 
as a treatment for OUD in 200223,24. BUP competitively binds at the mu-opioid receptor sites, 
displacing opioid mu agonists with its partial agonist action protecting against respiratory 
depression in opioid overdose25,26. The kappa antagonist property of BUP reduces dysphoric 
mood and produces a sense of well-being27. 
4.2.2 
Efficacy of buprenorphine in stimulant-dependent individuals 
The data supporting evaluation of BUP for the treatment of MUD are promising. In the CURB 
combination trial for cocaine addiction, XR-NTX plus high dose (16 mg/d) or low dose (4 mg/d) 
oral BUP compared to placebo did not significantly reduce cocaine use days (urine verified)9. 
However, when the urine drug screen results were analyzed as secondary outcomes, high dose 
BUP (16 mg/d) plus XR-NTX significantly reduced cocaine use measured by proportion of urine 
samples negative for cocaine (p=0.022) and by proportion who achieved ≥75% negative urine 
samples during the trial (p=0.008) compared to placebo. Using blood levels assessing the “as-
treated” population, both low (4 mg/d) and high (16 mg/d) dose BUP conditions produced 
significantly more cocaine negative urine samples compared to placebo (p=0.02; p=0.01, 
respectively)28. These consistent signals using biomarkers of outcome, and especially in the “as-
treated” group with measurable blood levels of BUP, provide the clearest signal yet favoring 


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investigation of BUP. The availability of an injectable BUP product to eliminate medication 
adherence problems builds the rigor and significance for conducting this study now. 
4.2.3 
Support for buprenorphine in treating individuals with 
methamphetamine use disorder 
Despite the biological rationale for using BUP as a pharmacotherapy for MUD, there has been 
limited exploration for evaluating this medication for treatment. One study conducted in Iran 
studied the effects of BUP in reducing MA cravings during withdrawal. When added to an existing 
behavioral treatment approach, BUP resulted in individuals experiencing fewer MA cravings 
compared to those receiving placebo28. Perhaps the strongest uncontrolled data yet, a recent 
report in the State of Washington shows that among people who remained in treatment for OUD, 
BUP also significantly decreased MA use over time12. 
In order to isolate focus on the kappa antagonist action of buprenorphine in this trial, it is not 
desirable to combine a mu antagonist with a long-acting partial agonist, such as using combined 
XR-NTX plus Sublocade™. This is because for those with moderate to severe methamphetamine 
use disorder who co-use opioids, induction onto XR-NTX may cause opioid withdrawal symptoms 
and contribute to screen fails and lack of interest in screening for the study from the population. 
This is a significant sub-group of people with moderate to severe methamphetamine use disorder. 
There is substantial epidemiological evidence documenting the increasing prevalence of 
Americans who simultaneously use opioids and methamphetamine29. Data documenting 
contemporaneous shifts in exposure to fentanyl and co-use of methamphetamine are observed 
nationwide and in the West, Southwest30. This issue is now observed in West Virginia31, where 
methamphetamine and opioid co-use is measured as a significant contributor to the ongoing 
overdose crisis in the US32. Given the substantial opioid exposure (up to and including potential 
episodic use of oral buprenorphine), there is rationale for the use of an extended-release 
buprenorphine (Sublocade™) medication tested against an injectable placebo condition, a design 
feature that would provide the kappa antagonist effect as well as strongly bind at the opioid mu 
receptor in the active medication condition. 
This study was designed to specifically evaluate BUP-Inj as a pharmacological monotherapy for 
individuals with moderate to severe MUD and co-occurring use of opioids. This therapy will be 
tested using the Sublocade™ product donated by Indivior, which will provide 300 mg of BUP 
extended-release via a monthly subcutaneous injection administered in clinic by qualified and 
licensed study personnel. This dose of BUP was informed by multiple sources of data to support 
our choice for 3 injections, each at 300mg dose. The data supporting Sublocade™’s efficacy in 
trials for OUD showed initial dosing of 300mg with subsequent injections at 300mg showing 
comparable efficacy to an initial injection of 300mg with subsequent injections at 100mg, with no 
increased risk for AEs at the higher dose33,34. Furthermore, this dosing strategy was more effective 
for getting to steady-state concentrations after repeated dosing. However, due to the novel use 
of this medication in this dual substance using population with less opioid use than what was 
evaluated in these primary Sublocade™ trials, we undertook consultation with clinicians actively 
working with these injectable products, with experts in clinical trial design and consulted the 
literature. Clinical experts were supportive of the higher dose, given the opioid experienced 


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population that were under study as well as supporting rigorous trial design. Results from the 
original CURB study indicated a poorer efficacy outcome using the lower 4mg dose of BUP as 
compared to the higher 16mg dose9. This higher dose produced superior outcomes of cocaine 
abstinence and higher blood level data, suggesting to us that there is a risk for underdosing using 
the lower formulation of buprenorphine-extended release based on these data. 
We further reviewed the literature for relevant experiences of initiating BUP in those who are 
currently using opioids, but not at levels that warrant MOUD. In the original development of BUP 
in humans, participants were experienced users of opioids who had a substantial break from 
opioid use, i.e., not tolerant or dependent on opioids at the time of BUP initiation35. These 
participants reported minimal adverse effects and repeated dosing over 2 weeks did not induce 
further toxic effects. Laboratory values for blood samples and urinalysis did not show clinically 
significant changes. Additional literature supports the use of BUP in a broad range of patients for 
pain management in comprehensive reviews36,37. These build confidence that we will not induce 
iatrogenic opioid use disorder for those assigned to the active condition in this research as all 
participants in the protocol will be opioid experienced. The Jasinski study also provided data 
detailing mild withdrawal symptoms following cessation of BUP35. These symptoms were noted 
to be of gradual and slow onset. For those participants in this protocol who desire to continue with 
treatment at the end of the study, referrals will be made for care at the conclusion of their 
participation in the study. 
The decision to maintain 3 doses of 300 mg/1.5 mL instead of reducing the third dose to 100mg, 
as recommended on the package insert, at Week 9 is justified by several reasons. Most 
importantly, the study is 12 weeks in length with the primary outcome variable defined as the 
comparison of the number of methamphetamine-negative urine drug screens collected in Weeks 
9 through 12 of the study. Changing the Sublocade™ dose at the beginning of this critical period, 
the efficacy window, risks invalidating the entire study. The risk of under-dosing is enhanced 
further in the measurement of the primary outcome variable and complicated by a lack of 
information regarding pharmacokinetic blood levels for Sublocade™ activity as a kappa 
antagonist for individuals with moderate to severe methamphetamine use disorder. While 
pharmacokinetic levels are well known for individuals with OUD38, and were used to advise 
recommended Sublocade™ dose on the package insert, this information is limited to using 
Sublocade™ as a treatment for OUD. 
Following these considerations, we elected to avoid possible underdosing and save cost by not 
testing both doses of medication. We therefore chose to maximize the probability to detect a 
signal in this trial by using three 300mg injections, matching a study design utilized by the 
manufacturer in the initial OUD efficacy trials and supported by our interpretation of the existing 
data that the higher 300mg injections would not cause undue risk to our opioid experienced 
participant population. The 12-week timeframe is in accordance with the pharmacokinetic data 
indicating increased circulating drug approaching steady state, as well as persistence of the 
medication in the body for 4-6 weeks. Following an induction onto BUP using sublingual BUP film, 
participants will then receive 3 study injections over the course of the 12-week medication phase. 
Participants will be randomized 1:1 to either this active product or placebo condition to test the 


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efficacy of this medication to stop or reduce MA use in this population. Opioid use will be 
monitored and evaluated as secondary outcomes for this study. 
4.2.4 
Ethical considerations of placebo for mild OUD or opioid misuse 
The issue of implementing an ethical placebo control condition in this trial of BUP-Inj for persons 
with moderate-to-severe MUD who co-use opioids (mild OUD or opioid misuse) requires careful 
consideration. First, participants to be included in this trial will have moderate-to-severe MUD as 
the primary substance use disorder being treated. We have included procedures to ensure that 
participants who have moderate-to-severe OUD co-occurring with moderate-to-severe MUD will 
instead be assisted in seeking medication for OUD and not enrolled in this research project. To 
support the diagnosis of mild OUD or opioid misuse, participants are required to produce at least 
one urine sample negative for opioids during the screening phase and a second urine sample 
negative for opioids on the day of randomization, and self-report at least two days of opioid use 
in the 30-day period prior to written consent using the TLFB. Potential participants who under-
represent the severity of their OUD during screening and present with opioid withdrawal 
symptoms will be excluded and referred to medication for OUD. Severity of withdrawal symptoms 
will be evaluated by the COWS. An inclusion criterion requires all participants report a score of 
≤8 at both a screening assessment when the participant tests negative for opioids and on the day 
of randomization. The protocol has an inclusion criterion requiring participants to meet moderate-
to-severe MUD and co-use opioids at a level that meets criteria for mild OUD or opioid misuse 
demonstrated by self-report of any use on the TLFB. Note that in the context of potential 
participants having moderate-to-severe MUD, any opioid use is considered misuse. Included 
participants may report physical symptoms of opioid tolerance and withdrawal, though cannot 
have criteria signaling severe opioid addiction. These procedures ensure selection of participants 
with moderate-to-severe MUD and mild opioid use disorder or opioid misuse as these participants 
do not warrant treatment with medication for OUD under standard clinical care. Potential 
participants whose opioid use does not allow for 48-72 hours without using opioids are excluded 
and instead referred to medication for opioid use disorder in their communities. 
It is not possible to use a matched placebo for the 2-3 lead-in days prior to the first long-acting 
injection as placebo available from the manufacturer is not packaged to look or to taste like the 
marketed SL-BUP product, which has markings on the packaging attesting to its active status. 
The only available placebo medication appears with completely different package markings and 
tastes completely different compared to the SL-BUP product. Comparison of take-home 
medications by participants risks dismantling the masking for the study. As well, given the opioid 
experienced nature of the group, many participants will be familiar with SL-BUP, both in product 
appearance and taste. For those assigned to placebo, the risk of breaking study masking to 
conditions is high. 
There is no possibility for placebo medication that would meet criteria for fully double-blinded 
sublingual lead-in products. It was recognized that using an active SL-BUP lead-in for all 
participants would be consistent with the procedures conducted in the phase 3 trial of 
Sublocade™39. As such, the procedures of using an active lead-in using SL-BUP for participants 
in both conditions is parallel to that used by Indivior. We recognize that this group of participants 
with moderate-to-severe methamphetamine use disorder who co-use opioids (have mild OUD or 


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opioid misuse) is distinctly different from that studied in the Sublocade™ trial who had moderate 
or severe OUD and were being treated with opioid agonists. In Haight et al., 201939 placebo-
assigned participants were given a much greater exposure to active SL-BUP during a much longer 
lead-in period (up to 2 weeks). Opioid withdrawal symptoms for placebo participants in the current 
study resulting from the 2 or 3 days of SL-BUP are expected to be mild and transitory and 
participants can be offered palliative medications for any symptoms they experience. In sum, we 
believe the regimen proposed allows ethical treatment, does not represent substantial exposure 
to SL-BUP for those assigned to the placebo condition, and protects the study masking to 
condition. 
This research protocol is specifically designed to evaluate BUP-Inj as a broad treatment for 
reducing methamphetamine use in this co-using group, therefore a placebo condition is necessary 
to measure the signal size for BUP-Inj. A key issue is that it is not possible to use an active 
medication control condition, such as injectable naltrexone and high-dose bupropion, as all 
participants regularly use opioids, which prevents the use of naltrexone-containing products. 
Thus, placebo compared to BUP product formulations will allow both scientific and ethical 
rationale as a condition for comparing outcomes to the experimental BUP-Inj condition. 
One final ethical consideration involves addressing withdrawal symptoms for participants 
assigned to the placebo condition, as participants assigned to the placebo condition will not 
benefit from the partial agonist feature of BUP-Inj, which protects against opioid overdose. To 
address differential reduction of overdose risks, all participants will be provided naloxone reversal 
kits and will be instructed to inform their family and friendship members of this increased sensitivity 
to opioids and the risk of overdose, as well as of how to use the kits in the setting of opioid 
overdose. Monitoring of ongoing opioid use is an integral part of this trial and we describe 
procedures for increased clinical attention for signs of escalating opioid use during the trial period 
(Section 10.7, Considerations Regarding Ongoing Opioid Use). 
4.2.5 
Significance of the project to the field 
From 2012 to 2018, overdoses associated with stimulants including MA have increased nearly 
five-fold40. Aside from MA’s detrimental health effects, its use also has severe social 
consequences: interactions with the criminal justice system19, homelessness19, and increased 
domestic violence41. Pharmacologic options for MUD treatment are urgently needed. The 
potential treatment of BUP-Inj is hoped to have a broad impact on the MA epidemic in the US, 
uniquely so in the Southwest and Western US. 
Identifying a broadly effective medication to help achieve abstinence, to prevent relapse to MA 
use – and importantly, to prevent overdose and potential deaths – is a key objective with 
considerable public health significance. This placebo-controlled trial will advance medication 
research and potentially confirm the use of injectable buprenorphine as the first effective 
pharmacotherapy for the treatment of stimulant use disorder involving MA in the context of mild 
OUD or opioid misuse. 


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4.3 
Risk/Benefit Assessment 
The use of BUP-Inj, as Sublocade™ in this trial, has not yet been directly evaluated as mono-
pharmacotherapy in those with MUD. Overall, the risks of using Sublocade™ for MUD are low. 
Further reducing risks, participants in this study will not be opioid naïve, will likely combine opioid 
use with methamphetamine use and meet criteria for mild OUD or demonstrate opioid misuse, 
which increases acceptability of this putative mono-pharmacotherapy strategy. The study will be 
conducted under an IND (Investigational New Drug) application, which strengthens oversight and 
monitoring of the study, with emphasis on evaluating safety and early efficacy. Other than the 
primary substance used by this population, no other existing differences are believed to increase 
the risks of using this medication as all other safety guidelines for use of BUP-Inj will be followed 
as detailed in the package insert for Sublocade™. 
There is a risk to untreated MUD, especially in the setting of opioid co-use, particularly ongoing 
risks for opioid overdose6. For participants assigned to the BUP-Inj condition, risks for opioid 
overdose will be reduced due to the partial agonist properties of BUP. Naloxone overdose reversal 
kits will be provided to participants in both conditions with instructions to participants and their 
friends/family members on their use in the setting of overdose in order to address opioid overdose 
risks. There remain risks for MA overdose for participants in both conditions; however, the risks 
for opioid overdose are reduced substantially for participants assigned to BUP-Inj and for 
participants in both conditions who are given naloxone reversal kits. Regular monitoring of 
ongoing opioid use during the trial allows for identification of those who warrant discontinuation 
of trial participation and immediate referral to treatment for their opioid use. 
Ongoing risks for opioid overdose, adverse events related to BUP-Inj and for events related to 
ongoing MA use will be assessed at a safety follow-up visit during Week 16 of the study. 
There are serious risks for overdose and death should BUP-Inj be injected intravenously. A chain 
of custody will be maintained and documented detailing transfer from the manufacturer to the 
study pharmacy to the site staff who will administer the BUP-Inj product to participants assigned 
to the BUP-Inj condition, under the oversight of the Medical Clinicians with DEA Registrations. No 
take home injectable medications will be provided – all study products will be prepared and 
administered to study participants at the research clinic. To document safety and drug 
accountability, the Risk Evaluation and Mitigation Strategy (REMS) procedures will be followed. 
There are expected adverse events to the BUP-Inj medication. Medication-related adverse events 
that occur in more than 5% of subjects when using BUP-Inj include constipation, headache, 
nausea, injection site pruritus, vomiting, increased hepatic enzymes, fatigue, and injection site 
pain. These are minor, will be treated with ancillary medications, and tolerable in comparison to 
protection from overdose and potential for treating MUD42. BUP-Inj medication is habit forming. 
The risks to PBO-Inj are mild, including injection site reactions and tolerable withdrawal 
symptoms. To avoid risks for iatrogenic illness, all participants must meet criteria for moderate to 
severe MUD and mild OUD or demonstrate opioid misuse. Throughout the study, management 
of complaints of opioid withdrawal symptoms for all participants will include provision of over-the-
counter medications for head and body aches (e.g., ibuprofen), insomnia (e.g., diphenhydramine), 
diarrhea (e.g., loperamide) and stomach upset (e.g., bismuth subsalicylate) and ongoing opioid 


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use will be monitored to ensure that any escalation of opioid use that suggests moderate or 
greater OUD is evaluated by the Medical Clinician. 
Participants assigned to the active condition may acquire opioid dependence by the end of the 
trial, though concern is mitigated somewhat by the requirement for participants to have mild OUD 
or opioid misuse. To enroll, individuals must be experienced in the use of opioids, perhaps even 
including buprenorphine. This risk is balanced by several factors: 
1. From the Sublocade™ package insert, withdrawal symptoms following discontinuation 
from Sublocade™ are mild and may not be observed for a month or more following last 
injection, if at all43. We commit to assisting participants in finding Sublocade™ 
prescribers for those who report unacceptable opioid withdrawal symptoms anytime 
following their study visit. 
2. Participants must have mild OUD or opioid misuse. This requirement ensures substantial 
experience with opioids, though not enough to warrant ongoing prescribed Sublocade™. 
3. For participants assigned to the placebo condition, the two to three days of sublingual 
buprenorphine will be insufficient to establish severe opioid dependence or moderate to 
severe OUD. In response, however, participants in both conditions who complain of 
opioid withdrawal symptoms can be offered medications for symptom relief. 
4. The investigator team has consistently consulted with Indivior and NIDA throughout 
protocol development to discuss the side effect profile and the risks to benefit ratio for 
the study. All agree that benefits would outweigh risks to participation for all participants 
in this trial as outlined. 


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5.0 
OBJECTIVES 
5.1 
Primary Objective 
The primary objective of this study is to evaluate whether assignment to 12 weeks of outpatient 
BUP-Inj compared to 12 weeks of outpatient PBO-Inj reduces MA use as measured by twice 
weekly UDS during Weeks 9-12 for participants with moderate to severe MUD with co-occurring 
mild OUD or opioid misuse not warranting MOUD. 
5.2 
Secondary Objectives 
Secondary objectives include evaluation of whether assignment to 12 weeks of outpatient BUP-
Inj compared to 12 weeks of outpatient PBO-Inj improves:  
1. Alternate measures of methamphetamine use: 
a. Total number of MA negative UDS (Treatment Effectiveness Score, TES) 
through Weeks 1-12 
b. Self-reported days of MA use (TLFB) through Weeks 1-12 
2. Measures of opioid use: 
a. Total number of opioid negative UDS (TES) through Weeks 1-12 
b. Self-reported frequency of opioid use (TLFB) during Weeks 1-12  
3. Measures of MA and opioid co-use: 
a. Total number of MA and opioid negative same-day UDS (TES) through Weeks 1-
12 
b. Self-reported days of MA and opioid co-use (TLFB) during Weeks 1-12 
5.3 
Exploratory Objective(s) 
Data will be collected to explore whether assignment to BUP-Inj compared to PBO-Inj over the 12 
week medication phase corresponds with: 
1. Measures of subjective effects of MA: 
a. MA withdrawal, as measured by scores on the Amphetamine Cessation 
Symptom Assessment during Weeks 1-12 
b. MA craving as measured by the Visual Analog Craving Scales (VAS) during 
Weeks 1-12 
2. Measures of opioid subjective effects: 
a. Observer rating of opioid withdrawal as measured by the Clinical Opiate 
Withdrawal Scale (COWS) on the day of randomization; each subsequent visit 
during induction in Week 1, if needed; prior to each injection in Weeks 1, 5, and 
9, and at Week 12. 
b. Self-reported rating of opioid withdrawal as measured by the Subjective Opiate 
Withdrawal Scale (SOWS) on the day of randomization; each subsequent visit 
during induction in Week 1, if needed; prior to each injection in Weeks 1, 5, and 
9, and at Week 12. 


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c. Self-reported opioid craving, as measured by Visual Analog Craving Scales 
(VAS), Weeks 1-12 
3. Self-reported craving for MA and opioid co-use, as measured by Visual Analog Craving 
Scales (VAS), Weeks 1-12 
4. Measures of mood, pain, and stress: 
a. Self-reported depressive symptoms as measured by the Inventory of Depressive 
Symptomology - Self-Report (IDS-SR) during Weeks 1-12 
b. Change in self-reported anxiety symptoms as measured by the Generalized 
Anxiety Disorder Scale-7 (GAD-7) during Weeks 1-12 
c. Changes in self-reported mood symptoms as measured by the Concise 
Associated Symptom Tracking Scale (CAST) during Weeks 1-12 
d. Changes in self-reported anhedonia as measured by the Dimensional Anhedonia 
Rating Scale (DARS) during Weeks 1, 5, 9, and 12 
e. Changes in reported pain as measured by the Pain Frequency, Intensity, and 
Burden Scale (P-FIBS) during Weeks 1-12 
f. Changes in self-reported stress as measured by the Perceived Stress Scale 
(PSS) during Weeks 1, 5, 9, and 12 
5. Retention: 
a. Participants retained in treatment (defined as present and providing urine drug 
samples) during Weeks 1-12 
6. Measures of infectious disease control, incidence, and risk: 
a. Biomarkers measured at Week 12: 
i. HIV-Negative Participants: Remaining HIV-negative  
ii. HCV-Negative Participants: Remaining HCV-negative 
b. Self-Reported HIV transmission risk behaviors measured at Weeks 1, 6 and 12: 
i. Self-reported number of new sexual partners  
ii. Self-reported number of sexual partners with condomless sex who are 
serodiscordant or unknown serostatus 
iii. Self-reported number of sexual partners with condomless sex who are 
serodiscordant or unknown serostatus with whom substances were used 
during sex (chemsex)  
iv. For men, self-reported number of male sexual partners  
v. Self-reported number of episodes sharing needles  
vi. Self-reported number of episodes sharing injection equipment and 
paraphernalia  
7. Measures of functioning: 
a. Self-reported assessment of Quality of Life (QoL) at Weeks 1 and 12 
b. Self-reported overall functioning as measured by the Treatment Effectiveness 
Assessment (TEA) at Week 12 


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8. Measures of adverse events: 
a. Number and severity of adverse events reported during Weeks 1-12 
b. Number and outcomes (non-fatal, fatal) of overdose events during Weeks 1-12 
9. Changes in other substance use measured by self-report (TLFB) and UDS. Alcohol, 
tobacco, and other drugs measured via self-report will be collated and counted, and 
UDS results will quantify the presence of barbiturates, benzodiazepines, cocaine, 
amphetamines, marijuana (THC), methadone, phencyclidine (PCP) and ecstasy 
(MDMA). 
10. Changes in disease transmission, with new chlamydia or gonorrhea diagnoses 
measured via urinalysis. 
11. Participants will complete the Iowa Gambling Task (IGT) at screening to determine if 
performance on the IGT predicts treatment response. The IGT is a standard computer-
based task with established performance in people receiving treatment for MUD 44.  


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6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
The primary objective of this study is to assess the efficacy of BUP-Inj as a pharmacotherapy for 
moderate to severe MUD in those with co-occurring mild OUD or opioid misuse not warranting 
MOUD by evaluating whether assignment to 12 weeks of outpatient BUP-Inj compared to 12 
weeks of outpatient PBO-Inj reduces urine-verified MA use measured during Weeks 9-12 of 
medication administration. It is hypothesized that BUP-Inj will produce a significantly greater 
number of MA-negative UDS test results relative to the PBO-Inj during this period. To assess this 
objective, a phase IIb double-blinded, randomized controlled trial will be conducted. Participants 
will be randomized in a one-to-one ratio to one of two study arms: BUP-Inj or PBO-Inj. The Data 
and Statistics Center (DSC) will generate and implement the randomization schema. 
There will be approximately 246 individuals randomized into the study across 4-8 clinical sites. 
Eligibility will be determined during a maximum 21-day screening period. To document an 
appropriate level of current MA use, prospective participants must have at least two positive UDS 
for MA out of a possible three tests to occur at clinic visits within a 10-day period, with at least two 
days between visits. In addition, participants must self-report MA use on 18 or more days in the 
30-day period prior to written consent using the TLFB and meet diagnostic criteria for moderate 
or severe MUD per DSM-5 (four or more criteria) at screening. In addition, prospective participants 
must also meet diagnostic criteria for mild opioid use disorder per DSM-5 (at least two but no 
more than three criteria) at screening or demonstrate opioid misuse by self-reporting opioid use 
on at least two days in the 30-day period prior to written consent using the TLFB. Additionally, 
participants must also provide a UDS negative for opioids at least once during the screening 
period and on the day of randomization, to demonstrate the ability to abstain from using opioids 
for a short period of time and have a COWS score of ≤8 at both a screening visit on which they 
provide a UDS negative for opioids and on the day of randomization. After screening is completed 
and eligibility is confirmed, participants will begin the 12-week medication phase of the trial. 
Participants will be randomized to receive either 1) BUP-Inj or 2) PBO-Inj. Injections will be 
provided in Weeks 1, 5, and 9. Participants will be asked to submit twice weekly urine samples, 
and complete once-weekly cognitive behavioral therapy based on a treatment manual adapted 
for stimulant use disorder specifically for this study. Participants will be asked to complete 
assessments as indicated on the schedule of assessments (see Section 11). 
The experimental treatment and placebo will be in injectable formulation, with the addition of a 
two- to three-day sublingual buprenorphine induction using a defined dosing strategy for titration 
prior to initiating the injections. Dosing will be as follows: 
6.1.1 
Sublingual Buprenorphine Induction 
Due to an inability to obtain placebo sublingual medication that is matched to sublingual 
buprenorphine in appearance and taste, starting on Day 0 of Week 1, participants in both 
conditions will receive two 4mg doses of sublingual buprenorphine (as SuboxoneTM, Indivior), 
followed by two 8mg doses on Day 1 and, if necessary, Day 2 to reach 16mg maximum oral dose. 


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This is designed to facilitate rapid transition to the injectable formulation while ensuring the safety 
of the participants and helping to support the blinded injectable phase. 
6.1.2 
Injectable Formulations 
BUP-Inj: 
• 
Beginning in Week 1 and following successful induction, BUP-Inj participants will then 
transition to injectable buprenorphine 300 mg (as Sublocade™, Indivior) as determined 
by the Medical Clinician and is expected about Day 3. Subsequent BUP-Inj injections will 
occur at Weeks 5 and 9.  
PBO-Inj: 
• 
Beginning at Week 1 and following successful induction, PBO-Inj participants will then 
transition to injectable placebo about Day 3 and will receive placebo injections at the 
same time points as the active medication group. The dose of sublingual buprenorphine 
in these participants with some opioid experience is not expected to confer risk for 
precipitated withdrawal once participants transition to the injectable placebo, since 
participants will be required to have a negative opioid UDS with a COWS score of ≤8 at 
the time of induction. 
6.2 
Duration of Study and Visit Schedule 
Participants will be involved in the study for approximately 19 weeks, including a screening period 
of up to 3 weeks (i.e., 21 days) and 12 weeks in the medication phase, plus one follow-up 
appointment in Week 16. The screening phase may differ by participant in the length of time 
needed to complete preliminary eligibility assessments.  
Enrollment is expected to take place over a period of approximately 18 months. 


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7.0 
OUTCOME MEASURES 
7.1 
Primary Outcome Measure 
The primary outcome measure is the number of MA-negative UDS results obtained during Weeks 
9 through 12 of the medication phase as measured for the BUP-Inj and PBO-Inj conditions.  
7.2 
Secondary Outcome Measures 
Secondary outcome measures include: 
1. Alternate measures and composites of methamphetamine use: 
a. MA Treatment Effectiveness Score (TES), as measured by number of UDS 
results negative for MA by condition, during Weeks 1-12 (possible 2 per week; 
score range 0-24)  
b. Self-reported days of MA use on the TLFB during Weeks 1-12 (possible 1 per 
day; score range 0-84) 
2. Measures of opioid use: 
a. Opioid Treatment Effectiveness Score (TES), as measured by number of UDS 
results negative for opioids by condition, during Weeks 1-12 (possible 2 per 
week; score range 0-24). Results from radio-immune assay strips will be used to 
measure opiates (OPI-300), oxycodone/synthetic opioids, fentanyl for each UDS. 
b. Self-reported frequency of opioid use on the TLFB during Weeks 1-12. Reports 
of any opioid used will be combined into one measure that includes opiates, 
oxycodone and synthetic opioids, fentanyl and analogues for each report during 
Weeks 1-12 (possible 1 per day; score range 0-84). 
3. Measures of MA and opioid co-use: 
a. MA and Opioid Co-Use compiled using Treatment Effectiveness Score (TES), as 
measured by number of UDS results negative for both MA and opioids by 
condition, during Weeks 1-12 (possible 2 per week; score range 0-24)  
b. Self-reported days of MA and opioid co-use on the TLFB during Weeks 1-12 
(possible 1 per day; score range 0-84) 
7.3 
Other Exploratory Measures 
Exploratory measures include: 
1. Measures of MA subjective effects: 
a. MA withdrawal, as measured by scores on the ACSA during Weeks 1-12 
b. MA craving as measured by the VAS during Weeks 1-12 
2. Measures of opioid subjective effects: 
a. Clinician rating of opioid withdrawal as measured by the COWS on the day of 
randomization; each subsequent visit during induction in Week 1, if needed; prior 
to each injection in Weeks 1, 5, and 9, and at Week 12 


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b. Self-reported rating of opioid withdrawal as measured by the SOWS on the day 
of randomization; each subsequent visit during induction in Week 1, if needed; 
prior to each injection in Weeks 1, 5, and 9, and at Week 12 
c. Self-reported opioid craving as measured by VAS, during Weeks 1-12 
3. Self-reported craving for MA and opioid co-use as measured by VAS, during Weeks 1-
12 
4. Measures of mood, pain, and stress: 
a. Changes in self-reported depressive symptoms as measured by the IDS-SR 
during Weeks 1-12 
b. Changes in self-reported anxiety symptoms as measured by the GAD-7 during 
Weeks 1-12 
c. Changes in self-reported mood symptoms as measured by the CAST during 
Weeks 1-12 
d. Changes in self-reported anhedonia as measured by the DARS during Weeks 1, 
5, 9, and 12 
e. Changes in reported pain as measured by the P-FIBS during Weeks 1-12 
f. Changes in self-reported stress as measured by the PSS during Weeks 1, 5, 9, 
and 12 
5. Retention: 
a. Participants retained in treatment, defined as present and providing urine drug 
samples during Weeks 1-12 
6. Measures of Infectious disease control, incidence, and risk: 
a. Biomarkers measured at Week 12: 
i. 
HIV-Negative Participants: Remaining HIV-negative obtained via blood 
tests 
ii. 
HCV-Negative Participants: Remaining HCV-negative obtained via blood 
tests 
b. Self-Reported HIV transmission risk behaviors measured at Weeks 1, 6 and 12: 
iii. 
Self-reported number of new sexual partners  
iv. 
Self-reported number of sexual partners with condomless sex who are 
serodiscordant or unknown serostatus 
v. 
Self-reported number of sexual partners with condomless sex who are 
serodiscordant or unknown serostatus with whom illicit substances were 
used during sex (chemsex)  
vi. 
For men, self-reported number of male sexual partners  
vii. 
Self-reported number of episodes sharing needles  
viii. 
Self-reported number of episodes sharing injection equipment and 
paraphernalia  
7. Measures of functioning: 
a. Changes in self-reported assessment of Quality of Life (QoL) at Week 1 and 12 
b. Self-reported overall functioning as measured by the Treatment Effectiveness 
Assessment (TEA) at Week 12 


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8. Measures of adverse events: 
a. Number and severity of adverse events reported during Weeks 1-12 
b. Number and outcomes (non-fatal, fatal) of overdose events during Weeks 1-12 
9. Self-reported measures of alcohol, tobacco and other drug use on TLFB at Weeks 1, 5, 9, 
and 12, and UDS results of other substance use not quantified for primary or secondary 
outcomes. 
10. Urinalysis results indicating a new chlamydia or gonorrhea diagnosis at Week 12 
11. IGT performance at screening 
7.4 
Study Timeline 
After receiving Center for the Clinical Trials Network (CCTN) approval of the full and final protocol, 
approximately 8 months of trial preparation activities will elapse prior to commencing enrollment. 
Trial preparation will include applying for and obtaining Institutional Review Board (IRB) approval, 
filing the IND application, developing the data collection systems, developing the Manual of 
Procedures (MOP), conducting all staff training, collecting required regulatory documents, and 
endorsing sites. If feasible, the study may be implemented in a single wave; however, sites may 
launch on a rolling basis. Recruitment is expected to take approximately 18 months, with the 
medication phase and follow-up continuing for approximately four months post completion of the 
recruitment phase. Two months will be allowed for data lock after the end of the follow-up period. 
Therefore, data lock is projected to occur at approximately 32 months after CCTN approval of the 
final protocol. 


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8.0 
STUDY POPULATION 
Approximately 246 males and females who meet eligibility criteria will be randomized. Eligible 
participants will meet criteria for moderate to severe MUD and have co-occurring mild OUD or 
opioid misuse not warranting MOUD. 
8.1 
Participant Inclusion Criteria 
Individuals must meet all of the inclusion criteria in order to be eligible to be randomized into the 
study. 
Study participants must: 
1. Be 18 to 65 years of age, inclusive; 
2. Able to understand and speak English or Spanish; 
3. Be interested in reducing or stopping MA use and not interested in pursuing MOUD; 
4. Meet DSM-5 criteria for moderate or severe MUD (4 or more criteria); 
5. Self-report MA use on 18 or more days in the 30-day period prior to written consent 
using the TLFB; 
6. Provide at least 2 urine samples positive for MA out of a possible 3 tests to occur at 
clinic visits within a 10-day period with at least 2 days between visits;  
7. Meet DSM-5 criteria for mild OUD (at least 2 but no more than 3 criteria) prior to 
randomization OR opioid misuse demonstrated by self-report of opioid use of at least 2 
days in the 30-day period prior to written consent using the TLFB; 
8. Provide at least 2 urine samples negative for opioids, at least one during the screening 
period and again on the day of expected randomization to indicate control over opioid 
use; 
9. Have a COWS score of ≤8 at both the screening visit on which they provide a UDS 
negative for opioids and on the day of randomization;  
10. If female, agree to both of the following: use an acceptable method(s) of birth control, as 
defined in the MOP, for the duration of study participation and for four months after the 
last injection of study medication; undergo periodic urine pregnancy tests for the duration 
of study participation, unless verifiably unable to get pregnant, as defined in the MOP; 
11.  Be willing and able to provide consent and comply with all study procedures and 
medication instructions; 


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8.2 
Participant Exclusion Criteria 
Individuals meeting any of the exclusion criteria will be excluded from being randomized into the 
study. 
Study participants must not: 
1. Have suicidal or homicidal ideation that requires immediate attention; 
2. Have evidence of prolongation of the QTc or any other finding on the screening ECG 
that, in the opinion of the Medical Clinician, would preclude safe participation in the study 
(e.g., hypokalemia, unstable atrial fibrillation) and be at significant risk for serious cardiac 
adverse events; 
3. Have a laboratory value with total bilirubin ≥1.5 × upper limit of normal (ULN), alanine 
aminotransferase (ALT) ≥3 × ULN, aspartate aminotransferase (AST) ≥5 × ULN, or 
serum creatinine >2 × ULN; 
4. Have been in a study of pharmacological or behavioral treatment for addiction within 6 
months prior to written study consent (smoking cessation excepted); 
5. Have taken an investigational drug in another study within 30 days prior to written study 
consent; 
6. Have been prescribed or have taken buprenorphine or methadone within 30 days prior 
to written study consent;  
7. Be concurrently enrolled in formal behavioral or pharmacological addiction treatment 
services or express the desire to initiate MOUD at the time of written consent;  
8. Be receiving ongoing treatment of medications that are clinically relevant CYP 3A4 or 
CYP 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals, macrolide antibiotics), 
Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or 
Class III antiarrhythmic medications (e.g., sotalol, amiodarone) at the time of 
randomization that, in the judgment of the Medical Clinician, could interact adversely 
with study medications or put them at significant risk for development of serotonin 
syndrome;  
9. Have a current pattern of alcohol, benzodiazepine, or other sedative hypnotic use which 
would preclude safe participation in the study as determined by the Medical Clinician; 
10. Have a surgery planned or scheduled, or other treatment that would require the use of 
opioid-containing medications (e.g., opioid analgesics) during the study period; 
11. Currently or soon to be in jail or prison; currently in any inpatient overnight facility as 
required by court of law or have pending legal action or other situation that could prevent 
participation in the study or in any study activities; 
12. If biologically female, be currently pregnant, breastfeeding, or planning on conception; 
13. Hypersensitivity (e.g., anaphylaxis) to buprenorphine or any component of the ATRIGEL 
formulation or their excipients; 


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14. Have an abdominal area unsuitable for subcutaneous injections by the judgment of the 
Medical Clinician;  
15. Have other medical, psychiatric or other factors that in the judgment of the Medical 
Clinician could make participation difficult or unsafe. 
8.3 
Strategies for Recruitment and Retention  
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 or other gathering 
areas. Information regarding the method of recruitment that led potential participants reaching out 
to study personnel will be recorded on the Prescreening Interview eCRF to optimize the most 
successful recruitment strategies and track the factors that lead to both recruitment of eligible 
participants and the reasons that others are deemed ineligible for participation. 
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 racial/ethnic minorities in the community where 
the site is located, including persons of African American and Latinx backgrounds. Recruitment 
procedures aiming to enhance enrollment of women and/or minorities will be conducted, with sites 
being encouraged to implement strategies such as linkages with medical sites, treatment 
programs, or community organizations that serve a large number of women and/or minorities, 
using targeted advertisement in media with a high female and/or minority audience, and 
partnerships with community organizations who work with these groups. This study aims to enroll 
a minimum of approximately 25% women in the total study population. 
For successfully enrolled participants, efforts will be made to encourage participation in the full 
duration of the trial. These efforts include regular participant contact, including reminders, to 
encourage visit attendance, reimbursement for study related activities, and a weekly cognitive 
behavioral therapy component which also will encourage and reinforce the importance of 
continuing in the trial as a key way to reduce methamphetamine use. 


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9.0 
SITE SELECTION 
9.1 
Number of Sites 
The trial will include 4-8 sites with each site randomizing approximately a total of 31-61 
participants. 
9.2 
Site Characteristics 
Participating sites must: 
1. Have a Site Principal Investigator (PI) who can commit the time necessary to take a 
leadership role and oversee all aspects of the study, perform assessments as licensure 
allows, confirm participant eligibility (if a MD or DO), review adverse events (if a MD or 
DO), and appropriately evaluate and respond to adverse reactions that may occur during 
the study (if a MD or DO).  
2. Have at least two Medical Clinicians (i.e., physician, physician’s assistant, or nurse 
practitioner) with a DEA Registration who can, in accordance with the state regulations 
where the site is located, make independent medical decisions and commit the time 
necessary to perform medical assessments as licensure allows, determine participant 
eligibility, confirm participant eligibility prior to randomization (if a MD or DO), order and 
administer study medication, review adverse events (if a MD or DO), and appropriately 
respond to adverse reactions that may occur during the study (if a MD or DO). One of 
these Medical Clinicians can also be the Site PI. 
3. Have staff to serve as unblinded medical personnel (RN, LVN, MA, or other qualified 
personnel trained in the administration of subcutaneous injection). These staff can only 
participate in study-related activities pertaining to preparing and administering 
medication injections, evaluating the injection site, and documenting injectable 
medication administration.  
4. Have standard operating procedures (SOPs) in place for handling medical and 
psychiatric emergencies. 
5. Have a Medical Clinician available to provide after-hours clinical back-up for study-
related emergencies. 
6. Have access to a phlebotomist or other qualified personnel to complete blood draws. 
7. Have the ability to meet storage and dispensing requirements for study medication, 
including access to adequate storage space, equipment, and appropriately qualified 
staff, as directed by the protocol and in accordance with local regulations and National 
Institute on Drug Abuse (NIDA) stipulations. 
8. 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. 
9. Have adequate facility space available to conduct study procedures. 


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9.3 
Rationale for Site Selection 
The sites selected for participation in this trial will be selected, in part, based on the Local Node’s 
interest in participating in the trial, the availability of a sufficient pool of potential study participants 
in the area that includes both male and female participants, 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 characteristics 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 MUD and co-occurring 
opioid use each month. 
2. Ability to rely on a centralized IRB and having personnel experienced with regulatory 
requirements to support timely preparation of necessary documents and facilitate an 
expeditious IRB submission, approval, modification, and continuing review processes in 
accordance with required IRB reliance procedures. 
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 
study medication, 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 (EDC) 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. 
 


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10.0 STUDY PROCEDURES 
10.1 PreScreening Assessment 
Prescreening assessment will be completed before participants sign the research consent and 
therefore, verbal consent to prescreening will be obtained. Those 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 and opioid use 
history, interest in participating in research to investigate medication that has potential to reduce 
MA use, ability and willingness to participate for the duration of the trial) will determine preliminary 
eligibility. Appointments to open the consent process and complete full screening appointments 
will occur for those who meet preliminary eligibility criteria. A waiver of HIPAA authorization will 
be obtained from the IRB of record for prescreening.  
10.2 Screening Visit 
Assessments administered during screening (after the participant signs informed consent) will 
determine whether participants meet eligibility criteria. Screening assessments will be conducted 
as shown in Table 11.1. Participants who do not complete all screening assessments within 21 
days of signing consent or who are otherwise found to be ineligible for participation in the study 
will be considered screen fails. With Sponsor approval, screen fails may be allowed one additional 
chance to return at a later date (at least 30 days past initial screen fail date) to repeat and restart 
the screening process. 
10.2.1 
Informed Consent Procedures for Participants 
Participants will be given a copy of the current, IRB-approved informed consent form(s). The 
entire consent form(s) including, study procedures and the potential risks and benefits of 
participating in the trial will be explained by qualified research staff. Staff will be available to 
answer questions about the consent form while participants are reviewing it. Given the multisite 
nature of the trial, it is possible that ancillary studies will be proposed before or after the study 
begins recruitment. For this reason, during the informed consent process, we will also seek 
permission to contact the participant in the future about other study opportunities.  
Prior to signing the consent form, the participant must pass a brief consent quiz to illustrate 
comprehension of the study activities. For participants who do not correctly answer all 
comprehension items, the study staff will re-explain the study, or may ask another study staff 
member to speak with the participant, with a focus on aspects candidates did not understand. 
The other study staff member may determine that the participant would benefit from coming back 
after having some time to review the study details and may return at a later date to engage in the 
informed consent process again. Participants may attempt the consent comprehension questions 
a maximum of three times before they are deemed unable to comprehend the study. If the 
participant is unable to comprehend what the study activities require of them, they will be unable 
to participate in the study. After passing the quiz and signing the consent form, participants will 
be given a copy of the signed forms to keep for their records. After the participant signs the 
informed consent, the rest of the screening assessments will be performed. 


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10.2.2 
HIPAA Authorization and Medical Record Release Forms 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. Sites will be responsible for communicating with their local IRB(s) 
or Privacy Boards and obtaining the appropriate approvals or waivers to be in regulatory 
compliance. 
10.2.3 
Screening Assessments 
After signing the IRB-approved consent form, participants enter into a maximum 21-day screening 
phase to complete assessments to determine eligibility. Screening assessment procedures must 
be completed across at least two screening visits. 
During the screening phase, participants must have at least 2 positive UDS for MA out of a 
possible 3 tests that must occur within a 10-day period, and at least 2 full days must pass between 
clinic visits. In addition, participants must self-report MA use on 18 or more days in the 30-day 
period prior to written consent using the TLFB. These criteria will be used to confirm current MA 
use and further substantiate a diagnosis of moderate to severe MUD. 
In addition, the participant must meet DSM-5 criteria for mild OUD (at least 2 but no more than 3 
criteria) or self-report opioid use on at least 2 days in the 30-day period prior to written consent 
using the TLFB. Additionally, at least once during the screening period and again on the day of 
expected randomization, the participant must provide a urine sample that is negative for opioids 
to demonstrate the ability to abstain from using opioids for a short period of time. The urine can 
be positive for MA. On these visits that the participant provides the required opioid-negative urine 
samples, the participants must also report a COWS score ≤ 8 to indicate opioid withdrawal 
symptoms do not present at moderate or severe levels (supporting that the participant has mild 
opioid use disorder or opioid misuse). If on the day of randomization, the participant instead 
provides a urine sample that is positive for opioids, they cannot be randomized to the study on 
that day and must delay study participation for at least one month. After at least one month, they 
can restart the screening phase. This is allowed only one time per participant in the course of the 
study. 
A physician (MD or DO) who serves in the Site PI or Medical Clinician study role must review and 
approve safety and eligibility assessments in order to confirm participant eligibility prior to 
randomization after the participant does the following: 
1. Completes all screening assessments, 
2. Has 2 MA-positive UDS tests and 1 opioid-negative UDS test per guidelines above, 
3. On the day randomization is expected, has a urine sample negative for BUP, methadone, 
and opioids (but can be positive for MA) and if capable of getting pregnant, has a negative 
urine pregnancy test, and  
4. Is found otherwise eligible for continued participation. 
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 


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considered screen fails. With Sponsor approval, screen fails may be allowed one additional 
chance to return at a later date (at least 30 days past initial screen fail date). Demographic data 
and the reasons for not meeting eligibility criteria will be documented for all screen fails. 
After the participant is deemed fully eligible and this is recorded in the Advantage eClinical system, 
the participant will then complete all assessments required on the day of randomization as 
detailed in Table 11.1 for Week 1. 
10.3 Randomization 
Following the collection of the assessments required for screening and eligibility, eligible 
participants will be randomly assigned to BUP-Inj or PBO-Inj in a 1:1 ratio. The randomization 
procedure will be conducted electronically by the Advantage eClinical system. The unblinded DSC 
Statistician will review the randomization data on a regular basis to ensure that the scheme is 
being implemented according to plan. If a participant drops out of the study at any point after 
randomization, the randomization slot will not be re-allocated to a new participant due to the intent-
to-treat nature of the study. All screening assessments must be completed before the participant 
is randomized and all assessments required on the day of randomization must be completed 
before the participant is administered any study medication. 
10.4 Study Intervention(s) Administration 
10.4.1 
Induction Phase 
Participants will receive sublingual film (BUP) on the day of randomization (Day 0) following 
randomization and collection of assessments required on the day of randomization. If a participant 
reports symptoms of withdrawal or side effects, ancillary medications may be used to manage 
symptoms. This includes management of head and body aches (e.g., ibuprofen), insomnia (e.g., 
diphenhydramine), diarrhea (e.g., loperamide) and stomach upset (e.g., bismuth subsalicylate). 
The Medical Clinician will guide the induction onto study medication using a defined dosing 
strategy to ensure that participants in either condition receive the exact same induction and that 
participants tolerate the medication before proceeding to the first injection. The induction phase 
will last between 2 and 3 days. If needed, participants may have subsequent study visits during 
the induction phase. 
10.4.2 
Injections 
Participants will receive the first subcutaneous injection of study medication (BUP-Inj or PBO-Inj) 
after determination by Medical Clinician that participants may advance from the induction phase. 
This will happen in Week 1 of the study. Subsequent subcutaneous injections of study medication 
should be administered at the beginning of Weeks 5 and 9 and shall be administered following 
the guidelines in the BUP-Inj package insert. Medical Clinicians will evaluate participants to 
ensure continued suitability for injectable study medication administration. If a participant reports 
uncomfortable symptoms or side effects, ancillary medications may be used to manage 
symptoms. Defined windows for injections will be outlined in the MOP. If a participant misses a 
window for an injection, they will not receive the injection but will be maintained in the study and 


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used in the Intent-to-Treat analysis. Given the long-lasting nature of BUP-Inj, these windows will 
be defined in a way to maximize the possibility for a participant to receive study medication. 
10.5 Study Intervention Adherence 
The primary study intervention is injectable medication. This prevents a number of adherence 
issues that come with oral administration. However, continued participation in the study for both 
those randomized to active medication and randomized to placebo is essential for successful 
study completion. In order to facilitate adherence to study procedures and to successfully 
complete the study, a weekly cognitive behavioral therapy (CBT) component modeled on 
traditional medical management is included in the study procedures.  
Participants will meet with trained study staff once weekly for an individual CBT session that 
utilizes a structured adherence enhancement manual designed for pharmacotherapy trials with 
participants with substance use disorder45. The goal of these CBT sessions is to achieve high 
quality supportive treatment that reinforces adherence to study procedures and study visits. A 
session will be approximately 20 minutes and focus on: 
1. Setting abstinence from MA as a goal, 
2. Learning a skill for instilling abstinence, preventing relapse or returning to abstinence in 
the setting of lapse or relapse, 
3. Participant adherence with study visits and procedures, and  
4. Current functioning. 
Study staff will also review adverse events, and communicate issues to Medical Clinicians (MD 
or DO) for consideration of potential medication side effects, and discussion of other pertinent 
issues in keeping with sound medical practice. Medical Clinicians may choose to provide ancillary 
medications for study medication-related adverse events as clinically indicated or for 
management of opioid withdrawal symptoms, such as anxiety, nausea, vomiting, diarrhea, muscle 
pain, and insomnia. At all CBT sessions, the study staff will remind participants about the 
importance of adhering to the study procedures, including attending scheduled clinic visits. Mutual 
help support group attendance will be encouraged. 
10.6 Premature Withdrawal of Participants 
All participants will be followed for the duration of the study unless they withdraw consent, die, or 
the PI or Sponsor decides to discontinue their enrollment for any reason. Reasons for the PI or 
Sponsor terminating a participant from the study may include but are not limited to: clinical 
deterioration, the participant becoming a threat to self or others, or early termination of the study 
for safety or effectiveness reasons. 
10.7 Considerations Regarding Ongoing Opioid Use 
The safety of the participants is foremost in the design of this study. There is a chance that 
participants may experience a worsening of their opioid use. In order to ensure participant safety 
throughout the trial, the following criterion will be used to trigger an evaluation of the severity of 


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the participant’s opioid use. Participants who provide two weeks of opioid positive UDS (4 
consecutive opioid positive UDS), independent of MA result in UDS, will trigger a safety review 
by the Medical Clinician. If in the Medical Clinician’s judgement continuing in the study is not safe 
for the participant due to worsening of opioid use, independent of status regarding MUD, the 
Medical Clinician (MD or DO) may elect to discontinue the participant from the medication aspect 
of the study and refer the participant to a clinic for treatment of OUD. In this instance, the study 
staff or Medical Clinician will assist the participant with obtaining an appointment with an 
outpatient MOUD provider. The study staff will follow-up with the participant within 48 hours of the 
appointment date to assist with transportation or other barriers reaching the appointment. If in the 
Medical Clinician’s judgment continuing in the study is safe for the participant and the opioid use 
is deemed to not exceed that of mild OUD, the participant will be provided with an additional 
Naloxone kit with specific instructions for the participant’s friends and family on proper usage. 
Follow-up evaluations of additional opioid positive UDS results by the Medical Clinician will 
document continued assessment of safety for the participant.  
10.8 Rules for Immediate Study Review 
The following rules will automatically trigger a review by the DSMB to determine if any action 
should be taken to adjust conduct of the trial: 
• 
Three or more participants experience severe adverse reactions. 
• 
Four or more participants have four consecutive positive urine toxicology screens for 
opioid use, and have been reevaluated through any means as having moderate to 
severe opioid use disorder. 
• 
One or more serious, unexpected and suspected adverse reaction (SUSAR). 
10.9 Follow-Up 
All enrolled participants will be asked to complete a post-medication phase follow-up visit in Week 
16 according to the schedule of assessments (see Table 11.1, Section 11). Given the long-lasting 
nature of BUP-Inj, there is no tapering possible therefore thorough assessment of side effects 
and AEs will be completed. Any participant who requests may receive a referral to treatment. 
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. 
10.10 Discontinuation of Study Intervention 
Participants will be withdrawn from further study medication administration if it is clinically 
determined that continuation may be unsafe or if they become unable to come to clinic for study 
visits (e.g., they become incarcerated). For example, women who become pregnant during the 
medication period will be immediately withdrawn from study medication administration. 
Participants who must start treatment with medications that may interact with BUP 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 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 
• 
Hypersensitivity reaction to the study product 
• 
Requirement for opioid analgesics for general anesthesia for surgery 
• 
Increase in LFT or decrease in platelet test results that may increase participant health 
risks. This includes any of the following: AST/ALT results >5 times upper limit of normal, 
total bilirubin >2 times upper limit of normal, or platelets below 75 x 103/μL 
A physician (MD or DO) who serves in the Site PI or Medical Clinician study role must make the 
decision to withdraw a participant from study medication. Also, participants may decide at any 
time that they no longer wish to continue to receive medication or participate in the study. 
Given the long-term nature of BUP-Inj, a taper is not possible, even if the Medical Clinician 
determines medication discontinuation is warranted for medical or psychiatric reasons. In the 
event a participant becomes pregnant during the medication period, the pregnant participant will 
be immediately discontinued from further study medication administration, referred for obstetric 
care, and the pregnancy followed until an outcome is known. 
In the event a participant is withdrawn from further administration of study medication, referrals to 
treatment programs or recommendations for medical care will be provided as appropriate. Unless 
consent is officially withdrawn, study staff will encourage participants who are withdrawn from 
study medication or who opt out of study medication to continue completing twice weekly visit 
assessments and complete all study assessments throughout the duration of the medication 
phase (Weeks 1-12) and the follow-up phase (Week 16). If a clinically significant finding is 
identified (including, but not limited to changes from participant’s baseline status prior to receiving 
study medication) after enrollment, the Medical Clinician will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE) if it meets the definition specified in Appendix A of the protocol. 


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10.11 Blinding 
10.11.1 
Type of Blinding 
This is a double-blind, placebo-controlled study. There are differences in appearance for active 
and placebo injection products and thus additional procedures, including use of unblinded staff to 
administer the injections and physical shielding of the injection syringe, will be utilized to maintain 
the blind for both participants and blinded study staff. 
10.11.2 
Maintenance of the Blind 
Only the DSC staff overseeing the random assignment schedule, a few CCC staff, the central 
research pharmacy staff preparing the study medication, and a single study staff role (Unblinded 
Medical Personnel) to administer the injections are unblinded; all other study personnel and 
participants will remain blinded to treatment arm until the nationwide completion of the trial and 
the database is formally locked. Detailed information on the study procedures regarding the 
double-blinding will be contained in a standalone Blinding Management Plan and Study Site 
Blinding Plan. A DSMB will review study data throughout the course of the trial in a blinded fashion 
(e.g., masked treatment assignments), however they can request to be unblinded at any time. 
10.11.3 
Breaking the Blind 
In rare cases, it may be necessary to break the blind for a particular study participant before 
completion of the trial (e.g., emergency surgical procedures or other medical necessity). Any 
participant who experiences a non-fatal overdose during the study will be unblinded and referred 
to treatment. The participant will also be withdrawn from all medication aspects of the study. The 
request to break the study blind for an individual participant will be made by the Medical Clinician 
after consultation with the Lead Investigator(s). Unblinding the participant should occur only in 
cases of medical emergency when knowledge of the treatment group/investigational agent may 
be necessary for clinical management and decision-making. The decision to break the blind for a 
participant will be made jointly by the Clinical Coordinating Center (CCC) Medical Monitor and at 
least one of the Lead Investigators. 
10.12 Participant Reimbursement  
Participants will be reimbursed for their participation in this study. Reimbursement will be in 
accordance with the IRB of record’s policies and procedures, and subject to IRB approval. Study 
participants will be provided with study medication and cognitive behavioral therapy at no cost. In 
addition, participants will receive gift cards or cash (based on local site requirements) as 
reimbursement for time, travel, parking, and other costs borne by the participant. Total 
reimbursement possible is suggested to be approximately $735, but can be increased based on 
the local site’s standard practice. 


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11.0 STUDY ASSESSMENTS 
11.1 Table of Assessments 
Study Phase 
Prescreening 
Screening  
Medication Phase 
Follow-
up 
Study Week 
  
-21 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
General Measures 
Verbal Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prescreening Interview  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed Consent 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics  
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
MINI Modules 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
Sexual Risk Behaviors 
  
  
X 
  
  
  
  
X2 
  
  
  
  
  
X2 
  
Self-Report of HIV Testing (PhenX Tier 1) 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self-Report of Hepatitis Testing and Treatment (PhenX 
Tier 1) 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
Alcohol and Substance Use (PhenX Tier 1) 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical and Psychiatric History 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
Safety Measures  
Physical Examination 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
X2 
  
Electrocardiogram  
  
X* 
  
  
  
  
  
  
  
  
  
  
  
X2 
  
Medication Side Effects 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
Buprenorphine-XR/Placebo Injection Site Evaluation 
  
  
  
X 
  
 
X2 
  
  
  
X2 
 
  
X2 
  
Concise Health Risk Tracking (CHRT) - Participant 
  
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concise Health Risk Tracking (CHRT) – Clinician Rated 
ModuleB 
  
X* 
  
  
  
  
  
X  
  
  
  
  
  
X  
  
Urine Pregnancy TestB 
  
X* 
2XA 
  
  
  
XA 
  
  
  
XA 
  
  
X 
 X 
Pregnancy and Birth Control Assessment 
  
X* 
X2 
  
  
  
X 
  
  
  
X 
  
  
X 
 X 
Vital Signs 
  
X* 
2X A 
X 
X 
X 
X A 
X 
X 
X 
X A 
X 
X 
X 
X 
Prior and Concomitant Medications 
  
X+ 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
X 
Adverse Events, Serious Adverse Events and Medical 
Review 
  
X+ 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
X 
Clinical and Efficacy Measures  
Urine Drug Screen 
  
X+ 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
X 
Buprenorphine Urine Drug Screen 
  
X+ 
  
  
  
  
  
  
  
  
  
  
  
  
  


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Study Phase 
Prescreening 
Screening  
Medication Phase 
Follow-
up 
Study Week 
  
-21 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
Timeline Followback 
  
X+ 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
X 
Visual Analog Scales for Methamphetamine and Opioid 
Craving  
  
X+ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale 
  
XD 
X^ 
  
  
  
X 
  
  
  
X 
  
  
X 
X 
Subjective Opiate Withdrawal Scale 
  
  
X^ 
  
  
  
X 
  
  
  
X 
  
  
X 
X 
Inventory of Depressive Symptomology-Self-Report  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Generalized Anxiety Disorder Scale 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concise Associated Symptoms Tracking Irritability  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dimensional Anhedonia Rating Scale 
  
  
X 
  
  
 
X 
  
  
 
X 
  
  
X 
X 
Amphetamine Cessation Symptom Assessment 
  
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perceived Stress Scale 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
X 
Pain Frequency, Intensity, and Burden Scale 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cognitive Behavioral Therapy Documentation  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Iowa Gambling Task and Documentation  
  
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
Treatment Effectiveness Assessment 
  
  
 
  
  
  
  
  
  
  
  
  
  
X2 
  
Cannabis Use Assessment 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Tobacco Use History (PhenX Tier 1) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X2 
 
Quality of Life (PhenX Tier 1) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X2 
 
Semi-Structured Qualitative Interview 
 
 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence Measures 
Buprenorphine-XR/Placebo Injection 
 
 
X2 
 
 
 
X 
 
 
 
X 
 
 
 
 
BUP-SL Dispensing 
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Evaluations 
Urine Screening for Disease 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
X 
  
Complete Blood Count 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood Chemistry 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Function Tests 
  
X* 
 
  
  
 
 
  
  
 
 
  
  
X 
  
Disease Serology  
  
X* 
  
  
  
  
  
  
  
  
  
  
  
X 
  
Blood Sample for UTSW Repository 
  
X* 
  
  
  
  
  
  
  
  
  
  
  
X 
  
Blood Sample for NIDA Genetic Testing and Family 
Origin  
  
  
 
  
  
  
 XC 
  
  
  
  
  
  
  
  


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Study Phase 
Prescreening 
Screening  
Medication Phase 
Follow-
up 
Study Week 
  
-21 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
Buprenorphine Blood Levels 
  
  
  
  
  
  
XA 
  
  
  
XA 
  
  
X 
  
Administrative and Other Forms 
Locator Form 
  
X* 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Eligibility - Randomization (Enrollment Form) 
  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Visit Documentation Form 
 
X+  
 2X 
2X  
2X
  
2X
  
2X  
2X
  
 2X 
2X
  
2X  
2X  
2X  
2X  
X  
Mental Health Follow-Up AssessmentB 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
End of Medication Form 
  
  
  
  
  
  
  
  
  
  
  
  
  
X2 
  
Protocol Deviation and ReviewB 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Treatment Satisfaction 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Study Completion  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
NOTES:  
X* = once during screening 
X+ = at each screening visit 
X^ = at each induction visit, including if additional induction visits are required during the medication phase, and on the day of first injection 
X = a procedure or assessment performed once per week and preferably at the first visit of the week, unless otherwise noted 
2X = a procedure or assessment performed twice per week 
X1 = on the day of induction only 
X2 = collected at the second visit of the week 
A Must be collected prior to administration of any medications at the visit 
B Completed as applicable 
C If consent is provided, collect sample on day of 2nd injection if possible. Otherwise, to be collected at any future visit with blood draw.  
D Collected at screening visit(s) with a UDS negative for opioids and on the day of expected randomization 
E If verbal consent is provided, interviews can be conducted anytime after the last administration of any medication (sublingual or injectable medication). Note: Participants must 
have taken at least one dose of sublingual medication to be eligible for the interview. 
 


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11.2 General Measures 
11.2.1 
Prescreening Interview 
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 Prescreening Interview, staff will provide a brief overview of the study and will 
obtain and document verbal consent. The Prescreening Interview consists of questions to assess 
essential information in determining potential eligibility. 
11.2.2 
Informed Consent 
Prior to beginning any study assessments, all participants will review and sign the current, IRB-
approved consent form and any other related documents in accordance with IRB and state 
requirements. The date the IRB-approved consent form was signed will be entered into the 
electronic data capture system. 
11.2.3 
Demographics 
The Demographics form will incorporate PhenX Core 1 items and will collect information about 
demographic characteristics of the participant, including sex, gender, date of birth, ethnicity, race, 
education, employment status, and marital status. 
11.2.4 
Mini International Neuropsychiatric Interview (MINI) Modules 
The MINI will be used to provide diagnostic information to support the inclusion/exclusion criteria 
related to both MUD and OUD46. Specific modules will be used to assess the presence and history 
of a major depressive episode (MDE) or major depressive disorder (MDD), suicide behavior, 
bipolar disorder, alcohol use, and substance use.  
11.2.5 
Sexual Risk Behaviors 
The Sexual Risk Behaviors assessment will 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, drug paraphernalia, and alcohol during sex. 
11.2.6 
PhenX Tier 1 
The Substance Abuse and Addiction Collection of the PhenX Toolkit (http://www.phenxtoolkit.org) 
includes measures that are being adopted across NIDA-funded research. The Core Tier 1 
collection includes measures for demographics (age, ethnicity, gender, race, educational 
attainment, employment status, and marital status), body mass index, quality of life, and HIV risk 
and status; substance use measures include age of onset, past 30-day quantity and frequency, 
lifetime use for alcohol, tobacco and other substances. Where possible, answers to Core Tier 1 
questions are populated from the answers to questions from other assessments, but some 
additional questions may be incorporated to accommodate this requirement. Quality of Life and 
Tobacco Use History are 2 such additions. In addition, although not considered a part of the 
PhenX toolkit, self-report of hepatitis testing and treatment will be collected in conjunction with 
the PhenX self-report of HIV status assessment. 


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11.2.7 
Alcohol and Substance Use  
The Alcohol and Substance Use form will be completed at screening to incorporate PhenX Core 
Tier 1 items47. The participant will be asked whether they have ever used alcohol and/or various 
substances as well as the 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. 
11.2.8 
Medical and Psychiatric History 
The medical and psychiatric history will document participants’ past and present health conditions 
to help determine eligibility and to provide baseline information. 
11.3 Safety Measures 
11.3.1 
Physical Examination 
A physical examination will be completed to collect baseline information regarding the 
participant’s physical health and to ensure there are no exclusionary medical conditions. The 
exam will include an examination of the participant’s abdominal area and the planned injection 
site(s) to assess appropriateness for subcutaneous injections. The exam will be completed again 
at study exit to confirm the health of the participant. 
11.3.2 
Electrocardiogram (ECG) 
A 12-lead ECG will be administered to assist in determination of participant eligibility and again 
to assess safety. The ECG tracings will be reviewed by a 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 Medical Clinician. 
11.3.3 
Medication Side Effects 
At the visit after the participant receives sublingual buprenorphine (Week 1, 2nd Visit), participants 
will be asked to report any expected adverse reactions experienced after taking SL-BUP using 
the Medication Side Effects form. The self-administered form lists different expected adverse 
reactions, and participants will rate each possible reaction according to the severity of their 
perceived reaction. Events that are documented on the Study Medication Side Effect form will not 
be duplicate-reported as AEs unless one or more SAE criteria are met.  
11.3.4 
Buprenorphine-XR/Placebo Injection Site Evaluation 
Unblinded medical personnel will examine the injection site during the study visit following each 
subcutaneous injection. These examinations will usually occur at visits immediately following 
injections but should occur at the next attended visit if any of the aforementioned visits are missed. 
Additional monitoring may also be required. Participants will be asked to immediately report any 
injection site reactions to allow evaluation, monitoring, and possible referral, as needed. In the 
event an injection site reaction is reported by a participant or an abnormality is identified during 
an injection site evaluation, it will be captured on this form. All injection site reactions should be 
documented on the Buprenorphine-XR/Placebo Injection Site Evaluation form throughout study 
participation (from first injection through Week 16 Follow-up). If the abnormality results in a 


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Serious Adverse Event (SAE), the Adverse Event forms must also be completed. Well-developed 
precautionary procedures will be followed to avoid adverse events associated with injectable 
study medication administration. For example, abdominal area will be assessed during the 
physical exam at screening to assure that subcutaneous depot administration is feasible. 
Individuals whose abdominal area is unsuitable for subcutaneous depot injection will be excluded 
from the study. 
11.3.5 
Concise Health Risk Tracking (CHRT) —Participant (CHRT-SR) 
The CHRT-SR is a 16-item participant self-report assessment of suicidality and related thoughts 
and behaviors48. The scale is designed to quickly and easily track suicidality in a manner 
consistent with the Columbia Classification Algorithm of Suicide Assessment (C-CASA)49. The 
CHRT-SR will assess high risk suicidal ideation by a positive response (Agree or Strongly Agree) 
on any of the last three questions (thoughts of, thoughts of how and/or a specific plan to commit 
suicide). A positive response will prompt completion of the Concise Health Risk Tracking (CHRT) 
– Clinician Rated Module before the participant leaves the clinic, and completion of the Mental 
Health Follow-up Assessment form. 
11.3.6 
Concise Health Risk Tracking (CHRT) —Clinician Rated Module 
(CHRT-CR) 
The CHRT-CR is a brief clinician-rated assessment of suicidal thoughts, actions, or related 
behaviors. The assessment will be completed once during Screening, Week 6, and Week 12 
during the same visit as the CHRT-SR. Additionally, the Medical Clinician should complete the 
assessment during any visit for which it is clinically indicated and must complete the CHRT-CR 
when a participant indicates high-risk suicidal ideation on the CHRT-SR (see assessment detail 
for specific criteria). 
11.3.7 
Urine Pregnancy Test, Pregnancy and Birth Control 
Assessment 
For biologically female participants, who are of childbearing potential as defined in the MOP, urine 
pregnancy test (UPT) administration, test results, and self-reports of birth control method(s) will 
be documented during screening. A UPT will be performed at the first screening visit to confirm 
that a woman is not pregnant before proceeding with screening. A UPT will be performed to 
confirm that a woman is not pregnant before receiving any study medication at randomization, 
before receiving an injection at each subsequent visit, at the end of the medication phase, and at 
Week 16. A UPT may also 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 medication, given an 
appropriate referral, and followed until resolution of the pregnancy. Self-reports of birth control 
method(s) will be documented if applicable at each injection visit during the medication phase, at 
the end of the medication phase, and at Week 16. 
11.3.8 
Vital Signs 
Vital signs (e.g., body temperature, blood pressure, pulse, respiration rate) will be collected at 
least once during screening. During study medication injection clinic visits, vitals will be collected 


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before participants receive the study medication. On non-injection clinic visits, vitals should be 
collected weekly. Following the first administration of sublingual BUP and following the first BUP-
Inj, additional vital signs will be collected after medication administration to monitor for participant 
medication tolerance and safety. Vital signs can be repeated to confirm the reading or on more 
frequent intervals, as clinically indicated. 
11.3.9 
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. 
Participants may be excluded based on medications reported during screening. At subsequent 
visits, the form will document medications taken since the previous data collection visit. 
Participants will be instructed to contact the Medical Clinician before taking any non-study 
medications, including prescription medications, over-the-counter preparations, and herbal 
supplements, during the course of the study. 
11.3.10 
Adverse Events, Serious Adverse Events, and Medical Review  
Medical or psychiatric adverse events (AEs) will be collected by inquiring of participants, for 
example: “How have you been feeling since your last visit?”, and both elicited or spontaneously 
reported AEs should be recorded at each visit after consent, according to the adverse event 
reporting definitions and procedures. After randomization, for participants who report opioid use 
on Timeline Followback or who have a positive urine drug screen for opioids the Medical Clinician 
will offer facilitated linkage to MOUD. If interested, participants would be withdrawn from the 
medication aspect of the study. In the event that participants decline MOUD, this will be recorded 
in the participant’s study record. If an AE or abnormality suggests medical or psychological 
deterioration, it will be brought to the attention of the Medical Clinician (MD or DO) for further 
evaluation. All AEs and SAEs will be medically managed, reported, and followed in accordance 
with applicable regulatory requirements, including any required reporting to the DSMB. Adverse 
event (medical and/or psychiatric) assessment will initiate with participant written consent and 
follow-up of ongoing adverse events will continue through resolution or 30 days post last study 
visit. 
11.4 Clinical and Efficacy Assessments 
11.4.1 
Urine Drug Screen (UDS) 
Urine samples will be collected at every clinic visit. Urine drug screen (UDS) testing will be 
performed on site using a Federal Drug Administration (FDA)-cleared for use one-step urine drug 
dip card and/or dipsticks following the manufacturer's recommended procedures. Fentanyl 
dipsticks are not FDA cleared; therefore, results cannot be used for clinical care. Results can only 
be used to add to the research database to characterize a study population. 
The UDS will test for the presence of fentanyl, opiates (including heroin, morphine, codeine), 
oxycodone, barbiturates, benzodiazepines, cocaine, amphetamines, methamphetamine, 
marijuana (THC), methadone, phencyclidine (PCP) 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 


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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. If 
the only out of range value from the first sample is a high specific gravity on the adulterant test 
strip and there are no visible precipitants, this sample may be considered unadulterated and can 
be drug tested. If the specimen is considered adulterated, the first urine sample will be discarded, 
and the participant will be asked to provide another sample following oral hydration. Similar to the 
first, 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 
unadulterated 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. 
During screening and on the day of randomization, urine will also be tested to evaluate urine BUP 
levels to confirm inclusion/exclusion criteria. 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. 
11.4.2 
Timeline Followback (TLFB) 
The Timeline Followback procedure50 will be used to elicit the participant’s self-reported use of 
substances, including MA, opioids, and MA/opioid co-use during the screening phase and 
throughout study participation. During the screening phase, this form will be used to assess 
substance use for the 30-day period prior to written consent. During the trial, TLFB will be 
administered to document the participant’s self-reported use of substances for each day since the 
previous TLFB assessment. For participants who report opioid use or who have a positive urine 
drug screen for opioids during the trial, Medical Clinicians will offer them the opportunity to 
withdraw from the medication aspects of the trial and to initiate MOUD through a referral to 
appropriate care. In the event that participants decline this offer, this will be recorded in the 
participant’s study record.  
11.4.3 
Visual Analog Scales for Methamphetamine and Opioid Craving 
Participants’ craving for methamphetamine and opioids will be documented on visual analog 
scales (VAS) that ranges from 0 (no craving) to 100 (most intense craving possible)51. 
11.4.4 
Clinical Opiate Withdrawal Scale (COWS) 
Participants’ signs and symptoms of opiate withdrawal will be documented with the Clinical Opiate 
Withdrawal Scale (COWS), which is an 11-item scale administered by a Medical Clinician that 
can determine the stage or severity of opiate withdrawal and assess the level of physical 
dependence on opioids52. 


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11.4.5 
Subjective Opiate Withdrawal Scale (SOWS) 
Participants will self-assess their symptoms of opioid withdrawal through the Subjective Opiate 
Withdrawal Scale (SOWS), which contains 16 symptoms whose intensity are rated on a scale of 
0 (not at all) to 4 (extremely)53. 
11.4.6 
Inventory of Depressive Symptomology - Self-Report (IDS-SR) 
Participants’ depressive symptoms will be assessed through the Inventory of Depressive 
Symptomology - Self-Report (IDS-SR), which is a 30-item questionnaire measuring depressive 
symptoms on a four-point scale from 0 to 354. Responses of 2 or 3 on question 18 (Thoughts of 
Death or Suicide), will prompt a clinician assessment for suicide risk before the participant leaves 
the clinic, and completion of the Mental Health Follow-up Assessment form. 
11.4.7 
Generalized Anxiety Disorder Scale (GAD-7) 
Participants’ anxiety symptoms will be assessed through the Generalized Anxiety Disorder Scale 
(GAD-7), which is a 7-item scale that can be summed to produce a score that relates to mild, 
moderate, or severe anxiety55. 
11.4.8 
Concise Associated Symptoms Tracking Irritability Scale 
(CAST-IRR) 
Participants’ associated mood symptoms will be assessed using a version of the Concise 
Associated Symptom Tracking Scale (CAST-IRR), a 10-item self-report scale that assesses 
irritability56,57. 
11.4.9 
Dimensional Anhedonia Rating Scale (DARS) 
Participants’ anhedonia will be assessed using the Dimensional Anhedonia Rating Scale (DARS), 
a 17-item scale that measures desire, motivation, effort and pleasure58. 
11.4.10 
Amphetamine Cessation Symptom Assessment (ACSA) 
Participants’ symptoms of amphetamine withdrawal will be assessed through the Amphetamine 
Cessation Symptom Assessment (ACSA), a 16-item scale that assesses severity of withdrawal 
from amphetamines59. 
11.4.11 
Perceived Stress Scale (PSS) 
Participants’ perceived level of stress will be assessed with the Perceived Stress Scale (PSS), a 
10-item self-administered scale that is used to measure an individual’s level of perceived stress 
in the past month60. 
11.4.12 
Pain Frequency, Intensity, and Burden Scale (P-FIBS) 
Participants’ pain will be assessed through the Pain Frequency, Intensity, and Burden Scale (P-
FIBS), a 4-item scale that measures pain symptoms related to frequency, intensity, and burden61. 


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11.4.13 
Cognitive Behavioral Therapy Documentation 
This form will note the completion of cognitive behavioral therapy sessions and if the participant 
is attending any mutual help support groups. 
11.4.14 
Iowa Gambling Task (IGT) and Documentation 
The Iowa Gambling Task is a computer task of impulse inhibition. Psychology Experiment Building 
Language (PEBL) 0.14 computerized version of the IGT will be used62. It consists of four virtual 
decks of cards, A, B, C, and D, each associated with a unique combination of short-term fixed 
rewards and probabilistic losses, in addition to an associated long-term net payout. Riskier decks 
(A and B) present short-term high-reward and high-loss contingencies, with consistent choices of 
such decks yielding low cumulative totals. In contrast, optimal decks (C and D) are linked to short-
term low-reward and low-loss contingencies, yielding moderately high cumulative totals. The 
objective of the IGT is to maximize long-term cumulative payout earned on the task by learning 
to shift or avoid selection of riskier, disadvantageous decks A and B and favor safer, more 
advantageous decks C and D within 100 trials. Results from this task will be added to an eClinical 
documentation form. 
11.4.15 
Treatment Effectiveness Assessment 
The Treatment Effectiveness Assessment is a 4-item self-administered assessment that uses a 
Likert scale (1-10) to document changes in four life domains: substance use, health, lifestyle, and 
community63. 
11.4.16 
Cannabis Use Assessment 
This form assesses participants' recreational and medical cannabis/marijuana use frequency over 
the past 12 months, including reasons for use (e.g., to address medical/psychological concerns, 
to replace other substances or medications), method of administration, and perceived harm or 
benefit associated with use. 
11.4.17 
Tobacco Use History 
The Tobacco Use History assessment will incorporate PhenX Core Tier 1 items47. Tobacco use 
items assessed include lifetime use, 30-day quantity and frequency, and age of first tobacco use. 
11.4.18 
Quality of Life 
Quality of Life will be assessed using items from the PhenX Core Tier 147. Participants will be 
asked to provide ratings of general health, physical health, and mental health during the past 
week. 
11.4.19 
Semi-Structured Qualitative Interview 
Participants who have taken at least one dose of sublingual medication are eligible for a qualitative 
interview, which allows for an open conversation about the participant’s experiences taking the 
sublingual and injectable medications. The goal is to understand processes and experiences 
taking the medication and whether these experiences may influence their responses to 
methamphetanie and their decision to seek treatment in the future. Qualitative interviews will be 


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conducted using a interview guide, by site and/or LN staff, and recorded via a video and audio-
conferencing platform (e.g., Zoom).  
11.5 Adherence Measures 
11.5.1 
Buprenorphine-XR/Placebo Injection 
This form will document the in-clinic administration of injectable study medication and will be 
completed at each visit when injectable medications are administered throughout the study. All 
required REMS procedures will be fully detailed in the MOP and will be explicitly followed. 
11.5.2 
BUP-SL Dispensing 
This form will document the dispensing of sublingual buprenorphine and will be completed at each 
visit when sublingual medications are administered throughout the study. All required REMS 
procedures will be fully detailed in the MOP and will be explicitly followed. 
11.6 Laboratory Evaluations 
Specific instructions detailing the preparation, handling, and storage of specimens will be detailed 
in the Manual of Operations (MOP). 
11.6.1 
Urine Screening for Disease 
Urine samples will be collected and submitted to screen for the sexually transmitted infections 
chlamydia and gonorrhea. An accredited local laboratory (College of American Pathologists or 
equivalent) that meets Clinical Laboratory Improvement Amendments (CLIA) guidelines will 
perform testing, provide normal values, and provide proof of lab certifications. 
11.6.2 
Complete Blood Count, Blood Chemistry, and Liver Function 
Tests  
Complete blood counts (CBC), blood chemistry (BUN and creatinine), and liver function tests 
(AST, ALT, ALP, and bilirubin) will be performed to help determine eligibility at screening. A CBC 
and LFTs will be repeated for safety monitoring in the final week of the medication phase. An 
accredited local laboratory (College of American Pathologists or equivalent) that meets CLIA 
guidelines will perform testing, provide normal values, and provide proof of lab certifications. 
11.6.3 
Disease Serology 
Serology for HIV and Hepatitis C will be performed at screening and will be repeated ideally during 
the final week of the medication phase. An accredited local laboratory (College of American 
Pathologists or equivalent) that meets CLIA guidelines will perform testing, provide normal values, 
and provide proof of lab certifications. 
11.6.4 
Blood Sample for UTSW Repository 
Participants will have approximately 27 mL (2 tablespoons) of blood collected during screening 
and in Week 12 to be stored at the UTSW Central Repository for later evaluation of blood-based 
factors that may affect treatment outcomes. Participants may consent to allow these samples to 
be used in future genetic research. 


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11.6.5 
Blood Sample for NIDA Genetic Testing and Family Origin 
NIDA CCTN has requested that samples for genetic analysis be collected for all new CTN 
pharmacotherapy trials. Randomized participants who provide consent for genetic testing will 
have approximately 27 mL (2 tablespoons) of blood drawn for genetic analyses and will complete 
a Family Origin form. This sample will ideally be collected on the day of the second injection. If 
the sample cannot be collected on the day of the second injection, the sample may be collected 
at any other future visit with a blood draw. The blood sample will be sent to the NIDA Genetics 
Consortium Repository for storage and future analysis. The blood sample will be coded and only 
the local investigators will know the true identity of the participant providing the blood sample. 
The Family Origin Form is designed to be interviewer administered. It collects information about 
the participant and her/his biological family members’ race/ethnicity, place of birth, and ancestry. 
If a participant does not know the information requested, the participant may answer unknown. 
11.6.6 
Buprenorphine Blood Levels 
Existing data suggests that metabolism of BUP may differ between Caucasian and minority 
populations. BUP is heavily metabolized by cytochrome P450 (CYP) hemoenzymes, specifically 
subfamily CYP3A4. This is the primary enzyme that is noted as a key drug-drug interaction site 
for the use of BUP and specifically the injectable version, Sublocade™, which will be used in this 
study. Polymorphisms of CYP3A4 have been shown to affect the metabolism of BUP64, and may 
play more of a role for African-Americans due to the enrichment of the CYP3A4*1B variant, which 
is present in 66% of African-Americans in contrast to 4% of Europeans and 0% of Asian 
populations65. An accelerated metabolism of OUD treatments, including BUP, has been shown in 
patients with CYP3A4*1B compared to the wild-type CYP3A4*1A variant, and those patients 
reported requiring higher doses of BUP to obtain full clinical effects66. The majority of these 
patients were African-American and those that were classified as ultra-metabolizers based on 
CYP3A4 phenotype also reported withdrawal symptoms more frequently than those classified as 
intermediate or extensive metabolizers. 
The evidence for key pharmacogenomic interactions affecting treatments used for opioid use 
disorder are extensive and growing67. Investigation of the contribution of this CYP3A4*1B variant 
in the metabolism of BUP has to date been limited. Evidence for this polymorphism to affect drug 
response is found in other pharmacogenomic interactions68 and an effect is detected in Caucasian 
populations with lesser variant prevalence. Thus, obtaining data further supporting understanding 
of this pharmacogenomic effect of BUP in African-Americans is timely and necessary. Given the 
pilot nature of this study and the preliminary examination of these differences in metabolism, this 
study will only compare blood levels of BUP between racial/ethnicity groups and not directly 
examine genetic information. In order to explore how differences in metabolism may affect the 
outcomes of the study, blood samples will be collected to test for buprenorphine and metabolites 
levels. 


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11.7 Administrative and Other Forms 
11.7.1 
Locator Form 
A locator form obtains information to assist in finding participants during screening, treatment and 
at follow-up. This form collects the participant’s current address, email address, phone numbers, 
etc. In order to facilitate locating participants if direct contact efforts are unsuccessful, addresses 
and phone numbers of family/friends who may know how to reach the participant are collected, 
as well as additional participant information such as social security number, driver’s license 
number, and other information to aid in searches of public records. This information will be 
collected at screening and should be updated when changes occur in addition to the required 
timeframes to confirm information noted on the Table of Assessments. No information from this 
form is used in data analyses, nor is this information captured in the data capture system. 
11.7.2 
Eligibility-Randomization (Enrollment Form) 
This 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 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. The Enrollment form is to be 
completed in the electronic data capture system after all screening procedures are complete. 
Final eligibility will be confirmed on expected day of randomization. Eligible participants will be 
randomized; ineligible participants will be excluded and deemed screen failures. 
11.7.3 
Visit Documentation 
This form documents visit attendance, non-visit attendance, and missed visits. This assessment 
has been developed to document visits that could occur out of window, off-site, or missed due to 
COVID-19. This is a visit-based form expected at all visits in which we would typically have a 
regular missed visit form. If a visit did not occur for any reason, this form will capture the reason 
for the missed visit. Completing this and indicating that the visit did not occur will remove the 
requirement for all assessments scheduled for that visit. Active tracking and follow-up should be 
performed for all missed visits. The form also captures specific data collection settings if 
applicable, such as in clinic, off-site, or remote. 
11.7.4 
Mental Health Follow-up Assessment 
This assessment must be completed if the participant endorses high risk suicidal ideation on 
either the Concise Health Risk Tracking (CHRT)—Participant (CHRT-SR) Suicidal Behavior 
Evaluation or on the Inventory of Depressive Symptomology - Self-Report (IDS-SR). Any 
response of agree or strongly agree on question 14, 15, and/or 16 of the CHRT-SR, and/or any 
response of 2 or 3 on question 18 of the IDS-SR will be considered as a high risk suicidal ideation 
and will require the completion of the Mental Health Follow-up Assessment form. The completion 
of the Mental Health Follow-up Assessment form documents that a physician (MD or DO) who 
serves in the Site PI or Medical Clinician study role has been notified. Evaluation of the participant 
by a physician (MD or DO) who serves in the Site PI or Medical Clinician study role will be 
conducted according to the site-specific SOP. Only one Mental Health Follow-up Assessment 
form will be completed per study visit. If a physician (MD or DO) who serves in the Site PI or 


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Medical Clinician study role is unavailable, a non-study physician (MD or DO) may complete the 
assessment. If a non-study physician is unavailable, the site should refer to their site-specific SOP 
for additional instructions.  
11.7.5 
End of Medication 
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 final Medication Phase visit. 
11.7.6 
Protocol Deviation and Review 
These forms should be entered into the electronic data capture system whenever a protocol 
deviation occurs. These forms 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. This form will also capture if 
protocol deviations were a result of COVID-19 specific restrictions. 
11.7.7 
Treatment Satisfaction 
Satisfaction with medication and other study procedures will be recorded on the Treatment 
Satisfaction form completed at the Week 16 visit. This form will be used to evaluate the 
acceptability of the medication. 
11.7.8 
Study Completion 
This form tracks the participant’s status in the study. 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. It is expected to be completed at the Week 16 
visit or once the Week 16 follow-up visit window lapses for participants who do not complete this 
final follow-up. This form is used in data analyses to address variables such as treatment retention 
and completion. This form also provides a location for the Site PI attestation of review of all study 
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12.0 MEDICATION PACKAGING / HANDLING / STORAGE / 
ACCOUNTABILITY 
12.1.1 
Study Medication Management 
Each research site is required to observe local, state, and federal regulations regarding receipt, 
custody, dispensing, and disposition of all study medications. Each site will maintain an adequate 
supply of unexpired study medications on site. 
Appropriately qualified and trained study personnel maintain accurate and current accounting of 
all study medication by utilizing drug accountability records which are made available for review 
by study monitors and other appropriate research personnel. 
Accurate drug accountability records: 
• 
Demonstrate that the study medication was dispensed according to the protocol. 
• 
Document receipt of the study medication, date, lot # and expiration date (if provided), 
quantity and dosage. 
• 
Account for unopened, un-dispensed, unused, returned, wasted or broken medication. 
• 
Dosing logs will record participant ID #, date dispensed, drug name, lot # and amount 
dispensed. 
• 
Indicate who dispensed or handled the study medication.  
• 
Temperature logs should show a daily record of medication storage temperature. 
12.1.2 
Dispensing of Study Medication 
All injectable study medications shall be prepared by unblinded research site staff members or 
pharmacist appropriately trained and authorized to prepare and administered only by an 
unblinded licensed/certified medical practitioner (RN, LVN, MA, or other healthcare provider) 
appropriately trained and authorized to inject these study medications per local and federal 
regulations.  
12.1.3 
Study Medication Storage 
Study medication should be stored in compliance with federal, state, and local laws and 
institutional policy. Study medication is stored in a secured location under the conditions specified 
by the package insert(s)/product guide. 
12.1.4 
Used/Unused Medication 
Unused study medication will be logged into a perpetual inventory of study medication. Damaged, 
expired, or unused study medication will be accounted for by the NIDA contract monitor and sent 
to the study central pharmacy which will arrange with a reverse distributor for eventual destruction 
due to the sublingual buprenorphine and BUP-Inj being scheduled medications. Expired 
sublingual buprenorphine and Sublocade™ (BUP-Inj) must be returned to the central pharmacy 
after a full drug accountability is conducted with the NIDA contract monitors/CRAs. 


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Other ancillary medications will not be required to be returned by a participant. If any is returned 
by choice of the participant, these ancillary medications will be destroyed on site or sent for 
destruction per local institutional policies. 
12.1.5 
Lost Medication 
The sublingual buprenorphine used during the induction period will be the only medication that 
will be dispensed to participants. At the discretion of the site study treatment team, very limited 
replacement of study medications is permitted. 
12.1.6 
Medication Packaging 
The study medication and placebo will be obtained from the study medication manufacturer and 
sent to the central pharmacy managed by the CCC. Details of the blinding techniques, 
procedures, and medication packaging will be described in detail in the Manual of Procedures 
(MOP). 


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13.0 GENETIC SAMPLING 
Participants may provide consent to optional genetic testing. If this consent is provided, the blood 
samples stored at the UTSW Repository may be used for genetic testing. Additionally, this 
consent would permit the collection of an additional blood sample to be provided to the NIDA 
CCTN for genetic testing. 


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14.0 TRAINING REQUIREMENTS 
14.1 Overall 
A comprehensive Training Plan will be developed to incorporate general training, study-specific 
training, mechanisms for competency assessment as well as a detailed description of training, 
supervision, and fidelity monitoring procedures. The Investigative Team is responsible for the 
development of a comprehensive Training Plan, instructional material, and delivery of the training, 
with the team comprised of the Lead Node, CCC, DSC, as well as other participating nodes and 
subject matter experts, as applicable. 
The CTN-0110 study staff will be trained as specified in the study Training Plan. Training will 
include Human Subjects Protection (HSP) and Good Clinical Practice (GCP) as well as protocol-
specific training on assessments, medication management for pharmacological studies, study 
interventions, safety and safety event reporting, study visits and procedures, data management, 
quality assurance, laboratory procedures, etc. The Lead Node is primarily responsible for 
development and delivery of study-specific training related to the study intervention(s) and 
procedures. The CCC is responsible for the development and delivery of non-intervention training, 
including regulatory and laboratory procedures, safety and safety event reporting, quality 
assurance and monitoring, etc. The DSC is responsible for training related to data management 
(DM), the electronic data capture system, and good DM practices. Other parties will contribute as 
needed based on the subject matter and material to be covered. The various sub-teams will 
collaborate to deliver quality instructional material designed to prepare research staff to fully 
perform study procedures based on the assigned research roles and responsibilities. 
In addition to general and study-specific training, the Training Plan will include a description of 
the delivery methods to be used for each training module (e.g., via self-study, online, webcast, or 
teleconference). Study staff is required to complete institutionally required training per their 
research site, Institutional Review Board(s), and authorities with regulatory oversight. Tracking of 
training completion for individual staff as prescribed for assigned study role(s) and responsibilities 
will be documented. As changes occur in the prescribed training, the Training Plan and training 
documentation tracking forms will be amended to reflect these adjustments. 


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15.0 CONCOMITANT THERAPIES OR INTERVENTIONS 
There are no concomitant therapies or interventions intended to treat substance use disorders 
allowed during participation in this trial. 
15.1 General 
During the trial, participants will be withdrawn from the study medication if they begin ongoing 
treatment with medications that are clinically relevant, such as CYP3A4 or CYP2C8 inducers or 
inhibitors (e.g., rifampicin, azole antifungals, macrolide antibiotics), Class IA antiarrhythmic 
medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications 
(e.g., sotalol, amiodarone) or medications that put them at significant risk for development of 
serotonin syndrome while possibly taking BUP-Inj. 
In addition, participants who have an intercurrent illness that requires treatment with opioid-
containing medications (e.g., to manage postoperative pain) for more than three days will be 
withdrawn from the study medication but remain in the study. 
15.1.1 
Medications and Interventions Allowed During Trial 
Ongoing medications that the participant is taking at the day of randomization will be allowed, 
unless specifically listed as exclusionary criteria. Medications additionally prescribed during the 
conduct of the trial or over-the-counter medications to manage conditions are also allowed, unless 
the Medical Clinician is concerned that the medications would then qualify as exclusionary criteria. 
All medications will be reported on the Prior and Concomitant Medications form (during all study 
visits) to provide a clear record that is available for analysis to ensure the integrity of the study 
outcomes. The only medications believed to affect the outcomes of this study are listed as 
exclusionary criteria. Participants are also allowed to attend mutual support groups, such as 
Narcotics Anonymous, during the trial but not engage in any other groups or treatments that are 
designed to treat substance use disorders. 


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16.0 STATISTICAL DESIGN AND ANALYSES 
A formal Statistical Analysis Plan (SAP) will be written for this study but the general design and 
statistical strategies are described below. 
16.1 General Design  
16.1.1 
Study Hypothesis 
Administration of BUP-Inj will produce a significantly greater number of MA-negative UDS tests 
obtained during Weeks 9-12 of the 12-week long medication phase, relative to the PBO-Inj. 
16.1.2 
Primary and Secondary Outcomes (Endpoints) 
The full descriptions of outcomes and the measures from which they are obtained are described 
in Section 7.0. The primary outcome measure is the number of MA-negative UDS results obtained 
during Weeks 9 through 12 of the medication phase as measured for the BUP-Inj and PBO-Inj 
conditions. 
16.1.3 
Randomization and Factors for Stratification 
Participants will be randomized in a 1:1 ratio to BUP-Inj or PBO-Inj, using a permuted block design 
with random block sizes and stratified by enrolling site. A separate randomization plan will be 
developed with additional details regarding treatment allocation. Given that the study is double-
blind, only certain staff at the DSC and CCC will be able to access individual treatment 
assignments and detailed information contained in a separate Blinding Management Plan. 
16.2 Rationale for Sample Size and Statistical Power 
A sample size of 246 was chosen for this study to provide 90% power to detect a statistically 
significant difference between the two treatments. Power was based on an effect size derived 
from the proportion of MA-negative urines during the last 4 weeks of Phase I of the ADAPT-2 
study (CTN-0068) comparing the active treatment arm to the placebo arm. Imputing all missing 
data as positive, the relevant proportions in ADAPT-2 were 0.17 and 0.07) in the treated (AMC) 
and control (PBO) arms respectively, so we take the treatment effect of interest for MURB to be 
a risk difference of 0.10 corresponding to an odds ratio of 2.72. This outcome from the ADAPT-2 
study was chosen because it was believed to be the most comparable available result using this 
substance-using population to the BUP-Inj outcome for this study.  
To simulate data for CTN-0110, we first imputed all missing ADAPT-2 visits as UDS-positive for 
MA, then bootstrapped the ADAPT-2 participants, keeping the participant’s site and visits 
together, thus respecting whatever temporal and site-dependent correlations might exist in the 
data. We assumed equal treatment allocation. To draw bootstrap samples of size N, we 
bootstrapped differently under null and alternative hypotheses as follows: 
• 
Null: We treated the two simulated treatments the same way: for each of the N/2 
simulated participants receiving that treatment, we flipped a fair coin to decide which 
ADAPT-2 arm (109 AMC and 294 PBO) to draw it from, and then drew it randomly with 
replacement from that arm. 


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• 
Alternative: For AMC, we drew N/2 observations randomly with replacement from the 
109 AMC patients. For PBO, we drew N/2 observations randomly with replacement from 
the 294 PBO patients. 
To simulate 2 UDS per week we used all 8 visits of a participant in order. The model under which 
we performed the power analysis is the same as that to be used for the primary analysis, 
discussed in Section 16.3. 
Simulated power for the generalized estimating equation69 is shown as a function of total N (N/2 
in each arm) in Table 16.1 and in Figure 16.1, in which the total sample size required for power 
(0.8, 0.9) is interpolated from the simulated data using a logistic function, and estimated to be  
(182, 246). 
Table 16.1: Simulated power for the GEE as a function of total N (N/2 in each arm) 
Total N 
Power 
100 
0.55 
150 
0.74 
200 
0.84 
250 
0.91 
300 
0.96 
350 
0.97 
 
Figure 16.1: Logistic function fitted to simulated power for the GEE as a function of total N (N/2 in 
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16.2.1 
Projected Number of Sites 
A total of 4-8 sites will participate in the trial. 
16.2.2 
Projected Number of Participants per Site 
It is anticipated that each site will randomize approximately 31-61 participants over the recruitment 
period. The enrollment for all sites will be competitive. 
16.3 Statistical Methods for Primary and Secondary Outcomes  
16.3.1 
Primary Outcome 
UDS will be collected twice a week during Weeks 9 through 12, or 8 assessments. For each 
assessment, the outcome will be 1 if the UDS is MA negative and 0 if the UDS is MA positive or 
missing. The probability of an MA negative UDS during Weeks 9-12 will be computed via a GEE 
approach postulating a binomial distribution with a logit link, an AR(1) correlation for the repeated 
observations of a single participant, and utilizing the robust (sandwich) estimator for the 
covariance of the regression betas. Despite other possible sources of variance such as random 
site effects, the regression coefficients will be asymptotically unbiased with consistent standard 
errors using this estimation strategy. The model will have a term for treatment group (BUP-Inj and 
PBO-Inj) as the between-subjects factor. The model will be used to compute an average 
probability of MA-negative UDS across Weeks 9 through 12 in each group. Letting 𝑦𝑖𝑡 be an 
indicator of whether the UDS for participant i (i=1, …, n) at timepoint t during this evaluation period 
(t=1, …, 8), and 𝑧𝑖 is an indicator of participant i being assigned to the BUP-Inj arm, the logistic 
model is given by 
𝑙𝑜𝑔𝑖𝑡 𝑃(𝑦𝑖𝑡= 1) =  𝛼+  𝛽 𝑧𝑖.  
The hypothesis will be tested by the statistical significance of the odds ratio using a two-sided test 
(i.e., 𝐻0: 𝑒𝛽= 1; 𝐻1: 𝑒𝛽 ≠1). An a priori alpha (i.e., type I error) of 0.05 will be used for this 
analysis.  
SAS code to estimate the primary outcome follows: 
 proc genmod data = dat; 
class patid treat; 
model metneg(event = "1") = treat / dist = bin link = logit; 
repeated subject = patid / type = ar(1); 
run; 
Where patid is the participant’s unique identifier, treat is an indicator of being assigned to the 
BUP-Inj treatment arm, and metneg is an indicator of whether the UDS is negative for MA. 
16.3.2 
Secondary Outcomes (medication phase, Weeks 1-12): 
1. Alternate measures of methamphetamine use: both 
a. MA Treatment Effectiveness Score (TES), as measured by number of UDS 
results negative for MA by condition, during Weeks 1-12 (score range 0-24) will 
be analyzed as count data, which typically follows a Poisson distribution. 


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However, we expect there will be more subjects with 24 negative UDS than 
would be expected based on the Poisson distribution (ceiling effect). Also, there 
may be more subjects with 0 negative UDS than determined by the Poisson 
distribution (floor effect). Given the presence of ceiling and floor effects a more 
flexible model is needed than the hurdle model or zero-inflated Poisson model 
that would typically be used with count data with floor effects. Therefore, a beta-
binomial regression model is anticipated70. In this approach, the number of 
negative UDS is modeled as the number of ‘successes’ in 24 trials where each 
trial can result in a success or failure (UDS negative or positive) outcome. The 
probability of success across subjects is modeled with the beta distribution which 
is flexible enough to allow for a ‘U’ shaped distribution with both ceiling and floor 
effects or only ceiling effects depending on which parameters of the beta 
distribution are selected. The model will have terms for time, treatment group, 
treatment group by time interaction, baseline measure of the outcome, and any 
covariates. The primary hypothesis will be tested by significance of the main 
effect or interaction effect71. 
b. Self-reported days of MA use during Weeks 1-12 (score range 0-84) will be 
analyzed using TLFB data that will be collected in Weeks 1-12 with days of use 
counted over that period. Count data typically follow a Poisson or Negative 
Binomial distribution. However, we expect that there will be more participants 
with zero positive UDS than expected under these distributions (floor effect). We 
do not expect ceiling effects for this outcome. We will deal with the excess zeros 
using a hurdle model in which it is assumed that all participants have the 
potential to use drugs but “resistance” to drug use, or a hurdle, must be 
overcome before drugs are used. The existence of the hurdle results in an 
excess of participants with zero positive UDS72. The hurdle model will contain a 
random participant effect, treatment group (buprenorphine vs control), baseline 
number of use days (in the 30 days before written consent) and any other 
covariates needed to improve balance between the intervention and control 
groups. If the data are not zero-inflated, Poisson regression will be used. 
2. Measures of opioid use: both  
a. Opioid Treatment Effectiveness Score (TES), as measured by number UDS 
results negative for opioids by condition, during Weeks 1-12. Results from radio-
immune assay strips will be used to measure opiates (OPI-300), oxycodone / 
synthetic opioids, fentanyl for each UDS and 
b. Self-reported frequency of opioid use during Weeks 1-12. Reports of any opioid 
used will be combined into one measure that includes opiates, oxycodone and 
synthetic opioids, fentanyl and analogues for each report, will be analyzed using 
a hurdle model (ceiling effects are not expected) similarly as described for the 
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3. Measures of MA and opioid co-use: both  
a. MA and Opioid Treatment Effectiveness Score (TES), as measured by number of 
same-day UDS results negative for MA and opioids by condition, during Weeks 1-12 
and  
b. Self-reported days of both MA and opioid use during Weeks 1-12. All data related to 
opioid use will be compiled as detailed in secondary outcome 2 and will be analyzed 
using a hurdle model (ceiling effects are not expected) similarly as described for the 
secondary outcome 1b. 
16.4 Significance Testing 
The primary outcome will be evaluated using a two-sided test with a type I error rate of 5%. There 
are numerous secondary outcomes; however, multiple comparisons will not be adjusted for since 
these are not part of the study’s primary objective. 
16.5 Interim Analysis 
When at least 50% of the final sample has attained endpoint assessment (i.e., Week 12), a 
sample-size re-estimation will be performed. Figure 16.2 shows sample sizes expected at the 
time of sample-size re-estimation, assuming recruitment is constant over time. The blue line in 
Figure 16.2 depicts recruitment, while the red line depicts attainment of primary endpoint. As 
noted previously, recruitment is anticipated to take 18 months to attain a sample size of 246. 
Primary endpoint data accumulates starting at month 3 and will terminate at month 21. Since 
missing UDS data will be assumed as MA-positive, the primary endpoint is always observed. Half 
of the 246 primary endpoints (i.e., 123 endpoints) will be attained at month 12, at which time a 
sample size re-estimation will be conducted. We expect at that time to have recruited 67% of our 
final sample size, or 164 of 246 participants. 
Figure 16.2: Sample sizes during sample-size re-estimation. 
 


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The objective of sample size re-estimation is not to re-calculate the sample size using a treatment 
effect different from that posited during trial design, but rather to discover whether nuisance 
parameters, such as the site effect or the within-subject autocorrelation, were mis-specified, thus 
rendering invalid the original sample size calculation. Given that the study is double-blinded, only 
data from participants in the control (i.e., PBO-Inj) arm will be used in the re-estimation to preclude 
the need to break the blind during the conduct of the study. Modified bootstrapping will also be 
used for the sample size re-estimation as was done for the original sample size calculation. The 
unit of bootstrapping with be the entire participant history, together with the participant’s site. 
Missing observations will be imputed to be MA-positive. Only control participants completed will 
be used in the sample size re-estimation bootstrap. There will be many bootstrap iterations. After 
each one, there will be a simulated test of the null hypothesis. The proportion of iterations in which 
the simulated two-sided test is significant at level 0.05 will be taken as the prediction of final power 
under the design alternative. 
Participants with the endpoint assessment in the control arm will be randomly chosen with 
replacement to attain the desired sample size in the simulated control arm. In each bootstrap 
iteration, the entire simulated control arm will be recreated de novo. That is, the already-enrolled 
control participants will not be maintained together as a group within the simulated set of control 
participants. 
To choose participants for the simulated treated arm, we will perform biased bootstrap sampling 
of the already-completed patients in the control arm. The method for performing biased bootstrap 
sampling will be discussed in the standalone Statistical Analysis Plan, but basically, some control 
patients will be preferentially chosen to allow Pr(success) in the simulated treated arm to be as 
desired. Biased bootstrap sampling will allow us to calculate power under the design alternative. 
More specifically, computer code will (1) estimate 𝑝̂ = Pr (𝑠𝑢𝑐𝑐𝑒𝑠𝑠) in the control arm, (2) use 
biased bootstrap sampling of the participants in the control arm to force their mean simulated 
probability of success to be 𝑝̂ + Δ, where Δ is the design treatment effect, namely 0.10. This can 
be done without explicitly calculating the observed treatment effect or revealing it to trial 
personnel. 
The results of the sample size re-estimation will be presented to the DSMB, who will make 
recommendations to the Sponsor who will then decide what action, if any, should be taken. We 
anticipate re-estimation will be used only to increase trial recruitment, not to curtail it. 
16.6 Exploratory Analysis 
Exploratory analyses include: 
1. Measures of MA subjective effects: both (a) MA withdrawal, as measured by scores on 
the Amphetamine Cessation Symptom Assessment during Weeks 1-12 and (b) self-
reported MA craving as measured by the Visual Analog Craving Scales (VAS) during 
Weeks 1-12 will be analyzed by repeated-measures mixed-effects model. The model will 
have terms for time, treatment group, treatment group by time interaction, baseline 
measure of the outcome, and any covariates. Person effects will be random and all other 
effects fixed. 


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2. Measures of opioid subjective effects: All measures, (a) Observer rating of opioid 
withdrawal as measured by the Clinical Opiate Withdrawal Scale (COWS) on the day of 
randomization; each subsequent visit during induction in Week 1, if needed; prior to 
each injection in Weeks 1, 5, and 9; and at Week 12 ; (b) Self-reported rating of opioid 
withdrawal as measured by the Subjective Opiate Withdrawal Scale (SOWS) on the day 
of randomization; each subsequent visit during induction in Week 1, if needed; prior to 
each injection in Weeks 1, 5, and 9; and at Week 12; (c) Self-reported opioid craving, as 
measured by Visual Analog Craving Scales (VAS), during Weeks 1-12 will each be 
analyzed using repeated-measures mixed-effects models, with terms for time, treatment 
group, treatment group by time interaction, baseline measure of the outcome, and any 
covariates. Person effects will be random and all other effects fixed. 
3. Self-reported craving for MA and opioid co-use: As measured by Visual Analog Craving 
Scales (VAS), during Weeks 1-12 will each be analyzed using repeated-measures 
mixed-effects models, with terms for time, treatment group, treatment group by time 
interaction, baseline measure of the outcome, and any covariates. Person effects will be 
random and all other effects fixed. 
4. Measures of mood, pain and stress: All measures, (a) Changes in self-reported 
depressive symptoms as measured by the IDS-SR during Weeks 1-12, (b) Changes in 
self-reported anxiety symptoms as measured by the GAD-7 during Weeks 1-12, (c) 
Changes in self-reported mood symptoms as measured by the CAST-IRR during Weeks 
1-12, (d) Changes in self-reported anhedonia as measured by the DARS during Weeks 
1, 5, 9, and 12, (e) Changes in self-reported pain as measured by the P-FIBS during 
Weeks 1-12, and (f) Changes in self-reported stress as measured by the PSS during the 
Weeks 1, 5, 9, and 12 will each be analyzed using repeated-measures mixed-effects 
models, with terms for time, treatment group, treatment group by time interaction, 
baseline measure of the outcome, and any covariates. Person effects will be random 
and all other effects fixed. 
5. Retention, defined as the number of visits (0-24) present and providing urine drug 
samples during Weeks 1-12 will be analyzed similarly as described for the secondary 
outcome. 
6. Measures of Infectious disease control, incidence, and risk: 
a. Defined as the biomarkers measured at Week 12, remaining HIV-negative for 
those that started the trial HIV-Negative and remaining HCV-negative for those 
that started the trial HCV-Negative, will be analyzed using logistic regression with 
HIV status and HCV status as the outcomes, respectively, and treatment group 
and other covariates as predictors. 
b. Self-Reported HIV transmission risk behaviors measured at Weeks 1, 6 and 12, 
defined as (a) Self-reported number of new sexual partners, (b) Self-reported 
number of sexual partners with condomless sex who are serodiscordant or 
unknown serostatus, (c) Self-reported number of sexual partners with 
condomless sex with partners who are serodiscordant or unknown serostatus 
with whom illicit substance were used (chemsex), (d) For men, self-reported 


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number of male sexual partners, (f) Self-reported number of episodes sharing 
needles, and (g) Self-reported number of episodes sharing injection equipment 
and paraphernalia will each be analyzed using a repeated measures mixed 
effects model for count data outcomes. If zero-inflation is observed a zero-
inflated poisson, negative binamial, or hurdle model will be used depending on 
which model best fits the data. However, if an outcome has low counts, we may 
collapse it into a binary (presence/absence) outcome. If the data are very sparse, 
we may collapse across weeks and use a logistic regression model.  
7. Measures of functioning: 
a. Changes in self-reported assessment of Quality of Life (QoL) at Week 1 and 
Week 12 will be analyzed using repeated-measures mixed-effects model, with 
terms for time, treatment group, treatment group by time interaction, baseline 
measure of the outcome, and any covariates. Person effects will be random and 
all other effects fixed. 
b. Self-reported overall functioning as measured by the Treatment Effectiveness 
Assessment (TEA) at Week 12 will be analyzed using analysis of covariance. 
8. Measures of adverse events: both (a) Number and severity of adverse events reported 
during Weeks 1-12 and (b) Number and outcomes (non-fatal, fatal) of overdose events 
during Weeks 1-12 will be analyzed using Chi-square tests for each measure of AEs. 
9. Self-reported measures of alcohol, tobacco and other drug use on TLFB at Weeks 1, 5, 
9, and 12, and UDS results of other substance use not quantified for primary or 
secondary outcomes will be analyzed using a repeated-measures mixed-effects model 
for continuous outcome (amount of use) or binary outcome (presence/absence of use). 
The models will have terms for time, treatment group, treatment group by time 
interaction, baseline measure of the outcome, and any covariates. Person effects will be 
random and all other effects fixed. 
10. Urinalysis results indicating a new chlamydia or gonorrhea diagnosis at Week 12 will be 
analyzed using a logistic regression with the presence of a Week 12 diagnosis as the 
outcome and treatment group and other covariates and predictors. 
11. IGT at screening as a predictor of treatment response will be analyzed using the primary 
outcome analysis being repeated with the addition of terms for baseline IGT 
performance and IGT by time interaction. 
16.7 Missing Data and Dropouts 
In the primary analysis, missing and drop-out urine drug testing data will be imputed as MA use. 
On trial completion we will consider sensitivity analyses to investigate the extent to which the 
results of the main analysis of the primary outcome depend on the assumptions made about 
missing values. An extremely simple approach imputes missing as non-use and re-analyzes the 
outcome. If the conclusions are the same, there is little else necessary to do, but this is unlikely. 
Multiple imputation (MI) is one way to explore more complex possibilities. In MI, non-missing data 
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unlikely hypothesis in a substance use trial, but the missing-not-at-random (MNAR) hypotheses 
may be introduced to explore sensitivity as detailed below. 
To explore MNAR alternatives, we shift the values of the imputations by a chosen shift value. We 
choose the shift value for the two arms of the trial separately. A p-value for the primary outcome 
can then be calculated for every shift pair via multiple imputation. The pair can be plotted on two 
axes: one axis for the control shift, and one for the treated shift. This generates a p-value surface 
showing regions in which the trial is significant or not as a function of the MNAR assumptions. 
The primary outcome is a single point on this surface. If the primary outcome is surrounded by a 
large region of MNAR assumptions that agree with the primary concerning the significance of the 
outcome, this will lend credence to the primary outcome. But if the primary outcome is close to 
points that disagree, this will cast doubt on the primary analysis’ conclusion. 
Sensitivity analyses will be done for secondary analyses where appropriate to determine the 
possible effects of missing data on the final results. 
16.8 Demographic and Baseline Characteristics  
Baseline demographic and clinical variables will be summarized for participants enrolled in the 
active medication phase of the trial. Descriptive summaries of the distribution of continuous 
baseline variables will be presented with percentiles (median, 25th and 75th percentiles), and with 
mean and standard deviation. Categorical variables will be summarized in terms of frequencies 
and percentages. 
16.8.1 
Subgroup Analyses 
Per NIH policy, subgroup analyses will be implemented to assess whether sex, race and/or 
ethnicity are effect modifiers. For each demographic, a model will be fit including an interaction 
with treatment assignment and the subgroup effect will be reflected by a two-sided test of whether 
the interaction regression coefficient is different from zero. Additionally, the treatment effect will 
be presented for each category of the demographic factor from these interaction models. 
16.9 Safety Analysis 
Treatment emergent adverse events (AEs), including treatment emergent serious adverse events 
(SAEs), will be summarized by presenting the number of events, number of participants 
experiencing AEs, and the severity and relatedness of adverse events by treatment arm. All 
adverse events will be coded using MedDRA® (The Medical Dictionary for Regulatory Activities). 
The number and proportion of participants experiencing each treatment emergent AE will be 
provided overall and by treatment arm. Treatment emergent adverse events will be summarized 
by System Organ Class (SOC) and Preferred Term (PT). If a participant experiences multiple 
episodes of an event, then the event is only counted once. Detailed listings of treatment emergent 
adverse events and non-treatment emergent events in the safety population by treatment arm will 
be provided and include severity, relationship to study medication(s), and action taken, as 
available. The criteria for an immediate study review by the DSMB will be monitored closely. 
These criteria are either (1) three or more participants experience severe adverse reactions; (2) 
four or more participants have four consecutive positive urine toxicology screens for opioid use, 


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and have been reevaluated through any means as having moderate to severe opioid use disorder; 
or (3) one or more SUSAR. 


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17.0 REGULATORY COMPLIANCE, REPORTING AND MONITORING 
17.1 Statement of Compliance 
This trial will be conducted in accordance with the current version of the IRB-approved protocol, 
in full conformity with the ethical principles outlined in the Declaration of Helsinki, the Protection 
of Human Subjects described in the International Council for Harmonisation Good Clinical 
Practice (GCP) Guidelines, applicable US Code of Federal Regulations (CFR), the NIDA Terms 
and Conditions of Award, and all other applicable state, local, and federal regulatory 
requirements. The Principal Investigator will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the Sponsor and documented approval from 
the IRB except where necessary to eliminate an immediate hazard(s) to the trial participants. An 
Operations Manual will be provided as a reference guide and study quality assurance tool. 
17.2 Institutional Review Board Approval  
Prior to initiating the study, participating site PIs will obtain written approval from the Ethics Review 
Committee (ERC) or Institutional Review Board (IRB) to conduct the study at their respective site, 
which will include approval of the study protocol. If changes to the study protocol become 
necessary, protocol amendments will be submitted in writing by the PIs for IRB approval prior to 
implementation. In addition, IRBs will approve all consent forms, recruitment materials, and any 
materials given to the participant, and any changes made to these documents throughout study 
implementation. Approval of both the protocol and the consent form(s) must be obtained before 
any participant is consented. For changes to the consent form, a decision will be made regarding 
whether previously consented participants need to be re-consented. IRB continuing review will be 
performed annually, or at a greater frequency contingent upon the complexity and risk of the 
study. Each site principal investigator is responsible for maintaining copies of all current IRB 
approval notices, IRB-approved consent documents, and approval for all protocol modifications. 
These materials must be received by the PI prior to the initiation of research activities at the site 
and must be available at any time for audit. Unanticipated problems (UP) involving risk to study 
participants will be promptly reported to and reviewed by the IRB of record, according to its usual 
procedures. 
UT Southwestern will serve as the single IRB (sIRB) of record for the protocol and will provide 
study oversight in accordance with 45 CFR 46. Participating sites/institutions will agree to rely on 
the sIRB and will enter into reliance/authorization agreements for Protocol CTN-0110. The sIRB 
will follow written procedures for reporting its findings and actions to appropriate officials at each 
participating institution. Some sites may meet Exception Criteria to the National Institutes of 
Health (NIH) sIRB Policy and may not utilize the IRB of Record. 
17.3 Research Advisory Panel of California (California sites only) 
Prior to initiating the study at a California site, the Sponsor or designee will obtain written approval 
from the Research Advisory Panel of California (RAP-C) for applicable research. Any planned 
research project to be conducted in California requiring the use of a Schedule I or Schedule II 
Controlled Substance as its main study medication, as well as research for the treatment of 
controlled substance addiction or abuse utilizing any drug, scheduled or not (Substance Abuse 
Treatment studies), must be submitted to RAP-C for review and approval prior to study start-up. 


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Study approval is based on review of the study protocol, consent form, and other pertinent study 
documents. Yearly reports will be provided to the RAP-C by the Sponsor or designee in order to 
obtain continuing study approval. Protocol amendments will also be submitted, and it is required 
that the Panel be notified of any significant study medication related adverse events that may 
emerge during conduct of the study at the California sites only. The Panel must also be notified 
of study conclusion. 
17.4 Informed Consent 
The informed consent process is a means of providing study information to each prospective 
participant and allows for an informed decision about participation in the study. Informed consent 
continues throughout the individual’s study participation. The informed consent form(s) will include 
all of the required elements of informed consent and may contain additional relevant consent 
elements and NIDA CCTN specific additional elements. Each study site must have the study 
informed consent(s) approved by the IRB of record. Prior to initial submission to the IRB and with 
each subsequent consent revision, the consent form(s) must be sent to the CCC and the LN to 
confirm that each consent form contains the required elements of informed consent as delineated 
in 21 CFR 50.25(a) and CFR 46.116(b), as well as pertinent additional elements detailed in 21 
CFR 50.25(b) and 45 CFR 46.116(c) and any applicable CCTN requirements. Every study 
participant is required to sign a valid, IRB-approved current version of the study informed consent 
form prior to the initiation of any study related procedures. The site must maintain the original 
signed informed consent for every participant in a locked, secure location that is in compliance 
with all applicable IRB and institutional policies and that is accessible to the study monitors. Every 
study participant should be given a copy of the signed consent form. Additionally, participants at 
California sites should be provided with a copy of the California Research Participant’s Bill of 
Rights. 
During the informed consent process, research staff will explain the study to the potential 
participant and provide the potential participant with a copy of the consent form to read and keep 
for reference. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and their rights as 
research participants. Extensive discussion of risks and possible benefits will be provided to the 
participants. Participants will have the opportunity to carefully review the written consent form and 
ask questions prior to signing. The participants should have the opportunity to discuss the study 
with their family and close friends or think about it prior to agreeing to participate. If the participant 
is interested in participating in the study, a qualified staff member will review each section of the 
IRB-approved informed consent form in detail and answer any questions the participant may 
pose. The participant, or participant’s legally authorized representative, will consent by signing 
and dating the consent document. The person obtaining consent and a witness, if required by the 
IRB of record, will also sign and date the consent document. It is strongly recommended that 
another research staff member review the consent after it is signed to ensure that the consent is 
properly executed and complete. Staff members delegated by the PI to obtain informed consent 
must be listed on the Delegation of Responsibility and Staff Signature Log and must be approved 
by the IRB, if required. All persons obtaining consent must have completed appropriate GCP and 
Human Subjects Protection training, as mandated by NIDA standard operating procedures. 


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The informed consent form must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect participants’ 
participation in the trial. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. The participant will be informed that their participation is voluntary and 
they may withdraw from the study at any time, for any reason without penalty. Individuals who 
refuse to participate or who withdraw from the study will be treated without prejudice. Study sites 
will be responsible for maintaining signed consent forms as source documents for quality 
assurance review and regulatory compliance. 
17.5 Quality Assurance Monitoring  
In accordance with federal regulations, the study Sponsor is responsible for ensuring proper 
monitoring of an investigation and ensuring that the investigation is conducted in accordance with 
the protocol. Qualified monitors will oversee aspects of site conformity to make certain the site 
staff is operating within the confines of the protocol, and in accordance with GCP. This includes 
but is not limited to protocol compliance, documentation auditing, monitoring of drug disposition, 
and ensuring the informed consent process is being correctly followed and documented. Non-
conformity with protocol and federal regulations will be reported as a protocol deviation and 
submitted to the study Sponsor and study IRB of record, (as applicable), for further review. 
17.6 Participant and Data Confidentiality 
Participant confidentiality and privacy are strictly held in trust by the participating PIs, their staff, 
the safety and oversight monitor(s), and the Sponsor(s) and funding agency, and will be 
maintained in accordance with all applicable federal regulations and/or state/Commonwealth law 
and regulations. This confidentiality is extended to the data being collected as part of this study. 
Data that could be used to identify a specific study participant will be held in strict confidence 
within the research team. No personally-identifiable information from the study will be released to 
any unauthorized third party without prior written approval of the Lead investigator, Sponsor, the 
funding agency (NIDA), and the participant. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or representatives 
from companies or organizations supplying the product, may inspect all documents and records 
required to be maintained by the PI, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
Participant records will be held confidential by the use of study codes for identifying participants 
on Case Report Forms (CRFs), secure storage of any documents that have participant identifiers, 
and secure computing procedures for entering and transferring electronic data. The study 
participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as denoted in Section 17.12, Records Retention and Requirements. 


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By signing the protocol signature page, the PI affirms that information furnished to the PI by the 
Sponsor will be maintained in confidence and such information will be divulged to the IRB/Privacy 
Board, Ethical Review Committee, or similar expert committee; affiliated institution; and 
employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. 
17.6.1 
Certificate of Confidentiality 
To further protect the privacy of study participants, the Secretary, Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, 
behavioral, clinical or other human subjects research funded wholly or in part by the federal 
government. Recipients of NIH funding for human subjects research are required to protect 
identifiable research information from forced disclosure per the terms of the NIH Policy (see 
https://humansubjects.nih.gov/coc/index). This protects participants from disclosure of sensitive 
information (e.g., drug use). It is the NIH policy that PIs and others who have access to research 
records will not disclose identifying information except when the participant consents or in certain 
instances when federal, state, or local law or regulation requires disclosure. NIH expects PIs to 
inform research participants of the protections and the limits to protections provided by a 
Certificate issued by this Policy. 
17.6.2 
Health Insurance Portability and Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. Sites will be responsible for communicating with the IRB or 
Privacy Board of record and obtaining the appropriate approvals or waivers to be in regulatory 
compliance. Releases of participant identifying information that are permitted by the HIPAA 
regulations, but which are prohibited by other applicable federal regulations and/or 
state/Commonwealth law and regulation, are prohibited. 
17.7 Investigator Assurances 
Each site must have on file an active Federalwide Assurance (FWA) with the HHS Office for 
Human Research Protection setting forth the commitment of the organization to establish 
appropriate policies and procedures for the protection of human research subjects in alignment 
with 45 CFR 46, Subpart A, with documentation sent to the Sponsor and NIDA or its designee. 
Research covered by these regulations cannot proceed in any manner prior to Sponsor and NIDA 
receipt of certification that the research has been reviewed and approved by the IRB provided for 
in the assurance (45 CFR 46.103). Prior to initiating the study, the principal investigator at each 
study site will sign a protocol signature page and investigator agreement, providing assurances 
that the study will be performed according to the standards stipulated therein. 
17.7.1 
Financial Disclosure/Conflict of Interest 
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. Everyone with decision-making responsibilities regarding the protocol will confirm to the 
Sponsor annually that they have met their institutional financial disclosure requirements. 


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17.7.2 
DEA Registration 
All Drug Enforcement Administration (DEA) requirements must be met, including registration, 
inspection if required, and certification, as applicable. In order to receive shipments of study drug, 
sites must have a DEA registration (facility research registration or a practitioner registration) that 
has the address where study drug will be shipped on the registration. Additionally, dispensing any 
controlled substance requires a DEA registration unless exempt by federal or state law or 
pursuant to CFR Sections 1301.22-1301.26. 
17.7.3 
IND Requirements 
An IND application will be submitted to the FDA for this study. Any subsequent amendments to 
this clinical trial submitted to the FDA will reflect awareness of and compliance with U.S Code of 
Federal Regulations 45 CFR 46 and its subparts, as well as the International Council for 
Harmonization Good Clinical Practice Guidelines (ICH E6 R2). This IND study will also be 
conducted in accordance with all applicable FDA regulations and will comply with all applicable 
laws and regulations at clinical research sites. 
17.8 Clinical Monitoring 
PIs will host periodic visits by NIDA contract monitors who will examine whether study procedures 
are conducted appropriately and that study data are generated, documented and reported in 
compliance with the protocol, GCP, and applicable regulations. These monitors will audit, at 
mutually agreed upon times, regulatory documents, case report forms (CRFs), informed consent 
forms and corresponding source documents for each participant. Monitors will have the 
opportunity and ability to review any study-associated document or file. 
NIDA-contracted monitors will assess whether submitted data are accurate and in agreement with 
source documentation and will also review regulatory/essential documents such as 
correspondence with the IRB. Areas of particular concern will be participant informed consent 
forms, protocol adherence, reported safety events and corresponding assessments, and principal 
investigator oversight and involvement in the trial. Reports will be prepared following the visit and 
forwarded to the site principal investigator, the Lead Investigator, Sponsor, and NIDA CCTN. 
Qualified node personnel (Node QA monitors) or other designated party(ies) will provide site 
management for each site during the trial. Node QA staff or other designated party(ies) will audit 
source documentation, including informed consent forms and any other separate regulatory 
forms, including HIPAA or state-specific forms. This will take place as specified by the local 
protocol team, node PI or lead team and will occur as often as needed to help prevent, detect, 
and correct problems at the study sites. Node QA personnel will verify that study procedures are 
properly followed and that site personnel are trained and able to conduct the protocol 
appropriately. If the node personnel’s review of study documentation indicates that additional 
training of site study personnel is needed, node QA personnel will undertake or arrange for that 
training. Details of the contract, node QA and data monitoring are found in the study QA 
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17.9 Inclusion of Women and Minorities 
The study sites should aim and take steps to enroll a diverse study population, with additional 
focus on enrolling a minimum of 25% women of total study enrollment. In addition, specific 
attention should be given to enrolling the representative minorities who are reported to have MA 
and co-use of opioids by population health studies. Minority enrollment at each study site should 
reflect the relevant local population. If difficulty is encountered in recruiting an adequate number 
of women and/or minorities, the difficulties involved in recruitment will be discussed in national 
conference calls and/or group-to-group individual meetings. Sites will be encouraged to 
implement strategies such as linkages with medical sites, treatment programs, or community 
organizations that serve a large number of women and/or minorities, using targeted advertisement 
in media with a high female and/or minority audience, and partnerships with community 
organizations who work with these groups. In compliance with NIH policy, subgroup analyses will 
be performed to evaluate the interaction with treatment assignment for sex, race and ethnicity. 
17.10 Prisoner Certification 
As per 45 CFR 46 Subpart C, there are additional protections pertaining to prisoners as study 
participants. A prisoner is defined as any individual involuntarily confined or detained in a penal 
institution. The term is intended to encompass individuals sentenced to such an institution under 
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment 
procedures which provide alternatives to criminal prosecution or incarceration in a penal 
institution, and individuals detained pending arraignment, trial, or sentencing. In order to meet 
these additional protections, the institution’s IRB will obtain certification from the Office of Human 
Research Protections (OHRP) to enroll prisoners and follow-up with participants who become 
prisoners during the course of the study, as necessary. 
17.11 Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be checked at each participating site for 
regulatory document compliance prior to study initiation, throughout the study, as well as at study 
closure. 
17.12 Records Retention and Requirements 
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, audio and video recordings, and regulatory files) are to be maintained by the PI 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, Lead Investigator, and NIDA must be notified in writing and 
acknowledgment from these parties must be received by the site prior to the destruction or 
relocation of research records. 
17.13 Reporting to Sponsor 
The site principal investigator agrees to submit accurate, complete, legible and timely reports to 
the Lead Investigator, and Sponsor, as required. These include, but are not limited to, reports of 
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participants. Safety reporting will occur as previously described. At the completion of the trial, the 
Lead Investigator will provide a final report to the Sponsor and NIDA. 
17.14 Audits 
The Sponsor has an obligation to ensure that this trial is conducted according to good clinical 
research practice guidelines and may perform quality assurance audits for protocol compliance. 
The Lead Investigator and authorized staff from the Big South/West Node; the National Institute 
on Drug Abuse Clinical Trials Network (NIDA CTN, the funding agency); NIDA’s contracted 
agents, monitors or auditors; and other agencies such as the Department of Health and Human 
Services (HHS), the Office for Human Research Protection (OHRP) and the Institutional Review 
Board of record may inspect research records for verification of data, compliance with federal 
guidelines on human participant research, and to assess participant safety. 
17.15 Study Documentation 
Each participating site will maintain appropriate study documentation (including medical and 
research records) for this trial, in compliance with ICH E6 R2 and regulatory and institutional 
requirements for the protection of confidentiality of participants. Study documentation includes all 
case report forms, workbooks, source documents, monitoring logs and appointment schedules, 
Sponsor-Investigator correspondence, and signed protocol and amendments, Ethics Review 
Committee or Institutional Review Board correspondence and approved consent form and signed 
participant consent forms. As part of participating in a NIDA-funded study, each site will permit 
authorized representatives from NIDA, the Sponsor and regulatory agencies to examine (and 
when permitted by law, to copy) clinical records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress, and data validity. 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document, and that it is marked to indicate it is a photocopy. 
17.16 Protocol Deviations 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol. 
The noncompliance may be either on the part of the participant, the PI, or the study site staff. As 
a result of deviations, corrective actions will be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP: 
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3 
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1 
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2. 
Any departure from procedures and requirements outlined in the protocol will be classified as 
either a major or minor protocol deviation. The difference between a major and minor protocol 
deviation has to do with the seriousness of the event and the corrective action required. A minor 


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protocol deviation is considered an action (or inaction) that by itself is not likely to affect the 
scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a study 
participant. Major protocol deviations are departures that may compromise the participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and could be cause for 
corrective actions if not rectified or prevented from re-occurrence. Sites will be responsible for 
developing corrective action plans for both major and minor deviations as appropriate. Those 
corrective action plans may be reviewed/approved by the Lead Node and the CCC with overall 
approval by the IRB of record as needed. All protocol deviations will be monitored at each site for 
(1) significance, (2) frequency, and (3) impact on the study objectives, to ensure that site 
performance does not compromise the integrity of the trial.  
All protocol deviations should be recorded in the EDC system via the Protocol Deviation CRF. 
The CCC, DSC and the LI must be contacted immediately if an unqualified or ineligible participant 
is randomized into the study. 
Additionally, each site is responsible for reviewing the IRB of record’s definition of a protocol 
deviation or violation and understanding which events need to be reported. Sites must recognize 
that the CTN and IRB definition of a reportable event may differ and act accordingly in following 
all reporting requirements for both entities. 
17.17 Safety Monitoring 
A physician (MD or DO) who serves in the Site PI or Medical Clinician study role  will review or 
provide consultation for each Adverse Event (AE) and Serious Adverse Event (SAE), as needed. 
These reviews will include an assessment of the possible relatedness of the event to the study 
intervention or other study procedures. The physician (MD or DO) who serves in the Site PI or 
Medical Clinician study role will also provide advice for decisions to exclude, refer, or withdraw 
participants as required. In addition, the Sponsor will assign a Medical Monitor to this protocol to 
independently review the safety data, present it to the DSMB for periodic review, and provide PIs 
a Safety Letter when necessary. The Medical Monitor will determine which safety events require 
expedited reporting to the Sponsor, NIDA, Indivior, the DSMB and regulatory authorities. This will 
include events that are serious, related and unexpected. The study staff will be trained to monitor 
for and report AEs and SAEs. 
Each of the sites has established practices for managing medical and psychiatric emergencies, 
and the study staff will continue to utilize these procedures. 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. 
17.17.1 
Data and Safety Monitoring Board (DSMB) 
An independent CTN DSMB will examine accumulating data to assure protection of participants’ 
safety while the study’s scientific goals are being met. The CTN DSMB is responsible for 
conducting periodic reviews of accumulating safety and efficacy data. It will determine whether 
there is support for continuation of the trial, or evidence that study procedures should be changed, 
or if the trial should be halted, for reasons relating to the safety of the study participants, the 
efficacy of the treatment under study, or inadequate trial performance (e.g., poor recruitment). 


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17.17.2 
Safety Monitor / Medical Monitor 
The CCC Safety Monitor/Medical Monitor is responsible for reviewing all adverse events and 
serious adverse events reported. All SAEs will be reviewed within one business day of being 
reported in the eClinical. The Safety Monitor/Medical Monitor will also indicate concurrence or not 
with the details of the report provided by the site. Where further information is needed, the Safety 
Monitor/Medical Monitor will discuss the event with the site. Reviews of SAEs will be conducted 
in the Advantage eClinical data system and will be a part of the safety database. All AEs are 
reviewed on a regular basis to observe trends or unusual events. 
The CCC Safety Monitor/Medical Monitor will summarize each SAE and will provide a report to 
the Lead Investigator, Sponsor, and NIDA. If the event meets the criteria for FDA-defined 
expedited reporting, the CCC safety team and regulatory team will work together to submit an 
expedited safety report to the FDA. A copy of the expedited report will be submitted to the DSMB 
through the DSC. A copy of the expedited report will be submitted to Indivior and all participating 
sites. Other safety reports will be generated and presented at the scheduled Data Safety 
Monitoring Board (DSMB) meetings. 
17.17.3 
Adverse Events (AEs) 
Standard definitions for adverse events and serious adverse events, their identification, 
characterization regarding severity and relationship to therapy, and processing are described in 
Appendix A. 
For the purpose of this study, all AEs will require reporting in the electronic data system. 
Events that are temporally associated with SL-BUP use, but that are not recorded using either 
the Medication Side Effects form, or a different study-specific CRF (e.g., withdrawal on the 
COWS/SOWS, Buprenorphine-XR/Placebo Injection Site Evaluation), will be recorded as an AE. 
Events related to the injection of the study medication are recorded on the Injection Site 
Examination form and will not be duplicate reported on an AE form, unless they meet the SAE 
definition.  
Events related to withdrawal symptoms are captured on the COWS and SOWS forms and will not 
be duplicate reported on an AE form, unless the event meets the definition of an SAE. Withdrawal 
symptoms not captured by scheduled COWS and SOWS form should be reported as an AE. Any 
spontaneous reporting of withdrawal symptoms by the participant will be captured using the AE 
form in the following situations: withdrawal symptoms reported at visits without scheduled specific 
structured questionnaires (COWS and SOWS CRFs) and withdrawal symptoms not listed in the 
specific structured questionnaires (COWS and SOWS CRFs) reported at any visit. 
Any of these events that meet the definition of an SAE are reported on the AE/SAE form set. 
17.17.4 
Serious Adverse Events 
For the purpose of this study, all SAEs will require reporting in the electronic data capture system. 
Reporting of AEs and SAEs is described in Appendix A. The study sites are responsible for 
reporting all AEs and SAEs to the IRB of record (and local IRB, as applicable) per IRB guidelines. 


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17.17.5 
Known Potential Toxicities of Study Medication 
Specific known potential toxicities of the study medication include risk of overdose. 
Buprenorphine, as Sublocade™ in this study, is a Schedule III controlled substance. An IND will 
be on file with the FDA to provide safety monitoring. The medication will be handled and 
administered using the required REMS procedures. All other clinical considerations regarding risk 
for use of this medication, such as possible drug interactions or hepatic impairment, have been 
integrated in the exclusion criteria and safety monitoring procedures utilized in this study. 
Refer to the package insert for Sublocade™ for complete list of adverse reactions and toxicities. 


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18.0 DATA MANAGEMENT 
18.1 Design and Development 
This protocol will utilize a centralized Data and Statistics Center (DSC). The DSC will be 
responsible for development of the electronic case report forms (eCRFs), development and 
validation of the clinical study database, ensuring data integrity, and training site and participating 
node staff on applicable data management procedures. Advantage eClinical, a web-based 
distributed data entry system, will be implemented. This system will be developed to ensure that 
guidelines and regulations surrounding the use of computerized systems used in clinical trials are 
upheld. The remainder of this section provides an overview of the data management plan 
associated with this protocol. 
18.2 Qualitative Data Management 
Qualitative data will be collected and analyzed by the study investigators. The study investigators 
will be responsible for developing the qualitative interview guide, obtaining IRB approval, training 
staff, as well as the collection and analysis of qualitative data.  
 
18.3 Site Responsibilities  
The data management responsibilities of each individual site will be specified by the DSC and 
outlined in the Advantage eClinical User’s Guide and CRF Manual. 
18.4 Data Center Responsibilities 
The DSC will 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide final Case Report Forms (CRFs) and electronic CRFs 
(eCRFs) for the collection of all data required by the study, 3) develop data dictionaries for each 
eCRF that will comprehensively define each data element, 4) prepare instructions for use of 
Advantage eClinical and for completion of CRFs/eCRFs, 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. 
18.5 Data Collection and Entry 
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical or will be collected via direct entry into the eCRF. In the event that 
Advantage eClinical is not available, the DSC will provide the sites with CRF paper source 
documents and completion instructions. Data entry into Advantage eClinical should be completed 
according to the instructions provided, project specific training and guidelines established by DSC. 
Data entry into eCRFs shall be performed by authorized individuals. The investigator is 
responsible for maintaining accurate, complete and up-to-date records, and for ensuring the 
completion of the eCRFs for each research participant. Selected eCRFs may also require the 
investigator’s electronic signature. In some situations, data collected on source documents will 


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not be entered into Advantage eClinical, but when it is entered, it will follow the guidelines stated 
above. 
18.6 Data Editing  
 Data will be entered into the DSC automated data acquisition and management system 
(Advantage eClinical). eCRFs will be monitored for completeness and accuracy throughout the 
study. Dynamic reports listing missing values and forms are available to sites at all times in 
Advantage eClinical. These reports will be monitored regularly by the DSC. In addition, the DSC 
will identify inconsistencies within eCRFs and between eCRFs and post data clarification requests 
or queries in Advantage eClinical on a scheduled basis. Sites will resolve data inconsistencies 
and errors and enter all corrections and changes into Advantage eClinical. 
The CCC will conduct regular monitoring visits, during which audits comparing source documents 
to the data entered on the eCRF will be performed. Any discrepancies identified between the 
source document and the eCRF will be corrected by the site. 
Trial progress and data status reports, which provide information on items such as recruitment, 
availability of primary outcome, treatment exposure, regulatory status, and data quality, will be 
generated daily and posted to a secure website. These reports are available to the site staff, the 
local node staff, the lead node, the coordinating centers, NIDA CCTN and the Sponsor to monitor 
study progress overall and at each individual participating site. 
18.7 Data Transfer/Lock 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DSC. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by DSC staff will be secured and password protected.  
The DSC will conduct final data cleaning activities and “lock” the study database from further 
modification. The final raw analysis datasets will be transferred to the Lead Investigator, Sponsor 
or designee and to NIDA, as requested, for storage and archive. De-identified versions of these 
datasets will also be provided to the NIDA CCTN-designated party for storage and archiving. 
These datasets may be posted on the NIDA Data Share website. 
18.8 Data Training 
The training plan for site staff includes provisions for training on assessments, eCRF completion 
guidelines, data management procedures, and the use of Advantage eClinical. 
18.9 Data Quality Assurance 
To address the issue of data entry quality, the DSC will follow a standard data monitoring plan. 
An acceptable quality level prior to study lock or closeout will be established as a part of the data 
management plan. Data quality summaries will be made available during the course of the 
protocol. 


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19.0 DATA SHARING, PUBLIC ACCESS AND PUBLICATIONS  
This study will comply with the NIH Data Sharing Policy and Implementation Guidance 
(https://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm) and the HEAL 
Public Access and Data Sharing Policy (https://www.nih.gov/research-training/medical-research-
initiatives/heal-initiative/research/heal-public-access-data-sharing-policy). Investigators will also 
register and report results of the trial in ClinicalTrials.gov, consistent with the requirements of the 
Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials 
Registration (https://grants.nih.gov/policy/clinical-trials/reporting/understanding/nih-policy.htm). 
Primary data for this study will be available to the public in the NIDA data repository, per NIDA 
CTN policy. For more details on data sharing please visit https://datashare.nida.nih.gov/. 
The primary outcome(s) publication will be included along with study underlying primary data in 
the 
data 
share 
repository, 
and 
it 
will 
also 
be 
deposited 
in 
PubMed 
Central 
http://www.pubmedcentral.nih.gov/ per NIH Policy (http://publicaccess.nih.gov/). 
Every attempt will be made to publish results in peer-reviewed journals. The planning, 
preparation, and submission of publications will follow the policies of the Publications Committee 
of the CTN. Considerations for ensuring confidentiality of any shared data are described in 
Section 17.6. 


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20.0 PROTOCOL SIGNATURE PAGE  
SPONSOR/SPONSOR’S REPRESENTATIVE  
 
 
 
 
 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
• 
I am in receipt of version 8.0 of the protocol and agree to conduct this clinical study in 
accordance with the design and provisions specified therein. 
• 
I agree to follow the protocol as written except in cases where necessary to protect the 
safety, rights, or welfare of a participant, an alteration is required, and the Sponsor and IRB 
have been notified prior to the action. 
• 
I will ensure that the requirements relating to obtaining informed consent and institutional 
review board (IRB) review and approval in 45 CFR 46 are met. 
• 
I agree to personally conduct or supervise this investigation at this site and to ensure that 
all site staff assisting in the conduct of this study are adequately and appropriately trained 
to implement this version of the protocol and that they are qualified to meet the 
responsibilities to which they have been assigned. 
• 
I agree to comply with all the applicable federal, state, and local regulations regarding the 
obligations of clinical investigators as required by the Department of Health and Human 
Services (HHS), the state, and the IRB. 
SITE’S PRINCIPAL INVESTIGATOR 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
Clinical Site Name  
 
      
Node Affiliation  
 
      
 


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21.0 PROTOCOL AMENDMENT HISTORY 
The table below is intended to briefly capture changes of IRB-approved versions of the protocol, 
including a description of the major change(s) and rationale (only the most meaningful, substantial 
changes to the protocol should be documented here). Use of this table is recommended, but not 
required.  
 
Version 
Date 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Wesson DR, Ling, W. . The Clinical Opiate Withdrawal Scale (COWS). Journal of 
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Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new 
rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987; 13(3): 293-308. 
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Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive 
Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26(3): 477-86. 
55. 
Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized 
anxiety disorder: the GAD-7. Arch Intern Med 2006; 166(10): 1092-7. 
56. 
Trivedi MH, Wisniewski SR, Morris DW, et al. Concise Associated Symptoms Tracking 
scale: a brief self-report and clinician rating of symptoms associated with suicidality. J Clin 
Psychiatry 2011; 72(6): 765-74. 
57. 
Jha MK, Minhajuddin A, South C, Rush AJ, Trivedi MH. Irritability and Its Clinical Utility in 
Major Depressive Disorder: Prediction of Individual-Level Acute-Phase Outcomes Using Early 
Changes in Irritability and Depression Severity. Am J Psychiatry 2019; 176(5): 358-66. 
58. 
Rizvi SJ, Quilty LC, Sproule BA, Cyriac A, Michael Bagby R, Kennedy SH. Development 
and validation of the Dimensional Anhedonia Rating Scale (DARS) in a community sample and 
individuals with major depression. Psychiatry Res 2015; 229(1-2): 109-19. 
59. 
McGregor C, Srisurapanont M, Mitchell A, Longo MC, Cahill S, White JM. Psychometric 
evaluation of the Amphetamine Cessation Symptom Assessment. J Subst Abuse Treat 2008; 
34(4): 443-9. 
60. 
Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc 
Behav 1983; 24(4): 385-96. 


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61. 
dela Cruz AM, Bernstein IH, Greer TL, et al. Self-rated measure of pain frequency, 
intensity, and burden: psychometric properties of a new instrument for the assessment of pain. J 
Psychiatr Res 2014; 59: 155-60. 
62. 
Bechara A, Damasio AR, Damasio H, Anderson SW. Insensitivity to future consequences 
following damage to human prefrontal cortex. Cognition 1994; 50(1-3): 7-15. 
63. 
Ling W, Farabee, D., Liepa, D., Wu, L.T. . The Treatment Effectiveness Assessment 
(TEA): an efficient, patient-centered instrument for evaluating progress in recovery from addiction. 
. Journal of Substance Abuse and Rehabilitation 2012; 3(1): 129-36. 
64. 
Ettienne EB, Chapman E, Maneno M, et al. Pharmacogenomics-guided policy in opioid 
use disorder (OUD) management: An ethnically-diverse case-based approach. Addict Behav Rep 
2017; 6: 8-14. 
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Lolodi O, Wang YM, Wright WC, Chen T. Differential Regulation of CYP3A4 and CYP3A5 
and its Implication in Drug Discovery. Curr Drug Metab 2017; 18(12): 1095-105. 
66. 
Ettienne EB, Ofoegbu A, Maneno MK, et al. Pharmacogenomics and Opioid Use Disorder: 
Clinical Decision Support in an African American Cohort. J Natl Med Assoc 2019; 111(6): 674-81. 
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CNS Drugs 2018; 32(4): 305-20. 
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Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis. PLoS 
One 2015; 10(6): e0127995. 
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Liu CF, Burgess JF, Jr., Manning WG, Maciejewski ML. Beta-binomial regression and 
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Schmidli H. Overdispersion Models in SAS. Journal of Biopharmaceutical Statistics 2013; 
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data. Statistical Modelling 2005; 5: 1-19. 
 


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23.0 APPENDIX A: ADVERSE EVENT REPORTING AND 
PROCEDURES  
Each participating site’s Principal Investigator is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified and trained 
study personnel to assess, report, and monitor adverse events. 
Definition of Adverse Events and Serious Adverse Events 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered study medication related which occurs during the conduct of a clinical trial. Any 
change from baseline in clinical status, ECGs, lab results, x-rays, physical examinations, etc., that 
is considered clinically significant by the Medical Clinician are considered AEs.  
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the study medication/intervention caused the adverse event. A reasonable possibility implies that 
there is evidence that the study medication caused the event. 
Adverse reaction is any adverse event caused by the study medication. 
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 Medical Clinician or Sponsor, it: 
1) 
Results in death: A death occurring during the study or which comes to the attention of 
the study staff during the protocol-defined follow-up period, whether or not considered 
caused by the study medication(s), must be reported. 
2) 
Is life-threatening: Life-threatening means that the study participant was, in the opinion 
of the Medical Clinician or Sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention.  
3) 
Requires inpatient hospitalization or prolongation of existing hospitalization.  
4) 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
5) 
Is a congenital abnormality or birth defect. 
6) 
Is an important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event.  
 
 


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Definition of Expectedness 
Any adverse event is considered “unexpected” if it is not listed in the investigator brochure or the 
package insert or is not listed at the specificity or severity that has been observed. If neither is 
available then the protocol and consent are used to determine an unexpected adverse event. 
Pregnancy 
Any pregnancies that occur while a participant is enrolled in the study will be captured on a 
pregnancy CRF and not separately reported as an AE or SAE. Women who become pregnant 
during the active treatment period will be discontinued from further medication administration, 
referred for medical care, and the pregnancy followed until an outcome is known. 
Medical and Psychiatric History 
A thorough medical and psychiatric history during the screening phase should record any chronic, 
acute, or intermittent preexisting or current illnesses, diseases, symptoms, or laboratory signs of 
the participant, to avoid reporting pre-existing conditions as new AEs and to assist in the 
assessment of worsening in intensity or severity of these conditions that would indicate an AE. 
Stable chronic conditions, such as arthritis, which are present prior to clinical trial entry and do 
not worsen are not considered AEs.  
Site’s Role in Eliciting and Reporting Adverse Events 
Appropriately qualified and trained personnel will elicit participant reporting of AEs and SAEs at 
each study visit designated to collect AEs. Adverse events (medical and/or psychiatric) 
assessment will initiate with participant consent and follow-up of ongoing adverse events will 
continue through resolution or 30 days post last study visit. Study personnel will obtain as much 
information as possible about the reported AE/SAE to complete the AE/SAE forms and will consult 
with the Safety Monitor/Medical Monitor as warranted.  
Standard reporting, within seven days of the site becoming aware of the event, is required for 
reportable AEs. Expedited reporting (within 24 hours of the site’s becoming aware of the event) 
is required for reportable SAEs (including death and life-threatening events). Sites are responsible 
for reporting SAEs to the IRB of record, per the IRB of record’s guidelines. 
Sites are required to enter reportable AEs and SAEs in the Advantage eClinical system. The AE 
form is used to capture reportable AEs and SAEs (as defined in the protocol). Additional 
information may need to be gathered to evaluate SAEs and to complete the appropriate CRFs 
and the summary. This process may include obtaining hospital discharge reports, medical 
records, autopsy records or any other type records or information necessary to provide a complete 
and clear picture of the serious event and events preceding and following the event. If the SAE is 
not resolved or stable at the time of the initial report or if new information becomes available after 
the initial report, follow-up information must be submitted as soon as possible. 
Reportable adverse events will be followed until resolution, stabilization or study end. Any serious 
adverse reactions will be followed until resolution or stabilization even beyond the end of the 
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Site’s Role in Assessing Severity and Causality of Adverse Events 
Appropriately qualified and trained study personnel will conduct an initial assessment of 
seriousness, severity, and causality when eliciting participant reporting of adverse events. A 
physician (MD or DO) who serves in the Site PI or Medical Clinician study role will review 
reportable AEs for seriousness, severity, and causality within the established reporting timeline.  
Guidelines for Assessing Severity 
The severity of an adverse event refers to the intensity of the event: 
Grade 1 
Mild 
Transient or mild discomfort (typically < 48 hours), no or minimal 
medical intervention/therapy required; hospitalization not 
necessary (non-prescription or single-use prescription therapy may 
be employed to relieve symptoms, e.g., aspirin for simple 
headache, acetaminophen for post-surgical pain). 
Grade 2 
Moderate 
Mild to moderate limitation in activity, some assistance may be 
needed; no or minimal intervention/therapy required, 
hospitalization unlikely 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/ therapy required, hospitalization possible. 
 
Guidelines for Determining Causality 
A physician (MD or DO) who serves in the Site PI or Medical Clinician study role will use the 
following question when assessing causality of an adverse event to study medication/intervention 
where an affirmative answer designates the event as a suspected adverse reaction: 
Is there a reasonable possibility that the study medication caused the event?  
Site’s Role in Monitoring Adverse Events 
Local quality assurance monitors will review study sites and respective study data on a regular 
basis and will promptly advise sites to report any previously unreported safety issues and ensure 
that the reportable safety-related events are being followed to resolution and reported 
appropriately. Staff education, re-training or appropriate corrective action plan will be 
implemented at the participating site when unreported or unidentified reportable AEs or serious 
events are discovered, to ensure future identification and timely reporting by the site.  
Sponsor’s Role in Safety Management Procedures of AEs/SAEs 
A Sponsor-assigned Safety Monitor/Medical Monitor is responsible for reviewing all serious 
adverse event reports. All reported SAEs will generate an e-mail notification to the Safety 
Monitor/Medical Monitor, Lead Investigator, and designees. All SAEs will be reviewed by the 
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be requested. The Safety Monitor/Medical Monitor will also report events to the Sponsor, NIDA, 
and the DSMB. The DSMB will receive summary reports of all adverse events annually, at a 
minimum. The DSMB or the Sponsor-assigned Safety Monitor/Medical Monitor may also request 
additional and updated information. Details regarding specific adverse events, their treatment and 
resolution, will be summarized by the Safety Monitor/Medical Monitor in writing for review by the 
Lead Investigator, Sponsor, and the DSMB. Subsequent review by the Safety Monitor/Medical 
Monitor, DSMB, FDA and ethics review committee or IRB, the Sponsor, NIDA, or relevant local 
regulatory authorities may also suspend further trial treatment at a site. The Sponsor, NIDA, the 
DSMB, and FDA retain the authority to suspend additional enrollment and treatments for the entire 
study as applicable. 
Regulatory Reporting for an IND study 
All serious and unexpected suspected adverse reactions are reported by the Medical Monitor on 
behalf of the Sponsor to the FDA in writing within 15 calendar days of notification. Suspected 
adverse reactions that are unexpected and meet the criteria for death or immediately life-
threatening also require notification of the FDA as soon as possible but no later than 7 calendar 
days of notification of the event, with a follow-up written report within 15 calendar days of 
notification of the event. The Medical Monitor will prepare an expedited report (MedWatch Form 
3500A or similar) for the FDA and other regulatory authorities, the Sponsor, NIDA, the DSMB, 
Indivior and copies will be distributed to all sites. Expedited reports will be placed in the site 
regulatory files upon receipt. A copy of all expedited reports will be forwarded to the site’s local 
IRB, if required. 
Reporting to the Data and Safety Monitoring Board 
The DSMB will receive listing of AEs and summary reports of all SAEs at a frequency requested 
by the DSMB, but at least annually. Furthermore, the DSMB will be informed of expedited reports 
of SAEs.  
Participant Withdrawal 
The Medical Clinician must apply his/her clinical judgment to determine whether or not an adverse 
event is of sufficient severity to require that the participant be withdrawn from further study 
medication administration/study intervention. A physician (MD or DO) who serves in the Site PI 
or Medical Clinician study role must make the decision to withdraw a participant from study 
medication. If necessary, a Medical Clinician (MD or DO) 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 
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23.1 Adverse Event Reporting (Chart) 
 


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24.0 APPENDIX B: DATA AND SAFETY MONITORING PLAN (DSMP) 
24.1 BRIEF STUDY OVERVIEW 
This study will randomize approximately 246 individuals to 12 weeks of outpatient BUP-Inj or to 
12-weeks of outpatient PBO-Inj to test if BUP-Inj reduces urine-verified MA use in Weeks 9-12 of 
the study. Eligibility will be determined during a maximum 21-day screening period and 
participants must have at least 2 positive UDS for MA of a possible 3 tests to occur at clinic visits 
within a 10-day period, with at least 2 days between visits, must self-report MA use on 18 or more 
days in the 30-day period prior to written consent using the Timeline Followback (TLFB) and meet 
diagnostic criteria for moderate or severe MUD per DSM-5 (4 or more criteria) at screening. 
Participants must also have at least one negative UDS for opioids during the screening period 
and on the day of expected randomization, and must meet diagnostic criteria for mild opioid use 
disorder per DSM-5 (at least 2 but no more than 3 criteria) or opioid misuse demonstrated by self-
report of opioid use of at least 2 days in the 30-day period prior to written consent using the TLFB 
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 receive either 1) BUP-
Inj or 2) PBO-Inj. Injections will be provided in weeks 1, 5, and 9. Participants will be required to 
submit twice weekly urine samples, and complete once-weekly cognitive behavioral therapy 
based on a treatment manual adapted for stimulant use disorder specifically for this study. The 
primary outcome measure is the number of MA-negative UDS results obtained during Weeks 9 
through 12 of the medication phase as measured for the BUP-Inj and PBO-Inj conditions.  
24.2 OVERSIGHT OF CLINICAL RESPONSIBILITIES 
A. Site Principal Investigator 
Each participating site’s Principal Investigator (PI) is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified and trained 
study personnel to assess, report, and monitor adverse events.  
All adverse events (AEs) occurring during the course of the clinical trial will be collected, 
documented, and reported according to the Protocol.  
The occurrence of AEs and serious adverse events (SAEs) will be assessed at each clinic visit 
during the study. Serious adverse events will be followed until considered resolved or stable.  
Reportable AEs are required to be entered into the data system within 7 days of the site staff 
becoming aware of the event. Reportable SAEs (including death and life-threatening events) are 
required to be entered into the data system within 24 hours of site's knowledge of the event. 
B. CCC Medical Monitor 
The NIDA CTN Clinical Coordinating Center’s (CCC) Medical Monitor or designee is responsible 
for reviewing all adverse events and serious adverse events reported. The CCC Medical Monitor 
is alerted via email each time an SAE is reported in Advantage eClinical. All SAEs will be reviewed 
at the time they are reported in the EDC. The Medical Monitor or designee will also indicate 
concurrence or not with the details of the report provided by the site. Where further information is 


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needed, the Medical Monitor or designee will discuss the event with the site staff. Reviews of 
SAEs by the CCC Medical Monitor or designee will be documented in the Advantage eClinical 
data system and will be a part of the safety database. All AEs are reviewed on a weekly basis to 
observe trends or unusual events. 
Mandatory Regulatory Reporting in IND Trials: 
For trials conducted under IND, the CCC Safety Monitor/Medical Monitor or designee will report 
events to the regulatory authorities if the event meets the definition of an expedited event 
(21CFR312.32). All SAEs that meet expedited reporting will be reported to the FDA/Regulatory 
Authorities in writing within 15 calendar days of notification of the CCC. If the SAE also meets the 
criteria for death or immediately life-threatening, the CCC will notify the FDA/Regulatory 
Authorities electronically, by phone or by fax as soon as possible but no later than 7 calendar 
days of notification of the CCC pharmacovigilance team, with a follow-up written report within 15 
calendar days of notification of the CCC. The CCC pharmacovigilance team will prepare an 
expedited report (MedWatch Form 3500A or similar) for the FDA/Regulatory authorities and 
copies will be distributed to all participating site investigators. 
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. Reports will be generated and 
presented for Data and Safety Monitoring Board (DSMB) meetings. The DSMB will receive listings 
of AEs and narratives of all SAEs at a frequency requested by the DSMB and CCTN, but at least 
annually. Furthermore, the DSMB will be informed of expedited reports of SAEs. The DSMB will 
make recommendations to NIDA CCTN as to whether there is sufficient support for continuation 
of the trial, evidence that study procedures should be changed, or evidence that the trial (or a 
specific site) should be halted for reasons relating to safety of the study participants or inadequate 
trial performance (e.g., poor recruitment). This includes the rules for triggering immediate DSMB 
review, defined as three or more participants experiencing severe adverse reactions; four or more 
participants have four consecutive positive urine toxicology screens for opioid use, and have been 
reevaluated through any means as having moderate to severe opioid use disorder; or one or more 
serious, unexpected and suspected adverse reactions. 
Following each DSMB meeting, the NIDA CCTN will communicate the outcomes of the meeting, 
based on DSMB recommendations, in writing to the study Lead Investigator. This communication 
summarizing study safety information will be submitted to participating IRBs. 
D. Quality Assurance (QA) Monitoring 
The monitoring of the study site(s) will be conducted on a regular basis using a combination of 
NIDA CCTN CCC monitors (if applicable) and the local Node QA Monitors (if applicable). 
Investigators will host periodic visits for the monitors. The purpose of these visits is to assess 
compliance with the protocol, GCP requirements, and other applicable regulatory requirements, 
as well as to document the integrity of the trial progress. The investigative site will provide direct 
access to all trial related sites (e.g., pharmacy, research office), source data/documentation, and 
reports for the purpose of monitoring and auditing by the monitors, as well as for inspection by 


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local and regulatory authorities. Areas of particular concern will be the review of 
inclusion/exclusion criteria, participant Informed Consent Forms, protocol adherence, safety 
monitoring, IRB reviews and approvals, regulatory documents, participant records, study drug 
accountability, and Principal Investigator supervision and involvement in the trial. The monitors 
will interact with the site staff to identify issues and re-train the site as needed to enhance research 
quality. 
Site Visit Reports will be prepared by the NIDA CCC Clinical Research Associates (CRAs) 
following each site visit. These reports will be sent to the site Principal Investigator, the study Lead 
Investigator and NIDA CCTN.  
Local Node QA site visit reports will be prepared following each site visit, as applicable. These 
reports are sent to those entities required of them by the Lead Investigative team, generally 
including the Lead Investigator, site Principal Investigator, Node PI and a CCC representative, 
usually the Clinical Study Manager for the study. 
E. Management of Risks to Participants 
Confidentiality 
Confidentiality of participant records will be secured by the use of study codes for identifying 
participants on CRFs, and secure storage of any documents that have participant identifiers on 
site, as well as secure computing procedures for entering and transferring electronic data. The 
documents or logs linking the study codes with the study participant on site will be kept 
locked/securely stored separately from the study files and the medical records. No identifying 
information will be disclosed in reports, publications or presentations. 
Information That Meets Reporting Requirements 
The consent form will specifically state the types of information that are required for reporting and 
that the information will be reported as required. These include suspected or known sexual or 
physical abuse of a child or elders, or threatened violence to self and/or others. 
Participant Protection 
The site’s study Medical Clinician or other designated and qualified individual will evaluate all 
pertinent screening and eligibility assessments prior to participant randomization to ensure that 
the participant is eligible and safe to enter the study. This will further be confirmed by a physician 
(MD or DO) who serves in the Site PI or Medical Clinician study role in order to proceed formally 
to randomization. AEs and concomitant medications will be assessed and documented at each 
study visit. Individuals who experience an AE that compromises safe participation in a study 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. 
 
 


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Pregnancy 
Participants may not be currently pregnant, breastfeeding, or planning on conception in order to 
be included in the study. In order to support this exclusion criterion, urine pregnancy tests will be 
completed to confirm a negative result before randomization and at each study visit before 
administration of the next study medication injection. A positive pregnancy test post-
randomization will result in the cessation of study medication and, if necessary, referral to 
appropriate obstetric care. The site staff will follow the participant until an outcome of the 
pregnancy is known and reported. 
Study Specific Risks 
There is a risk to untreated MUD, especially in the setting of opioid co-use, particularly ongoing 
risks for opioid overdose which will be reduced due to the partial agonist properties of BUP. 
Naloxone overdose reversal kits will be provided to participants in both conditions with instructions 
to participants and their friends/family members on their use in the setting of overdose in order to 
address opioid overdose risks. There are serious risks for overdose and death should BUP-Inj be 
injected intravenously. A chain of custody will be maintained and documented detailing transfer 
from the manufacturer to the study pharmacy to the study staff who will administer the BUP-Inj 
product to participants assigned to the BUP-Inj condition. No take home injectable medications 
will be provided – all study products will be prepared and administered to study participants at the 
research clinic. To document safety and drug accountability, the Risk Evaluation and Mitigation 
Strategy (REMS) procedures will be followed. 
There are expected adverse events to the BUP-Inj medication. Medication-related adverse events 
that occur in more than 5% of subjects when using BUP-Inj include constipation, headache, 
nausea, injection site pruritus, vomiting, increased hepatic enzymes, fatigue, and injection site 
pain. These are minor, will be treated with ancillary medications, and tolerable in comparison to 
protection from opioid overdose and potential for treating MUD32. Concerns for hepatic impairment 
is managed through exclusion criteria justified by LFTs to assess liver function during screening. 
BUP-Inj medication is habit forming. The risks to PBO-Inj are mild, including injection site 
reactions and tolerable withdrawal symptoms. To avoid risks for iatrogenic illness, all participants 
must meet criteria for moderate to severe MUD and mild OUD or demonstrate opioid misuse. 
Throughout the study, management of complaints of opioid withdrawal symptoms for all 
participants will include provision of over-the-counter medications for head and body aches (e.g., 
ibuprofen), insomnia (e.g., diphenhydramine), diarrhea (e.g., loperamide) and stomach upset 
(e.g., bismuth subsalicylate) and ongoing opioid use will be monitored to ensure that any 
escalation of opioid use that suggests moderate or greater OUD is evaluated by the Medical 
Clinician. 
Overdose Risks: Death or serious harm can happen if you take benzodiazepines, sleeping pills, 
tranquilizers, muscle relaxants, sedatives, or if you drink alcohol in excess. For safety, participants 
with excess use of other substances deemed unsafe by the Medical Clinician will not be allowed 
to participate. Substance use will also be recorded and monitored at each visit throughout the 
study using TLFB and Prior and Concomitant Medications (PCM) forms, which will be used to 
monitor safety related to other substance use.  


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24.3 DATA MANAGEMENT PROCEDURES 
This protocol will use a centralized Data and Statistics Center (DSC). Advantage eClinical, a web-
based distributed data entry system, will be implemented. This electronic data capture system will 
be developed to ensure that guidelines and regulations surrounding the use of computerized 
systems in clinical trials are upheld. 
24.3.1 
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 final Case Report Forms (CRFs) and electronic Case 
Report Forms (eCRFs for the collection of all data required by the study, 3) develop data 
dictionaries for each eCRF that will comprehensively define each data element, 4) prepare 
instructions for the use of Advantage eClinical and for the completion of CRFs/eCRFs, 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 the final 
study database lock. 
24.3.2 
Data Collection and Entry 
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical, or will be collected via direct entry into the eCRF. In the event that 
Advantage eClinical is not available, the DSC will provide the sites with CRF paper source 
documents and completion instructions. Data entry into Advantage eClinical should be completed 
in accordance with the instructions provided during protocol-specific training and guidelines 
established by the DSC. Data entry into the eCRFs is performed by authorized individuals. 
Selected source documents and eCRFs may also require the investigator’s signature (wet or 
electronic). In some situations, data collected on source documents will not be entered into 
Advantage eClinical, but when it is entered, it will follow the guidelines stated above.  
The Principal Investigator at the site is responsible for maintaining accurate, complete and up-to-
date research records. In addition, the Principal Investigator is responsible for ensuring the timely 
completion of eCRFs for each research participant. 
24.3.3 
Data Monitoring, Cleaning and Editing 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and missing forms are available to sites at all times in Advantage eClinical. 
These reports will be monitored regularly by the DSC. In addition, the DSC will identify 
inconsistencies within eCRFs and between eCRFs and post queries in Advantage eClinical on a 
scheduled basis. Sites will resolve data queries by entering all corrections and changes directly 
into Advantage eClinical or verifying the data are correct as is. 
The CCC will conduct regular monitoring visits, during which audits comparing source documents 
to the data entered on the eCRF will be performed. Any discrepancies identified between the 
source document and the eCRF will be corrected by the site. 
Trial progress and data status reports, which provide information on items such as recruitment, 
availability of primary outcome, treatment exposure, attendance at long term follow-up visits, 


NIDA CTN-0110 Protocol 
Version 8.0 
MURB 
November 01, 2023 
 
STU2021-0118, Trivedi, FormA3-Protocol_v7.0_to_v8.0_RLSO_01Nov2023, Mod_17, 11-08-23 (2) (1)                                    RESTRICTED 
101 
regulatory status, and data quality, will be generated daily and posted to a secure website. These 
reports are available to the site staff, local Node staff, the Lead Investigators, the coordinating 
centers, and NIDA CCTN, to monitor each site’s progress on the study. 
24.3.4 
Database Lock and Transfer 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DSC. Individual participants and their research 
data will be identified by a unique study identification number; further, some identifiable data may 
be collected in eClinical. The study data entry and study management systems used by clinical 
sites and by DSC staff will be secured and password protected.  
At the conclusion of data collection for the study, the DSC will perform final data cleaning activities 
and will “lock” the study database from further modification. The final raw analysis datasets will 
be transferred to the Lead Investigator, Sponsor or designee and to NIDA upon request. De-
identified versions of these datasets will also be provided to the NIDA CCTN-designated party for 
storage and archiving. These datasets will be posted on the NIDA Data Share website. 
Reference: http://grants.nih.gov/grants/guide/notice-files/not98-084.html 

ICF_001.pdf: 
 
 
 
 
 
 
NCT05283304 
 
INFORMED CONSENT FORM 
 
Title: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of 
monthly injectable buprenorphine for methamphetamine use disorder (MURB) 
IRB# STU2021-0118 
Date: March 1, 2023 
 


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 1 of 19 
Consent to be part of a Research Study 
To be conducted at  
The University of Texas Southwestern Medical Center 
University of California- Los Angeles Vine Street Clinic  
Oklahoma State University-Center for Health Sciences 
CODA Inc.  
Alameda Health System- Highland Hospital Bridge Clinic 
University of Washington - Harborview Medical Center 
 
 
Key Information about this Study  
 
The purpose of this study is to test if extended-release injectable buprenorphine (BUP-Inj, 
SublocadeTM) compared to injectable placebo (PBO-Inj) reduces methamphetamine use over a 12-
week period in people with moderate to severe methamphetamine use disorder (MUD) who also use 
opioids. You will be randomly assigned to either take the active medication or a placebo. This 
medication is given to you as an injection in your stomach and releases medication slowly into your 
body over the course of a month. This medication is being tested because there is research that 
suggests this medication may help people stop or reduce their substance use and is approved by the 
U.S. Food & Drug Administration (FDA) for the treatment of opioid use disorder (OUD). There are no 
currently available FDA-approved medications to treat methamphetamine use disorder.  
 
As a participant in this study, you will attend approximately 28 visits over about 19 weeks (up to 3 
weeks in screening, 12 weeks getting study medication and a follow-up visit 4 weeks after you finish 
medication), and most visits will last about 1 to 4 hours, but some may be shorter or longer. You will 
be asked about your substance use and your mental and physical health, and complete 
questionnaires to tell us about your feelings and symptoms. You will need to provide urine samples, 
twice weekly, to test for drugs in your system. You will not be penalized for drugs detected in your 
samples at any time. Your participation in the study may help the study team see if BUP-Inj can help 
people stop or reduce their methamphetamine use. The study team will work with you to help make 
sure you get to all your visits. Extended-release injectable buprenorphine (BUP-Inj, SublocadeTM) is 
an investigational medication “Investigational” means that the medication has not yet been approved 
by the FDA for treating methamphetamine use disorder. 
 
All medications can cause side effects and people have different experiences with the type of side 
effects, the frequency, and the intensity. There are risks to taking part in this study. The most likely 
risk is that you may have side effects while on the study medication, such as constipation, nausea, 
headache, fatigue, or changes in liver enzymes. Side effects from these medications will usually go 
away after you stop taking them. In some cases, side effects can be long lasting. The study staff will 
ask you about side effects and can provide some medications that may help you manage them. The 
study staff will also do blood testing during the study to monitor your physical safety. If you are 
currently not dependent on opioids, you may become dependent on buprenorphine and other opioids 
by the end of the study. You may test positive for opioids, including failing drug tests, for up to one 
year. Withdrawal signs and symptoms may occur when the study medication is discontinued. Other 
risks to being in the study include loss of confidentiality. The study staff have put things in place to 
help keep those risks as low as possible.  
 
If you are interested in learning more about this study, please continue to read below. 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 2 of 19 
 
 
Information about this form 
 
You may be eligible to take part in this research study. This form gives you important information 
about the study. This is a multi-site study, meaning it will take place at several locations, so the 
informed consent form will include two parts. This form is Part 1 and includes information that applies 
to all study sites, like the purpose of the study and the research procedures to be done. 
 
Part 2 of the consent form will include information specific to the study site where you are being 
asked to enroll, such as the local contact information for the study team.  
 
Please take time to review this information carefully. You should talk to the study staff about the study 
and ask them any questions you have. You may also wish to talk to others (for example, your friends, 
family, or a doctor) about your participation in this study. If you decide to take part in the study, you 
will be asked to sign this form. Before you sign this form, be sure you understand what the study is 
about, including the risks and possible benefits to you. 
 
Please tell the study staff if you are taking part in another research study. 
 
Voluntary Participation - Taking part in this investigational study is completely voluntary. You do not 
have to participate if you don't want to. You do not have to participate in this study to get standard 
medical treatment. You may also leave the study at any time. If you leave the study before it is 
finished, there will be no penalty to you, and you will not lose any benefits to which you are entitled. 
Sometimes during a study, the Sponsor may learn new information about the study medication, the 
risks, or something else. Your study clinician/staff will tell you in a timely manner if there is any new 
information that might make you change your mind about being in the study. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status will not be 
affected in any way. 
 
General Information - Who is conducting this research? 
 
Study Sponsor and Funding Agency 
Madhukar Trivedi, MD, Department of Psychiatry at University of Texas Southwestern (UTSW) 
Medical Center, is the CTN-0110 study Sponsor. The Sponsor is the person/entity who takes 
responsibility for and initiates a clinical investigation. The National Institute on Drug Abuse (NIDA), a 
federal agency that promotes scientific research, is funding this study. NIDA is providing 
money to each research site so the researchers can conduct the study. 
 
Lead Investigator 
The Lead Investigator (LI) is the researcher directing this study; the LI is responsible for protecting the 
rights, safety, and welfare of participants in the study. The LI for this study is Steven Shoptaw, PhD, 
Department of Family Medicine at the University of California, Los Angeles (UCLA). His email 
address is sshoptaw@mednet.ucla.edu and his phone number is (310) 794-6206. 
 
Principal Investigator 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 3 of 19 
The Principal Investigator (PI) is the person directing this study at your local site; the PI is responsible 
for protecting your rights, safety, and welfare as a participant in this research study. Part 2 of the 
consent form will have more information regarding your site and site PI.  
 
Why is this study being done? 
 
The purpose of this study is to test if extended-release injectable buprenorphine (BUP-Inj) compared 
to injectable placebo (PBO-Inj) reduces methamphetamine use over a 12-week period in people with 
moderate to severe methamphetamine use disorder (MUD) who also use opioids. You will be 
randomly assigned (like the flip of a coin) to either receive the active medication or a placebo, given 
as an injection in your stomach that releases medication slowly into your body over the course of a 
month. This medication is being tested because it may help people stop or reduce their substance 
use and is approved by the FDA for the treatment of opioid use disorder.  
 
You are asked to participate in this research study because there are no FDA-approved medications 
currently available for MUD. The researchers are testing if BUP-Inj can help people seeking treatment 
for MUD. Instead of taking part in this study, you may choose to receive treatment with other 
medications or treatments available to you. The study clinician will explain to you the benefits and 
risks of other treatments and will answer any questions you may have.  
 
The researchers hope to learn whether BUP-Inj is better than PBO-Inj in helping to stop or reduce 
methamphetamine use over 12 weeks of study. 
 
Investigational Use of Drug  
 
This study involves the use of an investigational medication called extended-release injectable 
Buprenorphine (BUP-Inj), SublocadeTM, 300mg dose. “Investigational” means that the medication has 
not yet been approved by the FDA for treating methamphetamine use disorder. The investigational 
medication will be given in the form of an injection that goes into your stomach and sits under your 
skin (abdominal subcutaneous depot injection). The FDA has given us permission to conduct this 
study. This study is being performed under an Investigational New Drug application.  
 
This study will compare the effects, good and/or bad, of BUP-Inj in people with MUD who co-use 
opioids, to those of placebo, an injection without active medication. The safety of this medication in 
humans has been tested in prior research studies; however, some side effects may not yet be known.  
 
The other treatment is buprenorphine combined with naloxone that is placed under the tongue 
(sublingual). Sublingual buprenorphine plus naloxone (SuboxoneTM) has also been Food and Drug 
Administration (FDA)-approved for patients with opioid use disorder. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
Who is participating in this research? 
 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 4 of 19 
You are being asked to be a participant in this study because you met initial prescreening criteria 
indicating you possibly have MUD with co-use of opioids and are interested in reducing or stopping 
your methamphetamine use. 
 
How many people are expected to take part in this study?  
 
This study will enroll approximately 246 study participants across 4-8 sites. 
 
What will be done if you decide to be in the research? 
 
While you are taking part in this study, you will be asked to attend around 28 visits with the study 
staff. This study is divided into 3 phases: Screening, Medication, and Follow-up. The time of your 
participation in this study will be approximately 19 weeks. In rare cases, it may be necessary for you 
to return to the hospital/clinic more often for repeating blood tests or to assess side effects, if needed. 
 
Study Procedures Overview: 
 
The table below provides a summary of study procedures and how often you will engage in them. The 
list of procedures to be done at each individual visit is outlined below the table. 
 
Procedures 
Description 
Frequency 
Urine Samples 
To test for substances used (and common infectious 
diseases as needed) 
Every visit 
Timeline 
Followback 
To record your self-reported use of substances  
Every visit 
Self-Report 
Questionnaires 
To record important information about how you are doing 
in the study 
Every visit 
Pregnancy Tests  
If capable of becoming pregnant, to make sure you are not 
pregnant before receiving study medication 
As needed 
Blood Draw (2-4 
tablespoons 
depending on visit) 
To check red blood cell and white blood cell counts, liver 
function, general health, study medication levels, and test 
for Hepatitis C; some blood will be stored for later testing; 
and if you agree, some blood will be collected for genetic 
testing;  
Screening,  
Week 5, 9, 12 
HIV Test 
For those who have not tested positive for human 
immunodeficiency virus (HIV), the virus that causes AIDS, 
blood will be tested for HIV; counseling will be provided 
before and after you get test results 
Screening, Week 
12 
Vital Signs 
Blood pressure, heart rate and temperature 
Every visit 
Physical 
Examination 
Exam including only height, weight, and listening to your 
heart and lungs 
Screening,  
Week 12 
Clinician 
Interviews 
To check on physical and mental health, sexual risk-taking 
behaviors, substance use history, depressive symptoms, 
mood, and feelings 
Every Visit 
Computerized 
Cognitive Test 
Task that takes about 5-10 minutes on the computer; you 
will be given specific instructions prior to the task 
Screening 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 5 of 19 
Electrocardiogram 
(ECG) 
Sticky patches will be placed on your chest and connected 
to a machine that shows the electrical activity of your heart 
Screening, 
Week 12 
Administer Study 
Medication 
Sublingual buprenorphine over 2-3 days prior to receiving 3 
subcutaneous injections of study medication 
Week 1, 5, 9 
Cognitive 
Behavioral 
Therapy (CBT) 
Weekly 20-minute CBT session to support your participation 
and help you learn skills to reduce your substance use 
Weekly 
Review of Side 
Effects and 
Medications 
Review your current medications (and any changes 
throughout the study), and any side effects 
Every visit 
Injection Site 
Evaluation 
Check on injection site and document any findings for 
follow-up, if necessary 
Week 2, 5, 9, 12 
 
Screening Phase (Up to 3 weeks): 
  
After you sign this consent to participate, you will be asked to complete some exams, tests, and/or 
procedures to help decide if you can continue in the study. This process is called screening and may 
take up to three weeks. During screening, you will be asked to come to the clinic at least twice for 
around 5 hours total for all the needed screening assessments. You will be compensated for your 
time no matter the results. You may prefer to break up screening assessments into multiple days. 
However, we need all assessments to be completed within 21 days and will collect urine samples at 
2-3 different visits that must occur within a 10-day period, having at least 2 days between each 
sample collection. Thus, you may need to provide between 2 and 6 urine samples during screening.  
 
Screening Procedures: 
 
The following screening activities will be completed over a maximum of 3 weeks and will help us 
determine if you qualify to participate in the study. For more information regarding each procedure, 
please see the table above. 
 
• Clinician Interviews, Timeline Followback, and Self-report Questionnaires about your drug and 
alcohol use, lifestyle, involvement with criminal justice system, and physical and mental health 
• Physical Examination about your medical history, vital signs (heart rate, blood pressure, 
temperature) and an Electrocardiogram (ECG) to test your heart functioning 
• Urine Sample Collections for drug tests, common infectious diseases, and urine pregnancy 
test for women who can become pregnant 
• Blood Samples will be collected for lab testing (including HIV and Hepatitis C) and storage for 
later testing at the UTSW Repository 
• Review of Medications to make sure you are not taking any medications that would make your 
participation in this study dangerous 
• Computerized Cognitive Test to test your ability to win in a gambling experiment 
• Administrative Paperwork including Demographics Forms  
 
Medication Phase and Randomization: 
 
The results of the screening exams, tests, and/or procedures will be reviewed to determine whether 
you will be allowed to continue in the study. If the study staff confirm and document that you are 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 6 of 19 
eligible to continue, you will transition to the Medication Phase, complete some baseline 
assessments, and be randomized (see process described for group assignment below).  
 
 
Assignment to Treatment Groups: 
 
There are two treatment groups in the study. You will have a 50/50 chance of being put into each 
group (like flipping a coin):  
 
• Extended-release injectable buprenorphine (BUP-Inj)  
• Injectable placebo (PBO-Inj) which contains no active medication  
 
During this study, neither you nor the study staff will know which treatment group you are in. 
However, if needed for a medical emergency, the study clinician/staff can quickly find out which 
treatment group you are in. You will receive the study medication for approximately 12 weeks. 
Administrative paperwork including reviewing and updating the locator form will be done each week. 
 
On the day you are randomized (Week 1, Day 0), you will start what is called an “Induction” onto the 
study medication. Prior to receiving your first injection, you will receive a form of study medication that 
goes under your tongue (sublingual). This Induction will take two to three days, and the study 
clinicians will help make sure you tolerate the medication appropriately before transitioning you to 
BUP-Inj or PBO-Inj. Once you have completed the induction on sublingual medication, you will 
receive your first injection. During these visits, you will be asked to remain at the site for monitoring 
after you receive your dose. You may feel the effects of the medication or feel tired after receiving the 
medication. While you wait, you may complete some questionnaires and you might feel some 
discomfort while answering the questions. 
 
This first visit in the Medication Phase may take approximately 4 hours. The other visit during your 
first week may take approximately 2 hours.  
 
Week 1, First Visit (~4hrs): 
 
• Interviews such as Timeline Followback to assess your substance use 
• Urine sample to test for drugs 
• Vital signs to check your health 
• Pregnancy test (if you can become pregnant) 
• Review of ongoing or new medications 
• Self-report questionnaires about your mood, stress, pain, drug cravings, or withdrawal 
symptoms 
• Cognitive Behavioral Therapy to help support your participation in the study 
 
• Start study medication in Induction Phase (sublingual medication for 2-3 days) 
 
Starting Injectable Medication: 
 
Once the study clinician decides that you are tolerating the study medication and the Induction is 
successful, you will start the injectable medication. During this medication phase you will be expected 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 7 of 19 
to return to clinic once more in Week 1 for your first injection, then twice a week for the rest of the 
medication phase, for a total of approximately 24 visits over a 12-week period. The study medication 
should be the only treatment you receive for substance use disorders while in the study.  
 
Depending on which group you are assigned to, researchers will inject BUP-Inj or PBO-Inj under the 
skin over your stomach (abdomen). You may see or feel a small bump under your skin at the injection 
site for several weeks. Do not rub against or massage the injection site.  
 
Week 1, Second Visit (~2hrs): 
 
• Pregnancy test before you get an injection of study medication 
• Start injectable study medication and make sure you feel ok as you receive the medication 
• Self-report questionnaires  
• Interviews such as Timeline Followback to assess your substance use 
• Urine sample to test for drugs 
 
• Review of side effects and medications  
 
Week 2, 3, 4 Visits (~2hrs total each week): 
 
• Self-report questionnaires  
• Interviews such as Timeline Followback to assess your substance use 
• Vital signs to check your health  
• Urine sample to test for drugs 
• Injection site check to make sure everything went ok after getting the injection (Week 2) 
• Review of side effects and medications  
• Cognitive Behavioral Therapy to help support your participation in the study  
 
Week 5, 9, 12 Visits (~3-4hrs total each week): 
 
• Injectable study medication (projected for first visit of the week during Weeks 5 and 9)  
• Pregnancy test before you get injections of study medication and at the end of the medication 
phase 
• Blood draw to check your health (Week 12), how much study medication is in your system, test 
for HIV and Hepatitis C (Week 12), storage for later testing at the UTSW Repository (Week 
12), and, if you agree, for the NIDA genetic sample (Week 5). 
• Self-report questionnaires  
• Interviews such as Timeline Followback to assess your substance use 
• Urine Sample to test for drugs and common infectious diseases (Week 12) 
• Injection site check (projected for next visit after injection) 
• Review of side effects and medications  
• Cognitive Behavioral Therapy to help support your participation in the study  
• Vital signs to check your health  
• Physical exam and ECG to make sure you are well after taking the medication (Week 12)  
 
Week 6, 7, 8, 10, 11 Visits (~1-2hrs total each week): 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 8 of 19 
 
• Self-report questionnaires  
• Interviews such as Timeline Followback to assess your substance use 
• Vital signs to check your health  
• Urine Sample to test for drugs 
• Review of side effects and medications  
• Cognitive Behavioral Therapy to help support your participation in the study  
 
If you become incarcerated at any point during the study, you will no longer be given the study drug. 
The researchers may still arrange research visits and any needed assessments and procedures the 
institution will allow to be completed.  
 
Follow-Up Phase (Week 13-16): 
 
During the Follow-Up Phase, you will no longer be taking the study medication. The follow up visit will 
occur approximately four weeks after the end of the medication phase or if you stop the study early. 
This visit will take place at the clinic and will involve the following procedures:  
 
Follow-Up Visit Week 16 (~1.5hrs): 
 
• Self-report questionnaires  
• Interviews such as Timeline Followback to assess your substance use 
• Vital signs to check your health 
• Urine sample to test for drugs 
• Review of side effects and medications  
• Pregnancy test (if you can become pregnant) 
 
 
OPTIONAL GENETIC TESTING  
As part of the study, you have the option to decide whether research can be done with your blood 
samples that involves genetic testing. The genetic testing would be done from blood stored at the 
UTSW Repository and at the NIDA Genetics Consortium Repository (a facility where genetic material 
can be stored safely) to see whether your genetics relates to how you do in treatment and in this 
research study.  If you agree, study staff will collect additional tubes of blood at one of your scheduled 
blood draws. You will not have another needle stick for the collection of this blood. This genetic 
testing is only for research. It is not clinical genetic testing, which means the results will not be 
available to you and won't tell you anything about your health. If you would like such clinical genetic 
testing, we can refer you to a service that does it.  
 
Your samples will be de-identified, which means that your name or other identifying information will 
not be connected to it, only a code number. Your DNA may be used not only for this study, but for 
other research studies in the future. 
 
Below is a list of terms and abbreviations specifically related to genetics studies: 
 
DNA: DNA is the material inside cells that carries genetic information. 
 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 9 of 19 
Genetics: Genetics is a term for the study of heredity, or how certain traits are passed down 
from parents to their biological children 
 
Genes: Genes are the fundamental units of heredity and are responsible for how certain traits 
are passed down from parents to their biological children. Genes are composed of DNA and 
are found in all cells of the body. 
 
Genetic Material: Genetic material refers to DNA, blood components, and cells that are 
extracted from your blood and used for genetic research. 
 
Repository: A repository is a facility where genetic material such as DNA, blood components, 
and cells can be deposited for storage or safekeeping. 
 
Traits: Traits are characteristics that you may inherit from your family members. Traits may be 
passed down from generation to generation. Examples of traits are height, eye color, and 
susceptibility to certain diseases. 
 
Your blood contains DNA. DNA makes up the genes that serve as the "instruction book" for the cells 
in our bodies. By studying genes, researchers can learn more about diseases such as cancer. There 
are many different types of genetic tests. The testing on your blood samples might include genetic 
testing called whole genome sequencing (WGS). WGS looks at all the known genes in your cells. 
This type of testing can provide useful information to researchers. It can also present risks if the test 
results became known to others, for example you could have problems with family members or insurance 
companies. There is also a risk that these test results could be combined with other genetic information to 
identify you. 
 
Will my samples be stored for future use? 
Samples stored at UTSW Repository will be stored until the end of the study. Samples stored at the 
NIDA Genetics Consortium Repository will be stored for an unlimited amount of time, Genetic 
material (DNA, blood components and cells) will remain frozen at the central repositories and will be 
tested in future genetics studies. From the frozen cells, researchers may create a living tissue sample 
called a “cell line.” This cell line provides an unlimited supply of genetic material for future studies; 
therefore, you will not have to provide any additional blood samples. Future research on your sample 
may include WGS. The researchers will keep your samples until they are all gone, become unusable, 
or until the researchers or Sponsor decide to discard the samples. If your samples remain stored 
beyond your lifetime, your samples will be used as described in this document. 
 
Will the results of research tests be reported to me? 
Knowledge of how genes and other factors affect health and disease is gathered by studying groups 
of people. This study and other genetics studies are not meant to test your individual medical status. 
Therefore, neither you nor your medical provider will be given the results of the research on your 
genetic material. However, the researchers will share what they learn with other health professionals 
and scientists through research publications. If you have questions about whether any genetic tests 
would be useful to you, please ask your medical provider or health professional. 
 
Will my genetic information be kept confidential? 
To protect your privacy, your blood samples will have only a code number that is different from your 
study code number to identify it. Researchers at this site and the study’s Data and Statistical Center 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 10 of 19 
(DSC) and Clinical Coordinating Center (CCC) will have the code numbers that connect your genetic 
information to your identifying information. The DSC and CCC are run by Emmes. The genetics 
researchers will not have access to the link between your identifying information and your code 
number. At no time will your name or address or any other identifying information be released for 
research purposes. We are doing everything possible to prevent anyone outside the study from 
learning your private genetic information. 
 
End of Optional Genetic Testing Section 
 
Retention of Blood Samples for Future Research  
 
Some or all your blood samples may also be kept and used for up to 15 years. This will allow for 
scientific research to be done in the future as new discoveries are made. The Sponsor will ensure 
that your samples are kept secure. You can withdraw your consent for your samples to be used for 
future research. In this case your samples will be destroyed only after they are no longer needed for 
the main study. You will need to tell the study staff that you are withdrawing your consent for your 
samples to be used for future research. This will not affect your access to the care, medicine, and 
equipment you would otherwise be getting. This can be done at any time and for any reason. 
 
To protect your privacy, your blood samples will be labeled with the study number and your 
participant number. No personal identifiers are used (such as name, initials, social security number). 
The scientists doing the research will not know your identity.  
 
Your blood samples may also be shared with research partners for scientific research purposes. Your 
blood samples will not be sold, loaned, or given to any other independent groups for their own use. 
Research partners working with the Sponsor are not allowed to share blood samples with anyone 
who is not authorized by the Sponsor. The Sponsor will manage what is done with your blood 
samples.  
 
You will not be paid for any use of your blood samples, results, or inventions made from research on 
them. You are providing your blood samples, for use by the Sponsor. The Sponsor (and research 
partners, where applicable), will own the use of results, treatments, or inventions that can be made 
from this research. 
 
What do I have to do while in the study?  
 
While you are in the study you must:  
• Give correct information about your health history, substance use, and health conditions  
• Tell the study clinician/staff about any changes to your medicines or drugs you may take 
• Tell the study clinician/staff about any health problems you have during the study  
• Come to all study visit appointments  
• Complete all required study questionnaires  
• Comply with study medication administration per the study schedule  
• Not take part in any other medical research studies  
• Not take any other medications or remedies unless the study clinician/staff has approved them 
beforehand, including prescription and over-the-counter drugs such as vitamins and herbs 
 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 11 of 19 
Could your participation end early?  
 
There are several reasons why study staff may need to end your participation in the study, including:  
• The researcher believes that it is not in your best interest to stay in the study 
• You become ineligible to participate 
• Your health condition changes, and you need treatment not allowed while you are in the study 
• You do not follow instructions from the study staff 
• The study is stopped 
 
Can I change my mind about participating?  
 
Yes, you can agree to be in the study now and change your mind at any time and for any reason. You 
can withdraw from the study without any penalty or loss of benefits from your regular care with your 
doctors. You can talk to the study clinician and study staff first before making this decision.  
 
Please be aware that if you become incarcerated while participating in this study, your decision to 
participate in this study will not affect your sentence, parole, or probation. Your participation cannot 
be used by any prisoner authorities, in any manner, to affect your conditions at the institution where 
you are held. If you stop participating, your sentence, parole, or probation will not be affected. 
 
What happens if I stop the study early?  
 
If you stop the study early, the study clinician/staff will ask that you come for a final follow-up visit to 
have final evaluations. This is to make sure that you are in good health. This information will be 
added to your study record. 
 
If you stop the study early and withdraw your consent at any time, you agree not to limit the use of 
your study information collected through your last visit. The Sponsor will not collect any new 
information from you for any parts of the study from which you have withdrawn. Your collected blood 
samples will continue to be analyzed as described in this form unless you specifically ask for your 
blood samples to be destroyed. This is to protect the quality of the study. 
 
Can I take the study medication after the study is over?  
 
After the study is over, the Sponsor will not continue to provide you with the study medication. Your 
study clinician and study staff will discuss your future medical care options with you.  
 
What other treatments are there outside of this study?  
 
Instead of taking part in this study, you may choose other alternative treatments.  
 
There are no FDA-approved medications for methamphetamine use disorder, but other non-drug 
treatments are available, such as behavioral therapy.  
 
There are medications that are available to treat opioid use disorder. 
 
The study clinician will discuss with you and inform you of alternative treatment options.  
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 12 of 19 
 
What about my current medications?  
 
You must tell the study clinician/staff about all prescription and over-the-counter medications you 
take, including vitamins and herbs. Some medications are not allowed during the study. The study 
clinician will tell you if this applies to you. No medications will be stopped solely for the purpose of 
making you able to enroll in this study. You should not stop taking any of your current medications 
unless your doctor tells you to do so.  
 
 
You must also tell the study clinician all treatments (including psychotherapy) you are using for your 
methamphetamine use. You should also disclose any medical conditions you suffer from such as high 
blood pressure, diabetes, high cholesterol, heart disease etc. Also, if anything changes with your 
medical history you should inform the study staff. 
 
Clinically Relevant Results: 
 
It is possible that tests done as part of this study will give information about you that was previously 
unknown, such as disease status or risk. You will be told about any clinically relevant test results. 
Clinically relevant means that you may be at risk for a serious illness known at the time of testing to 
be treatable and it can be confirmed. In that case, we will attempt to notify you using the contact 
information you have provided. There may also be test results that we have to tell you and other 
agencies about as required by law. You may decide now that you do not want to be notified about 
these test results; you can change your mind about this decision at any time by talking to the study 
staff.  
 
Please initial below as to whether or not you would like to be notified of these clinically relevant test 
results.  
 
_____(initial here) Yes, please notify me of any clinically relevant test results found from this 
research. 
 
_____(initial here) No, please do not notify me of any clinically relevant test results found from this 
research, except as required by state or local laws or site policies. 
 
What are the risks of participation in the research? 
 
Risks from the Investigational Medication 
All medications can cause side effects; the extent to which this occurs differs. There are risks to 
taking part in this study. You may have side effects while on the study medications. Side effects from 
this treatment will usually go away soon after you stop taking the medication; however, in some 
cases, side effects can be long lasting.  
 
Everyone taking part in the study will be watched carefully for any side effects and receive blood 
testing to make sure that the medication does not cause any damage. However, the clinicians don’t 
know all the side effects that may happen. You should talk to your study clinician about any side 
effects or other problems that you have while taking part in the study.   
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 13 of 19 
 
Side effects can range from mild to serious. Serious side effects are those that may require 
hospitalization, are life threatening or fatal (could cause death). The frequency that people feel a 
certain side effect can range from many (likely), few (less likely) or only one or two (rarely).   
 
Injection site reactions have been the most common side effects associated with BUP-Inj. Other risks 
and side effects related to BUP-Inj include those that are: 
 
 
 
Likely, some may be serious 
In 100 people, approximately 21 – 25 people may have: 
• Gastrointestinal distress, like nausea, vomiting, or constipation 
• Fatigue 
• Injection site reactions, including pain, discomfort, erythema, or itching 
 
 
Less Likely, some may be serious 
In 100 people, approximately 4 – 20 people may have: 
• Changes in liver enzymes 
• Headache, sedation, tiredness or dizziness 
 
Rare and serious 
In 100 people, approximately 1 or less may have: 
• Severe injection site itching and irritation 
• Adrenal insufficiency (dizziness, low blood pressure) 
• Severe allergic reaction (anaphylaxis) 
• Liver injury (jaundice, where the skin or white part of your eyes turns yellow; dark urine; 
light stool color; decreased appetite; stomach/abdomen pain; confusion; or nausea 
 
BUP-Inj may block the effects of opioid pain medications. If you need medications for pain relief while 
on this study, it is important that you tell your doctor that you are in a study and may be on BUP-Inj. 
BUP-Inj will not affect response to non-opioid pain medications such as aspirin or acetaminophen. 
 
If you receive BUP-Inj, you will be physically dependent on BUP at the end of this study. If you 
have side effects, we can stop giving you injections but it will take a while to wear off. You may test 
positive for BUP for a year or more. 
 
The medication used in the Induction, SuboxoneTM (sublingual BUP, sublingual buprenorphine), 
contains the same medication in the BUP-Inj, so the risk and side effects are very similar. 
SuboxoneTM also contains Naloxone which can also cause some of the same side effects, such as 
gastrointestinal distress, nausea, and vomiting. Dental problems, including tooth decay, cavities, oral 
infections, and loss of teeth, can occur with the use of transmucosal buprenorphine (e.g., 
buprenorphine tablets and films that dissolve in the mouth, such as sublingual buprenorphine) and 
can be serious. These dental problems have been reported even in patients with no history of dental 
issues. Please discuss any dental concerns with your study team.  
 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 14 of 19 
It is important that you take the sublingual SuboxoneTM exactly as instructed by the study clinician and 
make sure that you keep it in a safe place where you are the only person who can access it. Many of 
these side effects can be managed with other medications that can be provided by study staff.  
 
There is a risk of withdrawal from sublingual BUP or BUP-Inj if you stop the medication at any point. 
There is also a risk of withdrawal if you are dependent on full agonist opioids, because BUP is only a 
partial agonist. If you feel any agitation, muscle aches, insomnia, nausea, or abdominal cramping, 
those symptoms will be treated with appropriate medications. Please contact study staff if you feel 
any discomfort.  
 
There are also some dangerous risks for interactions of sublingual BUP or BUP-Inj with some 
medications that you may take. Life-threatening respiratory depression (breathing difficulty), 
death, or serious harm can happen due to overdose or toxicity if you take anxiety medicines 
or benzodiazepines, sleeping pills, tranquilizers, muscle relaxants, sedatives, antidepressants, 
or antihistamines, or drink alcohol during treatment with SublocadeTM (BUP-Inj) or SuboxoneTM  
(sublingual BUP). It is very important to not use these substances while in the study and to tell the 
study staff and study clinicians all the medications and drugs that you take for any reason.  
 
BUP can be abused in a manner like other opioids so there are risks for becoming dependent on 
BUP; however, the risks for untreated methamphetamine use or opioid misuse are believed to be far 
more serious. You will be carefully monitored to make sure that your dependence on opioids does not 
become more of a problem. If you become more dependent on opioids, you will be referred to clinical 
care. For more information about risks and side effects, ask one of the study staff. 
 
Both BUP-Inj and PBO-Inj injections will be performed using safe and sterile techniques but may 
cause pain, tenderness, hardening, damage of body tissues, swelling, redness, bruising, itching, or 
infection at the injection site. The injection site will be monitored after each of the injections. You 
should report any injection site reactions, such as pain, redness, or swelling, immediately to study 
staff.  The medication will be injected into the fat layer underneath the skin. If the medication is 
injected by mistake into a muscle or into the middle layer of the skin, there may be a more serious 
injection site reaction. If this happens, you will receive the appropriate treatment and care. We will 
treat any pain you feel with a non-opioid analgesic whenever possible. If treatment of your pain 
requires opioid therapy, we will monitor you closely. 
 
Throughout this study, you will be carefully monitored for side effects. Please contact your study 
clinician as soon as you feel any side effects at home. There may be risks with the use of this new 
medication that are not yet known. Sometimes during a study, the Sponsor may learn new facts about 
the study medication. It is possible that this information might make you change your mind about 
being in the study. If new information is discovered, study staff will tell you about it right away.  
 
Genetic Informational Risks  
 
This research study includes optional genetic testing. Human blood contains genes that determine 
many of a person’s physical characteristics, such as the color of eyes and hair. In some cases, 
genetic testing of blood can be used to indicate a risk for the development of certain 
diseases. Genetic information is unique to each individual and there is a risk that these test results 
could be combined with other genetic information to identify you. It could also potentially be used to 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 15 of 19 
discover possible changes in a person’s future health status or life expectancy, or that of his/her 
children and family members.  
 
Releasing this information to you could cause psychological distress, anxiety, or family problems.  
Releasing this information to others, like including it in your medical record, could lead to 
discrimination, or make it hard to get or keep disability, long-term care, or life insurance. These risks 
would occur if your information were mistakenly released. The measures being taken to protect your 
privacy are discussed below and make this possibility unlikely. 
 
Even though the results of genetic testing may not be linked to you, it is possible that people of your 
ethnic background may be found to be at more risk for certain diseases based on future genetic 
research and this information might harm you in the future as a member of the group. Also, there may 
be unknown risks of genetic testing in the future. 
 
As technology advances, there may be new ways to access and trace information back to you (or 
your close biological relatives) that we cannot predict. The Sponsor will use reasonable measures 
within its control to safeguard your information. Even though no one would be able to know just from 
looking at your genetic data that the information belongs to you, there is a potential risk to you and to 
your family. This is because your genetic information is unique to you. Therefore, there is a chance 
that someone could trace the information back to you or your close biological relatives. This could 
happen if you (or your biological relatives) had DNA testing done another time that could be matched 
against your results from this study. The risk of this happening is small but could grow in the future.  
 
Risk of Psychological Stress  
 
Some of the questions we will ask you may make you feel uncomfortable. You may refuse to answer 
any of the questions, take a break, or stop your participation in this study at any time.  
 
You may feel anxious or sad after receiving the results from your HIV test.  A counselor will be 
available if you want to talk about how you are feeling. 
 
Risk of blood draw  
  
There are minor risks and discomforts associated with blood draw. The risks of a blood draw include 
pain, bruising, fainting, and in rare cases, infection.  
 
Risk of loss of confidentiality  
 
Any time information is collected; there is a potential risk for loss of confidentiality. Every effort will be 
made to keep your information confidential; however, this cannot be guaranteed.  
 
Are there Risks related to withdrawing from the study?  
 
If you decide to withdraw from this treatment early, please discuss with the local site study clinician. 
The study clinician may ask you to complete treatment withdrawal procedures at a final treatment 
visit. Because BUP-Inj stays in your system for over a month after you receive your injection, there 
may be a risk to you if you do not understand how the medication can affect you after receiving it. 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 16 of 19 
However, you may choose to not complete the final withdrawal procedures. You will need to formally 
communicate your wishes to withdraw to your Site Principal Investigator. 
 
Reproductive Risks  
 
 
Concerns for sexually active men and women:  
 
You should not become pregnant while taking part in this study because we do not know how the 
study drugs/procedures could affect a fetus, if a woman becomes pregnant during the study. It is 
important that you talk to your study clinician about avoiding pregnancy during this study. If you think 
you might have become pregnant while you are in this study, you must tell one of the study clinicians 
right away so that you can stop receiving study medication, and to discuss management of the 
pregnancy and the possibility of stopping the study. There is some evidence that both female and 
male fertility may be reduced by taking opioid medications like the study medication. 
 
Birth control and pregnancy during the study  
 
If you are a woman able to get pregnant:  
 
• Taking part in the study might harm your unborn child or breastfed baby 
• You cannot take part in this study if you are pregnant or breastfeeding a child  
• Women must agree to use highly effective methods of birth control throughout the study and 
for 4 months after the last injection 
 
Examples of highly effective methods of birth control that can be used while in this study include:  
 
• Oral contraceptives (like “the pill”) in combination with barrier method  
• Contraceptive injections or patches in combination with barrier method  
• Intrauterine devices in combination with barrier method  
• Male partner sterilization 
• Abstinence (avoiding sexual intercourse) 
 
The type of birth control you use must be discussed with the study clinician before you begin the 
study. The study clinician must approve the method you use before you can enter the study.  
 
If you get pregnant during the study, you must tell the study clinician immediately. You will have to 
stop taking the study medication. Your child might experience Neonatal Opioid Withdrawal Syndrome 
(NOWS), which can be treated. The study clinician will advise you about your medical care and will 
ask you to allow him/her to collect information about your pregnancy and the health of your baby. The 
study clinician may share this information with the Sponsor and the Institutional Review Board/Ethics 
Committee that monitors the trial.  
 
Risks to babies who are being breastfed:  
 
Women who are breastfeeding cannot take part in this study because we know that some of the study 
medication can enter the breast milk and can affect the nursing child. 
 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 17 of 19 
Are there risks if you also participate in research or other investigational research studies? 
 
Being in more than one investigational research study at the same time, may increase the risk to you. 
It may also affect the results of the studies. You should not take part in more than one investigational 
study without approval from the study staff.  
 
For more information about risks and side effects, ask one of the study clinicians or study staff. 
 
How could you or others benefit from your taking part in this study? 
 
Taking part in this study may help you stop or reduce your drug use and/or improve the symptoms 
associated with substance use disorders. If you receive BUP-Inj, you may be protected from having 
effects from an overdose (from opioids or fentanyl) while in the study. However, there is no guarantee 
or promise that you will receive any benefit from this study. During the study, your condition may stay 
the same or get worse. Your participation may help future patients have other treatments for stopping 
or reducing methamphetamine use.  
 
What other options are there to participation in this study? 
 
Instead of taking part in this study, you may choose other alternative treatments. The study clinician 
will discuss and inform you of available alternative treatment options.  
 
Will there be any payments for participation? 
 
Please see your Part 2 of the consent form for details regarding compensation and your method of 
payment. 
 
How will your records be kept confidential? 
 
Information we learn about you in this study will be handled in a confidential manner, within the limits 
of the law. If we publish the results of the study in a scientific journal or book, we will not identify you. 
The Institutional Review Board and other groups that have the responsibility of monitoring research 
may want to see study records which identify you as a participant in this study.   
 
Certificate of Confidentiality: 
 
To help us further protect your information, this research is covered under a Certificate of 
Confidentiality from the U.S. Department of Health and Human Services (HHS). This Certificate adds 
protections for research information that identifies you and will help study staff protect your privacy.  
 
With this Certificate of Confidentiality, the study staff cannot be forced to disclose information that 
may identify you in any judicial, administrative, legislative, or other proceeding, whether at the federal, 
state, or local level. There are situations, however, where we will voluntarily disclose information 
consistent with state or other laws, such as: 
• to HHS for audit or program evaluation purposes; 
• information regarding test results for certain communicable diseases to the State’s 
Department of Health Services, including, but not limited to HIV and Hepatitis; 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 18 of 19 
• if you pose imminent physical harm to yourself or others; 
• if you pose immediate mental or emotional injury to yourself; 
• if the study staff learn that a child has been, or may be, abused or neglected; or 
• if the study staff learn that an elderly or disabled person has been, or is being, abused, 
neglected or exploited. 
 
The Certificate of Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about your involvement in this research study. In addition, the study staff may 
not use the Certificate to withhold information about your participation in this research study if you 
have provided written consent to anyone allowing the study staff to release such information 
(including your employer or an insurance company). This means that you or your family must also 
actively protect your privacy. 
 
A Certificate of Confidentiality does not represent an endorsement of this research project by the 
Department of Health & Human Services or any other Federal government agency. 
 
How will my information and/or samples be used? 
 
With appropriate permissions, your blood samples and collected information may also be shared with 
other researchers here, around the world, and with companies. 
 
By agreeing to participate in this study, your information or blood samples could be used for future 
research studies or sent to other investigators for future research studies without additional consent 
from you. The information that identifies you will first be removed from your information or blood 
samples. If you do not want your information or blood samples to be used for future research studies 
without your consent, you should not participate in this study. 
 
De-identified data (which cannot be used to identify you) from this study will be available to 
researchers on another website, https://datashare.nida.nih.gov/ after the study is complete and the 
data analyzed. The primary outcome(s) publication for the full study will also be included along with 
study underlying primary data in the data share repository, and it will also be deposited in PubMed 
Central http://www.pubmedcentral.nih.gov/. These websites will not include information that can 
identify you. You can view these websites at any time. 
 
Will you be contacted for future studies? 
 
You may be contacted for future studies if the researchers think you may qualify, but you are under 
no obligation to participate in a new study.  Participation in any additional study is entirely voluntary 
and refusing to volunteer for an additional study will not affect your participation in the primary study.  
 
Who can you contact if you have questions, concerns, comments or complaints? 
 
Please see Part 2 of the consent form for contact information for your study site. If you have 
questions now, feel free to ask your study team. If you have additional questions, concerns, 
comments or complaints later or you wish to report a problem which may be related to this study 
please contact the individuals listed in Part 2 of the consent form.  
 
IRB Approved Date: 3/1/2023


Title of Study: NIDA CTN Protocol 0110 Randomized, double-blind, placebo-controlled trial of monthly 
injectable buprenorphine for methamphetamine use disorder  
 
STU2021-0118, Trivedi, FormE-Consent-Part1-AllSitesExcept-CASites, Mod_7, 03-01-23 
 
 
 
Consent Document (Part 1 of 2) v4.0, 02/14/2023 
 
 
Page 19 of 19 
The University of Texas Southwestern Medical Center Human Research Protection Program (HRPP) 
oversees research on human subjects. HRPP and Institutional Review Board (IRB) representatives 
will answer any questions about your rights as a research subject, and take any concerns, comments, 
or complaints you may wish to offer. You can contact the HRPP by calling the office at 214-648-3060  
or e-mail at HRPP@UTSouthwestern.edu located at 5323 Harry Hines Boulevard, Dallas, Texas, 
75390-8843. 
 
 
Concise Summary  
This is a research study to find out if a drug called SublocadeTM is safe and effective for treatment of 
MUD for people who also use opioids. 
SublocadeTM is given via an injection in your stomach at the clinic. You will have tests, exams, and 
procedures while in the study. Each clinic visit will last 1-4 hours but some may be shorter or longer. 
Study medication will be given during Weeks 1, 5, and 9. After each injection, you will be evaluated, 
and you may continue to receive study medication if you have had no bad side effects. 
There are risks to this study medication that are described in this document.  
If you are interested in learning more about this study, please continue reading Part 2. 
IRB Approved Date: 3/1/2023