Repeated-dose Behavioral Intervention to Reduce Opioid Overdose: A Two-Site Randomized-Controlled Efficacy Trial (REBOOT)
Phase: NA
Conditions: Opioid-Related Disorders, Drug Overdose
Sponsor: San Francisco Department of Public Health

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SAN FRANCISCO DEPARTMENT OF PUBLIC HEALTH
STUDY PROTOCOL
Study Title:
Repeated-dose behavioral intervention to reduce opioid 
overdose: A two-site randomized-controlled efficacy trial
Sponsor:
National Institute on Drug Abuse at the National Institutes of 
Health
IND No.:
N/A
Indication:
At-risk for opioid overdose
Principal Investigator:
Phillip O. Coffin, MD MIA
Director of Substance Use Research
San Francisco Department of Public Health
25 Van Ness Ave, Suite 500
San Francisco, CA 94102
Telephone:
415-437-6282
E-mail: Phillip.coffin@sfdph.org
Regulatory Affairs:
This study is overseen by the following IRB:
UCSF Committee on Human Research  
3333 California Street, Suite 315
University of California, San Francisco, CA 94118
Phone: 415-476-1814
Fax: 415-502-1347
Email: irb@ucsf.edu
 

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TABLE OF CONTENTS
STUDY PROTOCOL .....................................................................................................................1
TABLE OF CONTENTS................................................................................................................2
PROTOCOL SYNOPSIS................................................................................................................4
1.
INTRODUCTION................................................................................................................11
1.1.
Background..............................................................................................................11
1.2.
Overall Risk/Benefit Assessment ............................................................................11
1.3.
Compliance..............................................................................................................12
2.
OBJECTIVES.......................................................................................................................13
3.
STUDY DESIGN .................................................................................................................14
3.1.
Adaptation................................................................................................................14
3.2.
Study Treatment and Duration of Treatment...........................................................14
3.3.
Treatment Discontinuation Criteria .........................................................................15
4.
SUBJECT POPULATION ...................................................................................................16
4.1.
Number of Subjects and Subject Selection..............................................................16
4.2.
Inclusion Criteria .....................................................................................................16
4.3.
Exclusion Criteria ....................................................................................................16
5.
STUDY PROCEDURES......................................................................................................18
5.1.
Subject Enrollment and Treatment Assignment......................................................18
5.2.
Pretreatment Assessments .......................................................................................18
5.3.
Screening Visit.........................................................................................................18
5.3.1.
Enrollment Visit ......................................................................19
5.3.2.
Interim Contact........................................................................19
5.4.
Follow-up Visits (Month 4, 8, 12 and 16) ...............................................................20
5.5.
Validation Substudy Visit........................................................................................20
5.6.
Assessments.............................................................................................................20
5.6.1.
Labs .........................................................................................20
5.6.2.
Research Electronic Data Capture (REDCap).........................20
5.6.3.
Administrative data .................................................................21
5.6.4.
Data Management ...................................................................22
6.
ADVERSE EVENTS MANAGEMENT..............................................................................23
6.1.
Definition of Adverse Events and Serious Adverse Events ....................................23
6.2.
Management of SAEs and other study risks............................................................24
6.3.
Reporting of SAEs...................................................................................................24
7.
CHANGES TO STUDY PROTOCOL.................................................................................25
7.1.
Reporting of IRB actions and DSMB reports to NIDA...........................................25
7.2.
Report of changes or amendments to the protocol ..................................................25
7.3.
Trial stopping rules..................................................................................................25
7.4.
Disclosure of conflicts of interest............................................................................25
8.
STATISTICAL CONSIDERATIONS .................................................................................26
8.1.
Analysis Objectives .................................................................................................26
8.1.1.
Analysis Objectives.................................................................26
8.2.
Analysis Conventions..............................................................................................26
8.3.
Demographic Data and Baseline Characteristics.....................................................26
8.4.
Data Analysis...........................................................................................................26

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8.4.1.
Primary Analysis.....................................................................26
8.4.2.
Exploratory Analyses ..............................................................27
9.
RESPONSIBILITIES ...........................................................................................................29
9.1.
Investigator Responsibilities....................................................................................29
9.1.1.
Good Clinical Practice ............................................................29
9.1.2.
Institutional Review Board (IRB) Approval ...........................29
9.1.3.
Informed Consent....................................................................29
9.1.4.
Confidentiality.........................................................................30
9.1.5.
Study Files and Retention of Records.....................................30
9.1.6.
Case Report Forms (CRFs) .....................................................31
9.1.7.
Protocol Compliance...............................................................31
9.1.8.
Study Discontinuation.............................................................31
10.
APPENDICES......................................................................................................................32
10.1.
Appendix 1. Study Procedures Table ......................................................................33
10.2.
Appendix 2. REBOOT 2.0 Counseling Manual ......................................................34
10.3.
Appendix 3. Descriptions and Dates of Amendments.............................................57

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PROTOCOL SYNOPSIS
San Francisco Department of Public Health
25 Van Ness Ave, Suite 500
San Francisco CA 94102
Study Title:
Repeated-dose behavioral intervention to reduce opioid overdose: a 
two-site randomized-controlled efficacy trial 
IND Number:
N/A
Study Center(s) 
Planned:
2 sites in the United States: San Francisco Department of Public 
Health in San Francisco, CA and Boston Medical Center in Boston, 
MA.
Number of Subjects 
Planned:
At least 300 subjects (150 subjects at each site)
Target Population:
Adult naloxone recipients with moderate to severe opioid use disorder 
(OUD) who have overdosed
Duration of 
Treatment:
Subjects will be enrolled in trial for approximately 16 months
Objectives:
The primary objectives of this study are as follows:
1) To adapt REBOOT intervention to ensure relevance in a 
setting heavily affected by fentanyl using the ADAPT-ITT 
process.
2) To determine if REBOOT, compared to attention control, 
reduces during 16 months of follow-up
a.
the number of opioid overdose events, or 
b. the occurrence of any opioid overdose.
3) To determine if REBOOT, compared to attention control, 
increases 
a.
the number of days abstinent from opioid use, or
b. days in substance use treatment.
The exploratory objectives of this study are as follows:
1) To determine the efficacy of REBOOT first by site, then in 
affecting several secondary outcomes, such as modifiable risk 
behaviors and management of witnessed overdose. 

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Study Design:
We will enroll at least 300 (150 at each site) naloxone recipients with 
opioid use disorder and a prior opioid overdose who will be 
randomized 1:1 to receive repeated doses of a 30-45-minute IMB 
(Informational-Motivational-Behavior)-based counseling session in 
overdose prevention versus attention control. All participants will 
complete opioid urine screening at all in-person visits and 
assessments at enrollment and months 4, 8, 12, and 16. Participants 
will either receive counseling sessions or control (i.e., viewing videos 
or listening to podcasts), at months 0 (enrollment), 4, 8, and 12.   
Inclusion Criteria:
(1) Age 18-65 years; 
(2) Self-reported use of non-prescribed opioids in past 14 days;
(3) Current moderate to severe opioid use disorder by DSM-5; 
(4) Urine positive for opioids during screening by point-of-care 
testing (or self-reported illicit opioid use in the past 4 days, confirmed 
by a trusted source, for remote or other visits in which urine cannot be 
collected); 
(5) History of prior opioid overdose within past 3 years; 
(6) Previously received take-home naloxone; 
(7) No life-threatening illness likely to progress clinically during trial; 
(8) Able and willing to provide informed consent, provide adequate 
locator information, communicate in English, adhere to visit schedule.
Exclusion Criteria:
(1) Suicide plan or attempt within 12 months prior to screening; 
(2) Urine positive only for prescribed agonist maintenance therapy 
and negative for cocaine and methamphetamine (or self-report of 
ongoing receipt of agonist maintenance therapy for remote or other 
visits in which urine cannot be collected);
(3) Currently participating in another interventional research study 
that could possibly impact the study's outcomes of interest; 
(4) Planning to leave San Francisco/Boston metro area during study;
(5) Previously exposed to REBOOT counseling intervention;
(6) Any condition that, in the Principal Investigator’s judgment, 
interferes with safe study participation or adherence to study 
procedures.
Study Procedures/
Frequency:
All subjects will complete the following study visits: prescreening, 
screening, enrollment, study visits every 4 months for a total of 16 
months.  All study visits, including screening visits, may be done 
remotely when COVID-19 safety precautions do not permit in-person 
visits. Follow-up visits may be done remotely when other events 
restrict a participant from attending in-person visits (e.g. 
hospitalization, incarceration, inpatient rehabilitation, moving to 
another part of the country, etc.). Participants may complete a mix of 
both in-person and remote visits throughout their 16-month 
participation in the study. A subset of participants will be asked to 

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attend one final visit after 16 weeks for a validation substudy. Remote 
visits are conducted by phone or by video, using the Zoom video 
conference platform. 
Prescreening: Prior to conducting informed consent procedures, 
research staff will administer a brief prescreener questionnaire to 
interested individuals either in person or over the phone. If 
participants meet prescreen eligibility criteria, they will be invited to 
complete an in-person or remote screening visit.
Screening visit: Informed consent will be obtained at the beginning 
of the screening visit. After consent is obtained and eligibility is 
determined, a locator form is completed and HIPAA and release of 
information (ROI) forms are signed. In the case of remote screening 
visits, verbal HIPAA authorization will be obtained, and the ROI will 
be omitted or postponed until the participant’s written signature can 
be obtained. The screening visit will also include an evaluation of 
opioid use disorder by DSM-5 criteria, a screening for suicide risk, 
and a urine drug screen with expanded opioids, including fentanyl. 
For remote screening visits or other visits that do not permit urine 
collection, in lieu of a urine drug screen, the name of a trusted source, 
provided by the participant, will be asked to verify the participant’s 
recent opioid use. Consent will be obtained from the participant to 
contact the trusted source and the trusted source will be informed of 
this agreement through either signed consent or verbal consent (e.g. 
3-way call).
Enrollment (month 0): At the enrollment visit, participants will 
provide a urine for toxicology testing, update the locator form, have 
their picture taken to store with their locator form (if not done at 
screening), and will undergo the baseline assessment (administered by 
a staff-person blinded to study assignment). The photo for the locator 
form will be omitted for remote enrollment visits; urine drug 
screening will be omitted for enrollment visits that are remote or 
otherwise do not allow for collection of urine.  
Participants will then be randomized to receive either the behavioral 
intervention (n=150) or attention control (n=150). Randomization 
will be 1:1, stratified by site, using permuted blocks of randomly 
selected sizes. Participants will then undergo the initial counseling 
visit for the intervention or attention control for the control arm. 
Attention control will involve watching videos during in-person visits 
and listening to podcasts during remote visits. 
The next visit will be scheduled and participants will be compensated 
for their time.

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Months 2, 6, 10, 14: Participants will be contacted by study staff to 
update locator form. If contact is successful, participants will be 
reimbursed $3 at that time or at their next visit. Staff may attempt 
more frequent contact with participants at-risk to being lost-to-follow-
up, but participants will not be compensated for these additional 
contacts.
Follow-Up Visits (Months 4, 8, 12, and 16): At months 4, 8, and 12, 
participant will be seen for urine drug screen (in-person visits only), 
updating of their locator form, assessment (administered by a staff-
person blinded to participant’s study assignment), followed by 
counseling for the intervention arm or video or podcast for the control 
arm.
At month 16, participants will complete activities listed for the 
monthly visits. Participants in the treatment arm will not receive 
counseling at month 16 and participants in the control arm will not 
watch a video nor listen to a podcast, at month 16. Participants will 
not update their locator form at month 16.
The assessment, which is administered at enrollment and months 4, 8, 
12, and 16 includes demographic information (enrollment only); drug 
use history (enrollment only); extensive opiate overdose questions; 
drug use, treatment and drug-related risk behaviors; questions about 
incarceration, severity of dependence, hopelessness, impulsivity, 
participant satisfaction with the study. The assessment also includes a 
COVID-19 Impact Assessment with questions about COVID-19 risk, 
testing, and vaccination history; drug use behaviors; and access to 
resources during the COVID-19 pandemic.
Validation Substudy Visit: Participants may be invited to complete 
an additional interview after study completion in which they will 
complete one repeat assessment to assess the validity of the data 
collection methodology. 
Treatment Arm:
REBOOT participants in the treatment arm will receive repeated 
doses of a 30-45-minute IMB (Informational-Motivational-Behavior)-
based counseling session in overdose prevention at enrollment and 
months 4, 8, and 12.
Reference Arm:
Participants in the reference arm will receive attention control, which 
consists of 30-45-minute videos or podcasts, unrelated to overdose, 
substance use, or health issues such as HIV. Attention control videos 
will be administered at enrollment and months 4, 8, and 12. 

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Statistical Methods
Specific Aim 1: We will utilize ADAPT-ITT to ensure REBOOT’s 
relevance in the context of fentanyl. We will produce a manuscript 
describing the process and outcomes, similar to that which we 
produced for a prior adaptation study of Personalized Cognitive 
Counseling that was accepted as a CDC Evidence-Based Intervention 
(https://tinyurl.com/ybx3oqep). While the manuscript will describe the 
process and outcomes from each ADAPT-ITT Phase, a major element 
of this analysis will be the theater test and focus group (Phase 3). 
Sessions will be audio-recorded and transcribed verbatim. Two 
independent analysts will develop a codebook and independently code 
the focus group transcript. The transcript will then be analyzed using 
standard thematic content analysis. The topical expert review (Phase 6) 
will also be a key element in describing the adaptation process, as well 
as the final product of the adapted intervention manual.
Specific Aim 2a: To determine if REBOOT, compared to attention 
control, reduces the occurrence of any opioid overdose event, we will 
use generalized estimating equations (GEE) models for the occurrence 
of any overdose event in each reporting period, with robust standard 
errors to account for within-subject correlation of the repeated 
measures. Overdose events will be determined by a modified time-line 
follow-back every 4 months to determine the approximate date(s) of 
non-fatal overdose(s). We will review EMS and ED records for fatal 
episodes and to verify reliability of self-report data for a subset of 
participants. Based on patterns observed in our pilot, the overdose rate 
in controls will be flexibly modeled by treating visit as categorical, 
while the treatment effect—that is, the between-group difference in 
overdose risk—will be modeled as linearly increasing over follow-up.  
Because odds-ratios can be misleading when interpreted as relative 
risks in contexts where outcomes are common, we will use log-link 
rather than logistic models to obtain relative risks directly. Further, 
because log-link binomial models do not reliably converge, we will use 
instead the Poisson model, noting that robust standard errors 
accommodate the violation of the Poisson assumption of variance equal 
to the mean. The primary analysis will be by intention to treat, without 
regard to adherence.  Several sensitivity analyses will be performed: 1) 
with multiple imputation of missing outcomes; 2) with adjustment for 
any prognostic baseline covariates; 3) using an alternative model 
assuming a constant rather than linearly increasing treatment effect; 
and 4) using inverse probability of retention weights to account for 
potentially informative loss to follow-up. In view of the excellent 
participant retention and visit adherence in our past studies, we do not 
expect these sensitivity analyses to affect conclusions.
Specific Aim 2b: To determine if REBOOT, compared to attention 
control, reduces the number of opioid overdose events, we will use 

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GEE Poisson models for the number of overdose events in each 
reporting period, set up in the same way as the model for Aim 1. In this 
case, robust standard errors will be needed to account for within-
subject correlation and potential over-dispersion (rather than under-
dispersion) of the count outcome. We expect that repeated overdose 
events may be reasonably common in a subset of higher risk 
participants. The sensitivity analyses proposed for Aim 1 will be 
repeated for this outcome.
Specific Aim 3: To determine if REBOOT, compared to attention 
control, increases the number of days abstinent from opioid use or days 
in substance use treatment, we will use GEE Poisson models for each 
of these outcomes, both set up in the same way as the models for Aims 
1 and 2. In addition, we will implement a Number-of-Beyond-
threshold-Weeks-of-Success (NOBWOS) analysis, which will track by 
week the proportions of participants in each group who have achieved 
abstinence lasting through the end of the study.
Sample size justification:  We estimate that the proposed sample of 300 
participants, randomized 1:1 to REBOOT and attention control, will 
provide 80% power to detect net 59% reductions in the prevalence of 
any overdose by the final reporting period in the REBOOT group, 
conservatively accounting for net loss of 15% of participants by the 
end of the study. This is considerably smaller than the 83% net 
reduction observed in the pilot study. In making these calculations, we 
used data from the pilot to estimate baseline outcome rates by visit in 
the control condition, as well as the intra-class correlation of the 
repeated outcomes.  
Exploratory Aims: Exploratory analyses will estimate the efficacy of 
REBOOT first by site, then in affecting several secondary outcomes. 
Some of these include modifiable risk behaviors and management of 
witnessed overdose. To estimate the effect of REBOOT, compared to 
attention control on overdose risk behaviors, as measured by frequency 
of using opioids concomitant with alcohol or benzodiazepines (the 
most common modifiable overdose risk behavior), we will use GEE 
Poisson models with robust standard errors. We will also use GEE 
Poisson models with robust standard errors to assess evidence that the 
intervention increases the use of naloxone during overdose events 
witnessed by participants. We will also conduct descriptive analyses of 
overdose risk behaviors and events in the prospectively-followed and 
sizable control population. Results will also be analyzed by pre and 
post-COVID-19 pandemic and remote versus in-person visits.
Biological Variables:  Sex and age may affect the efficacy of 
REBOOT for primary as well as secondary outcomes. We will conduct 

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additional analyses assessing modification of the REBOOT 
intervention by these factors.
 
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.

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1.
INTRODUCTION
1.1.
Background
The United States is amidst an opioid crisis, with increasing rates of opioid overdose mortality. 
While naloxone distribution has demonstrated benefits in reducing opioid overdose mortality, 
more is needed, particularly interventions to reduce the risk of overdose occurring in the first 
place. We developed a brief motivational interviewing intervention, based on the IMB model of 
behavior change, to address opioid overdose among persons who already have access to 
naloxone but remain at high risk for opioid overdose.
1.2.
Overall Risk/Benefit Assessment
Primary Patient Risks: 
We do not anticipate any moderate, severe, or life-threatening adverse events as a result of study 
participation. If a participant should report or display urgent medical or mental health concerns 
(such as hyperventilation, active suicidal ideation, serious emotional distress, or similar 
problems) study staff will suggest that a call be placed to an appropriate referral agency or crisis 
hotline. The staff member may also call 911 if deemed necessary. For remote visits, participants 
will be asked for their location in the event 911 needs to be called. Referral lists for mental 
health and substance abuse services and crisis hotlines will be available for reference at all times 
and provided to participants upon request. Study staff will be trained in how to identify, manage, 
and respond to these events. If needed, study staff will arrange for counselors or medical 
personnel to provide assistance to those participants that experience any serious effects during 
the course of the study. 
Potential risks from study participation will be explained through the informed consent process. 
The study will not dispense naloxone to participants. Prior to enrollment, participants will have 
received naloxone; prior receipt of take-home naloxone is one of the study inclusion criteria. 
Therefore, this behavioral study does not pose any additional risks of pharmacologic agents nor 
does it raise ethical concerns about withholding this potentially life-saving agent. However, 
participants are informed of potential risks involved in study participation. Potential risks to 
participants include: unauthorized disclosure of confidential information; discomfort or 
embarrassment related to specimen collection or questionnaires dealing with personal habits and 
lifestyle, including drug or alcohol use; possible unwanted encounters with friends or associates 
in the research setting; possible cell phone charges from the participant’s cell phone carrier from 
study texts and calls; and continued drug use, with its attendant risks, including risk of overdose. 
There is potentially an increased risk to the participant's privacy when participating in remote 
visit procedures as the environment in remote settings may be more difficult to control than in an 
office setting. Additionally, participants who agree to the trusted source verification process may 
experience discomfort or embarrassment at having their drug use discussed among study staff 
and their trusted source. Study staff will provide guidance to participants to help minimize these 
risks (e.g., to be in a private setting for remote visits, to choose confidential trusted sources). 
Alternative treatments and procedures in place to mitigate patient risks: Participants have 
the alternative of not participating in the study. We will explain to participants that their decision 

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will in no way influence their treatment by any universities, hospitals, programs or organizations 
affiliated with the study sites. We will also offer referrals to inpatient and outpatient substance 
use treatment facilities and services in San Francisco and Boston, upon request.
Benefits:   Potential benefits to participants include: possibly becoming more aware of ways to 
reduce risk of overdose, however participants may not receive any benefit. Potential benefits to 
society include determining whether an IMB (Informational-Motivational-Behavior)-based 
intervention reduces opioid overdose risk among persons with opioid use disorder.
1.3.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. There is a DSMB for this study.

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2.
OBJECTIVES
The primary objectives of this study are:
1) To adapt REBOOT intervention to ensure relevance in a setting heavily affected by 
fentanyl using the ADAPT-ITT process.
2) To determine if REBOOT, compared to attention control, reduces during 16 months of 
follow-up
a.
the number of opioid overdose events, or 
b. the occurrence of any opioid overdose.
3) To determine if REBOOT, compared to attention control, increases
a.
the number of days abstinent from opioid use, or
b. days in substance use treatment.
Exploratory objectives of this study are:
1) To determine the efficacy of REBOOT first by site, then in affecting several secondary 
outcomes, including modifiable risk behaviors and management of witnessed overdose.

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3.
STUDY DESIGN
3.1.
Adaptation
To ensure REBOOT can impact participants in a region hit by synthetic opioids, we will 
complete an “ADAPT-ITT” process, modified as some phases of the process do not apply to 
designing a full trial of an intervention. The intervention is already selected (Phase 2) and a 
needs assessment (Phase 1) has been completed by the CDC and affiliated investigators, 
including numerous qualitative interviews. We have already utilized these data to determine 
adjustments to the REBOOT intervention and, without changing the core elements and 
underlying theory of REBOOT, we will produce a first draft of an adapted intervention (early 
Phase 4). This draft will, for example, incorporate (a) the use of “tester shots”, an approach to 
reducing risk that had fallen out of favor, but has again become common due to the extreme 
variations in potency of street opioids; (b) the importance of evaluating the appearance of the 
drug as products containing fentanyl/analogues tend to appear different both as solids and in 
solution; and (c) the importance of contacting EMS, employing chest compressions as cardiac 
arrest may be more rapid, and administering sufficient naloxone. We will then implement theater 
testing (Phase 3), in which 12 persons representative of the Boston target population (i.e., illicit 
opioid users who have previously experienced opioid overdose events) will observe a mock 
session, complete a survey and engage in a discussion about the strengths, weaknesses, and 
potential ways to improve the intervention. From this we will produce the second draft (Phase 4). 
Phase 5 involves review by topical experts, the results of which are integrated in Phase 6. The 
final phases, testing the intervention, will occur within the context of the full trial, with a single, 
flexible curriculum utilized in both sites. 
3.2.
Study Treatment and Duration of Treatment
This is a two-site full randomized-controlled trial of REBOOT, combining an established 
overdose education curriculum with motivational interviewing principles to leverage personal 
and witnessed overdose to reduce opioid overdose events.
Three hundred subjects (150 at each site) will be enrolled in one of the following two study arms.
Group 1: IMB Counseling (REBOOT)
■
Treatment arm participants will receive a single 30-45 minute session of IMB 
counseling on overdose prevention at enrollment and months 4, 8, and 12.
Group 2: Attention control

Participants in the reference arm will receive attention control, which consists of 30-
45 minute videos or, for remote visits, podcasts, unrelated to overdose, substance use 
or health issues such as HIV.

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3.3.
Treatment Discontinuation Criteria
There are no formal trial-stopping rules for this study. However, a formal interim efficacy 
analysis will be conducted. Please see DSMP section 7.1 for details of the interim analysis and 
stopping rules, including stopping for benefit, harm, or futility.    
If it becomes clear that the trial puts undue safety risk on study participants, outcomes are poor, 
or the trial will not achieve its enrollment goals, consideration will be given to stopping the trial, 
after consultation with the IRB and NIDA program officer (PO). 
The overall safety risk to study participants will be determined through regular monitoring 
procedures. Safety issues will be evaluated as they arise. Study staff will consult with Dr. Coffin, 
the study Principal Investigator and San Francisco site medical director, or Dr. Walley, the study 
Co-Investigator and Boston site Principal Investigator, on these safety issues on a case-by-case 
basis as they are reported by the participant. Non-urgent clinical issues that arise during the 
course of the study are discussed at the next weekly meeting with Drs. Coffin or Walley. During 
weekly meetings, study staff will review all the safety issues and incident adverse events for the 
study overall, by system category, and by possible relationship to the behavioral intervention. 
The PI will alert the NIDA PO immediately if at any point the team observes an unexpected 
frequency of serious AEs possibly related to the intervention. 

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
At least 300 subjects will be enrolled in this study (150 at each site).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
(1) Age 18-65 years; 
(2) Self-reported use of non-prescribed opioids in past 14 days;
(3) Current moderate-to-severe opioid use disorder by DSM-5;
 
(4) Urine positive for opioids by point-of-care testing during screening (or self-reported 
illicit opioid use in the past 4 days, confirmed by a trusted source, for remote or other 
visits in which urine cannot be collected)
(5) History of prior opioid overdose within past 3 years; 
(6) Previously received take-home naloxone; 
(7) No life-threatening illnesses likely to progress clinically during trial; 
(8) Able and willing to provide informed consent, provide adequate locator information, 
communicate in English, adhere to visit schedule.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
(1) Suicide plan or attempt within 12 months prior to screening;
(2) Urine positive only for prescribed agonist maintenance therapy and negative for 
cocaine and methamphetamine (if urine cannot be collected precautions, this criterion 
will not apply); 
(3) Currently participating in another interventional research study that could possibly 
impact the study's outcomes of interest; 
(4) Planning to leave San Francisco/Boston metro area during study;
(5) Previously exposed to REBOOT counseling intervention;

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(6) Any condition that, in the Principal Investigator’s judgment, interferes with safe study 
participation or adherence to study procedures.

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5.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Error! Reference source not found.1 and described in the text that follows. 
The investigator will document any deviation from protocol procedures and notify appropriate 
regulatory authorities (e.g., IRB and/or NIH).
5.1.
Subject Enrollment and Treatment Assignment
Active recruitment will occur at a variety of community locations including, but not limited to, 
syringe access sites, naloxone distribution sites, the Boston Public Health Commission 
Engagement Center (Boston site only), local community-based organizations, and SUD 
treatment centers. Additionally, we will utilize passive recruitment methods through distribution 
of recruitment materials such as posters, cards, and flyers which will be left at places frequented 
by opioid users. We will also recruit participants via snowball sampling. Any enrolled REBOOT 
participant (who was consented, screened, and completed the baseline visit) may refer 
individuals to the study. Participants will be compensated $40 per person who they refer who is 
eligible and enrolls in the study (for a total of up to 5 people or $200). Participants will be 
informed of the snowball sampling process during study visits. 
Individuals who express interest will complete a brief prescreening questionnaire administered 
by staff either over the phone or in person. Those deemed eligible per the prescreener will then 
be scheduled for a screening visit where informed consent will be signed, or verbal consent will 
be given (for remote or other visits in which urine cannot be collected), and final eligibility will 
be determined. Eligible participants will be scheduled for an enrollment visit at which time they 
will complete the baseline assessment and be randomized to either the counseling intervention or 
the attention control group, as described below. Follow-up visits will occur every four months 
for 16 months and will be completed primarily in person, but may also be completed over the 
phone if necessary. 
5.2.
Pretreatment Assessments
N/A
5.3.
Screening Visit 
Participants will be prescreened by trained research staff using IRB-approved procedures. Staff 
will inform participants of the study, emphasize that participation is voluntary, and provide them 
with IRB-approved flyers that describe the study. Research staff will administer the prescreening 
questionnaire to interested participants either over the phone or in person. Those who remain 
eligible will complete an in-person or remote screening visit. Participants will be informed 
before the visit that they may still be found ineligible for the study but that they will be 
compensated for their time. 

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Informed consent will be obtained at the beginning of the screening visit. After consent is 
obtained and eligibility is determined, a locator form is completed and HIPAA and release of 
information forms are signed for review of medical/criminal records. In the case of remote 
screening visits, verbal consent will be obtained for the informed consent and HIPAA, and the 
release of information will be omitted. The screening visit will also include Structured Clinical 
Interview for DSM-5 for opioid use disorder and assessment for suicidal ideation, as well as a 
urine drug screen with expanded opioids and fentanyl.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
study site within 28 days after screening for enrollment into the study; enrollment may occur 
remotely if absolutely necessary due to COVID-19 precautions. Subjects who do not complete 
enrollment within 28 days may be considered for rescreening on a case-by-case basis, dependent 
upon the reason for non-enrollment.
Participants will be compensated $20 for the screening visit. Participants will not be 
compensated for completing the prescreener.
5.3.1.
Enrollment Visit
Enrollment procedures will be completed prior to randomization and receipt of the first 
counseling or attention control session.
For in-person enrollment visits, participants will provide a urine sample for toxicology testing 
and research staff will administer the baseline assessment. Participants will update the locator 
form and have their picture taken to store with their locator form (this may also be done at 
screening if deemed appropriate). In the event of an remote enrollment visit, urine sample and 
photo will not be collected. 
After completing the baseline assessment, participants will be randomized to receive either the 
behavioral intervention (n=150) or attention control (n=150). Randomization will be 1:1 using 
permuted blocks of randomly selected sizes. Randomization will be followed by initial 
counseling for the treatment group and attention control for the reference group. The next visit 
will be scheduled and participants will be compensated for their time. 
Participants will be compensated $50 for the enrollment visit. 
5.3.2.
Interim Contact
Study staff will attempt to contact participants at two-month intervals between scheduled study 
visits (i.e. months 2, 6, 10, and 14) in order to update locator forms. This contact may be made 
by phone, other electronic means, or in person. Participants will be compensated $3 for updating 
contact information, either at the time of updating or at their next in-person visit. 
Staff may attempt more frequent contact with participants at-risk to being lost-to-follow-up, 
however participants will not be compensated for these additional contacts.

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5.4.
Follow-up Visits (Month 4, 8, 12 and 16)
Participants will complete follow-up assessments every 4 months. 
At months 4, 8 and 12, participants will provide a urine drug screen (for in-person visits only), 
complete the assessment, update their locator form, and receive counseling for the treatment 
group or attention control for the reference group.
At month 16, participants will provide a urine drug screen (for in-person visits only) and 
complete the assessment. REBOOT participants will not receive counseling at month 16, and 
attention control participants will not watch a video nor listen to a podcast at month 16. 
Participants will not update their locator forms at month 16.
If participants are in a facility at the time of the follow-up visit (i.e. hospital, substance use 
disorder treatment facility), every effort will be made to reach that participant to complete visit 
activities. These activities may be completed at the facility if feasible to staff and approved by 
the facility. Alternatively, assessments may be completed in-person or over the phone if 
intervention/control sessions are not feasible. 
Subjects who have a phone will be compensated as follows: $60 for month 4 visit, $70 for month 
8, $80 for month 12, and $100 for month 16. Payments are in the forms of cash or gift card.
As a retention strategy, participants who are not reliably reachable will be required to accept a 
study cell phone with unlimited minutes in lieu of the cash or gift card stipend. Participants will 
be informed of this requirement during the informed consent process. If at any visit a participant 
has their own phone, they will not be required to accept a study cell phone as payment.
5.5.
Reliability Substudy Visit
REBOOT participants that complete the Month 16 visit may be invited to participate in one 
additional brief assessment (Timeline Follow Back re-test). Consent for this substudy visit will 
be obtained separately. In this visit, the participant will be administered the portion of the 
assessment for a time period already assessed during the study. The purpose of this re-test is to 
assess the reliability of the data captured in the assessment. We aim to re-test up to 100 
participants. Participants will be compensated $50 for the additional visit. 
5.6.
Assessments
5.6.1.
Labs
Urine drug screen (drugs of abuse screen/expanded opioids) will be done at all in-person visits.
5.6.2.
Research Electronic Data Capture (REDCap)
Research staff will verbally administer assessments to participants using REDCap at enrollment 
and months 4, 8, 12, and 16. Assessments may be completed on paper and later entered into 
REDCap (e.g. if research staff are not permitted to bring electronic devices when conducting 

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interviews in a jail). The assessment will always be conducted by a staff person blinded to the 
participant’s study arm and prior to administration of the REBOOT intervention or control arm 
procedures.
The assessment, which is administered at enrollment and months 4, 8, 12, and 16 includes items 
related to demographics (enrollment only), drug use history (enrollment only), opiate overdose, 
drug use, treatment, drug-related risk behaviors, incarceration, hopelessness, impulsivity, 
participant satisfaction with treatment, and questions related to COVID-19 and its impact on 
various aspects of participants’ lives. As part of the assessment, we will record participants’ 
COVID-19 vaccination status.  
Primary and secondary outcome variables will be obtained from standardized scales or 
established approaches. We will utilize overdose measures developed in collaboration with other 
investigators (Drs Caleb Banta-Green, Traci Green, Amy Bohnert, and Alex Walley) to 
maximize comparability among overdose studies.
The following standardized scales will be administered and included in the assessment, 
regardless of study arm:

Severity of Dependence Scale: This 5-item questionnaire measures severity of 
dependence on opioids (Gossop et al., 1995). It will be administered at all study visits. 

Abbreviated Impulsiveness Scale (ABIS): Derived from the Barratt Impulsiveness 
Scale version 11 (BIS-11), the ABIS is a 13-item measure of trait impulsivity (Coutlee et 
al., 2015). This scale will be administered at enrollment and month 16.

Brief-Neg-H & Brief-Pos-H: This brief (4-item) measure of hopelessness contains two 
negatively-worded items and two positively-worded items, and has demonstrated 
concurrent validity with the Beck Hopelessness Scale (BHS) and the Center for 
Epidemiologic Studies Depression (CES-D) scale (Fraser, et al., 2014). It will be 
administered at all visits.

Addiction Severity Index (ASI): We will administer an adapted version of the ASI Drug 
Use Module at each study visit (McClellan et al., 1980). 
5.6.3.
Administrative data 
If research staff learn that a participant has died during their participation in the study, date and 
cause of death will be ascertained from Vital Records, as well as from contacts listed on locator 
forms. Deaths will be reported as SAEs in accordance with IRB and GCP procedures.
Data from local emergency departments and hospitals may be obtained on some or all 
participants through signed ROIs during enrollment in order to assess for opioid overdose-related 
visits, as a means of validating self-report data. 

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5.6.4.
Data Management
Data will be maintained in REDCap (tracking, administrative, and survey data). REDCap is more 
secure than Microsoft Excel or Access and can be accessed from any device with an internet 
connection and web browser. It is HIPAA-compliant, offers daily backups, and has an audit trail 
for increased security. Any paper forms will be stored with participant files in locked offices, 
separate from identifying information per GCP guidelines.

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6.
ADVERSE EVENTS MANAGEMENT
6.1.
Definition of Adverse Events and Serious Adverse Events
Participants will be queried as to adverse events at the beginning of each visit. We will use the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 
2.1, July 2017, available at: http://rsc.tech-res.com/safetyandpharmacovigilance/
We will record and report all AEs in accordance with these NIH guidelines. Safety monitoring 
will include the assessment, follow-up, and reporting of clinical AEs and serious AEs (SAEs).  
Each AE will be classified by the study clinician/principal investigator as serious or non-serious, 
and appropriate reporting procedures will be followed.
All AEs that are serious and meet the reporting criteria will be reported to NIDA and the DSMB 
within 72 business hours of learning of the SAE and to the UCSF IRB within 5 working days if 
they meet IRB reporting requirements. UCSF IRB is the primary IRB for both study sites.
A Serious Adverse Event (SAE) will be defined according to the guidelines set forth by the FDA 
(http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm) with the modification for 
the primary outcome of overdose. 
A serious AE is any untoward medical occurrence:  

results in death, 

is life-threatening (defined as an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe), 

requires inpatient hospitalization or causes prolongation of existing hospitalization, 

results in persistent or significant disability/incapacity, 

is a congenital anomaly/birth defect, 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above).  
Overdose events will be reported as SAEs if they result in hospitalization or death. Follow-up 
information which becomes available as the SAE evolves, as well as supporting documentation 
(e.g., hospital discharge summaries and autopsy reports), will be collected subsequent to 
reporting, if not available at the time of the initial report, and immediately sent using the same 
procedure as the initial SAE report.
SAE reporting will include a narrative that will provide details of relevant screening measures, 
medical history and physical, treatment compliance, participant reports of SAEs, and any other 
required information. The completed SAE form will contain the participant’s ID#, gender, and 
age; the title and date of the SAE; and narrative explanation. The SAE form will track how the 
research staff was notified of the event; dates of consent, randomization, and study screening for 
inclusion/exclusion; study treatment received (visits attended, as staff will be blinded to 

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treatment arm); other relevant clinical information; dates and circumstances of the 
hospitalization/death; whether alcohol or drugs were known to be involved; and participant status 
at last clinical or research contact.  The investigators will state whether the event was expected 
and assess its relatedness to the study intervention. A summary report of all AEs (including 
SAEs) will be submitted to the DSMB in the annual progress report. 
For more information on protocol for AEs and SAEs, please refer to the DSMP protocol. 
6.2.
Management of SAEs and other study risks
We do not anticipate significant risks to the safety of participants due to study participation. An 
interim analysis will be conducted as described in section 7.1 of the DSMP to ensure that the 
study is not continued as designed if there is clear benefit or harm to the intervention or if there 
is no hope of demonstrating an effect of the intervention; this will be determined by analyzing 
the frequency of overdose events. 
Should participants require acute medical care during study participation, they will be treated 
on-site by a clinician if available and, once stabilized, taken to the appropriate hospital for care; 
if a clinician is not available, emergency medical assistance will be sought and the participant 
transported to the appropriate hospital.
In the case of remote visits, staff will be able to reach the clinical psychologist, nurse 
practitioner or medical doctor by phone or text, if needed. At the beginning of remote visit calls, 
participants will be asked for their current location so that staff may provide that information to 
a 911 operator, if necessary.
6.3.
Reporting of SAEs
All AEs that are serious and meet the reporting criteria will be reported to NIDA and the DSMB 
within 72 business hours of learning of the SAE and to the UCSF IRB within 5 working days if 
they meet IRB reporting requirements. UCSF IRB is the primary IRB for both study sites. 
A Serious Adverse Event (SAE) will be defined according to the guidelines set forth by the 
FDA (http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm) with the modification 
described in 6.2 of the DSMP for the primary outcome of overdose. 
An expedited reporting of SAE will adhere to the following guidelines:
a) Apply regardless of the investigator’s assessment of the relatedness of the SAE to the 
intervention under study.
b) Apply equally to trials requiring an IND and those not requiring an IND.
c) Apply to any SAE that occurs during the post-treatment observation period defined by the 
protocol.
d) Apply to suicidal or homicidal behavior that causes an SAE in the subject or someone else 
(e.g. hospitalization or death).

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7.
CHANGES TO STUDY PROTOCOL
7.1.
Reporting of IRB actions and DSMB reports to NIDA
Through the study project officer, NIDA will be informed of IRB actions regarding the study and 
provided the annual DSMB report. When significant revisions to the protocol are planned, IRB 
and DSMB communications will be forwarded to the NIDA Project Officer (PO), Dr. Will 
Aklin, phone 310-827-5909, email: aklinwm@mail.nih.gov.
7.2.
Report of changes or amendments to the protocol
All changes and amendments to the study protocol will require IRB approval prior to their 
implementation. When appropriate, the NIDA project officer will be informed of changes or 
amendments to the study protocol. Changes to the DSMP must also be approved by the DSMB 
and NIDA prior to implementation.
7.3.
Trial stopping rules
Please see section 7.1 of the DSMP for details of interim analysis and stopping rules, including 
stopping for benefit, harm, or futility.
In addition, if it becomes clear that the trial puts undue safety risk on study participants or the 
trial will not achieve its enrollment goals, consideration will be given to stopping the trial, after 
consultation with the DSMB, IRB, and NIDA PO. 
The overall safety risk to study participants will be determined through regular monitoring 
procedures. Study staff will consult with Drs. Coffin and/or Walley on these safety issues on a 
case-by-case basis as they are reported by participants. Non-urgent clinical issues that arise 
during the course of the study are discussed by the research staff at the next weekly meeting with 
Drs. Coffin or Walley. During weekly meetings, study staff will review all safety issues and 
incident adverse events for the study overall, by system category, and by possible relationship to 
the behavioral intervention. The PI will alert the DMSB and the NIDA P.O. immediately if at 
any point the team observes an unexpected frequency of serious AEs possibly related to the 
intervention. Of note, to maintain the partial blind, only interventionists will know the study arm 
of each participant.
7.4.
Disclosure of conflicts of interest
Staff are required to disclose any financial conflicts of interest with the study. Signed 
documentation of conflicts of interest (or lack thereof) by study investigators will be provided to 
the IRB as required by the initial and continuing review process.

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8.
STATISTICAL CONSIDERATIONS 
8.1.
Analysis Objectives 
8.1.1.
Analysis Objectives
The primary objectives of this study are:
1. To adapt REBOOT intervention to ensure relevance in a setting heavily affected by 
fentanyl using the ADAPT-ITT process.
2. To determine if REBOOT, compared to attention control, reduces during 16 months of 
follow-up
a.
the number of opioid overdose events, or 
b. the occurrence of any opioid overdose
3. To determine if REBOOT, compared to attention control increases 
a.
the number of days abstinent from opioid use, or
b. days in substance use treatment.
The exploratory objectives of this study are:
1) To determine the efficacy of REBOOT first by site, then in affecting several secondary 
outcomes, such as modifiable risk behaviors and management of witnessed overdose. 
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using STATA software. 
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment group and overall.
Demographic data will include sex, self-identified race/ethnicity, and age.
8.4.
Data Analysis
8.4.1.
Primary Analysis
1) Specific Aim 1: We will utilize ADAPT-ITT to ensure REBOOT’s relevance in the 
context of fentanyl. We will produce a manuscript describing the process and outcomes, 
similar to that which we produced for a prior adaptation study of Personalized Cognitive 
Counseling that was accepted as a CDC Evidence-Based Intervention 
(https://tinyurl.com/ybx3oqep). While the manuscript will describe the process and 
outcomes from each ADAPT-ITT Phase, a major element of this analysis will be the 
theater test and focus group (Phase 3). Sessions will be audio-recorded and transcribed 
verbatim. Two independent analysts will develop a codebook and independently code the 
focus group transcript. The transcript will then be analyzed using standard thematic 
content analysis. The topical expert review (Phase 6) will also be a key element in 

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describing the adaptation process, as well as the final product of the adapted intervention 
manual.
2) Specific Aim 2a: Number of overdose events occurring during follow-up
a.
To determine if REBOOT, compared to attention control, reduces the occurrence 
of any opioid overdose event, we will use generalized estimating equations (GEE) 
models for the occurrence of any OD event in each reporting period, with robust 
standard errors to account for within-subject correlation of the repeated measures. 
3) Specific Aim 2b: Occurrence of any opioid overdose event during follow-up
a.
To determine if REBOOT, compared to attention control, reduces the number of 
opioid overdose events, we will use GEE Poisson models for the number of OD 
events in each reporting period, set up in the same way as the model for Aim 2a.
4) Specific Aim 3: Number of days not using opioids and number of days engaged in 
treatment for opioid use disorder during follow-up
a.
To determine if REBOOT, compared to attention control, increases the number of 
days abstinent from opioid use and days in substance use treatment, we will use 
GEE Poisson models for each of these outcomes, both set up in the same way as 
the models for Aims 1 and 2.
8.4.2.
Exploratory Analyses
Exploratory analyses will estimate the efficacy of REBOOT first by site, then in affecting several 
secondary outcomes. Some of these include modifiable risk behaviors and management of 
witnessed overdose. To estimate the effect of REBOOT, compared to attention control, on 
overdose risk behaviors, as measured by frequency of using opioids concomitant with alcohol or 
benzodiazepines (the most common modifiable overdose risk behavior), we will use GEE 
Poisson models with robust standard errors. We will also use GEE Poisson models with robust 
standard errors to assess evidence that the intervention increases the use of naloxone during 
overdose events witnessed by participants. We will also conduct descriptive analyses of overdose 
risk behaviors and events in the prospectively-followed and sizable control population. 
COVID-19 Variables: Using the adapted REBOOT intake and follow up assessments we will 
assess whether COVID-19 infection status is associated with an increased risk of opioid 
overdose. First, we will estimate the proportion of the REBOOT cohort with a history of 
infection by COVID-19 based on combined TLFB and health record review, then assess trends 
in this proportion beginning in January 2020. The association of COVID-19 infection with 
overdose rates will be assessed using the Anderson-Gill extension of the Cox model for repeated 
failure events, with calendar date as the time scale. 
We will also assess the changes during the COVID-19 pandemic in participant OUD treatment 
and overdose prevention service use (e.g. naloxone rescue kit access at syringe service programs) 
using GEE repeated measures models for these outcomes in each reporting period. Predictors of 
primary interest will include indicators for self-report of COVID-19 infection in the current or 
previous reporting period, the proportion of the current reporting period covered by a local 
shelter in place order, other COVID-19 public health mandates, and other policy factors. We will 
also assess trends in self-reported reduced service use due to the public health mandates. Overlap 

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of participant-specific 4-month reporting periods will be accommodated by including the 
reported outcomes in the assessment of included calendar month, with robust standard errors 
accounting for the repeated measures.
COVID-19 analyses: Sex, age, gender, race/ethnicity, OUD treatment status, medical and 
mental health comorbidities, incarceration, and homelessness may affect COVID-19 infection 
severity and overdose risk. Therefore, we will assess associations of overdose with indicators of 
any history of COVID-19 infection as well as time since the infection, controlling for these fixed 
and time-dependent confounders. These variables may also affect OUD service utilization and 
the impact of shelter in place orders. Therefore the GEE models will control for these fixed and 
time-dependent confounders. Results will also be analyzed by pre and post-COVID-19 pandemic 
and remote versus in-person visit status.
Biological Variables:  Sex and age may affect the efficacy of REBOOT for primary as well as 
secondary outcomes. We will conduct additional analyses assessing modification of the 
REBOOT intervention by these factors. 
Sample Size
Sample size justification: We estimate that the proposed sample of 300 participants, 
randomized 1:1 to REBOOT and attention control, will provide 80% power to detect net 59% 
reductions in the prevalence of any overdose by the final reporting period in the REBOOT group, 
conservatively accounting for net loss of 15% of participants by the end of the study. This is 
considerably smaller than the 83% net reduction observed in the pilot study. In making these 
calculations, we used data from the pilot to estimate baseline outcome rates by visit in the control 
condition, as well as the intra-class correlation of the repeated outcomes. Given the extremely 
high rates of overdose reported in fentanyl-affected areas, our power may exceed current 
estimates. 

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their conflicts of interest. This documentation must be provided 
prior to the investigator’s (and any sub-investigator’s) participation in the study. Study 
completion is defined as the date when the last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB) Approval
UCSF IRB is the primary IRB for both study sites. The investigator (or sponsor as appropriate 
according to local regulations) will submit this protocol, informed consent form, and any 
accompanying material to be provided to the subject (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) to the IRB. The 
investigator will not begin any study subject activities until approval from the IRB has been 
documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IRB approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
9.1.3.
Informed Consent
Study staff are responsible for obtaining written or verbal (for remote visits) informed consent 
from each individual participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study and before undertaking any study-related 
procedures. The investigator will use the most current IRB approved consent form for 
documenting written and verbal (for remote visits) informed consent. For in-person visits the 
informed consent will be appropriately signed and dated by the subject and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or by 
local requirements. If the informed consent process is done remotely, verbal consent will be 
obtained from the participant and appropriate documentation of the process will be completed by 
the staff person leading the consent discussion. The consent form will inform subjects about 
sample retention and use of retained samples.

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9.1.4.
Confidentiality
The investigator will assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and a 
unique identifier (as allowed by local law) will be recorded on any form or biological sample 
submitted to the Sponsor, IRB, or laboratory. Laboratory specimens will be labeled in such a 
way as to protect subject identity while allowing the results to be recorded to the proper subject. 
Refer to specific laboratory instructions. NOTE: If given signed or verbal permission by the 
subject, the investigators keep locator forms showing names, date of birth and addresses for all 
subjects screened and for all subjects enrolled in the trial. The information may be written on 
paper forms, recorded in REDCap, or both. Subject data will be processed in accordance with all 
applicable regulations.
9.1.5.
Study Files and Retention of Records
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria;

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Participant study start and end date, including treatment arm;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Date of study completion and reason for early discontinuation, if it occurs.

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9.1.6.
Case Report Forms (CRFs)
For each subject consented, a CRF will be completed by an authorized study staff member whose 
training for this function is documented according to study procedures. CRFs should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Prior to database lock (or any interim time points as described in the clinical data 
management plan), study staff will use his/her log in credentials to confirm that the forms have 
been reviewed, and that the entries accurately reflect the information in the source 
documents. The CRFs capture the data required per the protocol schedule of events and 
procedures.  
9.1.7.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.1.8.
Study Discontinuation
The investigator reserves the right to terminate the study at any time. Should this be necessary, 
the investigator will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRB. 

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10.
APPENDICES
Appendix 1. Study Procedures Table
Appendix 2. REBOOT 2.0 Counseling Manual

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10.1.
Appendix 1. Study Procedures Table 
Screening, Enrollment, Monthly Visits 
Visit identified by 
study month
Post-study 
Visit
Procedure
Screening 
visits
Enrollment
4
8
12
16
Informed consent
X
Locator form
X
X
X
X
Urine drug screen (expanded opioids and 
other drugs of abuse)*
X
X
X
X
X
X
Opioid use disorder, DSM-5
X
X
Suicide plan/attempt  (past year)
X
Randomization
X
Intervention
X
X
X
X
REDCap assessment
X
X
X
X
X
X**
* Urine drug screens will not be completed for remote or other visits in which urine cannot be 
collected.
**Partial assessment

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10.2.
Appendix 2. REBOOT 2.0 Counseling Manual
REBOOT 2.0
Intervention Guide
v. 1.3 (04/25/19)
Introduction (3 minutes)
Key Objectives
Provide time frame for today’s conversation as well as future sessions 
Explain purpose of today’s conversation (intervention)
Engage participant and build rapport
Review definitions (if needed)
Assess opioid use
Outline and Sample Prompts
1. Introduce yourself and explain the purpose of the intervention.

Thank you for participating in REBOOT. We really appreciate it.

This portion of the study visit will take about 45 minutes. 

Today we’ll be discussing your experience with witnessing an overdose and your own 
most recent overdose. 

We will also talk about what increases risk for an overdose and what can reduce 
overdose risk

Then we will discuss what all you might want to do to reduce your risk for another 
overdose.

Before we dive in, do you have any questions for me? Do you need something more to 
drink or eat?  
2. Review definitions.

For this session, we will be using the same definition of opioids provided during the 
survey you completed. Do you have any questions about that?

For an opioid overdose, please think of something that happens when a person uses more 
opioids than their body can handle at that time. 

A person who is experiencing an overdose is not responsive, lost consciousness after 
using drugs, is turning blue, or is not breathing normally. 
Interventionist Note:
You do not need to review the definitions unless the participant would like a refresher.

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Opioids: Common drugs like heroin, fentanyl, and morphine. Also includes many prescription 
drugs like oxycodone, hydrocodone, hydromorphone, OxyContin, Vicodin, Dilaudid, MSContin, 
Percocet, methadone and Suboxone. 
Naloxone: Also known as Narcan, the medication that pulls people out of an opioid overdose.
3. Briefly Assess Participant’s Opioid Use.

Just so I have an idea of your opioid use, please share a little with me about your use, for 
example, how frequently you use, where and with whom (if anyone) you use, and how you 
typically use (route).

Thank you for providing me with that brief summary. That helps me get a good picture of 
your use.  
   Witnessed Overdose History (4 minutes)
Now I would like to ask you some personal questions about overdose experiences. These 
experiences may be difficult to share. Please let me know if at any point you need to take a 
moment.
Outline and Sample Prompts
1. Explore participant’s experience of witnessing an overdose.

Please think back to the last time you saw someone overdose and walk me through 
what happened.
Example prompts to establish narrative:

Where did the overdose occur?

What substances was the person using?
2. Assess participant’s knowledge of how to recognize and define and overdose.

How did you know it was an overdose? What are some other signs that someone may 
be 
overdosing?
Interventionist Note: 
1) Check in to see how participant is doing and if they need support around this event. If 
appropriate, provide referrals for mental health/trauma resources at the end of session.
Example responses:
•     I’m sorry to hear that happened, it’s a good thing you were there to help. 
Key Objectives
Discuss most recent witnessed overdose experience
Assess participant’s knowledge of how to recognize and define an overdose
Begin to identify risk factors for overdose

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•     That sounds like that was a hard/upsetting/traumatic experience.
2) If participant reports never witnessing an overdose, inquire about an overdose they’ve heard 
about.
3.
Explore risk factors for witnessed overdose.

Looking back on that event, what do you think contributed to this person’s overdose?
o
[If participant doesn’t know, use prompt]: 
In general, what things do you think can contribute to overdose?
Personal Overdose History (6-10 minutes)
Outline and Sample Prompts
1. Explore participant’s own experience of overdosing.

Now let’s discuss the last time you experienced an overdose. Thinking back to that 
time, please tell me the story of your most recent (or most significant) overdose.
Example prompts to establish narrative:

When and where did it occur?

Who all, if anyone, was with you?

What, if any, other drugs or alcohol had you used that day?

What, if anything, was different about your use this time?
2. Elicit potential risk factors for this overdose.

Looking back on that event, what things (factors) do you think contributed to your 
overdose?
Example prompts to probe for additional risk factors:

You mentioned that _____ [see prompts below]______, how might  this have 
contributed to your overdose?

You had just gotten out of jail/treatment/detox/the hospital

You had bought from a new dealer / used a new batch

You didn’t know how strong the batch was
Key Objectives 
Discuss participant’s most recent, or most significant, personal overdose
Assess participant’s view of own overdose risk 
Identify participant’s risk factors for overdose
Begin to elicit motivation for behavior change

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
You had used other drugs or medications that day
If not described in narrative: Do you think that ______ contributed to your overdose this 
time?
3. Explore participant’s experience after the overdose and motivation for change.

What happened next?
Example prompts to establish narrative:

Who was with you when you were using? 
o
Were they using also? 
o
Did you use at the same time, or take turns?

Did someone give you naloxone to wake you up?

Did someone call 911? If not, did someone stay with you until you were okay?
o
What happened when they came? 
o
Did you go to the hospital?

Since this overdose, what thoughts (if any) have you had about your use?
Example response:

I’m sorry to hear that this happened and am glad you’re here today.
Provide Information on Risk Behaviors and Prevention (10 minutes)
Key Objectives
Using Handout A, first discuss overdose risk factors: 
Using more or stronger opioids
Using fentanyl
Mixing opioids with other drugs
Injecting
Using after a break
Using alone and/or in a place where nobody will find you
Not having naloxone nearby
Having overdosed before
Using Handout B, then discuss overdose prevention strategies:
Test drug w/ fentanyl test strips 
Tester shot/go slow
Changing route of administration (from injection to less risky)
Using with others/taking turns
Making injection spaces safer (e.g. better lighting, not rushing, etc.)
Carrying naloxone/using with someone who has naloxone
Medications like methadone and buprenorphine
Interventionist Notes: 

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Counselor should use open-ended questions to elicit participant’s own knowledge around 
overdose risks. Counselor should affirm participant knowledge and fill in any gaps in 
knowledge. Refer to Handouts A & B during the discussion.
Outline and Sample Prompts
2) Review overdose risks with participant

Statistically, people who have overdosed before are more likely to overdose again. So 
just by having overdosed in the past, you are at a greater risk for having an overdose in 
the future. 

It is also true that people who practice certain harm reduction strategies can greatly 
reduce their risk of overdose, no matter what their overdose history is.

Let’s talk about other things that increase a person’s risk of having an overdose and the 
things people do that reduce their chances of an overdose.
Example prompts to promote discussion:

In general, what things do people do that can lead to an overdose? 
Example responses:

You’re right, _____________ are things that we know can lead to an overdose. May I 
share some additional information about overdose risk?
Provide participant with Handout A: Behaviors that Contribute to Overdose Risk. 

Here is a handout that lists things that have been proven to increase the chances of a 
person overdosing, some of which you already mentioned.
Counselor and ppt take turns reading Handout A out loud, if possible, while the other follows 
along.
Example scripts to promote discussion and provide information:

Which of these, if any, are new to you?

Which of these, if any, are relevant to you (i.e. potentially contribute to your risk of 
an overdose)?
If participant is uncertain, counselor may offer some factors potentially relevant to the participant 
based on their earlier description of use patterns and overdose experience.
3) Review overdose harm reduction with participant.
Example prompts to promote discussion:

Now let’s review some of the practices that have been proven to reduce a person’s 
chance of having an overdose. 
Provide participant with Handout B: Behaviors/Activities that Can Reduce Risk of 
Overdose. 

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Counselor and participant take turns reading Handout B out loud, if possible, while the other 
follows along.
Example prompts to promote discussion:

Thinking about the things you mentioned earlier that increase your chance of having an 
overdose, which of these, if any, do you already do to protect yourself?

Which of these things, if any, are you willing or interested in doing to further protect 
yourself and further reduce your chance of overdosing again?
Interventionist Note: Participants may report non-evidence-based strategies to reduce their 
overdose risk. You should acknowledge that this method may have worked for them or for 
others in the past, and encourage them to incorporate evidence-based methods into their plan.
Interventionist Note: If at any time during the session the participant expresses a desire for 
substance use disorder treatment, provide referrals for treatment options at the end of the session.
Methadone and buprenorphine are opioid agonists that help to maintain the body’s ability to 
tolerate opioids and help to control other opioid use by reducing craving and avoiding 
withdrawal – both effects that reduce the risk of overdose.
Motivation and Change Plan (10 minutes)
Key Objectives
Reinforce that overdose can be avoided
Reinforce principles of harm reduction
Elicit motivation for behavior change
Assist participant in developing realistic overdose prevention plan
Work with participant to create harm reduction pocket card
Outline and Sample Prompts
1. Reinforce that overdose can be avoided.

Just in the same way that going to a needle exchange and using sterile equipment allows 
people to avoid getting HIV or Hep C, there are ways to prevent overdose.
OR
•
As mentioned before, people who practice certain harm reduction strategies can greatly 
reduce their risk of overdose, regardless of the number of overdoses experienced. 
2. Reinforce Principles of Harm Reduction.

What does the term “harm reduction” mean to you?

Yes, those are good points you mention. May I add a little more to what you shared?

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
Harm reduction is a set of practical strategies used to reduce the negative consequences 
associated with drug use.

Harm reduction is also built on a belief in, and respect for, the rights of people who use 
drugs.

Harm reduction affirms that drugs users themselves are the primary agents of reducing 
the harms of their drug use, and seeks to empower users to share information and 
support each other in strategies that meet their actual conditions of use.
3. Elicit motivation for behavior change, and address ambivalence and barriers.
Example prompts to elicit motivation:

Based on our conversation thus far, it sounds like ____________ are things that you 
might realistically be ready to do to avoid overdoses in the future. Do I understand 
correctly?

On a scale from 0-10, how ready are you to make that change?
o
If a “0”, discuss barriers: 

What would have to happen to move to a “4” or “5”?
o
If a “1”-“9”, elicit change talk: 

Please tell me why you are a “2” or __ and not a “0”?

What would have to happen for you to move from a “2” or _ to “6” 
or a”7”?

Then reflect change talk back:
o
What if anything, are you willing to do starting this week or 
next to reduce your risk of overdose?

If a “10”, discuss plan to implement.

What are the reasons you want to make this change?
Example responses to reflect change talk and address barriers:

If ready to make a change: 
o
It sounds like ______ is really important to you. Making these changes can 
help you protect yourself and the people you care for.

If not ready to make a change:
o
What, if anything, might you consider changing down the road?
o
What would have to happen for you to be more prepared to make a change?
4. Discuss details of participant’s plan to implement these changes.
Example prompts:

Let’s walk through a typical day for you. What would happen and how would you 
incorporate these strategies?
o
What things could interfere with your plan? How might you overcome these?

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
Who might support you in making these changes who you could share the plan with? 
o
When do you want to make these changes?
5. Create harm reduction pocket card with participant.

Some people like having a reminder card with their plan to hold on to (and possibly 
share with others). Once we write down the plan, you can decide where to keep it and 
whether to share it. 

You can keep it to help you remember your plan. When I see you again in 4 months, 
we can review it together and see if there are any changes that you might want to 
make. 
If possible, encourage participant to fill out the harm reduction card. Otherwise, encourage 
the participant to “dictate” what should be written down on the card. Whenever possible, use 
participant’s own language and direct quotes.
Review Overdose Response (5 minutes)
Key Objectives
Recognize overdose signs
Understand how to respond to overdose
Assess responsiveness (sternal rub)
Administer naloxone
Call 911
Do rescue breathing/chest compressions/follow 911 dispatch instructions
Know after-care best practices
Recovery position
Stay with the person
Interventionist Notes: 
SKOOP (“Skills and Knowledge on Overdose Prevention”) is a program designed by the Harm 
Reduction Coalition. 
Refer to Handouts C & D during this discussion. 
Outline and Sample Prompts

Let’s review the steps that you can take if you see someone else experiencing an overdose 
and want to help.
1. Review SKOOP curriculum (outlined below).
Provide participant with Handout C: 3 Steps in the Management of Witnessed Overdose

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
Step 1: Recognize an overdose
o
As we’ve discussed, someone might be having an overdose if they lose 
consciousness after using drugs, if their skin color looks bluish or grey, or they 
are not breathing normally.
o
Use a sternal rub to attempt to waken the individual. [Counselor to provide brief 
demonstration on self].

Step 2: Respond to the overdose
o
Administer naloxone as soon as possible.
o
Call 911. Tell the dispatcher that the person is unresponsive (or not breathing).
o
Provide rescue breathing and/or chest compressions. Also, 911 dispatchers can 
walk you through these procedures. 
Interventionist Note: If unknown, ask participant if they have ever administered naloxone 
before (or if they know how to administer naloxone), and if they have ever performed rescue 
breathing or chest compressions. If not, offer to perform naloxone, rescue breathing, and/or chest 
compression demonstration at the next session (unless participant asks for it to be done during 
current session).

Here are a few things to keep in mind about naloxone:
o
Always carry naloxone with you or know where it is so you can act quickly!
o
Naloxone can be used on anyone, so if you suspect an overdose, use it.
o
If they don’t respond after about 3 minutes, give another dose.
o
Naloxone expires. Be sure to replace your kit every 2 years if you have not 
used it. But if expired naloxone is all you have in an emergency, use it!
o
Fentanyl may cause a faster overdose – where the person stops breathing or 
their heart stops right away, so: 

You may need to do rescue breathing and/or chest 
compressions right away.

An ambulance may be needed sooner.

Naloxone might need to be given several times.

Step 3: Provide after-care
o
Place person in the recovery position. 
[Provide participant with Handout D: Diagram of recovery position].
o
Stay with the person until help arrives or they are awake for at least 2-3 hours 
(longer if using prescription opioids). Naloxone only lasts about an hour, so the 
effects of the opioid may come back and they may overdose again.
o
If you are not comfortable staying with them, make sure that someone (either a 
friend of theirs or a medical professional) is available to help.

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Interventionist Note: In Boston, if a participant expresses concern about staying with someone 
who has overdosed, you can provide them with information about the SPOT at Healthcare for the 
Homeless, where a nurse will monitor patients to make sure they are ok.
In SF and Boston, harm reduction programs are also a safe space to go when participants are 
extremely high.
Wrap Up (4 minutes)
Key Objectives
Remind participant of follow-up appointments
Provide harm reduction card and review plan
Allow participant to reflect on any final thoughts
Offer referrals, if applicable
Outline and Sample Prompts
1. Ensure participant has scheduled a follow-up appointment.

After today, your participation in the study will involve 4 more in-person visits (every 
4 months). At the first 3 of those, you will complete a survey and we will meet for 
another counseling session. The last visit (16 months from today) will just be for a 
survey.

Have you been scheduled for your next visit in 4 months?
2. Review harm reduction plan and provide participant with harm reduction card.

Here is the plan that you made to help reduce your risk of having another opioid 
overdose.
3. Reinforce participant’s interest in self-care.

Acknowledge steps participant has taken toward self-care in both receiving naloxone 
and participating in this study/counseling.

Point out and reinforce participant’s strengths that may help them reach their goals 
around substance use, and overdose prevention.

Thank participant for visit and express enthusiasm in working together during the 
next 16 months.
4. Close out the session.

Do you have any last questions before we wrap up for today?

During our session you mentioned ______________. Would you like any additional 
information/support about this?
o
Refer to resource guide and provide appropriate referrals to participant.

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Additional Sections (To be Completed by Session 4)
Naloxone Practice Session (5-10 minutes)
1. Assess participant’s knowledge of naloxone.
Example prompt:

Please tell me what you already know about naloxone (or Narcan) - what it is, 
what it does, how to get it - just anything you know or have heard about it. 
o
With participant’s permission, fill any gaps in their knowledge, if needed, 
so that they have a basic understanding of naloxone. 
Example prompts:
It seems like you have [quite a bit of/some] knowledge about Naloxone (Narcan). 
May I share some other important things to know about naloxone?
o
Based on participant’s knowledge and interest, more or less of the 
following information may be shared: 

Naloxone acts to reverse an opioid overdose, and does nothing more 
than that.

Naloxone is safe to give to anyone, even if you’re not sure if the person 
is overdosing, or overdosing on opioids. 

The effects of naloxone are short-acting and will wear off in 30 -90 
minutes (a half hour to an hour and a half). If there is still a large dose 
of opioids in a person’s system, the person may fall back into an 
overdose when the naloxone wears off.

Naloxone may cause a person to feel sick from withdrawal, but they 
will feel better again once the naloxone wears off. Encourage the 
person to ride out the withdrawal symptoms and let them know that to 
avoid another overdose, it is very important that they not use more 
opioids for a couple hours.

Naloxone will not reverse other kinds of overdoses, but there is no 
harm in trying, and it may still work if someone is overdosing on 
opioids in combination with other drugs.

Naloxone expires every 2 years, BUT if all you have on you is expired 
naloxone, use it!
2. Assess participant’s experience administering naloxone (if not already known).
Example prompt:
Tell me about your experiences, if any, giving naloxone to someone who was 
overdosing.

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Interventionist Note: Many participants will have had previous experience administering 
naloxone, some will have done so several times. Counselors should be mindful of participants’ 
past experiences and expertise.
3. Provide information and naloxone demonstration.
If a participant has extensive experience administering naloxone:

This next portion of our conversation will be review for you and maybe a chance to 
fine-tune your knowledge around naloxone administration. 

Invite participant to practice naloxone administration while you coach them through 
the process. 
Example prompt:

Please walk me through what you do to administer naloxone. 
If a participant has never administered naloxone and is unfamiliar with the process: 

Ask permission to share the steps of the process:
Is it okay if I share with you the steps to administering naloxone?
Intranasal administration (Boston site/SF site optional): 
1. Depending on participant’s knowledge/experience, the counselor may ask them to 
describe the steps to administering naloxone, filling in any information gaps, or the 
counselor may describe the steps while the participant goes through the motions with 
the demo kit. Peel back the package to remove the device. Hold the device with your 
thumb on the bottom of the plunger and two fingers on the nozzle.
2. Place and hold the tip of the nozzle in either nostril until your fingers touch the 
bottom of the person’s nose.
3. Press the plunger firmly to release the dose into the person’s nose.
4. Administer naloxone as many times as needed, 2-3 minutes between doses.
Intramuscular administration (SF site/Boston site optional):
Depending on participant’s knowledge/experience, the counselor may ask them to 
describe the steps to administering naloxone, filling in any information gaps, or the 
counselor may describe the steps while the participant goes through the motions with the 
demo kit.
1. Determine where naloxone will be injected: shoulder, buttock, or thigh.
2. Naloxone can be injected through clothing, including denim, but if necessary, remove 
any especially heavy clothing covering injection site (leather, puffy coats, multiple 
layers of thick clothing).

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3. Unwrap 25g syringe (in blue wrapper) or any syringe with a larger needle, like 23g, 
21g, or 18g. 
4. Remove orange cap from naloxone vial.
5. Plunge the needle of the syringe into the soft center of the top of the vial.
6. Turn the vial upside-down so that the point of the needle is submerged in the 
naloxone, draw up 1ml (most likely the entire vial).
7. With one fluid and assertive motion, stick the needle into injection site, deep enough 
to enter the muscle, probably the entire length of the needle. (It’s best to inject the 
naloxone into the muscle of the upper arm or thigh, but naloxone is still effective 
below the skin).
8. Depress plunger completely, administering full dose of naloxone. Withdraw needle.
9. If no reaction in 2-3 minutes, repeat the entire process, administering another 1ml of 
naloxone. 
10. Administer naloxone as many times as needed, 2-3 minutes between doses.
Review after care: 
1. Wait 2-3 minutes before giving a second dose, if necessary.
2. Perform rescue breathing/or chest compressions until person is responsive or help 
arrives.
3. If you can’t stay with the person until help arrives, put them in the recovery position 
before leaving.
Example prompts:

How long should you wait for the person to wake up before administering 
another dose of naloxone? (2-3 minutes)

It’s best to stay with the person to wait for help and ensure they don’t use 
again before the naloxone wears off.

You can put the person in the rescue position – which is on their side as if they 
were sleeping.
4. Address any questions about the demonstration.

What questions or concerns, if any, are coming up for you?
5. Evoke optimism about overdose prevention and health promotion.
Example prompts:

With all the naloxone available, many lives are saved from overdoses.

You are one of the people able to pull others out of an overdose. 

How does it feel that you may be able to save someone’s life?

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Rescue Breathing and Chest Compressions (5-10 minutes)
Outline and Sample Prompts 

In the event of an overdose where no naloxone is available, or when naloxone has 
been administered but it has not yet taken effect, knowing how to do rescue breathing 
and chest compressions can save someone’s life and prevent or limit any long-term 
damage they might otherwise suffer.
1. Assess participant’s knowledge and comfort around rescue breathing and chest 
compressions.
Example prompts:

How familiar are you, or what is your experience, with rescue breathing and chest 
compressions?

How likely is it that, if you knew what the steps were, you would perform rescue 
breathing on a friend who was overdosing? How about a stranger? And how likely is 
it that, if you knew what the steps were, you would perform chest compressions?
Interventionist Note: Participant may opt-out of learning rescue breathing (and 
combined rescue breathing and chest compressions). For example, if they report that they 
would never do rescue breathing, do not demonstrate.
2. Briefly coach participant through chest compressions with rescue dummy.
1. Position victim on back.
2. Push down in the center of the chest about 2 inches, 2 times per second.
3. Make sure to let the chest bounce back between pushes.
3. Briefly coach participant through rescue breathing with rescue dummy.
1. Position victim on back.
2. Tilt head back and pinch nose.
3. Cover the mouth with your mouth and blow until you see the chest rise.
4. Give 2 breaths, 1 second each.

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5. Continue with 1 breath every 5 seconds.
6. If something is obviously in the victim’s mouth, ok to take it out, but don’t fish around 
looking for something because that can drive it further into their airway.

You can do rescue breathing, chest compressions, or both, depending on which 
you’re more comfortable doing. If you do both, do cycles of 30 compressions followed 
by 2 breaths. 

If you call 911, we recommend doing whatever the dispatcher recommends.

Whatever you end up doing, chest compressions, rescue breathing, or both, keep 
doing it until the person show signs of being stable (regular breathing and pulse) or 
help arrives.
Interventionist Note: We do not know if recommending rescue breathing or chest compressions 
is superior. While opioid overdose is due to reduced breathing, rescue breathing is difficult to 
teach, people often don’t want to perform rescue breathing, and when people do rescue breathing 
they may do it poorly. Some experts believe that much of the benefit from rescue breathing in 
opioid overdose might actually be from stimulation rather than oxygen transfer, and chest 
compressions can provide both stimulation and some air transfer by moving the chest. 
Furthermore, if an overdose is not observed, it is possible that the person has progressed to 
cardiac arrest and will require chest compressions. Finally, 911 dispatchers generally recommend 
chest compressions so we want to avoid recommending people to go against dispatcher 
instructions.

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Evaluate readiness to change substance use (5 min)
Outline and Sample Prompts

We’ve spent a good amount of time talking about overdose prevention. Let’s spend 
some time today talking about overall substance use.
Example prompts:

What are the drugs you currently use?

What benefits do you get out of your drug use?

What are the drawbacks (or costs) of using those drugs?

How, if at all, does using get in the way of you taking care of yourself or others who 
depend on you?

How do you feel about your current drug use?
1. Discuss interest, expectations, and concerns about treatment for substance use.

What, if anything, do you want to change about your substance use?

On a scale of 0-10, 0 being not at all important and 10 being extremely important, 
how important is it for you to make that change?
o If a “0”, discuss barriers: 

What would have to happen to move from a “0” or “1” to a “4” or “5”?
o If a “1”-“9”, elicit change talk:

Please tell me why you are a “2” or __ and not a “0”?

What would have to happen for you to move from a “2” or _ to “6” or 
a”7”? 

Then reflect change talk back:

What if anything, are you willing to do starting this week or next to 
change your substance use?
If not ready to make changes: 

What would have to happen for you to be more interested in making some 
changes around your substance use?

If you choose to make no changes in your use, where do you see yourself in the 
next 3-5 years?

If you were to make some changes in your substance use, where might you see 
yourself in the next 3-5 years?
2. Discuss substance use disorder treatment options, based upon above discussion.
Example prompts:

What is your experience, if any, of receiving substance use treatment services?

What kind?
o
How did/does it help you?

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50
o
How, if at all, might treatment lower your overdose risk?

If you were to seek treatment, of all the treatments available, what treatment would 
appeal to you most? 

If and when you were to seek treatment services in the future, what steps would you 
take or how would you find a treatment agency?

At this time, what if anything, would you like from me regarding treatment services?
3. Keep the substance use treatment “door” open. 
Example prompts:

Thank you for being upfront about your thoughts/feeling about substance use 
treatment right now in your life.

Please let me know if you ever want to discuss substance use treatment options again.

If additional study visits remain:
o
Would it be okay if I check in with you about your substance use in general 
during future visits?

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Discuss HIV/HCV Risk Reduction (5 min)
Outline and Sample Prompts

We’ve talked a lot about overdose and overdose risk. But we haven’t yet talked about 
HIV/HCV, other possible, and preventable, risks of drug use.
1.
Assess HIV/HCV status and knowledge.
Example prompts:

How do you think preventing HIV/HCV is similar to preventing overdose?

Tell me about your experience with HIV/HCV testing? When was the last time you 
were tested and what were the results?

What do you already know about Hep C? What do you already know about HIV?
2.
Share information.

Do you mind if I share some additional information with you?
o
Hep C is a virus that causes inflammation of the liver. HIV is a virus that 
attacks the immune system.
o
Both Hep C and HIV can be acquired through sharing needles, but a person 
can also get Hep C through sharing other drug equipment with someone else 
who has Hep C and whose blood has contaminated a cooker, cotton, and even 
a preparation surface. Sometimes this can happen when people divide drugs 
in one syringe.
o
A person can get HIV from vaginal and anal sex (receptive is higher risk than 
insertive), but Hep C is not typically transmitted through anal, vaginal or oral 
sex, unless prolonged or rough sex causes tears and there is blood to blood 
contact.
o
Hep C is curable; HIV is treatable; and both are preventable, even when 
engaging in “higher risk” activities.
Interventionist Note: The counselor can use motivational interviewing to “meet participant 
where they’re at” and explore motivation/interest around whatever changes, if any, they’d like to 
make in relation to HIV/HCV prevention and care. 
Examples might be maintaining a negative status; starting or continuing treatment, starting PrEP, 
getting tested or increasing frequency of tests, talking to partners/friends they use with/have sex 
with about their status’; washing their hands before/after using, or sharing equipment with one 
person only.
3.
Discuss harm reduction around HIV/HCV.
Example prompts:

What do you already do to prevent HCV/HIV? What do you already do to care for 
yourself in regards to your HIV/HCV?

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
How easy or difficult is it for you to use a new needle each time you inject drugs [for 
vein health]? How easy or difficult is for you to use your own equipment each time 
you use [HCV prevention]? Do you use the needle exchange?

How often do you share equipment? In what situations have you either decided to 
share or felt that there was no choice but to share injection equipment? 

How do you protect yourself from getting HIV and other sexually transmitted 
infections?

Have you heard of PrEP for preventing HIV? What is your experience with PrEP? 
What have you heard about it?
 If HIV-positive:

What is your experience of taking HIV medications?

How long has it been since your viral load was last checked?

What all do you know or understand about U=U (undetectable 
VL=untransmissible)?  

What kind of care do you receive for your HIV? What is your relationship 
like with your doctor?
If HCV-positive: 

What do you know or what have you heard about HCV treatment?

What, if any, thoughts have you had about getting treated for HCV (if you 
get treated, you can’t pass it on to anyone else)?

What, if anything else, are you ready to do to reduce your risk for 
HIV/HCV (or manage your HIV/HCV)?
If participant reports doing all they can to stay negative, reports keeping up with their 
treatment, and is not interested in making any other changes, they may be more open to a 
conversation around maintaining their health program.
Example prompts:

It sounds like your health is very important to you, you’re doing all you can to stay 
healthy, and it sounds like there are no changes at this time that you’re interested in 
making. Do I understand correctly? 

Are there any situations, events or even people in your life that could compromise the 
stability of your health routine? 

What do you do, or can you do, to avoid those situations/events/people? If you can’t 
or don’t want to avoid them, what can you do to ensure that your health regimen is 
not jeopardized?
Some participants may express ambivalence, or apathy around HIV/HCV transmission.
Example prompt:

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53

What would have to happen for you to want to protect your health and maintain your 
negative status? 
OR

What would have to happen for you to want to receive care/treatment?
4.
Validate participant’s concerns for their health and conclude conversation.
Example prompts:

Good for you taking care of yourself in this/these ways.

You care a lot about your health and you’re willing to do what it takes to protect it. 
Thanks for talking about this with me and for sharing your experiences.

It sounds like you have some mixed feelings about making changes to reduce your 
risk of HIV/HCV infection (or starting treatment) and you know what changes you 
could make to reduce your risk. Thank you for being so engaged in this 
conversation, I really appreciate you sharing your thoughts.
For participants who don’t want to talk about HIV/HCV:

It sounds like you have had a lot of people talk with you about HIV/HCV and you feel 
confident in knowing what things you can do to protect your health. 

Please let me know if there are any concerns you have around this that have not already 
been addressed in past discussions.

Please also let me know if you want additional information (flyers/handouts) about 
HIV/HCV that I can provide you. 

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54
Intervention Overview

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Intro
ducti
on
•  Explain 
study 
participatio
n and 
purpose of 
counseling 
session
•  Review 
definitions 
(if needed)
•  Assess 
opioid use
Witn
essed 
Over
dose
•  Discuss 
most 
recent 
witnessed 
overdose
•  Assess 
participant'
s 
knowledge 
of how to 
recognize 
and define 
an 
overdose
•  Begin to 
idenitfy risk 
factors for 
overdose
Perso
nal 
Over
dose
•  Discuss 
participant'
s most 
recent 
overdose
•  Assess 
view of 
own 
overdose 
risk
•  Identify 
risk factors 
for 
overdose
•  Begin to 
elicit 
motivation 
for 
behavior 
change
Risk 
Beha
viors 
and 
Preve
ntion
•  Review 
overdose 
risk factors 
(Handout 
A) & risk 
reduction 
strategies 
(Handout 
B)
Moti
vatio
n & 
Chan
ge 
Plan
•  Reinforce 
principles 
of harm 
reduction 
•  Elicit 
goals and 
motivation 
to reduce 
overdose 
risk
•  Create 
overdose 
prevention 
plan and 
harm 
reduction 
pocket 
card
Over
dose 
Resp
onse
•  Review 
how to 
manage a 
witnessed 
overdose 
(Handouts 
C & D)
Wrap 
Up
•  
Acknowled
ge steps 
taken 
toward 
self-care
•  Thank 
participant 
and 
schedule 
follow-up 
visits
•  Make a 
copy of 
harm 
reduction 
card for 
our files 
and give 
original to 
participant
•  Offer 
referrals, if 
applicable

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Intervention Overview
Intro
ducti
on
•  Explain 
study 
participati
on and 
purpose of 
counseling 
session
•  Review 
definitions 
(if needed)
•  Assess 
opioid use
Witn
esse
d 
Over
dose
•  Discuss 
most 
recent 
witnessed 
overdose
•  Assess 
participant
's 
knowledge 
of how to 
recognize 
and define 
an 
overdose
•  Begin to 
idenitfy 
risk factors 
for 
overdose
•  Begin to 
elicit 
motivation 
for 
behavior 
change
Perso
nal 
Over
dose
•  Discuss 
participant
's most 
recent 
overdose
•  Assess 
view of 
own 
overdose 
risk
•  Identify 
risk factors 
for 
overdose
•  Begin to 
elicit 
motivation 
for 
behavior 
change
Risk 
Behav
iors 
and 
Preve
ntion
•  Review 
overdose 
risk factors 
(Handout 
A) & risk 
reduction 
strategies 
(Handout 
B)
Moti
vatio
n & 
Chan
ge 
Plan
•  Reinforce 
principles 
of harm 
reduction 
•  Elicit 
goals and 
motivation 
to reduce 
overdose 
risk
•  Create 
overdose 
prevention 
plan and 
harm 
reduction 
pocket 
card
Over
dose 
Resp
onse
•  Review 
how to 
manage a 
witnessed 
overdose 
(Handouts 
C & D)
Wrap 
Up
•  
Acknowled
ge steps 
taken 
toward 
self-care
•  Thank 
participant 
and 
schedule 
follow-up 
visits
•  Make a 
copy of 
harm 
reduction 
card for 
our files 
and give 
original to 
participant
•  Offer 
referrals, if 
applicable

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57
10.3.
Appendix 3. Descriptions and Dates of Amendments
Amendment: 08/06/2020
1. Adjusted eligibility criterion regarding urine drug screen results. Because of COVID-19 
precautions, one site may be in a new space that may not permit checking of urines. This 
amendment involves a "trusted source verification" protocol in which study staff contact 
professionals referred by the participant to confirm the participant’s recent use of 
opioids. The process includes a detailed SOP for determining the result of the inquiry.
2. Clarified that eligibility criterion allowing potential participants currently treated with 
methadone or buprenorphine for opioid use disorder who report illicit opioid use but test 
negative for illicit opioids on urine drug screen to be enrolled if they test positive for 
cocaine or methamphetamine does not apply for eligibility assessments that do not 
include a urine drug screen.
3. Allow verbal consent and redcap consent collection in some situations due to COVID-19 
precautions.
4. Added COVID-19 related questions and analyses, as well as remote versus in-person visit 
analysis plan, include adjustment to compensation for relevant visits.
5. Provide phone with plan in lieu of other compensation for visits when participant does 
not have personal phone.
Amendment: 12/28/2020
1. Increased screening payment from $10 to $20. 
Amendment: 08/16/2021
1. Added snowball referrals from participants to recruitment methods. Active study 
participants will be compensated $40 for up to five successful referrals to the study.
2. Added to procedures a one-time visit consisting of a brief assessment at the end of study 
participation. The purpose is to validate study activities in the assessment (specifically 
the time-line follow-back). Up to 40 participants will be compensated $50 for this 
assessment. Consent for this visit will be obtained separately.
3. Specify that we will begin to collect COVID-19 vaccination status during the assessment 
at follow-up visits.
Amendment: 05/09/2023

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58
1. Updated the number of participants who will be asked to participate in one-time visit 
consisting of a brief assessment at the end of study participation from 40 to 100.