NIDA CTN Protocol 0150: Personally-Tailored Opioid-overdose and Medication for Opioid Use Disorder (MOUD) Education (TOME) for Pregnant and Postpartum Persons in MOUD: A Pilot Randomized Trial (TOME Trial)
Phase: NA
Conditions: Opioid Use Disorder, Pregnancy Related, Substance Use, Drug Abuse, Drug Abuse in Pregnancy, Drug Addiction
Sponsor: T. John Winhusen, PhD

Study Title: NIDA CTN Protocol 0150: Personally-Tailored Opioid-overdose and Medicaton for 
opioid use disorder (MOUD) Educaton (TOME) for pregnant and postpartum persons in MOUD: 
A pilot randomized trial (TOME trial) 
NCT06262347 
Document Date: 4/9/2024 

NIDA CTN-0150
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March 6, 2024
NIDA CTN Protocol 0150
Personally-Tailored Opioid-overdose 
and Medication for opioid use 
disorder (MOUD) Education (TOME) 
for pregnant and postpartum persons 
in MOUD: A pilot randomized trial 
(TOME trial)
Lead Investigator: T. John Winhusen, PhD
Protocol Managers: Frankie Kropp, MS and Lindsay Bybee, MA
Funded by: Eunice Kennedy Shriver National Institute of Child Health 
and Human Development (NICHD) and National Institute on Drug 
Abuse (NIDA) 
March 6, 2024
Version 1.3

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Lead Investigator 
T. John Winhusen, PhD
Ohio Valley Node
University of Cincinnati
Protocol Managers:
Frankie Kropp, MS
Ohio Valley Node
University of Cincinnati 
Lindsay Bybee, MA
Ohio Valley Node
University of Cincinnati 
Data Analyst/Statistician:
Daniel Lewis
Ohio Valley Node
University of Cincinnati 
CCTN Scientific Officer:
Carmen Rosa, MS
National Institute on Drug Abuse

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TABLE OF CONTENTS
1.0
LIST OF ABBREVIATIONS ...............................................................................................5
2.0
STUDY SCHEMA...............................................................................................................6
3.0
STUDY SYNOPSIS ............................................................................................................7
3.1
STUDY OBJECTIVES ......................................................................................................7
3.2
STUDY DESIGN .............................................................................................................7
3.3
STUDY POPULATION......................................................................................................7
3.4
TREATMENTS ................................................................................................................7
3.5
ASSESSMENTS..............................................................................................................7
3.6
PRIMARY ANALYSIS.......................................................................................................7
4.0
BACKGROUND AND RATIONALE ..................................................................................8
5.0
STUDY OBJECTIVES........................................................................................................9
5.1
PRIMARY OBJECTIVE.....................................................................................................9
5.2
SECONDARY OBJECTIVE................................................................................................9
6.0
STUDY DESIGN...............................................................................................................10
6.1
OVERVIEW OF STUDY DESIGN .....................................................................................10
6.2
NUMBER OF SITES AND PARTICIPANTS.........................................................................10
6.3
STUDY DURATION .......................................................................................................10
6.4
SITE AND PARTICIPANT SELECTION..............................................................................10
6.4.1 Site Selection ............................................................................................................10
6.4.1.1
Site Characteristics ............................................................................................10
6.4.2 Participant Selection..................................................................................................10
6.4.2.1
Inclusion Criteria ................................................................................................10
6.4.2.2
Exclusion Criteria ...............................................................................................11
6.5 POTENTIAL FOLLOW-UP TRIAL..............................................................................................11
7.0
STUDY MEASURES ........................................................................................................12
7.1
KEY OUTCOME MEASURES OF THE PRIMARY OBJECTIVE..............................................12
7.1.1 Primary Outcome - MOUD knowledge score ............................................................12
7.1.2 Key Secondary Outcome – Opioid-overdose knowledge score................................12
7.2
SECONDARY OUTCOME MEASURES .............................................................................12
7.2.1 MOUD Internalized Stigma........................................................................................12
7.2.2 Drug Self-efficacy ......................................................................................................12
7.3
SAFETY MEASURES OF THE PRIMARY OBJECTIVE.........................................................13
7.3.1 Adverse Events (AEs) ...............................................................................................13
7.4
OTHER MEASURES......................................................................................................13
7.4.1 Screening Assessments............................................................................................13
7.4.2 Sample Characteristics .............................................................................................13
7.5
ADMINISTRATIVE FORMS .............................................................................................13
8.0
STUDY PROCEDURES ...................................................................................................15
8.1
STUDY OVERVIEW.......................................................................................................15
8.2
PARTICIPANT RECRUITMENT, PRE-SCREENING, AND CONSENT .....................................15
8.3
SCREENING/BASELINE.................................................................................................15
8.4
RANDOMIZATION PLAN ................................................................................................15

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8.5
PARTICIPANT REIMBURSEMENT ...................................................................................16
8.6
TRIAL DISCONTINUATION .............................................................................................16
9.0
STUDY TREATMENTS....................................................................................................17
9.1
TOME ........................................................................................................................17
9.2
CONTROL....................................................................................................................17
10.0
ANALYTICAL PLAN........................................................................................................18
10.1
STATISTICAL HYPOTHESES FOR PRIMARY OBJECTIVE...................................................18
10.1.1
Key Hypotheses.....................................................................................................18
10.1.2
Secondary Hypotheses..........................................................................................18
10.2
INTENT-TO-TREAT PARTICIPANT POPULATION ..............................................................18
10.3
ANALYSIS PLAN...........................................................................................................18
10.4
SAMPLE SIZE ANALYSIS...............................................................................................18
10.5
INTERIM ANALYSES .....................................................................................................18
10.6
MINORITY/SEX ANALYSES ...........................................................................................18
10.7
POST-HOC ANALYSES .................................................................................................19
11.0
REGULATORY COMPLIANCE, REPORTING, AND MONITORING..............................20
11.1
REGULATORY COMPLIANCE.........................................................................................20
11.2
STATEMENT OF COMPLIANCE.......................................................................................20
11.3
INSTITUTIONAL REVIEW BOARD APPROVAL ..................................................................20
11.4
REGULATORY FILES ....................................................................................................20
11.5
INFORMED CONSENT...................................................................................................21
11.6
PARTICIPANT AND DATA CONFIDENTIALITY...................................................................21
11.6.1
Health Insurance Portability and Accountability Act (HIPAA) ................................22
11.7
INVESTIGATOR ASSURANCES.......................................................................................22
11.7.1
Financial Disclosure/Conflict of Interest.................................................................22
11.8
QUALITY ASSURANCE MONITORING .............................................................................22
11.9
PRISONER CERTIFICATION...........................................................................................23
11.10
PROTECTIONS FOR PREGNANT WOMEN, FETUSES, AND NEONATES..............................23
11.11
RECORDS RETENTION AND REQUIREMENTS.................................................................23
11.12
REPORTING TO SPONSOR............................................................................................23
11.13
AUDITS .......................................................................................................................24
11.14
STUDY DOCUMENTATION.............................................................................................24
11.15
PROTOCOL DEVIATIONS ..............................................................................................24
11.16
SAFETY MONITORING ..................................................................................................25
11.16.1 Data and Safety Monitoring Board (DSMB)...........................................................25
11.16.2 Adverse Events (AEs)............................................................................................25
11.17
TRAINING REQUIREMENTS...........................................................................................25
12.0
DATA MANAGEMENT AND PROCEDURES .................................................................26
12.1 DESIGN AND DEVELOPMENT...............................................................................................26
12.2 SITE RESPONSIBILITIES......................................................................................................26
12.3 DATA CENTER RESPONSIBILITIES.......................................................................................26
12.4 DATA COLLECTION.............................................................................................................26
12.5 DATA ACQUISITION AND ENTRY ..........................................................................................26
12.6 DATABASE TRANSFER/LOCK ..............................................................................................26
12.7 DATA TRAINING .................................................................................................................27
12.8 DATA QA...........................................................................................................................27

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13.0 PUBLIC ACCESS AND DATA SHARING PLAN...............................................................28
14.0 PROTOCOL SIGNATURE PAGE.......................................................................................29
15.0
REFERENCES .................................................................................................................30
16.0 APPENDIX: DATA AND SAFETY MONITORING PLAN...................................................33
16.1 PROTOCOL SUMMARY........................................................................................................33
16.1.1 Protocol Description ..................................................................................................33
16.1.2 Key outcome measures ............................................................................................33
16.1.3 Inclusion/Exclusion Criteria: ......................................................................................33
16.1.4 Sample Size ..............................................................................................................33
16.2 TRIAL MANAGEMENT..........................................................................................................33
16.3 DATA MANAGEMENT AND ANALYSIS....................................................................................34
16.4 QUALITY ASSURANCE ........................................................................................................35
16.5 REGULATORY ISSUES ........................................................................................................36
16.6 TRIAL SAFETY....................................................................................................................36
16.7 TRIAL EFFICACY ................................................................................................................37
16.8 DSM PLAN ADMINISTRATION..............................................................................................37
16.9 DSM BOARD (DSMB) PLAN...............................................................................................38

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1.0
LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
BUP
Buprenorphine
CCTN
Center for Clinical Trials Network
CoC
Certificate of Confidentiality
CRF
Case report form
CTN
Clinical Trials Network
DSMB
Data and Safety Monitoring Board
GCP
Good Clinical Practice
HHS
Department of Health and Human Services
HIPAA
Health Insurance Portability and Accountability Act
IRB
Institutional review board
ITT
Intent-to-Treat
LI
Lead Investigator
MOUD
Medication for opioid use disorder
NIDA
National Institute on Drug Abuse
OHRP
Office for Human Research Protections
OOTAS
Opioid Overdose & Treatment Survey 
OUD
Opioid use disorder
OVN
Ohio Valley Node
PI
Principal Investigator
PP
Pregnant and postpartum 
PRISM
Psychiatric Research Interview for Substance and Mental Disorders
QA
Quality Assurance
RA
Research assistant
RCT
Randomized controlled trial
SAE
Serious Adverse Event
SAMHSA
Substance Abuse and Mental Health Services Administration
SOP
Standard Operating Procedure
SUD
Substance Use Disorder
TOME
Personally-Tailored Opioid-overdose and Medication for opioid use disorder 
(MOUD) Education
UC
University of Cincinnati

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2.0
STUDY SCHEMA
Figure 1. Study Schema
Interested and potentially eligible participants sign informed consent, 
complete screening/baseline, and are randomized
TOME (N=60)
Personally-tailored opioid-overdose and 
MOUD education; naloxone offered
Post-assessment at ~3 weeks post-intervention 
Control (N=60)
Opioid-overdose and MOUD education 
brochures provided; naloxone offered

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3.0
STUDY SYNOPSIS
3.1
Study Objectives
CTN-0150 includes two objectives:

Primary Objective: To evaluate the ability of the Personally-Tailored Opioid-overdose and 
Medication for opioid use disorder (MOUD) Education (TOME) intervention to increase MOUD 
and opioid-overdose knowledge in pregnant and postpartum (PP) persons.

Secondary Objective: To evaluate the ability of TOME to decrease MOUD-related internalized 
stigma and expected difficulty in avoiding drug use. 
3.2
Study Design
This is an intent-to-treat, two-arm, open-label, randomized controlled trial. Eligible participants will 
be randomized in a 1:1 ratio to TOME or Control, balancing on site. Participants will receive the 
assigned intervention following randomization and will complete a three week follow-up 
assessment.
3.3
Study Population
Approximately 120 PP persons will be randomized into the trial. CTN is conducting the Medication 
treatment for Opioid-dependent expectant Mothers (MOMs; CTN-0080) trial to compare mother 
and infant outcomes of pregnant persons with OUD treated with extended-release buprenorphine 
(BUP), relative to sublingual BUP. This study will be conducted with six CTN-0080 sites with 
sufficient census to randomize approximately four participants per month. Eligible participants will 
be pregnant or within 12 months postpartum and will be enrolled in MOUD treatment.
3.4
Treatments
All randomized participants will be offered naloxone. All participants will complete an opioid-
overdose and MOUD knowledge assessment during baseline. TOME participants will be offered 
a 15-minute intervention in which a trained research staff member reviews personal feedback 
reports with the recipient to provide information on the items missed on the knowledge 
assessment. Control participants will be offered three SAMHSA handouts: 1) “Opioid Overdose 
Prevention Toolkit: Safety Advice for Patients and Family Members”; 2) “Opioid Overdose 
Prevention Toolkit: Recovering from Opioid Overdose”; and 3) “Medication-Assisted Treatment 
for Opioid Addiction: Facts for Families and Friends”.  
3.5
Assessments
The primary outcome is MOUD knowledge score. The key secondary outcome is opioid-overdose 
knowledge score. The baseline and 3-week follow-up assessments will ideally occur at the clinic 
site; however, these visits may occur in whole or in part via telemedicine, at other institutionally-
affiliated clinical sites, or elsewhere in the community (including, but not limited to, home visits or 
other community sites affording appropriate safety and confidentiality) as permitted by the 
institution and other regulatory bodies. 
3.6
Primary Analysis
Baseline-Week-3 difference in MOUD knowledge will be tested using linear regression at the 5% 
Type I error rate (two-sided) for the intent-to-treat population. 

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4.0
BACKGROUND AND RATIONALE
From 2010 to 2017, opioid-related maternal deaths increased by 220%.1 Drug overdose deaths, 
particularly deaths involving synthetic opioids like fentanyl, reached record highs in 2020 and 
2021;2 drug overdose is now a leading cause of pregnancy-associated mortality in the United 
States.3 Interventions to decrease overdose risks in pregnant and postpartum (PP) persons are 
lacking and are needed in order to address the epidemic of opioid-related overdoses.3 Our team 
has developed and tested a brief personally-tailored opioid overdose prevention education and 
naloxone distribution (PTOEND) intervention that can be administered by bachelor’s level staff.4,5 
Our PTOEND intervention was designed to expand harm reduction by not only encouraging the 
use of naloxone but also educating individuals about factors that increase risk for opioid-overdose, 
including modifiable behaviors that increase risk. In addition, the PTOEND was designed to 
promote medication for opioid use disorder (MOUD) engagement, which is effective for preventing 
opioid-overdoses6,7 but is underutilized,8 in part due to inaccurate perceptions including 
misconceptions about its side effects and lack of efficacy.9-11 The results of a pre-post study of 
PTOEND suggested that it significantly increased opioid-overdose and MOUD knowledge and 
increased treatment readiness in out-of-treatment adult illicit opioid users having experienced an 
opioid-overdose.5 In addition, the MOUD education intervention was found to significantly 
decrease expected difficulty in avoiding drug use;5  which is important since improved self-efficacy 
has been associated with improved substance use outcomes.12 
The initial study of PTOEND was with out-of-treatment active opioid users but it is also applicable 
for people enrolled in MOUD. First, while MOUD significantly decreases the risk of opioid-
overdose, people enrolled in MOUD still overdose and the risk of overdose is heightened when 
MOUD is discontinued.13 Opioid-overdose education, including information about risk factors for 
overdose, has been found to decrease overdose-risk behaviors5 and, thus, would be expected to 
reduce opioid-overdose risk in individuals who continue to use illicit opioids while enrolled in 
MOUD or who relapse when they stop MOUD treatment. Second, the elements of PTOEND that 
increased readiness for MOUD should also serve to improve engagement and retention in MOUD. 
While the optimal length of MOUD has not been determined, a 6-month minimum is 
recommended.14-16 Six month MOUD retention estimates vary but research suggests an 
estimated 6-month retention rate of 50% for methadone17 and < 50% for buprenorphine.18 There 
is consensus that retention needs to be improved but no evidence-based interventions for 
increasing MOUD retention have been established.19 Stigma is one of the most commonly cited 
barriers to MOUD retention by individuals with OUD.20-22 The PTOEND, which corrects stigma-
eliciting misperceptions (e.g., MOUD is “just replacing one drug with another”, etc.), is 
hypothesized to reduce internalized stigma. Another common barrier to MOUD engagement/ 
retention is inaccurate perceptions of MOUD – including myths about its side effects and lack of 
efficacy.21  We evaluated the impact of the MOUD education component in a small (N=20) pre-
post study of recently-enrolled MOUD patients and found a significant increase in MOUD 
knowledge after MOUD education (p<.01). PTOEND has been found to increase patient’s belief 
in their ability to avoid drug use, which may be the result of correcting MOUD myths, including 
providing information about its effectiveness.5 
The present trial will test a modified version of the PTOEND intervention, referred to as the 
personally-Tailored Opioid-overdose and MOUD Education (TOME) intervention, in pregnant and 
postpartum (PP) persons. Modifications include updating the knowledge assessment/education 
to reflect changes in the drug supply (i.e., the current high prevalence of fentanyl and increasing 
prevalence of xylazine) and the addition of items specific to pregnancy. 

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5.0
STUDY OBJECTIVES
5.1
Primary Objective
The primary objective of this study is to evaluate the ability of TOME to increase MOUD and 
opioid-overdose knowledge in PP persons. 
5.2
Secondary Objective
The secondary objective is to evaluate the ability of TOME to decrease MOUD-related internalized 
stigma and expected difficulty in avoiding drug use.

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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is an intent-to-treat, two-arm, open-label, randomized controlled trial. Eligible participants will 
be randomized in a 1:1 ratio to TOME or Control, balancing on site. Participants will receive the 
assigned intervention following randomization and will complete follow-up assessments at~ 3 
weeks post-randomization. Key outcome measures are: 1) MOUD knowledge (primary); and 2) 
opioid-overdose knowledge (key secondary). 
6.2
Number of Sites and Participants
Approximately 120 participants, recruited from approximately 6 sites, will be randomized into the 
trial. Patients enrolled in MOUD (either buprenorphine or methadone) at the study site who are 
either pregnant or within 12 months postpartum will be recruited for the study. Participants may 
be recruited from a variety of other sources, including advertising if needed. Recruitment 
advertisements will be approved by the Institutional Review Board (IRB). Efforts will be made to 
recruit a study sample that reflects, or exceeds, the proportion of minorities in treatment at the 
sites.
6.3
Study Duration
Enrollment is expected to take place over a period of approximately 6 months. Duration of study 
participation will be approximately 3 – 4 weeks. 
6.4
Site and Participant Selection
6.4.1
Site Selection
CTN is conducting the Medication treatment for Opioid-dependent expectant Mothers (MOMs; 
CTN-008023) trial to compare mother and infant outcomes of pregnant persons with OUD treated 
with extended-release buprenorphine (BUP), relative to sublingual BUP. CTN-0080 has 
completed recruitment but has a very long active treatment phase (i.e., through 12 months post-
partum). Staff need to be retained through the CTN-0080 active treatment phase. The proposed 
study would be conducted with six CTN-0080 sites with sufficient census to enroll randomize 
approximately four participants per month. 
6.4.1.1
Site Characteristics
Participating sites should:
1.
have been a site in CTN-0080;
2.
have sufficient census to meet the target randomization of 4 per month
6.4.2
Participant Selection
6.4.2.1
Inclusion Criteria
Potential participants must be:
1.
18 years of age or older;
2.
pregnant or be within 12 months postpartum;

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3.
enrolled in MOUD (either buprenorphine or methadone) at the study site or affiliated 
clinic where enrollment can be confirmed;
4.
able to understand the study, and having understood, provide written informed consent 
in English
6.4.2.2
Exclusion Criteria
Potential participants must not:
1.
have suicidal or homicidal ideation requiring immediate attention
2.
be currently in jail, prison, or any inpatient overnight facility as required by court of law or 
have pending legal action
6.5 Potential Follow-up Trial
The conceptual model for TOME’s hypothesized ability to increase MOUD treatment retention is 
provided in Figure 2. The present pilot trial is being conducted with active CTN-0080 study sites 
and is limited to the time remaining for CTN-0080 implementation. As a consequence, the pilot 
trial is limited to a 3-week follow-up and, thus, is not testing TOME’s ability to increase MOUD 
retention. Instead, this pilot trial is testing TOME’s impact on the two hypothesized mediators by 
which TOME would improve retention. Finding that TOME significantly increases MOUD 
knowledge and significantly decreases MOUD stigma would provide support for a follow-up trial 
to test TOME’s ability to improve MOUD retention rates.

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7.0 STUDY MEASURES
7.1
Key Outcome Measures of the Primary Objective
7.1.1
Primary Outcome - MOUD knowledge score
The primary outcome is MOUD knowledge as measured by the Opioid Overdose and Treatment 
Awareness Survey (OOTAS) knowledge evaluation. The OOTAS is comprised of 4 sections: 1) 
opioid-overdose risk factors; 2) signs of an opioid-overdose; 3) how to respond to an opioid-
overdose; and 4) misconceptions about MOUD.4 The OOTAS has been successfully used to 
measure MOUD knowledge and knowledge change in two published studies4,5 and in a small 
(N=20) pre-post study of recently-enrolled MOUD patients, which found a significant increase in 
MOUD knowledge after MOUD education (p<.01). For the present trial, the OOTAS has been 
modified to include two additional questions specific to pregnancy (i.e., are methadone and BUP 
recommended during pregnancy and can babies be born addicted as a result of taking methadone 
or BUP during pregnancy).  The modified OOTAS includes 10 true-false questions to assess 
MOUD knowledge, yielding a potential score of 0-10.
7.1.2
Key Secondary Outcome – Opioid-overdose knowledge score
The key secondary outcome is opioid-overdose knowledge as measured by the first three 
sections of the OOTAS. The OOTAS has been successfully used to measure opioid-overdose 
knowledge and knowledge change in two prior studies conducted with individuals with OUD. For 
the present trial, the OOTAS has been modified to include two additional questions to assess the 
participant’s knowledge of the increase risk of opioid-overdose with fentanyl and potential 
increased risk with xylazine. The modified OOTAS includes 31 true-false questions to assess 
opioid-overdose knowledge, yielding a potential score of 0-31.
7.2
Secondary Outcome Measures 
7.2.1
MOUD Internalized Stigma
The Methadone Maintenance Treatment Stigma Mechanisms Scale (MMT-SMS) is a self-report 
questionnaire assessing three dimensions of stigma: anticipated, enacted, and internalized 
stigma.24 The MMT-SMS has demonstrated good internal consistency and validity.24 The MOUD 
education is expected to decrease internalized stigma by countering stigma-inducing myths (e.g., 
methadone/BUP is just replacing one drug with another, etc.) and, thus, the internalized stigma 
score is the outcome of interest. The MMT-SMS was designed for use with any MOUD medication 
and the wording will be modified to assess stigma related to the medication that the participant is 
receiving.
7.2.2
Drug Self-efficacy
Self-efficacy in avoiding drug use will be assessed with the Thoughts about abstinence (TAA) 
instrument.25 This measure assesses the participant’s desire to quit, expected success in quitting 
and estimated difficulty in avoiding drug use.25 Our MOUD education intervention has been found 
to increase expected success in avoiding drug use as measured by the TAA.5 

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7.3
Safety Measures of the Primary Objective
7.3.1
Adverse Events (AEs)
There are not specific guidelines for adverse event (AE) and serious adverse event (SAE) 
reporting for behavioral trials but it is important to assess for potential AEs that could result from 
exposure to a behavioral intervention.26 TOME is a low-risk intervention but staff will assess for 
two AEs that would be of clinical import: 1. Suicidal ideation and 2. Homicidal ideation. Research 
suggests that using the FDA definition of SAEs (i.e., an adverse event that results in any of the 
following outcomes: death; life threatening; requires hospitalization, initial or prolonged; results in 
disability; congenital anomaly; requires intervention to prevent permanent impairment or damage; 
or other significant medical event) for behavioral trials with substance using populations does not 
produce meaningful safety information in that many SAEs are reported but none judged to be 
related to the intervention.27 SAEs will only be reported for events related to a study-defined AE 
(e.g., hospitalization due to suicidal ideation, etc.).
7.4
Other Measures 
7.4.1
Screening Assessments
Pre-screen Interview: The pre-screen interview will include questions about pregnancy/ 
postpartum status and enrollment in MOUD treatment.
Demographics: Items from the PhenX Tier 1 of the Substance Abuse and Addiction core28 will be 
used to collect information on demographic characteristics.
Suicidal and Homicidal Screening Form (PRISM): The Suicide and Homicide Screening Form is 
a structured, reliable interview modified from the Psychiatric Research Interview for Substance 
and Mental Disorders- PRISM29 and will be completed by study staff during screening/baseline. 
A qualified mental health professional must assess participants reporting current suicidal/ 
homicidal intent as specified in the site clinical SOP. For visits held via telemedicine or at an 
external location, research staff will contact a qualified clinician via phone to coordinate an 
assessment via telemedicine as quickly as possible; ideally this assessment will occur while the 
staff and participant are together at the external location.
Treatment and Perinatal Status: The Treatment and Perinatal Status form will be used to assess 
study candidates’ status on study inclusion/exclusion criteria related to pregnancy / postpartum 
status and enrollment in MOUD treatment.
Prisoner Status: The Prisoner Status form will be used to assess study candidates’ status on the 
study exclusion criterion related to prisoner status.
7.4.2
Sample Characteristics
Substance use history: Participants will be asked the frequency with which they used alcohol, 
tobacco, and other drugs of abuse during their last active period of use. The wording for the 
assessment will be taken from the NIDA-Modified ASSIST V2.0, which is a modified version of 
the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test.30 
7.5
Administrative Forms
Locator Form(s): A locator form is used to obtain information to assist in finding participants during 
the study. This form is completed at the Screening/Baseline/Randomization visit and collects 

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contact information including the participant’s current address, email address, phone numbers, 
etc. In order to facilitate locating participants if direct contact efforts are unsuccessful, addresses 
and phone numbers of family/friends who may know how to reach the participant are collected 
along with releases of information.  No information from locator forms is used in data analyses. 
Study Eligibility: This form, which lists all the study inclusion and exclusion criteria, must be 
completed for every participant who has signed informed consent. Eligible participants will be 
randomized; ineligible participants will be excluded and deemed screen failures.
Study Intervention Provided: This form must be completed for every randomized participant. The 
purpose of the form is to capture the elements of the study intervention provided to the participant 
(e.g., naloxone provided, etc.).
Study Completion: This form, which indicates that the participant has formally terminated his/her 
study involvement, must be completed for every participant who has been randomized into the 
study. The purpose of the Study Completion Form is to document: 1) the date on which a 
randomized participant attended their final study visit, 2) whether the participant completed the 
study or ended study involvement prematurely, and 3) if the participant ended study involvement 
prematurely, the reason why that occurred. This form also provides a location for the site PI 
attestation of review of all study data.
Protocol Deviation: This form should be entered into REDCap whenever a protocol deviation 
occurs. This form will document a description of the deviation, how it occurred, the corrective 
action taken to resolve the specific deviation, as well as a description of the plan implemented to 
prevent future occurrences of similar deviations.
Mental Health Follow-up Assessment: This assessment must be completed by a qualified clinician 
if the participant endorses suicidality or homicidality in response to the AE assessment. The 
completion of the Mental Health Follow-up Assessment form requires direct evaluation of the 
participant for suicide/homicide risk by a qualified mental health professional according to the 
site’s specific SOP. This evaluation will ideally take place prior to the participant leaving the study 
visit. For visits held via telemedicine or at an external location, research staff will contact a 
qualified clinician via phone to coordinate an assessment via telemedicine as quickly as possible; 
ideally this assessment will occur while the staff and participant are together at the external 
location.

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8.0
STUDY PROCEDURES
8.1
Study Overview
The schedule of research visits and research assessments for all participants is delineated in 
Table 1. In accordance with the site’s institutional policies and procedures, study visits may occur 
at other locations affiliated with the institution or elsewhere in the community (including, but not 
limited to, home visits or visits at non-affiliated community sites), or via remote contact, such as 
by telephone or other institutionally-approved telemedicine mechanisms. All visits occurring 
outside of the primary research study site will be managed in such a way that there is no increased 
risk to participant safety.
8.2
Participant Recruitment, Pre-screening, and Consent
Potential participants will be primarily recruited from existing clients at participating sites. 
Advertisements may be used, as needed, but all participants must have completed intake at a 
study site to be eligible for randomization. Interested candidates will complete a pre-screen, which 
will include questions about pregnancy/postpartum and MOUD treatment status. Candidates who 
pass the pre-screen will be scheduled for a visit to complete the informed consent, 
screening/baseline, and randomization. The consent procedure will occur during a live interaction 
between the candidate and study staff; however, this interaction may occur face-to-face at the 
study site or at another approved location, or via telemedicine in accordance with institutional 
policies. If still interested after receiving an explanation of the study, the candidate will be given 
an opportunity to review, inquire about, and sign the informed consent form. Any participant who 
has difficulty understanding the information contained in the consent form will be asked to review 
the misunderstood portion(s) of the consent and discuss them with a research staff member until 
they show complete understanding of the information and may thus give full consent. Research 
staff members will work closely with the study candidates in an effort to help them understand the 
requirements of their participation. Persons with literacy problems will be assisted to the extent 
possible. Any participant who is unable to demonstrate understanding of the information 
contained in the informed consent will be excluded from study participation. In the event that the 
consent procedure occurs via telemedicine, the candidate will provide consent via a HIPAA-
compliant electronic system or will be provided with a prepaid shipper/envelope for returning the 
signed consent to the study team. No other study procedures will occur until the signed consent 
is received back from the candidate.
8.3
Screening/Baseline
After signing the informed consent form, the study participant will proceed through 
screening/baseline, which should be completed within a single session. 
8.4
Randomization Plan
Eligible participants will be randomized in a 1:1 ratio, stratified by site, to TOME or Control. 
Research staff will randomize participants to the TOME or Control arm, using REDCap’s 
randomization module; the randomization sequence will be unknown to the research staff.

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Table 1: Overview of Assessments and Procedures
Research Visits
Screen/baseline/
randomization
Week 3 visit
As Needed
Screening Assessments
Pre-screen interview
X
Informed Consent
X
Demographics
X
Treatment and Perinatal Status
X
Prisoner Status 
X
PRISM-Suicide/Homicide
X
Sample Characteristics
Substance use history
X
Safety Assessments
Adverse events
X
Efficacy Assessments
Opioid Overdose and Treatment 
Awareness Survey  (OOTAS)
X
X
Methadone Maintenance Treatment 
Stigma Mechanisms Scale (MMT-SMS
X
X
Thoughts about abstinence
X
X
Administrative Forms
Locator information form
X
Study Eligibility
X
Study Intervention Provided
X
Study Completion
X
Protocol Deviation
X
Mental Health Follow-up Assessment
X
8.5
Participant Reimbursement
Participants will be reimbursed for their transportation, inconvenience, and time. The form of this 
reimbursement will be determined by the study sites. Participants will be reimbursed $45 for 
completing screening/baseline and $30 for completing the Week 3 visit.  
8.6
Trial Discontinuation
The study sponsor has the right to discontinue the investigation at any time.

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9.0
STUDY TREATMENTS
All randomized participants will be offered naloxone. 
9.1
TOME
The TOME intervention is a modified version of the PTOEND intervention.5 Modifications include 
updating the knowledge assessment/education to reflect changes in the drug supply (i.e., the 
current high prevalence of fentanyl and increasing prevalence of xylazine) and the addition of 
items specific to pregnancy. Like PTOEND, TOME is a computer-guided intervention which 
utilizes REDCap31 to complete assessments and automatically generate personally-tailored 
feedback reports; the use of REDCap, which is an NIH-supported, secure, web-based research 
data platform, limits the technological costs of the intervention to the cost of an internet connection 
and a computer tablet.
TOME entails a trained RA: 1) administering a REDCap survey to assess an individual’s opioid-
overdose /MOUD knowledge; and 2) reviewing the personal feedback reports with the recipient. 
In the present study, the REDCap survey will be administered to all participants at baseline with 
only the TOME participants receiving the personal feedback reports. Opioid-overdose /MOUD 
knowledge is assessed with the OOTAS; see Winhusen et al4 for information about the survey. In 
brief, the OOTAS is comprised of 4 sections: 1) opioid-overdose risk factors; 2) signs of an opioid-
overdose; 3) how to respond to an opioid-overdose; and 4) misconceptions about MOUD. The 
first 3 sections include only evidence-based items supported by a literature review, while items 
for the fourth section were based on both a literature review and on input from the medical staff 
of the University of Cincinnati-affiliated methadone program. For the present trial, the OOTAS has 
been modified to include four additional questions: two to assess the participant’s knowledge of 
the increased risk of opioid-overdose with fentanyl and possible increased risk with xylazine and 
two MOUD knowledge questions specific to pregnancy (i.e., are methadone and BUP 
recommended during pregnancy and can babies be born addicted as a result of taking methadone 
or BUP during pregnancy). The Opioid Overdose & Treatment Survey (OOTAS) Feedback Report 
is generated from the OOTAS and includes a section corresponding to each of the four sections 
of the OOTAS. The report provides feedback on the questions answered incorrectly by the 
participant to provide targeted knowledge enhancement, including the correction of 
misconceptions about MOUD. TOME participants will be offered a copy of their personalized 
OOTAS Feedback Report; either a physical or electronic copy may be provided.
Training: Trainees will receive a training manual. Training sessions will provide didactic training 
on the background and rationale of the study, basic listening strategies, a review of the 
personalized OOTAS Feedback Report, and specific instruction on delivery of the TOME.  
9.2
Control
Participants randomized to the control condition will be offered three SAMHSA handouts: 1) 
“Opioid Overdose Prevention Toolkit: Safety Advice for Patients and Family Members”;32 2) 
“Opioid Overdose Prevention Toolkit: Recovering from Opioid Overdose”;33 and 3) “Medication-
Assisted Treatment for Opioid Addiction: Facts for Families and Friends”.34 These handouts can 
be offered as physical copies or electronically.

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10.0 ANALYTICAL PLAN
10.1
Statistical Hypotheses for Primary Objective
10.1.1
Key Hypotheses 
It is hypothesized that the TOME, relative to the control, group will have a greater increase in: 1) 
MOUD knowledge (primary); and 2) opioid-overdose knowledge (key secondary).
10.1.2
Secondary Hypotheses
It is also hypothesized that the TOME, relative to the control, group will have a significantly greater 
decrease in: 1) internalized stigma and 2) estimated difficulty in avoiding drug use.
10.2
Intent-to-Treat Participant Population
The intent-to-treat (ITT) population is defined as the participants who are randomized.
10.3
Analysis Plan
Each outcome measure will be analyzed for the intent-to-treat population. All statistical tests will 
be conducted at the 5% Type I error rate (two-sided). All regressions will use outcome as the 
response variable, treatment (TOME vs. Control) as the covariate of interest, and baseline 
outcome as a supporting covariate. Site and site-by-treatment will be initially included as 
supporting covariates and dropped if they are not significant. Baseline-Week-3 continuous 
outcomes such as the difference in MOUD knowledge will be tested using linear regressions. The 
Pearson Chi-Square test will be used to test for treatment group differences in AEs.
10.4
Sample Size Analysis
In our published PTOEND pre-post study we were able to detect a statistically significant increase 
in opioid-overdose and MOUD knowledge with 80 enrolled participants.5 In an unpublished pre-
post evaluation of the MOUD education component in patients recently enrolled in MOUD (either 
buprenorphine or methadone), a sample size of 40 was sufficient to detect a statistically significant 
increase in mean correct responses from baseline (6.1, SD=1.5) to post-PTOEND (7.3, SD=1.1). 
Assuming a two-sided test, an α= .05, that ≥88% of enrolled participants attend the week 3 visit, 
and mean correct post-intervention responses of 7.3 for the TOME and 6.7 for the Control group, 
the target sample size of 120 will provide 80% power to detect the difference as statistically 
significant. 
10.5
Interim Analyses
This trial has a relatively short recruitment period (approximately 6 months) and no interim 
analyses are planned. 
10.6
Minority/Sex Analyses
In accordance with National Institutes of Health guidelines, modelling of the key outcomes will be 
completed to determine whether treatment response was significantly affected by participant 
minority status using an interaction term between treatment arm and minority status being 
considered.

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10.7
Post-hoc Analyses
In addition to the analyses described above, a number of post-hoc analyses may be completed. 
An example of a possible analysis includes an exploration of participant screening/baseline 
variables that are predictive of outcome.

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11.0 REGULATORY COMPLIANCE, REPORTING, AND MONITORING
11.1
Regulatory Compliance
Written approval by the Institutional Review Board (IRB) of record for the study protocol, consent 
form, other supporting documents, and any advertising for participant recruitment will be provided 
to the sites prior to being utilized in the study. Any amendments to the protocol or consent 
materials must be approved by the IRB of record before they are implemented. Unanticipated 
problems involving risk to study participants will be promptly reported to, and reviewed, by the 
IRB of record, according to its usual procedures. Annual progress reports and local SAE reports 
will be submitted to the IRB, according to its usual procedures.
The study will be registered and updated as needed in www.ClinicalTrials.gov.
11.2
Statement of Compliance
This study will be conducted in accordance with the current version of the protocol, in full 
conformity with the ethical principles outlined in the Declaration of Helsinki, the Regulations for 
the Protection of Human Subjects codified in the International Council for Harmonisation GCP 
Guidelines, and all other applicable regulatory requirements. An Operations Manual will be 
provided as a reference guide and study quality assurance tool.
11.3
Institutional Review Board Approval
Per NOT-OD-16-094, the University of Cincinnati IRB (UC IRB) will be the IRB of record for the 
protocol and will provide study oversight in accordance with 45 CFR 46. Participating institutions 
will be asked to agree to rely on the UC IRB and will enter into reliance/authorization agreements 
for Protocol CTN-0150, as needed. The UC IRB will follow written procedures for reporting its 
findings and actions to appropriate officials at each participating institution.
Prior to initiating the study, the lead team will ensure that the local IRB at each site has entered 
into a reliance/authorization agreement with the IRB of record (UC IRB) and that written IRB 
approval has been secured from the IRB of record for each site involved. If changes to the study 
protocol become necessary, protocol amendments will be submitted in writing for approval by the 
IRB of record prior to implementation. In addition, the IRB of record will approve all consent forms, 
recruitment materials, any materials given to the participant, and any changes made to these 
documents throughout study implementation. For changes to the consent form, a decision will be 
made regarding whether previously consented participants need to be re-consented. IRB 
continuing review will be performed annually. Each site principal investigator (PI) is responsible 
for maintaining copies of all current IRB approval notices, IRB-approved consent documents, and 
approval for all protocol modifications. These materials must be received by the investigator prior 
to the initiation of research activities at the site and must be available at any time for audit.
11.4
Regulatory Files
Essential documents are those documents which individually and collectively permit evaluation of 
the conduct of a trial and the quality of the data produced. These documents serve to demonstrate 
the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all 
applicable regulatory requirements. The regulatory files should contain all essential documents, 
other 
required 
regulatory 
documents, 
study-specific 
documents, 
and 
all 
important 
communications. 

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11.5
Informed Consent
The informed consent form is a means of providing information regarding the trial to a prospective 
participant and allows for an informed decision about participation in the study. Informed consent 
continues throughout the individual’s study participation. Each study site must have the study 
informed consent approved by the UC IRB. Prior to initial submission to the IRB the consent form 
must be sent to the Lead Node to confirm that each consent form contains the required elements 
of informed consent as delineated in 21 CFR 50.25(a) and CFR 46.116(b), pertinent additional 
elements detailed in 21 CFR 50.25(b) and 45 CFR 46.116(c), and any applicable Center for 
Clinical Trials Network (CCTN) requirements. Every study participant is required to sign a valid, 
IRB-approved, current version of the study informed consent form prior to the initiation of any 
study related procedures. The site must maintain the original signed informed consent for every 
participant in a locked, secure location that is in compliance with all applicable IRB and institutional 
policies and that is accessible for quality assurance and study monitor review. Every study 
participant should be given a copy of the signed consent form.
Prior to signing the informed consent form, research staff who are knowledgeable about the study 
will explain the study to the potential participant and provide the participant with a copy of the 
consent to read during the consent process and to keep for reference. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and 
potential risks of the study and their rights as research participants. Extensive discussion of risks 
and possible benefits will be provided to the participants. Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. If the participant is 
interested in participating in the study, a researcher who is authorized by the PI to obtain informed 
consent and approved by the UC IRB, will review each section of the informed consent form in 
detail, answer any of the participant’s questions, and determine if the participant comprehends 
the information provided by administering the comprehension tool. The participant will consent by 
signing and dating the consent documents. The person obtaining consent will also sign and date 
the consent document. The consent must be properly executed and complete to be valid. It is 
strongly recommended that another research staff member review the consent after it is signed 
to ensure that the consent is properly executed and complete.
Staff members delegated by the PI to obtain informed consent must be listed on the Delegation 
of Responsibility and Staff Signature Log. All persons obtaining consent must have completed 
appropriate GCP and Human Subjects Protection training, as mandated by NIDA standard 
operating procedures.
The informed consent form must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect a 
participant’s participation in the trial. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. The participant will be informed that their participation is 
voluntary, and they may withdraw from the study at any time, for any reason, without penalty. 
Individuals who refuse to participate or who withdraw from the study will be treated without 
prejudice.
11.6
Participant and Data Confidentiality
Confidentiality will be maintained in accordance with all applicable federal regulations and/or 
state/Commonwealth law and regulations. By signing the protocol signature page, the investigator 
affirms that information furnished to the investigator by NIDA will be maintained in confidence and 
such information will be divulged to the IRB of record; affiliated institution; and employees only 

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under an appropriate understanding of confidentiality with such board or committee, affiliated 
institution, and employees.
This study will be covered by a federal Certificate of Confidentiality (CoC), which protects 
identifiable research information from forced disclosure. This protects participants against 
disclosure of sensitive information (e.g., drug use). The CoC allows the investigator and others 
who have access to research records to permanently refuse to disclose identifying information on 
research participation in any civil, criminal, administrative, legislative, or other proceeding, 
whether at the federal, state, or local level, excepting certain circumstances.
By protecting researchers and institutions from being compelled to disclose information that would 
identify research participants, the CoC helps achieve the research objectives and promote 
participation in studies by helping assure confidentiality and privacy to participants. Participant 
records will be held confidential by the use of study codes for identifying participants on CRFs, 
secure storage of any documents that have participant identifiers, secure transport of study 
documents while performing study visits at any off-site location, and secure computing procedures 
for entering and transferring electronic data.
11.6.1
Health Insurance Portability and Accountability Act (HIPAA)
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. Releases of participant identifying information that are permitted 
by the HIPAA regulations, but which are prohibited by other applicable federal regulations and/or 
state/Commonwealth law and regulation, are prohibited. Sites will be responsible for 
communicating with the IRB of record and obtaining the appropriate approvals or waivers to be in 
regulatory compliance.
11.7
Investigator Assurances
Each site must file (or have previously filed) a Federalwide Assurance with the Department of 
Health and Human Services (HHS) Office for Human Research Protection setting forth the 
commitment of the organization to establish appropriate policies and procedures for the protection 
of human research subjects in alignment with 45 CFR 46, Subpart A, with documentation sent to 
NIDA or its designee. Research covered by these regulations cannot proceed in any manner prior 
to NIDA receipt of certification that the research has been reviewed and approved by the IRB 
provided for in the assurance (45 CFR 46.103). Prior to initiating the study, the PI at each study 
site will sign a protocol signature page, providing assurances that the study will be performed 
according to the standards stipulated therein.
11.7.1
Financial Disclosure/Conflict of Interest
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. Everyone with decision-making responsibilities regarding the protocol will confirm to the 
sponsor annually that they have met their institutional financial disclosure requirements.
11.8
Quality Assurance Monitoring
In accordance with federal regulations, the study sponsor is responsible for ensuring proper 
monitoring of a clinical trial and ensuring that the trial is conducted in accordance with the protocol. 
Qualified monitors will oversee aspects of site conformity to make certain the site staff is operating 
within the confines of the protocol, and in accordance with GCP. This includes but is not limited 
to protocol compliance, documentation auditing, and evaluating whether the informed consent 

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process is being correctly followed and documented. Non-conformity with protocol and federal 
regulations can be reported as a protocol deviation and submitted to the study sponsor and study 
IRB for further review.
Qualified node personnel (Node Protocol Managers and/or Quality Assurance (QA) monitors) or 
other designated party(ies) will provide site management for each site during the trial. Node QA 
personnel or other designated party(ies) will audit source documentation, including informed 
consent forms and HIPAA forms. This will take place as specified by the local protocol team, node 
PI or lead team and will occur as often as needed to help prevent, detect, and correct problems 
at the study sites. Node QA personnel will verify that study procedures are properly followed and 
that site staff members are trained and able to conduct the protocol appropriately. If the node 
staff’s review of study documentation indicates that additional training of study personnel is 
needed, node staff will undertake or arrange for that training. 
11.9
Prisoner Certification
As per 45 CFR 46 Subpart C, there are additional protections pertaining to prisoners as study 
participants. A prisoner is defined as any individual involuntarily confined or detained in a penal 
institution. The term is intended to encompass individuals sentenced to such an institution under 
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment 
procedures which provide alternatives to criminal prosecution or incarceration in a penal 
institution, and individuals detained pending arraignment, trial, or sentencing. Prisoners will not 
participate in the present study.  
11.10 Protections for Pregnant Women, Fetuses, and Neonates
As per 45 CFR 46 Subpart B, there are additional protections pertaining to pregnant women, 
fetuses, and neonates involved in research. Pregnancy encompasses the period of time from 
implantation until delivery. Fetus is defined as the product of conception from implantation until 
delivery. In order to meet these additional protections, study staff will abide by conditions outlined 
in 45 CFR 46.201-206. Potential participants will be fully informed regarding the reasonably 
foreseeable impact of the research on the fetus or neonate.
11.11 Records Retention and Requirements
Research records for all study participants (e.g., CRFs, source documents, signed consent forms, 
audio and video recordings, and regulatory files) are to be maintained by the investigator in a 
secure location for a minimum of 3 years after the study is completed and closed. These records 
are also to be maintained in compliance with IRB, state and federal requirements, whichever is 
longest. The sponsor and LI must be notified in writing and acknowledgment must be received by 
the site prior to the destruction or relocation of research records.
11.12 Reporting to Sponsor
The site PIs agree to submit accurate, complete, legible and timely reports to the Sponsor, as 
required. These include, but are not limited to, reports of any changes that significantly affect the 
conduct or outcome of the trial or increase risk to study participants. At the completion of the trial, 
the LI will provide a final report to the Sponsor.
11.13 Audits
The Sponsor has an obligation to ensure that this trial is conducted according to GCP guidelines 
and may perform quality assurance audits for protocol compliance. The LI and authorized staff 

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from the Ohio Valley Node; the National Institute on Drug Abuse Clinical Trials Network (NIDA 
CTN, the study sponsor); monitors from the site’s local Node, and other agencies such as the 
HHS, the OHRP and the IRB of record may inspect research records for verification of data, 
compliance with federal guidelines on human participant research, and to assess participant 
safety.
11.14 Study Documentation
Each participating site will maintain appropriate study documentation for this trial, in compliance 
with ICH E6 and regulatory and institutional requirements for the protection of confidentiality of 
participants. Study documentation includes all data-related forms, workbooks, source documents, 
monitoring logs and appointment schedules; sponsor-investigator correspondence, and signed 
protocol and amendments; IRB correspondence; and approved consent form and signed 
participant consent forms. As part of participating in a NIDA-sponsored study, each site will permit 
authorized representatives from NIDA, monitors, or auditors, monitors from the site’s local Node, 
and regulatory agencies to examine (and when permitted by law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety, progress, and 
data validity.
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. If the original recording of an observation is the electronic 
record, that will be considered the source.
11.15 Protocol Deviations
Any departure from protocol-specified procedures and requirements will be classified as either a 
major or minor protocol deviation. The difference between a major and minor protocol deviation 
has to do with the seriousness of the event and the corrective action required. A minor protocol 
deviation is considered an action (or inaction) that by itself is not likely to affect the scientific 
soundness of the investigation or seriously affect the safety, rights, or welfare of a study 
participant. Major protocol deviations are departures that may compromise the participant safety, 
participant rights, inclusion/exclusion criteria, or the integrity of study data and could be cause for 
corrective actions if not rectified or prevented from re-occurrence. Sites will be responsible for 
developing corrective action plans for both major and minor deviations as appropriate. Those 
corrective action plans may be reviewed/approved by the Lead Node with overall approval by the 
IRB of record. All protocol deviations will be monitored at each site for (1) significance, (2) 
frequency, and (3) impact on the study objectives, to ensure that site performance does not 
compromise the integrity of the trial. Departures from SOPs not detailed within the protocol will 
not be considered to be protocol deviations.
Protocol deviations will be recorded in REDCap via the Protocol Deviation CRF. The LI must be 
contacted immediately if an unqualified or ineligible participant is randomized into the study or if 
another major protocol deviation occurs.
Each site is responsible for reviewing the IRB of record’s definition of a protocol deviation (minor 
deviation) or violation (major deviation) and understanding which events need to be reported to 
the IRB of record, and when reporting is to be done. Sites must recognize that the CTN and IRB 
definition of a reportable event may differ and act accordingly in following all reporting 
requirements for both entities.

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11.16 Safety Monitoring
11.16.1
Data and Safety Monitoring Board (DSMB)
The MOMs trial has a NIDA CTN DSMB that is responsible for conducting periodic reviews of 
accumulating safety, trial performance, and outcome data. Given the low risk associated with the 
TOME intervention and the brevity of the study time frame, a separate DSMB was not established 
for the TOME trial. Instead, should Dr. Winhusen feel the need for DSMB input (e.g., as the result 
of an AE or SAE etc.) he will request an ad hoc meeting with the MOMs DSMB. 
11.16.2
Adverse Events (AEs) 
There are not specific guidelines for adverse event (AE) and serious adverse event (SAE) 
reporting for behavioral trials but it is important to assess for potential AEs that could result from 
exposure to a behavioral intervention.26 TOME is a low-risk intervention but staff will assess for 
two AEs that would be of clinical import: 1. Suicidal ideation and 2. Homicidal ideation. Research 
suggests that using the FDA definition of SAEs (i.e., an adverse event that results in any of the 
following outcomes: death; life threatening; requires hospitalization, initial or prolonged; results in 
disability; congenital anomaly; requires intervention to prevent permanent impairment or damage; 
or other significant medical event) for behavioral trials with substance using populations does not 
produce meaningful safety information in that many SAEs are reported but none judged to be 
related to the intervention.27 SAEs will only be reported for events related to an AE (e.g., 
hospitalization due to suicidal ideation, etc.). The study staff will be trained to monitor for and 
report AEs and SAEs. Additionally, as applicable, sites will submit reporting of AEs/SAEs 
according to IRB requirements. Each of the sites has established practices for managing medical 
and psychiatric emergencies, and the study staff will continue to utilize these procedures. 
Treatment providers at each site will be responsible for monitoring participants for possible clinical 
deterioration or other problems, and for implementing appropriate courses of action.
11.17 Training Requirements 
A Training Plan will be developed to incorporate general training, study-specific training, 
mechanisms for competency assessment as well as a detailed description of training and 
supervision. The CTN-0150 study staff will be trained as specified in the study Training Plan. 
Training will include Human Subjects Protection and GCP as well as protocol-specific training on 
assessments, study interventions, safety and safety event reporting, study visits and procedures, 
data management, and quality assurance. The Lead Node is primarily responsible for 
development and delivery of study-specific training related to the study intervention(s) and 
procedures. 
In addition to general and study-specific training, the Training Plan will include a description of 
the delivery methods to be used for each training module (e.g., via self-study, online, webcast, or 
teleconference). Study staff is required to complete institutionally-required training per their 
research site, IRB, and authorities with regulatory oversight. Tracking of training completion for 
individual staff as prescribed for assigned study role(s) will be documented, endorsed by the site 
PI and the Lead Node. As changes occur in the prescribed training, the Training Plan and training 
documentation tracking forms will be amended to reflect these adjustments.

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12.0 DATA MANAGEMENT AND PROCEDURES
12.1 Design and Development
The OVN will be responsible for development of eCRFs, development and validation of the study 
database, ensuring data integrity, and training site and participating research staff on applicable 
data management procedures. The remainder of this section provides an overview of the Data 
Management Plan associated with this protocol. 
12.2 Site Responsibilities
The data management responsibilities of each individual site will be specified by the Lead Node.
12.3 Data Center Responsibilities
The OVN will: 1) develop a Data Management Plan and will conduct data management activities 
in accordance with that plan, 2) provide guidance for eCRFs for the collection of all data required 
by the study, 3) develop data dictionaries for each eCRF that will comprehensively define each 
data element, 4) conduct ongoing data monitoring activities on study data from all participating 
sites, 5) conduct any preliminary analysis data cleaning activities as needed, and 6) conduct final 
study data cleaning.
12.4 Data Collection
The data collection process consists of direct data entry by participants and research staff into 
the REDCap forms and surveys. Data entry into REDCap should be completed according to the 
instructions provided and project specific training. Assessments programmed in REDCap will use 
validation rules, integrity checks, and hard stops as needed to ensure that data are as complete 
and accurate as possible. For instance, validity checks will employ skip logic to ensure certain 
item sets are not available to respondents once initial responses are given. The investigator is 
responsible for maintaining accurate, complete, and up-to-date records, and for ensuring the 
completion of the eCRFs for each research participant.
12.5 Data Acquisition and Entry
Completed forms and electronic data should be entered into the data management system in 
accordance with the CRF Completion Guidelines established by the OVN. Only authorized 
individuals shall have access to electronic CRFs.
12.6 Database Transfer/Lock
Data will be transmitted by the OVN to the NIDA central data repository as requested by NIDA. 
The OVN will conduct final data quality assurance checks and “lock” the study database from 
further modification. The final analysis dataset will be returned to NIDA, as requested, for storage 
and archive. We will comply with the following policy regarding the preparation and transfer of the 
study data:
“Data from CTN trials are posted 18 months after the final database lock or after 
the primary manuscript is published, whichever comes first. All of the data are de-
identified, and only raw data (i.e., no analysis datasets or derived variables) are 

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provided. Data documentation, consisting of all annotated case report forms 
(CRFs), the data dictionary, and de-identification notes, is provided to users to 
assist in data interpretation. Protocol documentation, including a brief study 
description, the study protocol, and a link to the primary manuscript, is also 
provided, and users are encouraged to consult these documents for insight 
regarding proper interpretation of the data.”
12.7 Data Training
The Training Plan for research staff includes provisions for training on assessments, eCRF 
completion guidelines, data management procedures, and the use of REDCap.
12.8 Data QA
To address the issue of data quality, the OVN will follow a standard data monitoring plan. 

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13.0 PUBLIC ACCESS AND DATA SHARING PLAN
This study will comply with the NIH Data Sharing Policy and Implementation Guidance 
(https://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm). 
Primary data for this study will be available to the public in the NIDA data repository, per NIDA 
CTN policy. For more details on data sharing please visit https://datashare.nida.nih.gov/.
The primary outcome(s) publication will be included along with study underlying primary data in 
the data share repository, and it will also be deposited in PubMed Central 
http://www.pubmedcentral.nih.gov/ per NIH Policy (http://publicaccess.nih.gov/).
The planning, preparation, and submission of publications will follow the policies of the 
Publications Committee of the CTN. 

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14.0 PROTOCOL SIGNATURE PAGE
SPONSOR’S REPRESENTATIVE (CCTN SCIENTIFIC OFFICER OR DESIGNEE)
     
Printed Name
Signature
Date
ACKNOWLEDGEMENT BY INVESTIGATOR:

I am in receipt of version 1.3 of the protocol and agree to conduct this clinical study in 
accordance with the design and provisions specified therein.

I agree to follow the protocol as written except in cases where necessary to protect the 
safety, rights, or welfare of a participant, an alteration is required, and the sponsor and 
IRB have been notified prior to the action.

I will ensure that the requirements relating to obtaining informed consent and institutional 
review board (IRB) review and approval in 45 CFR 46 are met.

I agree to personally conduct or supervise this investigation at this site and to ensure that 
all site staff assisting in the conduct of this study are adequately and appropriately trained 
to implement this version of the protocol and that they are qualified to meet the 
responsibilities to which they have been assigned.

I agree to comply with all the applicable federal, state, and local regulations regarding the 
obligations of clinical investigators as required by the Department of Health and Human 
Services (HHS), the state, and the IRB.
SITE’S PRINCIPAL INVESTIGATOR
     
Printed Name
Signature
Date
Clinical Site Name 
     
Node Affiliation 
     

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Overdose Deaths in the US Before and During the COVID-19 Pandemic. JAMA psychiatry. 2023.
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Bruzelius E, Martins SS. US trends in drug overdose mortality among pregnant and 
postpartum persons, 2017-2020. JAMA. 2022;328(21):2159-2161.
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Winhusen T, Theobald J, Lewis D, Wilder CM, Lyons MS. Development and initial testing 
of a tailored telephone intervention delivered by peers to prevent recurring opioid-overdoses 
(TTIP-PRO). Health Education Research. Apr 2016;31(2):146-160.
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Winhusen T, Wilder C, Lyons MS, Theobald J, Kropp F, Lewis D. Evaluation of a 
personally-tailored opioid overdose prevention education and naloxone distribution intervention 
to promote harm reduction and treatment readiness in individuals actively using illicit opioids. 
Drug Alcohol Depend. Nov 1 2020;216:108265.
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Larochelle MR, Stopka TJ, Xuan Z, Liebschutz JM, Walley AY. Medication for Opioid Use 
Disorder After Nonfatal Opioid Overdose and Mortality. Annals of internal medicine. Mar 19 
2019;170(6):430-431.
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Sordo L, Barrio G, Bravo MJ, et al. Mortality risk during and after opioid substitution 
treatment: systematic review and meta-analysis of cohort studies. Bmj. Apr 26 2017;357:j1550.
8.
Volkow ND, Wargo EM. Overdose Prevention Through Medical Treatment of Opioid Use 
Disorders. Annals of internal medicine. Aug 7 2018;169(3):190-192.
9.
Peterson JA, Schwartz RP, Mitchell SG, et al. Why don't out-of-treatment individuals enter 
methadone treatment programmes? International Journal of Drug Policy. Jan 2010;21(1):36-42.
10.
Uebelacker LA, Bailey G, Herman D, Anderson B, Stein M. Patients' Beliefs About 
Medications are Associated with Stated Preference for Methadone, Buprenorphine, Naltrexone, 
or no Medication-Assisted Therapy Following Inpatient Opioid Detoxification. Journal of 
substance abuse treatment. Jul 2016;66:48-53.
11.
Zaller ND, Bazazi AR, Velazquez L, Rich JD. Attitudes toward methadone among out-of-
treatment minority injection drug users: implications for health disparities. International journal of 
environmental research and public health. Feb 2009;6(2):787-797.
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Witkiewitz K, Pfund RA, Tucker JA. Mechanisms of behavior change in substance use 
disorder with and without formal treatment. Annual review of clinical psychology. 2022;18:497-
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Brandt L, Hu M-C, Liu Y, et al. Risk of experiencing an overdose event for patients 
undergoing treatment with medication for opioid use disorder. American Journal of Psychiatry. 
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14.
Winhusen T, Walley A, Fanucchi LC, et al. The Opioid-overdose Reduction Continuum of 
Care Approach (ORCCA): Evidence-based practices in the HEALing Communities Study. Drug 
Alcohol Depend. Dec 1 2020;217:108325.
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Williams AR, Nunes EV, Bisaga A, et al. Developing an opioid use disorder treatment 
cascade: A review of quality measures. Journal of substance abuse treatment. Aug 2018;91:57-
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National Quality Forum (NQF). Behavioral health 2016–2017: Technical report. 2017; 
https://www.qualityforum.org/Publications/2017/08/Behavioral_Health_2016-
2017_Final_Report.aspx. Accessed November 10, 2022.
17.
Bao YP, Liu ZM, Epstein DH, Du C, Shi J, Lu L. A meta-analysis of retention in methadone 
maintenance by dose and dosing strategy. The American journal of drug and alcohol abuse. 
2009;35(1):28-33.
18.
Morgan JR, Schackman BR, Leff JA, Linas BP, Walley AY. Injectable naltrexone, oral 
naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid 
use disorder in a United States commercially insured population. Journal of substance abuse 
treatment. 2018;85:90-96.
19.
Chan B, Gean E, Arkhipova-Jenkins I, et al. Retention Strategies for Medications for 
Addiction Treatment in Adults With Opioid Use Disorder: A Rapid Evidence Review. . AHRQ 
Publication No. 20-EHC012. Rockville, MD: Agency for Healthcare Research and Quality; 2020.
20.
Mackey K, Veazie S, Anderson J, Bourne D, Peterson K. Barriers and facilitators to the 
use of medications for opioid use disorder: a rapid review. Journal of general internal medicine. 
2020;35:954-963.
21.
Randall-Kosich O, Andraka-Christou B, Totaram R, Alamo J, Nadig M. Comparing 
reasons for starting and stopping methadone, buprenorphine, and naltrexone treatment among a 
sample of white individuals with opioid use disorder. Journal of Addiction Medicine. 
2020;14(4):e44-e52.
22.
Anvari MS, Kleinman MB, Massey EC, et al. "In their mind, they always felt less than": The 
role of peers in shifting stigma as a barrier to opioid use disorder treatment retention. Journal of 
substance abuse treatment. Jul 2022;138:108721.
23.
Winhusen T, Lofwall M, Jones HE, et al. Medication treatment for opioid use disorder in 
expectant mothers (MOMs): Design considerations for a pragmatic randomized trial comparing 
extended-release and daily buprenorphine formulations. Contemporary clinical trials. Jun 
2020;93:106014.
24.
Smith LR, Mittal ML, Wagner K, Copenhaver MM, Cunningham CO, Earnshaw VA. Factor 
structure, internal reliability and construct validity of the Methadone Maintenance Treatment 
Stigma Mechanisms Scale (MMT-SMS). Addiction. Feb 2020;115(2):354-367.
25.
Hall SM, Havassy BE, Wasserman DA. Effects of commitment to abstinence, positive 
moods, stress, and coping on relapse to cocaine use. J Consult Clin Psychol. 1991;59(4):526.
26.
Papaioannou D, Cooper C, Mooney C, Glover R, Coates E. Adverse event recording failed 
to reflect potential harms: a review of trial protocols of behavioral, lifestyle and psychological 
therapy interventions. Journal of Clinical Epidemiology. 2021;136:64-76.

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27.
Petry NM, Roll JM, Rounsaville BJ, et al. Serious adverse events in randomized 
psychosocial treatment studies: safety or arbitrary edicts? J Consult Clin Psychol. Dec 
2008;76(6):1076-1082.
28.
Hamilton CM, Strader LC, Pratt JG, et al. The PhenX Toolkit: get the most from your 
measures. American journal of epidemiology. 2011;174(3):253-260.
29.
Hasin DS, Trautman KD, Miele GM, Samet S, Smith M, Endicott J. Psychiatric Research 
Interview for Substance and Mental Disorders (PRISM): reliability for substance abusers. 
American Journal of Psychiatry. 1996;153(9):1195-1201.
30.
Humeniuk R, Ali R, Babor TF, et al. Validation of the alcohol, smoking and substance 
involvement screening test (ASSIST). Addiction. 2008;103(6):1039-1047.
31.
Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Building an international 
community of software platform partners. Journal of biomedical informatics. Jul 2019;95:103208.
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Substance Abuse and Mental Health Services Administration. Opioid Overdose 
Prevention Toolkit: Safety Advice for Patients and Family Members. [Internet]. 2018; 
https://store.samhsa.gov/sites/default/files/d7/priv/safety-advice-for-patients-family-
members.pdf. Accessed July 7, 2023.
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Prevention 
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Treatment for Opioid Addiction: Facts for Families and Friends. [Internet]. 2011; 
https://portal.ct.gov/-/media/DMHAS/Opioid-Resources/MATInfoFamilyFriendspdf.pdf.

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16.0 Appendix: Data and Safety Monitoring Plan 
16.1 Protocol Summary
16.1.1 Protocol Description
The present trial will test a modified version of the PTOEND intervention, referred to as the 
personally-Tailored Opioid-overdose and MOUD Education (TOME) intervention, in pregnant and 
postpartum (PP) persons. The primary objective of this study is to evaluate the ability of TOME to 
increase MOUD and opioid-overdose knowledge in PP persons. The secondary objective is to 
evaluate the ability of TOME to decrease MOUD-related internalized stigma and expected 
difficulty in avoiding drug use.
16.1.2 Key outcome measures
The primary outcome is MOUD knowledge score. The key secondary outcome is opioid-overdose 
knowledge score.
16.1.3 Inclusion/Exclusion Criteria: 
Participant Inclusion Criteria 
Potential participants must be:
1.
18 years of age or older;
2.
pregnant or be within 12 months postpartum;
3.
enrolled in MOUD (either buprenorphine or methadone) at the study site or affiliated 
clinic where enrollment can be confirmed;
4.
able to understand the study, and having understood, provide written informed consent 
in English
Participant Exclusion Criteria 
Potential participants must not:
1.
have suicidal or homicidal ideation requiring immediate attention
2.
be currently in jail, prison, or any inpatient overnight facility as required by court of 
law or have pending legal action
16.1.4 Sample Size
Approximately 120 PP persons will be randomized into the trial.
.
16.2 Trial Management
1.
List of participating enrolling clinics or data collection centers: The participating study sites 
are: 1) Gateway Community Services (Jacksonville, FL); 2) Marshall Health (Huntington, WV); 
3) Medical University of South Carolina (Charleston, SC); 4) Pregnancy Recovery 

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Center/Magee Women's Hospital (Pittsburgh, PA); 5) SUPeRAD/ University of Utah Health 
System (Salt Lake City, UT); and 6) Vanderbilt University Medical Center (Nashville, TN).
2.
Project timetable: This study will take approximately 15 months to complete which includes 4 
months for protocol development, 2 months for pre-implementation, 6 months of active study 
implementation, and 3 months for closeout and data analysis.  
3.
Target population distribution: Based on the enrollment in the MOMs trial and the sites 
participating in TOME, the target population distribution is: 
For the Targeted/Planned Enrollment Table
 
 
 
Ethnic Category
Female
Hispanic or Latino (2%)
2
Not Hispanic or Latino (98%)
118
Unknown ethnicity
0
Ethnic Category All
120
 
 
Racial Categories
 
American Indian/ Alaska Native (1%)
1
Asian (1%)
1
Native Hawaiian or Other Pacific Islander (0%)
0
Black or African American (7.7%)
9
White (83.8%)
101
Multirace (5.2%)
6
Racial unknown/other (1.3%)
2
Racial Categories Total
120
16.3 Data Management and Analysis
1.
Data acquisition and transmission: Information will be obtained through REDCap, a web-
based electronic data capture and management system. All research staff will be trained 
in Good Clinical Practice (GCP) guidelines. All data will be de-identified. Only research 
staff members directly involved with the study will have access to identifying information 
for the participants.
2.
Data entry methods: De-identified demographic and clinical data will be managed in 
REDCap, a software toolset and workflow methodology for collection and management 
of clinical research data developed by Vanderbilt University, in collaboration with 
institutional partners including the University of Cincinnati Academic Health Center. Only 
the necessary study personnel will have access to the database.
3.
Data analysis plan: All analyses will be completed on the intent-to-treat (ITT) sample 
using SAS, Version 9.4 (SAS Institute, Inc.). Statistical tests will be conducted at a 5% 
Type I error rate (two-sided) for all measures. No interim efficacy analyses or adaptive 
features are planned. 

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4.
Efficacy Analyses: 
Each outcome measure will be analyzed for the intent-to-treat population. All statistical 
tests will be conducted at the 5% Type I error rate (two-sided). All regressions will use 
outcome as the response variable, treatment (TOME vs. Control) as the covariate of 
interest, and baseline outcome as a supporting covariate. Site and site-by-treatment will 
be initially included as supporting covariates and dropped if they are not significant. 
Baseline-Week-3 continuous outcomes such as the difference in MOUD knowledge will 
be tested using linear regressions. The Pearson Chi-Square test will be used to test for 
treatment group differences in AEs.
Sample Size and Power: In our published PTOEND pre-post study we were able to detect 
a statistically significant increase in opioid-overdose and MOUD knowledge with 80 
enrolled participants. In an unpublished pre-post evaluation of the MOUD education 
component in patients recently enrolled in MOUD (either buprenorphine or methadone), a 
sample size of 40 was sufficient to detect a statistically significant increase in mean correct 
responses from baseline (6.1, SD=1.5) to post-PTOEND (7.3, SD=1.1). Assuming a two-
sided test, an α= .05, that ≥88% of enrolled participants attend the week 3 visit, and mean 
correct post-intervention responses of 7.3 for the TOME and 6.7 for the Control group, the 
target sample size of 120 will provide 80% power to detect the difference as statistically 
significant.
5.
Database lock and transfer: At the conclusion of data collection for the study, the OVN will 
perform final data cleaning activities and will “lock” the study database from further 
modification. De-identified versions of these datasets will also be provided to the NIDA CCTN-
designated parties for posting on Datashare, as well as storage and archiving. We will comply 
with the following policy regarding the preparation and transfer of the study data: 
“Data from CTN trials are posted 18 months after the final database lock or after the 
primary manuscript is published, whichever comes first. All of the data are de-identified, 
and only raw data (i.e., no analysis datasets or derived variables) are provided. Data 
documentation, consisting of all annotated case report forms (CRFs), the data dictionary, 
and de-identification notes, is provided to users to assist in data interpretation. Protocol 
documentation, including a brief study description, the study protocol, and a link to the 
primary manuscript, is also provided, and users are encouraged to consult these 
documents for insight regarding proper interpretation of the data.”
16.4 Quality Assurance
1.
Procedures in place to ensure the validity and integrity of the data: Each site will be 
responsible for implementing management and oversight activities during the pre-
initiation, implementation, and close-out phases. These activities will be conducted 
by local project management staff located at each site and aim to provide 
management support to the research team in order to ensure adherence to the 
protocol, SOPs, and regulatory requirements. The Lead Team will provide on-going 
monitoring of study progress and will hold regular study management meetings to 
monitor any emergent problems or ongoing problematic trends, and may additionally 
hold individual meetings with site staff in order to assist in resolving any site-specific 
problems that impact the study.

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2.
Procedures to guarantee the accuracy and completeness of the data during data 
collection, entry, transmission and analysis: Assessments programmed in REDCap 
will use validation rules, integrity checks, and hard stops as needed to ensure that 
data are as complete and accurate as possible. The RA will check any data collected 
by paper source for completeness. 
16.5 Regulatory Issues
1.
Reporting of adverse events (AEs) and serious adverse events (SAEs) to the IRB, 
NIDA, and the FDA: All study-defined SAEs will be reported to the participating site’s 
IRB and NIDA within 72 hours of their discovery. This is a behavioral study and so 
FDA reporting is not required.  All participant information will be de-identified when 
reporting SAEs.  In a case where a reported SAE may be very severe and/or require 
a protocol amendment to be made, Dr. Winhusen may request an ad hoc review by 
the DSMB. All study-defined AEs and SAEs will be entered into a database that is 
de-identified and password protected to ensure confidentiality. 
2.
Reporting of IRB action to NIDA: All communications with and actions of the IRB will 
be kept in a regulatory binder specific for this study. Any protocol changes, 
amendments, or deviations will be submitted to the IRBs and NIDA and the IRB’s 
actions will then be reported to NIDA. Any other IRB actions will be submitted to 
NIDA.
3.
Report of changes or amendments to the protocol: All changes and amendments to 
the protocol will be submitted to the IRBs and NIDA. Only after IRB and NIDA 
approvals are granted will the changes and amendments be implemented. 
4.
Trial stopping rules: Individual study participants will be informed of their right to 
discontinue study participation at any time during the study. The PI may discontinue 
a participant from the trial if deemed clinically appropriate. NIDA has the right to 
discontinue the investigation at any time.
         
5.
Disclosure of conflict of interest: The investigators have no conflicts of interest. 
16.6 Trial Safety
1.
Potential Risks and benefits for participants: 
Risks:

Breach of confidentiality: As with any study, there is a potential risk of loss of 
confidentiality. To maintain participant confidentiality, study records and data will 
be stored in compliance with the International Conference on Harmonization 
(ICH) guidelines. Participant-reported data will be collected through REDCap, 
which is HIPAA-compliant and 21 CFR Part 11- ready for audit trails for tracking 
data manipulation and exports. Emails or text messages between researchers 
and participants, used in retention efforts, will be deleted after information 
exchange. All data will reside on password-protected computers, with only the 
investigators and key members of the research team having access. A variety of 
other measures will be taken to protect confidentiality, including: We will 1) 
assign a unique ID number to each patient to label all components of the 

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protocol, instead of patient names, 2) restrict access to the key linking names 
and ID numbers to key staff and the PI at each site, 3) store any paper with data 
in a locked area. Participants will be told that agents of the IRB, and QA monitors 
will be allowed to inspect sections of their research records related to this study, 
if requested. 

Emotional Discomfort: The participants may experience some emotional 
discomfort from answering sensitive and/or personal questions. There is the 
possibility that the participant will feel bored.   

TOME risks: The education intervention has been found to be safe and 
efficacious in prior studies. Participants may experience embarrassment if they 
receive feedback about missing numerous questions about opioid-overdose and 
MOUD. 
Benefits:  The results of the present study are unlikely to have a direct substantial societal 
impact. However, promising results would be used in support of a larger trial to test the 
efficacy of TOME. The study participants may directly benefit from study participation in 
that they will receive information about risks for overdose, the signs of overdose, how to 
respond to an overdose, and factors that can reduce the risk of an overdose. The study 
participants may also benefit from receiving naloxone. Consequently, the risk/benefit ratio 
is favorable and conduct of the research well justified.
2. Collection and management of AEs and SAEs: In general, the risks associated with trials 
employing behavioral interventions are presumed minimal relative to those evaluating 
pharmacologic interventions. An adverse event (AE) for this trial testing a low risk, education 
intervention is defined as: 1. Suicidal ideation and 2. Homicidal ideation.  
SAEs will only be reported for events related to an AE (e.g., hospitalization due to suicidal 
ideation, etc.). We will use FDA criteria for SAEs (i.e., an adverse event that results in any of the 
following outcomes: death, life threatening event, initial or prolonged hospitalization, disability, 
congenital anomaly, intervention to prevent permanent impairment or damage, or other significant 
medical event). The study staff will be trained to monitor for and report AEs and SAEs. 
Additionally, as applicable, sites will submit reporting of AEs/SAEs according to IRB requirements. 
Each of the sites has established practices for managing medical and psychiatric emergencies, 
and the study staff will continue to utilize these procedures. Treatment providers at each site will 
be responsible for monitoring participants for possible clinical deterioration or other problems, and 
for implementing appropriate courses of action.
16.7 Trial Efficacy
1.
Plans for interim analysis of efficacy data: There will be no interim analysis of efficacy 
data by the investigators. 
16.8 DSM Plan Administration
1.
Responsibility for data and safety monitoring: Site study staff will be responsible for the 
clinical management and safety monitoring of the study participants. 

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2.
Frequency of DSM reviews: Breaches of confidentiality will be reviewed by study 
leadership in regularly scheduled meetings for the duration of the study. 
3.
Content of DSM report: The DSM report, which will be contained in the final study report, 
will include a brief description of the study and any changes made. Additionally, we will 
report baseline sociodemographic characteristics, including age and race of the 
participants screened and randomized.  We will also report retention rates and the 
disposition for all study participants. Any quality assurance issues, regulatory issues, and 
breaches of confidentiality will be included in the report. 
16.9 DSM Board (DSMB) Plan
The MOMs (CTN-0080) trial has a NIDA CTN DSMB that is responsible for conducting periodic 
reviews of accumulating safety, trial performance, and outcome data. Given the low risk 
associated with the TOME intervention and the brevity of the study time frame, a separate DSMB 
was not established for the TOME trial. Instead, should Dr. Winhusen feel the need for DSMB 
input (e.g., as the result of an AE or SAE etc.) he will request an ad hoc meeting with the MOMs 
DSMB.