Subthreshold Opioid Use Disorder Prevention (STOP) Trial
Phase: NA
Conditions: Opioid-use Disorder
Sponsor: NYU Langone Health

Official Title:
Subthreshold Opioid Use Disorder Prevention (STOP) Trial  
NCT Number: 
NCT04218201 
Study Number:
19-00535
Document Type:  
 Protocol 
Date of the 
Document: 
October 5, 2022

CONFIDENTIAL 
 
 
 
 
 
 
 
NIDA CTN Protocol 0101 
 
Subthreshold Opioid Use Disorder 
Prevention (STOP) Trial 
(STOP Trial) 
 
Lead Investigator: Jennifer McNeely, MD, MS 
Co-Lead Investigator: Jane Liebschutz, MD, MPH 
Sponsor: National Institute on Drug Abuse (NIDA) 
 
 
October 5, 2022 
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Lead Investigator (LI):
Jennifer McNeely, MD, MS
New York Node
 
NYU School of Medicine 
 
Co-LI: 
Jane Liebschutz, MD, MPH
 
Appalachian Node
 
University of Pittsburgh School of Medicine
CCTN Scientific Officer:
Geetha Subramaniam, MD
 
National Institute on Drug Abuse 
Data and Statistics Center (DSC):
Jennifer McCormack, MS
 
DSC Principal Investigator 
 
Emmes
 
Clinical Coordinating Center (CCC):
Eve Jelstrom, CRNA, MBA 
 
CCC Principal Investigator 
 
Emmes
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be published or 
disclosed without prior approval of the Lead Investigator or other participating study leadership 
and as consistent with the NIDA terms of award. 

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TABLE OF CONTENTS
1.0
LIST OF ABBREVIATIONS.............................................................................................................. 8
2.0
STUDY SYNOPSIS.........................................................................................................................10
2.1
Study Objectives .........................................................................................................................10
Study Design and Outcomes ..................................................................................................11
Sample Size and Study Population.........................................................................................12
Treatment/Assessment/Intervention and Duration..................................................................12
Safety Reporting......................................................................................................................13
Analyses..................................................................................................................................14
3.0
STUDY SCHEMA ...........................................................................................................................15
3.1
Figure 1: Basic Study Schema....................................................................................................15
3.2
Key Research Site Roles ............................................................................................................16
4.0
INTRODUCTION.............................................................................................................................18
4.1
Background and Significance to the Field...................................................................................18
4.2
Figure 2: Social Ecological Framework of Risky Opioid Use......................................................22
4.3
Table 1: Mapping of the STOP Intervention Components to the Social Ecological 
Framework’s 4 Levels of Influence .............................................................................................23
5.0
OBJECTIVES..................................................................................................................................24
5.1
Primary Objective........................................................................................................................24
5.2
Secondary Objectives .................................................................................................................24
5.3
Exploratory Objectives ................................................................................................................25
6.0
STUDY DESIGN .............................................................................................................................27
6.1
Overview of Study Design...........................................................................................................27
6.2
Duration of Study and Visit Schedule .........................................................................................28
6.3
Figure 3: Study Design................................................................................................................29
7.0
OUTCOME MEASURES ................................................................................................................30
7.1
Primary Outcome Measure .........................................................................................................30
7.2
Secondary Outcome Measure(s) ................................................................................................30
Measures of Patient-Level Outcomes.....................................................................................30
Measures of Provider-Level Outcomes...................................................................................32
7.3
Other Outcome Measures...........................................................................................................33
7.4
Study Timeline.............................................................................................................................34
Pilot Study ...............................................................................................................................34
Table 2: Estimated Project Timeline .......................................................................................35
8.0
STUDY POPULATION ...................................................................................................................37

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8.1
Inclusion and Exclusion Criteria..................................................................................................37
PCP Inclusion and Exclusion Criteria......................................................................................37
Patient Participant Inclusion and Exclusion Criteria................................................................38
Patient Participant Inclusion and Exclusion Criteria for Additional Pilot Telephone 
Health Coaching for Training Purposes Only..................................................................39
8.2
Strategies for Recruitment and Retention...................................................................................39
Recruitment of PCPs...............................................................................................................39
Recruitment of Patients...........................................................................................................39
Table 3: Anticipated Patient Participant Screening and Enrollment for each of the 60 
PCPs Having Patients in the Study .........................................................................................41
9.0
SITE SELECTION...........................................................................................................................42
9.1
Number of Sites...........................................................................................................................42
Rationale for Site Selection.....................................................................................................42
10.0
STUDY PROCEDURES..................................................................................................................43
10.1
Screening and Informed Consent Procedures............................................................................43
Prescreening .......................................................................................................................43
Methods for Remote Screening and Enrollment.................................................................43
Methods for In-Person Prescreening, Screening and Enrollment.......................................45
Methods for Telehealth Prescreening, Screening and Enrollment .....................................45
10.2
Prescreening and Assessment of Study Eligibility......................................................................48
Screening for Eligibility........................................................................................................48
Informed Consent Procedures ............................................................................................49
HIPAA Authorization and Medical Record Release Forms.................................................50
10.3
Randomization ............................................................................................................................50
10.4
Baseline Assessment..................................................................................................................50
10.5
Pilot Study ...................................................................................................................................51
Additional Telephone Health Coaching for Training Purposes ...........................................52
10.6
Study Treatments........................................................................................................................52
Enhanced Usual Care (EUC)..............................................................................................53
STOP Intervention...............................................................................................................53
Table 4: Summary of Intervention Provider Roles and Timing of Patient Contacts............55
10.7
Premature Withdrawal of PCP or Patient Participants................................................................59
Withdrawal of PCP Participants ..........................................................................................59
Withdrawal of Patient Participants ......................................................................................60
10.8
PCP Participant Follow-Up..........................................................................................................60
10.9
Patient Participant Follow-Up......................................................................................................60
Follow-up with Prisoners (as defined by OHRP).................................................................61
10.10
Blinding....................................................................................................................................61
Type of Blinding...................................................................................................................61
Maintenance of the Blind.....................................................................................................61
Breaking the Blind ...............................................................................................................62
10.11
Patient Participant Compensation...........................................................................................62

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11.0
STUDY ASSESSMENTS................................................................................................................63
11.1
Table of Assessments.................................................................................................................63
Patient Participant Assessments.........................................................................................63
11.2
Table 6: Schedule of Patient Participant Assessments ..............................................................64
PCP Participant Assessments ............................................................................................66
Table 7: PCP Participant Assessments ..........................................................................66
11.3
Patient Participant Assessments.................................................................................................67
General Measures...............................................................................................................67
Inclusion/Exclusion Checklist..........................................................................................67
Locator Form...................................................................................................................67
Demographics Form........................................................................................................67
Study Completion Form ..................................................................................................67
11.4
Protocol Specific Assessments...................................................................................................68
Healthy Living Eligibility Screener.......................................................................................68
Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) Tool ........68
Modified World Mental Health Composite International Diagnostic Interview (CIDI)..........68
Current Opioid Misuse Measure (COMM) ..........................................................................68
11.5
Measures of Primary and Secondary Outcomes ........................................................................69
Days of Opioid Use (Healthy Living Monthly Survey) .........................................................69
Days of Non-Opioid Substance Use (Healthy Living Monthly Survey) ...............................69
Timeline Follow-Back (TLFB)..............................................................................................69
Psychiatric Diagnostic Screening Questionnaire (PDSQ) ..................................................69
Overdose Risk Behavior Questionnaire..............................................................................70
Non-Fatal Overdose Questionnaire ....................................................................................70
Brief Pain Inventory Short Form (BPI).................................................................................70
Depression and Suicidality (PHQ-8 and PSS)....................................................................70
PROMIS Anxiety Short Form ..............................................................................................71
Health-Related Quality of Life (SF-12)................................................................................71
Participant Reported ED Visits and Hospitalizations ..........................................................71
Chart Review.......................................................................................................................71
Exit Survey on PCP-Delivered Opioid Counseling..............................................................71
Marijuana Use Assessment ................................................................................................72
E-Cigarette and Vaping Assessment ..................................................................................72
PROMIS Sleep 4a Assessment ..........................................................................................72
11.6
Measures of Readiness to Change.............................................................................................72
PROMIS Instrumental and Emotional Health Measures.....................................................72
Addiction Treatment and Harm Reduction Services Utilization ..........................................72
Patient Experience Questionnaire.......................................................................................73
11.7
Fidelity Measures ........................................................................................................................73
Exit Survey on PCP-Delivered Opioid Counseling..............................................................73
Assessment of Blinding.......................................................................................................73
Qualitative Interviews ..........................................................................................................73
11.8
Clinical and Safety Assessments................................................................................................74
Mental Health Follow-Up Assessment ................................................................................74
Death Form .........................................................................................................................74
RA-recorded ED Visits and Hospitalizations.......................................................................74

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11.9
Drug Use Measures ....................................................................................................................74
Urine Drug Screen...............................................................................................................74
11.10
Administrative Forms ..............................................................................................................75
11.11
Out-of-Window and Missed Assessments ..............................................................................75
12.0
TRAINING, SUPERVISION, AND FIDELITY MONITORING.........................................................76
12.1
Research Staff Training ..............................................................................................................76
12.2
Primary Care Provider Training...................................................................................................76
12.3
Clinical Champion Training .........................................................................................................77
12.4
Nurse Care Manager Training.....................................................................................................77
Table 8: Outline of NCM Training........................................................................................77
12.5
Telephone Health Coach Training ..............................................................................................78
12.6
Fidelity Monitoring .......................................................................................................................78
13.0
CONCOMITANT THERAPY/INTERVENTION...............................................................................80
13.1
General........................................................................................................................................80
14.0
STATISTICAL DESIGN AND ANALYSES ....................................................................................81
14.1
General Design ...........................................................................................................................81
Study Hypothesis ................................................................................................................81
Secondary Objectives .........................................................................................................81
Exploratory Objectives ........................................................................................................82
14.2
Primary and Secondary Outcomes (Endpoints)..........................................................................83
Primary Outcome Measure .................................................................................................83
Secondary Outcome Measure(s) ........................................................................................83
14.3
Recruitment.................................................................................................................................87
14.4
Randomization and Factors for Stratification..............................................................................88
14.5
Rationale for Sample Size and Statistical Power........................................................................88
Figure 5: Mean Values in Treatment and Control Groups for Four Different Simulation 
Scenarios............................................................................................................................89
Table 9: Power Estimates Based on 1000 Simulations ......................................................90
Projected Number of Sites ..................................................................................................91
Projected Number of Participants per Site..........................................................................91
14.6
Statistical Methods for Primary and Secondary Outcomes ........................................................92
14.7
Significance Testing ....................................................................................................................94
14.8
Interim Analysis...........................................................................................................................94
14.9
Exploratory Analysis....................................................................................................................94
14.10
Missing Data and Dropouts.....................................................................................................95
14.11
Demographic and Baseline Characteristics ............................................................................95
14.12
Safety Analysis........................................................................................................................95

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15.0
REGULATORY COMPLIANCE, REPORTING AND MONITORING.............................................96
15.1
Statement of Compliance............................................................................................................96
15.2
Institutional Review Board Approval ...........................................................................................96
15.3
Informed Consent........................................................................................................................96
15.4
Quality Assurance Monitoring .....................................................................................................98
15.5
Participant and Data Confidentiality............................................................................................98
Certificate of Confidentiality ................................................................................................98
Health Insurance Portability Accountability Act (HIPAA) ....................................................99
15.6
Investigator Assurances..............................................................................................................99
Financial Disclosure/Conflict of Interest..............................................................................99
15.7
Clinical Monitoring.......................................................................................................................99
15.8
Inclusion of Women and Minorities ...........................................................................................100
15.9
Prisoner Certification.................................................................................................................100
15.10
Regulatory Files ....................................................................................................................100
15.11
Records Retention and Requirements..................................................................................101
15.12
Reporting to Sponsor ............................................................................................................101
15.13
Audits ....................................................................................................................................101
15.14
Study Documentation............................................................................................................101
15.15
Protocol Deviations ...............................................................................................................102
15.16
Safety Monitoring ..................................................................................................................102
Data and Safety Monitoring Board (DSMB) ......................................................................103
Safety Monitor/Medical Monitor.........................................................................................103
Adverse Events (AEs) .......................................................................................................103
16.0
DATA MANAGEMENT .................................................................................................................104
16.1
Design and Development..........................................................................................................104
16.2
Site Responsibilities ..................................................................................................................104
16.3
Data Center Responsibilities.....................................................................................................104
16.4
Data Collection..........................................................................................................................104
16.5
Data Editing...............................................................................................................................104
16.6
Data Transfer/Lock....................................................................................................................105
16.7
Data Training.............................................................................................................................105
16.8
Data Quality Assurance ............................................................................................................105
17.0
PUBLIC ACCESS AND DATA SHARING PLAN ........................................................................106
18.0
PROTOCOL SIGNATURE PAGE ................................................................................................107
19.0
REFERENCES..............................................................................................................................108

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20.0
APPENDIX A: DATA AND SAFETY MONITORING PLAN ........................................................112
 

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1.0
LIST OF ABBREVIATIONS
Abbreviation
Definition
ACASI
Audio Computer Assisted Self-Interview
AE
Adverse Event
BPI
Brief Pain Inventory 
CBT
Cognitive Behavioral Therapy
CCC 
Clinical Coordinating Center 
CCM
Chronic Care Model 
CCTN
Center for Clinical Trials Network
CFR
Code of Federal Regulations 
CIDI
Composite International Diagnostic Interview
CoC 
Certificate of Confidentiality 
Co-I 
Co-Investigator
Co-LI 
Co-Lead Investigator
COMM
Current Opioid Misuse Measure
COT
Chronic Opioid Therapy
CRF
Case Report Form 
CTN
Clinical Trials Network 
DM 
Data Management 
DSC
Data and Statistics Center
DSM-5
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data and Safety Monitoring Board
eCRF 
Electronic Case Report Form
ED
Emergency Department
EDC
Electronic Data Capture system
EMA 
Ecological Momentary Assessment
EHR
Electronic Health Record
EUC
Enhanced Usual Care
FDA
Food and Drug Administration
FWA
Federal Wide Assurance 
GCP 
Good Clinical Practice
HHS
Department of Health and Human Services
HIPAA
Health Insurance Portability and Accountability Act
HSP
Human Subjects Protection
ICF
Informed Consent Form
IRB
Institutional Review Board
LI 
Lead Investigator 
LN 
Lead Node
LT
Lead Team
MME 
Morphine Milligram Equivalents
MI
Motivational Interviewing 
MITI 
Motivational Interviewing Treatment Integrity
MOP
Manual of Procedures

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Abbreviation
Definition
MOUD
Medication for Opioid Use Disorder
NCM
Nurse Care Manager
NIDA
National Institute on Drug Abuse
NIH 
National Institutes of Health 
OEND 
Overdose Education and Naloxone Distribution 
OHRP
Office for Human Research Protection
OUD
Opioid Use Disorder
PCP
Primary Care Provider
PD
Protocol Deviation
PDSQ 
Psychiatric Diagnostic Screening Questionnaire 
PEG Tool 
Pain, Enjoyment of life, General Activity – a 3-item scale assessing pain 
intensity and interference
PhenX Toolkit
Phenotypes and Exposures Toolkit 
PHQ-8
Patient Health Questionnaire
PI
Principal Investigator
PRB
Protocol Review Board 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PS 
Protocol Specialist 
PSS 
Patient Safety Screener
QA 
Quality Assurance
QUIT 
Quit Using Drugs Intervention Trial
RA
Research Assistant
RC 
Research Coordinator
RCT
Randomized Control Trial 
SA 
Self-Administered
SAE 
Serious Adverse Event 
SBI
Screening and Brief Intervention
SBIRT
Screening, Brief Intervention, and Referral to Treatment
SCOPE 
Safer/Competent Opioid Prescribing Education  
SF-12
Short Form 12 – health related quality of life measure 
SOC 
Standard of Care
SOP
Standard Operating Procedure
STOP
Subthreshold Opioid Use Disorder Prevention 
SUD
Substance Use Disorder
TA 
Technical Assistance 
TAPS Tool
Tobacco, Alcohol, Prescription medicine, and other Substance use Tool 
TEACH
Targeting Effective Analgesia in Clinics for HIV
TLFB 
Timeline Follow-Back
TOPCARE
Transforming Opioid Prescribing in Primary Care
UDS
Urine Drug Screen

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2.0
STUDY SYNOPSIS
2.1
Study Objectives 
Concurrent to efforts to expand treatment to those currently experiencing an opioid use disorder 
(OUD), it is critically important to focus on the prevention of OUD among individuals with 
subthreshold OUD.[1-5] Subthreshold OUD is opioid use that is not severe enough to meet 
diagnostic criteria for moderate-severe OUD (that would require medication and more intensive 
treatment). As defined here, subthreshold OUD includes individuals with problem opioid use or 
mild OUD symptoms. Individuals with subthreshold OUD engage in risky opioid use behavior, 
which includes nonmedical use of prescribed opioids (taking a higher dose or taking an opioid 
more frequently than prescribed), any use of illicit opioids, or taking pharmaceutical opioids that 
were not prescribed to them. Although a minority (18%) of the 12 million Americans with past-
year illicit or nonmedical opioid use currently have an OUD, all of them are at high risk of 
developing OUD in the future.[5] 
This randomized clinical trial aims to examine the efficacy of a primary care Subthreshold Opioid 
Use Disorder Prevention (STOP) intervention to reduce opioid use and overdose risk, and to 
prevent progression of OUD in adult patients with risky opioid use. Specifically, STOP is a 
behavioral early intervention strategy targeting individuals with subthreshold OUD, with a goal of 
reducing risky opioid use, to prevent the development of moderate-severe OUD. STOP is a 
collaborative care model consisting of (1) a practice-embedded nurse care manager (NCM) who 
provides patient participant education and supports the primary care provider (PCP) in engaging 
and monitoring patient participants who have risky opioid use; (2) brief advice delivered to patient 
participants by their PCP; and (3) telephonic health coaching of patient participants to motivate 
and support behavior change. Patient participants who fail to improve after the telephone health 
coaching sessions can be stepped up to receive additional health coaching sessions that 
incorporate motivational interviewing and cognitive behavioral therapy. 
A cluster-randomized trial, randomized at the level of the PCP, aims to test the efficacy of STOP 
versus enhanced usual care (EUC). The trial will be conducted in 5 primary care sites, and across 
all sites will enroll approximately 100 PCPs and 300 adult primary care patients. Patient 
participants with providers assigned to the intervention condition can receive the full STOP 
intervention, in addition to primary care treatment as usual. Those with providers assigned to EUC 
will receive primary care treatment as usual plus printed educational materials addressing opioid-
related overdose prevention. 
The primary objective (Aim 1) is to determine the efficacy of the STOP collaborative care 
intervention, in comparison to enhanced usual care (EUC), for reducing risky opioid use in adult 
primary care patients. Our primary hypothesis is that patient participants with primary care 
providers assigned to the STOP intervention will have fewer days of risky opioid use, measured 
at 6 months post-baseline (primary outcome), and at 3, 9, and 12 months post-baseline 
(secondary outcome), in comparison to patient participants with primary care providers assigned 
to EUC. 

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Secondary objectives capture patient participant-level outcomes (Aim 2) and provider-level 
outcomes (Aim 3). Patient participants having primary care providers assigned to the STOP 
intervention, in comparison to those with providers assigned to EUC, are hypothesized to have 
fewer days of non-opioid substance use (including use that increases the risk of overdose), lower 
incidence of moderate-severe OUD, decreased overdose risk behavior and overdose events, 
better health-related quality of life, better sleep, fewer symptoms of depression or anxiety, and no 
worsening of pain (symptoms or functioning). Providers assigned to the STOP intervention, in 
comparison to those assigned to EUC, are hypothesized to adopt better treatment practices for 
patients with subthreshold OUD. Specifically, PCPs in the STOP condition are expected to have 
improved prescribing practices (lower rates prescribing of high-dose opioids [>90 morphine 
milligram equivalents (MME)], any chronic opioids, or benzodiazepines; more prescribing of 
naloxone kits) and more frequent monitoring (toxicology testing, diagnosis of OUD, higher visit 
frequency) for patients with risky opioid use, as well as higher rates of PCP counseling patients 
on the risks of opioid use.
Study Design and Outcomes
The study will be conducted at five sites, each having one or more participating primary care 
clinics. This is a cluster-randomized trial, randomized at the level of the PCP that will compare 
the STOP intervention to enhanced usual care (EUC) for 12 months from the date of initial 
intervention. Eligible PCPs and their eligible patients will be consented and enrolled in the study. 
PCP participants will be randomized 1:1 to the STOP or EUC condition. Patient participants will 
receive STOP or EUC, according to the assignment of their PCP. Patients will be informed that 
their PCP is participating in a “healthy living study” and will be blinded to the study condition of 
their PCP. Patients who do not enroll in the study will receive primary care as usual (i.e., standard 
of care primary care treatment).
After study launch at each site, PCP participants will complete questionnaires on demographic 
and clinic characteristics. Patients with subthreshold OUD (as determined by research screening 
tools and meeting study inclusion/exclusion criteria) will be enrolled after signing written or 
electronic informed consent. Patient participants will complete assessments with research staff 
electronically at baseline and for the following 12 months using structured questionnaires. An 
assessment of days of substance use, diet, exercise, and smoking in the past 30 days will be
completed by text message or online, at baseline and monthly. Other assessments will be 
administered at baseline and quarterly, or less frequently, and are completed online and by 
telephone. Urine Drug Screens (performed at baseline and twice during the follow-up period) will 
be used to verify self-reported information. Provider practices, including prescribing and 
Definitions
Risky opioid use: nonmedical use of prescribed opioids (taking a higher dose 
or taking an opioid more frequently than prescribed), any use of illicit opioids, 
or taking pharmaceutical opioids that were not prescribed to the individual 
taking them.
Subthreshold OUD: Risky opioid use, with 0-3 DSM-5 criteria for OUD

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monitoring for patient participants with subthreshold OUD, are assessed from the electronic health 
record (EHR).
The primary outcome (Aim 1) is days of risky opioid use in the past 180 days, assessed at 6
months. Secondary outcome measures for Aim 1 are days of risky opioid use assessed at earlier 
(3 months) and later (9 and 12 months) time points. Additional patient-level secondary outcomes 
(Aim 2) include substance use that increases opioid-related overdose risk (binge alcohol use, 
concurrent use of stimulants or sedatives with opioids), other drug use, drug and alcohol use 
disorders, overdose risk behaviors and nonfatal overdose events, pain symptoms and related 
functioning, mental health symptoms (depression, anxiety, suicidality), health-related quality of 
life, sleep, and acute health care utilization. Aim 3 provider-level outcome measures are collected 
from the EHR and include medications prescribed, lab tests, diagnosis of OUD and frequency of 
medical visits. Counseling on risk of opioid use will be provided by patient self-report.
Sample Size and Study Population
The sample consists of PCPs and their patients. We anticipate that the study will enroll
approximately 100 PCPs. We estimate, however, that 30-40% of the enrolled PCPs will have no 
participating patients because we will not identify patients who meet the eligibility criteria in their 
panel, leaving approximately 60 PCPs who will have patients that will enroll into the study. Each 
of these PCPs is expected to have approximately 5 patients participating in the study, although 
the study can achieve patient recruitment in a variety of ways (e.g., 60 PCPs may have 5 patients 
enrolled each; Or 50 PCPs may have 4 patients, 5 PCPs may have 6 patients, and 7 PCPs may 
have 10 patients). This results in a total of approximately 300 patient participants enrolled in the 
study. 
Original recruitment targets were based on 5 sites recruiting for the duration of the study. In 
October 2021, one site stopped recruiting, leaving 4 sites to continue. The sample of 
approximately 300 patients is thus comprised of recruitment from 5 sites for the initial 6 months, 
and from 4 sites for the remainder of the study.
PCPs eligible for participation will provide care to approximately 4 or more patients who receive 
chronic opioid treatment and/or have risky opioid use and see, on average, 40 or more adult 
patients (age 18 years) per week. The primary criteria for patient participant eligibility include: 
having a PCP who is enrolled in the study and having risky opioid use in the past 90 days. Patients 
will be excluded if they have moderate-severe OUD (4+ DSM-5 criteria); are currently receiving
or have received medication for OUD (MOUD) in the past 30 days; or are receiving opioids for 
end of life care. Participant characteristics are anticipated to reflect the characteristics of adult 
primary care providers and patients in the participating sites. Patient participants will include a 
diversity of racial and ethnic groups, males and females, and all will be at least 18 years of age.
Treatment/Assessment/Intervention and Duration
Treatment Intervention: STOP is a multi-component intervention with provider-facing and patient-
facing elements. Providers in the STOP condition work with a nurse care manager (NCM),
embedded in the clinic, who assists them with managing patient participants with subthreshold 
OUD. For all patient participants, the NCM provides patients with education and promotes self-
management for reducing risky opioid use and for overdose prevention, reviews medications and 

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alerts the PCP to unsafe prescribing (e.g., high dose opioids, benzodiazepines prescribed to 
patients with opioid use), and as needed recommends non-pharmacological interventions for pain 
management, links patient participants to mental health services, and supports patient
engagement in primary care. For patient participants on prescribed opioids, the NCM also 
provides medication monitoring (e.g., toxicology testing, pill counts), the level of which is adjusted 
based on the needs of the patient and concerns of the PCP. The NCM additionally monitors to 
ensure that the PCP regularly assesses patients for OUD.
Patient participants in the STOP condition receive Step 1 counseling. In Step 1, patients receive 
brief advice from their PCP and/or a “video doctor” (approximately 2 minutes of counseling 
modeled on the PCP’s brief advice). Participants are additionally offered 2 telephone health 
coaching sessions (approximately 2- and 4-weeks after the baseline visit). Coaching is conducted 
via phone and/or HIPAA compliant video chat software by telephone health coaches, who are 
trained health professionals. Health coaches attempt to conduct two sessions with patient
participants in the STOP condition, which focus on substance use behavior, stress/mood 
management, and quality of life issues. The sessions also emphasize opioid use and overdose 
risk and incorporate motivational interviewing (MI) techniques. Patient participants who may 
benefit from additional coaching (for example, those who do not improve or who experience 
clinical worsening of unhealthy opioid use) will be offered Step 2 enhanced telephone health 
coaching. In Step 2, the telephone health coach provides patient participants with approximately 
4 additional sessions (approximately once/week) over the telephone (with or without video). The 
telephone health coach will conduct a clinical assessment of motivation to reduce risky opioid 
use. For patient participants with low motivation to change current opioid use behaviors, the coach
will conduct additional MI. As patient participants increase their readiness to change, specific 
behavioral strategies for relapse prevention will be presented within a cognitive behavioral therapy 
(CBT) framework.
Study Assessments and Study Duration: The estimated time from initiation of enrollment to 
completion of data analysis is 44 months. Each site is anticipated to begin enrolling provider 
participants approximately 1-2 months before initiating the intervention, and to complete patient 
participant enrollment within approximately 26 months. Data will be collected from patient
participants for 12 months following the baseline assessment, and data will be collected from 
providers for the entire period during which their clinical site is engaged in the intervention 
(anticipated to be 37 months). Limited patient participant assessments will be completed monthly, 
while more comprehensive assessments will be completed at baseline and quarterly. Sites will 
thus complete data collection approximately 12 months after the completion of recruitment. Data 
analysis is anticipated to be completed 6 months after the end of data collection.
Safety Reporting
This is a minimal risk study. Therefore, no causally related Adverse Events and Serious Adverse 
Events are anticipated. Safety reporting will be limited to reporting the following Safety Events: 
Emergency Department (ED) visits, hospitalizations, overdose events, suicidal ideation, and 
deaths. These Safety Events will be reported on separate case report forms (CRFs). The sites 
will follow local standard operating procedures (SOPs) for managing any medical or psychiatric 
emergencies.

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Analyses
Demographic variables and baseline distributions of potential confounding variables will be 
summarized by treatment group. The primary outcome will be analyzed with a mixed effects 
generalized linear model with a negative binomial distribution. The model will include PCP random 
intercepts, fixed clinic effects, a fixed treatment effect, and the baseline value of the response 
variable. A secondary analysis will expand the model to include multiple time points for the 
response variable and treatment by time interactions. The mean number of days of use will be 
visualized by treatment group with 95% confidence intervals. Similar models will explore 
secondary outcomes.

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INTERVENTION
EUC
3.0
STUDY SCHEMA
3.1
Figure 1: Basic Study Schema
PCP randomization into EUC or STOP Intervention
Patients of participating PCPs
Prescreening/Screening
Brief Advice and/or Video 
Doctor
Nurse Care Manager
Educational Materials
Educational Materials
Video
Baseline Assessments
Monthly Healthy Living Survey
Months 1-12
Quarterly Assessments
Months 3, 6, 9, 12
Telephone health 
coaching (2 sessions)
If clinically indicated:
Enhanced telephone 
health coaching BI/CBT 
(4 sessions)
Patient Participant Consent

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3.2
Key Research Site Roles
Each site will designate individuals in the following roles: 
 
Site Principal Investigator (MD; DO; PhD). The Site PI will be responsible for working 
with the research team to facilitate the conduct of the study at the study site. 
 
Site Clinical Champion (NP; PA; MD; DO; Licensed Behavioral Health Clinician). The 
Clinical Champion will be a clinic provider who advocates for the study among their 
colleagues in the study clinic(s), assists with training of participating PCPs, and provides 
ongoing support to the PCP participants and NCM in carrying out the study 
interventions. 
 
Research Coordinator. One or more Research Coordinators (RCs) will be assigned to 
each site to coordinate and help with oversight of study activities. 
 
Research Assistant. One or more research assistants (RAs) will be assigned to each 
site to conduct recruitment, enrollment, and data collection. 
 
Nurse Care Manager (RN; LPN with RN supervision). A full-time nurse care manager 
(NCM) will be assigned to each site to carry out the STOP intervention. The position can 
be split (e.g., 50:50, 40:60) and if the site has a cluster of practices, the NCM can 
practice at more than 1 site to make the system workable and support the PCPs and 
patients. If the position is split, both NCMs will do weekly reporting jointly to the technical 
assistance (TA) team (as if one site) and both will attend the training program. 
 
Practice Manager. The site practice manager will be tasked with assisting research staff 
with administrative tasks at the sites throughout the course of the study. 
Required qualifications of the nurse care manager (NCM): 
 
Registered Nurse (RN). This can be diploma, BSN or MSN. LPN with RN supervision 
 
Willingness to enroll 3-5 patients per week. 
 
Willingness to provide weekly reporting. 
 
Willingness for regular interactions with the technical assistance team. 
 
Enthusiasm and energy/leadership ability to lead the team and for working with patients 
with addiction and pain as well as providers and clinical leaders in the system and 
community, as relevant. 
Preferred qualifications of the NCM: prior behavioral health, pain or addiction experience, and 
adequate experience to function as the nurse manager of the program. 
Telephone health coaches will be centrally located and serve all participating sites. Because the 
telephone health coaches are not located at a study site, this is not considered a site role. 
Coaches will be social workers, counselors, or individuals with other professional training that 
qualifies them to deliver the STOP counseling intervention. Preferred qualifications of telephone 
health coaches include prior experience working with patients who have subthreshold substance 
use disorders, and in health coaching and behavior change interventions. A Research 

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Coordinator will be hired to work with the coaches to manage administrative tasks (e.g., 
participant scheduling, tracking and retention) and monitor fidelity of health coaching sessions. 

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4.0
INTRODUCTION
4.1
Background and Significance to the Field
The United States is experiencing an opioid crisis that is driven by a high prevalence of untreated 
opioid use disorder (OUD). Concurrent to efforts to expand treatment to those currently 
experiencing an OUD, it is critically important to focus on the prevention of OUD among individuals 
with subthreshold OUD.[1-5] Subthreshold OUD is opioid use that is not severe enough to meet 
diagnostic criteria for moderate-severe OUD (that would require medication and more intensive 
treatment). As defined here, subthreshold OUD includes individuals with problem opioid use or 
mild OUD symptoms. Individuals with subthreshold OUD engage in risky opioid use behavior, 
which includes nonmedical use of prescribed opioids (taking a higher dose or taking an opioid 
more frequently than prescribed), any use of illicit opioids, or taking pharmaceutical opioids that 
were not prescribed to them. An estimated 12 million Americans have past-year risky opioid use. 
Another 5 to 8 million individuals are receiving long-term opioid therapy.[6] While a minority (18%) 
of individuals with illicit or prescription opioid exposure are thought to currently have a moderate-
severe OUD, all of them are at high risk for this condition.[5] 
Opioid-related research has primarily focused on treatment interventions for individuals who have 
already developed moderate-severe OUD. Little is currently known about the trajectories of 
individuals who have subthreshold OUD, including how likely, and within what timeframe, they 
may develop a more severe OUD or experience opioid-related overdose. OUD prevention efforts 
have focused on regulatory efforts and published guidelines about prescribing opioid analgesics, 
particularly by primary care physicians.[7] There is increasing concern that curbing prescribing 
could be contributing to the opioid crisis when opioid tapers are not accompanied by interventions 
that actively engage patients and providers in preventing the development or worsening of 
subthreshold OUD, treat underlying pain, and provide access to effective treatment and overdose 
prevention strategies for individuals who already have a moderate-severe OUD.[8, 9] 
Individuals with subthreshold OUD may experience few symptoms or consequences of their 
opioid use, and rarely seek addiction services.[5, 10] However, these individuals are frequently 
encountered in primary care settings where they receive routine medical care and, in some cases, 
prescription opioids for pain management. Although prevalence of subthreshold OUD in primary 
care settings varies based on the patient population, a prior 5-site study conducted in the Clinical 
Trials Network (CTN) (CTN-0059) found prevalence of risky opioid use to be 5-10% among adult 
primary care patients.[11, 12] Prevalence of subthreshold OUD is much higher (21-29%) among 
patients who are receiving prescribed opioids.[13] 
Definitions
 
Risky opioid use: nonmedical use of prescribed opioids (taking a higher dose or 
taking an opioid more frequently than prescribed), any use of illicit opioids, or 
taking pharmaceutical opioids that were not prescribed to the individual taking 
them. 
 
Subthreshold OUD: Risky opioid use, with 0-3 DSM-5 criteria for OUD. 

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The important role of primary care. Primary care clinics are optimally positioned to identify and 
provide early intervention for individuals at risk for developing moderate-severe OUD because 
they are the largest prescribers of opioid analgesics,[14] and they are often the only point of health 
care contact for individuals whose opioid use is not yet severe enough to require intensive 
addiction treatment.[15] Yet there has been almost no research on interventions to halt the 
progression to OUD among primary care patients with risky opioid use. 
Prior approaches to reducing risky subthreshold drug use in primary care patients have relied on 
single-contact brief interventions that are not well integrated with medical care.[16-19] Brief 
interventions have had mixed results for reducing drug use, and the limited number of trials of 
brief intervention approaches have not informed care for the large population of patients with 
subthreshold OUD.[16, 17, 19, 20] The “Quit Using Drugs Intervention Trial” (QUIT) Protocol is 
one of the only brief interventions for drug use with experimental efficacy among U.S. adults.[21-
25] Additionally, one study using similar strategies as drug use brief interventions, but focused on 
overdose risk rather than consumption alone, showed efficacy for reductions in opioid misuse and 
overdose risk behavior.[26] 
The promise of collaborative care. In contrast to brief intervention approaches, collaborative care 
interventions have been consistently shown to improve patient outcomes and increase guideline 
adherence and quality of care for a wide range of diseases, particularly behavioral health 
conditions. Collaborative care is a team-based approach to managing chronic health conditions 
in primary care. Collaborative care is grounded in the Chronic Care Model (CCM) for chronic 
disease management,[27, 28] which seeks to improve patient outcomes through integrative 
systems changes, including organizational support, clinical information systems, delivery system 
redesign, decision support, self-management support, and community resources. Collaborative 
care teams typically consist of a primary care provider (PCP) working with a care manager who 
maintains a registry to proactively track and manage care delivery, and a health coach who 
supports patients in disease self-management.[29] Collaborative care approaches have been 
found effective for the care of a number of chronic diseases, including substance use disorders 
and depression.[21, 30-33] The “Massachusetts Model” for office-based OUD treatment is a 
collaborative intervention utilizing a nurse care manager, and is currently being studied in a 
pragmatic trial conducted within the CTN (PROUD Trial, CTN-0074). 
Preliminary studies. STOP is a collaborative care model that combines elements of two evidence-
based interventions: (1) Transforming Opioid Prescribing in Primary Care (TOPCARE),[33] a 
provider-facing intervention that relies on a nurse care manager using population management 
skills to improve opioid prescribing practices for patients receiving opioids for chronic pain; and 
(2) Quit Using Drugs Intervention Trial (QUIT),[21] a patient-facing intervention utilizing brief 
advice and motivational counseling to reduce moderate-risk illicit drug use. In STOP, counseling 
is tailored for patients with subthreshold OUD use by incorporating elements of an emergency 
department intervention that employed motivational interviewing to reduce risky opioid use and 
overdose risk.[34] 
TOPCARE was tested in a cluster RCT [33] (Trial Registration ClinicalTrials.gov ID 
NCT01909076, Protocol ID DA034252, http://www.clinicaltrials.gov (Lasser and Liebschutz, PIs)) 
that demonstrated improvement in guideline concordant care by PCPs (AOR, 6.0; 95% CI, 3.6-

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10.2), and reduced opioid prescribing (AOR, 1.6; 95% CI, 1.3-2.1). The TOPCARE cluster RCT 
tested whether a bundle of interventions for primary care practices can improve guideline 
adherence for chronic opioid therapy (COT). PCP participants and their 985 patients at 4 urban 
primary care practices were randomized to the multicomponent TOPCARE intervention (nurse 
care manager working with a registry for population management, clinical decision support tools, 
and academic detailing) or clinical decision support tools alone. The TOPCARE intervention 
improved guideline concordant care (urine drug screening and controlled substance agreements, 
65.9% vs. 37.8%; P < .001; AOR, 6.0; 95% CI, 3.6-10.2), but not early refills (20.7% vs. 20.1%; 
AOR, 1.1; 0.7-1.8).[33] Intervention patients were more likely than controls to have either a 10% 
dose reduction or opioid treatment discontinuation (AOR, 1.6; 95% CI, 1.3-2.1; P < .001). In 
adjusted analyses, intervention patients had a mean (SD) morphine daily dose 6.8 (1.6) milligrams 
lower than controls (P < .001). TEACH (Targeting Effective Analgesia in Clinics for HIV) (Trial 
Registration 
ClinicalTrials.gov 
ID 
NCT02564341, 
Protocol 
ID 
H-33269/DA037768, 
http://www.clinicaltrials.gov (Liebschutz, PI)) extended the TOPCARE approach to clinical centers 
for treating HIV-infected patients. Initial results (manuscript under review) reveal a marked 
improvement in provider guideline adherence and no difference in viral suppression (88% vs. 
84%, AOR 1.14 (0.63, 2.04)). 
QUIT demonstrated efficacy for reducing moderate-risk drug use in two trials (Trial Registration 
ClinicalTrials.gov ID NCT01942876, Protocol ID DESPR DA022445, http://www.clinicaltrials.gov 
and P30DA027828-02S1/S2 (Gelberg, PI)).[21, 23] The QUIT multi-component brief intervention 
approach is the only screening and brief intervention (SBI) for drug use in primary care settings 
that has exhibited efficacy among U.S. adults.[21, 35, 36] QUIT is a primary care-integrated 
approach consisting of 1) brief advice (<4 minutes) by the patient’s own primary care provider, 
that leverages the trusted doctor-patient relationship; 2) video doctor: 2 minute video modeled on  
the provider’s brief advice; and 3) health coaches who proactively reach out to patients at 
approximately 2 and 4 weeks after the primary care visit, to support and enhance substance use 
reduction behavior change. Coaches use motivational interviewing (MI) and cognitive behavioral 
therapy (CBT) techniques and focus on quality of life issues and referral to resources. In the initial 
trial (R01DA022445), QUIT reduced patients’ highest scoring drug use by 33% (10.5 to 7 days/mo. 
at 3-months),[21] and by 44% (11 to 6.5 days/mo.) in the QUIT replication study (P30DA027828-
02S1/S2).[23] While not powered for drug-specific analyses, participants in QUIT had fewer days 
of risky opioid use (11.6 days/mo. in control vs. 3.8 days/mo. in QUIT, at 3-months).[21] 
STOP further draws on the Safety and Prevention Outcomes Study (SPOS) (Trial Registration 
ClinicalTrials.gov ID NCT01894087, Protocol ID R49CE002099, http://www.clinicaltrials.gov 
(Bohnert, PI)), which specifically targeted prescription opioid misuse among patients presenting 
to the emergency department. The SPOS trial achieved significantly lower levels of risky opioid 
use and overdose risk behaviors with a 30-minute motivational interviewing intervention, in 
comparison to brief educational pamphlets.[37] Specifically, the level of opioid misuse, from the 
Current Opioid Misuse Measure, was reduced by 50% at 6 months in the intervention group, 
compared to a 39.5% reduction in the comparison group. Similar reductions were seen in 
overdose risk behavior, which decreased by 40.5% in the intervention group, in comparison to a 
14.7% reduction in the comparison group. 

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Study rationale. Our hypothesis is that the STOP intervention can decrease the quantity and 
frequency of illicit and nonmedical opioid use among primary care patients with subthreshold 
OUD, thereby reducing their risk for important health outcomes including the development of 
moderate-severe OUD and opioid-related overdose. STOP is a collaborative care model 
consisting of (1) a practice-embedded nurse care manager (NCM) who provides patient education 
and supports the primary care provider (PCP) in engaging and monitoring patients who have risky 
opioid use; (2) brief advice delivered to patients by their PCP; and (3) remote coaching of patients 
by telephone health coaches to motivate and support behavior change. 
There have been no prior studies examining the efficacy of a collaborative care approach to 
prevent progression of subthreshold OUD; our study will close this evidence gap. The proposed 
research directly addresses the dual objectives of the Helping to End Addiction Long-termSM
(HEAL) initiative to prevent opioid misuse and addiction by intervening with patients who are at 
high risk for OUD, while enhancing clinical practice for pain management by supporting primary 
care providers in providing guideline-recommended care to patients receiving opioids for chronic 
pain. STOP draws upon interventions that independently show promise for addressing 
subthreshold OUD and integrates them into a single model that can be implemented in regular 
primary care practice. The study poses minimal risk to participants and has the potential to make 
a significant contribution to scientific knowledge and medical practice regarding interventions to 
prevent the highly morbid condition of OUD. 
Sustainability. Our proposed study is the culmination of years of work within the CTN to increase 
the capacity of medical settings to screen for drug use (CTN-0059), integrate screening into the 
EHR (CTN-0062) and treat OUD in primary care settings (CTN-0074). Although this is an efficacy 
trial, the STOP intervention is designed for delivery in routine primary care practice and works 
with patients and their PCPs in the context of existing clinical care. If our trial shows positive 
results, we will further test STOP in a subsequent multi-site implementation-effectiveness trial that 
will characterize the cost effectiveness of the intervention and barriers and facilitators of its 
implementation, which will inform health system and payor decisions about adopting the STOP 
model more broadly. Attesting to the potential sustainability of the model, in the TOPCARE study, 
2 of the 4 participating clinics continued the intervention by funding the nurse care manager role 
after the study ended. Behavioral health counseling such as the telephone health coaching 
provided in STOP is increasingly covered by insurance, including by the Screening, Brief 
Intervention, and Referral to Treatment (SBIRT) billing codes and other models of reimbursement 
for collaborative care models. At study close, we will facilitate dissemination of the STOP 
intervention by developing a guide for its implementation into practice. 
Conceptual model. The STOP stepped-care intervention integrates patient- and provider-facing 
interventions and is informed by Wagner’s Chronic Care Model,[28] Ewart’s Social Action 
Theory,[38] Social Ecological Frameworks for health promotion,[39] and the opioid use literature. 
As depicted in Figure 2, subthreshold OUD is influenced by multiple factors, including (1) patient-
level individual factors such as knowledge, attitudes, beliefs, motivation, behavioral skills, self-
efficacy, pain intensity, physical functioning, social determinants of health (e.g., homelessness, 
poverty, trauma), mental health disorders, and other substance use; (2) interpersonal factors such 
as perceived approval of risky opioid use by members of one’s social system (e.g., family and 
peers), and use of opioids by family/friends; (3) organizational factors such as utilization of clinical 

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information systems to enhance communication and efficiency, decision support for evidence-
based care, and use of interprofessional treatment teams; and (4) community factors such as 
availability of community resources (e.g., housing, food assistance, transportation, health/mental 
health programs), and other neighborhood/community factors (e.g., drug availability, violence, 
community poverty rates). While STOP does not directly intervene on all of the factors that impact 
a patient’s risky opioid use, it is designed to address each level of the social ecological framework. 
Table 1 maps the STOP intervention components to the Social Ecological Framework’s 4 levels 
of influence. Addressing each of these multiple systems of influence enables individuals to reduce 
their risky opioid use, which can in turn lead to reduction in moderate-severe OUD and opioid-
related events, such as overdose and death. Bold items in Figure 2 denote targets of the STOP 
intervention.
4.2
Figure 2: Social Ecological Framework of Risky Opioid Use
*Individual factors that 
specifically impact risky 
opioid use

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4.3
Table 1: Mapping of the STOP Intervention Components to the Social 
Ecological Framework’s 4 Levels of Influence
Levels of 
Influence
STOP Intervention Components
1.
Individual
Brief advice from PCP enhances knowledge about the health risks of 
opioids and increases motivation to reduce opioid misuse. 
 
Video Doctor reinforces PCP message. 
 
Telephone health coach provides counseling that increases motivation, self-
efficacy, and skills to reduce opioid misuse. Stepped-up health coaching 
sessions utilize MI/CBT to target knowledge, motivation, attitudes, beliefs, 
and behavioral skills for treatment refractory patients, with specific emphasis 
on reducing opioid misuse and related risk behaviors, managing chronic 
pain, and/or preventing substance-related relapse. 
 
Nurse Care Manager provides individualized patient education (including 
overdose prevention, risk reduction, and self-management skills), 
assessment, and ongoing monitoring.
2.
Interpersonal 
Telephone health coach educates patients on how to talk with peers about 
opioid use and overdose prevention (including normative behavior); teaches 
assertive communication with family and peers and ways to maintain their 
own appropriate opioid use despite others’ misuse. 
 
Nurse care manager provides Overdose Education and Naloxone 
Distribution (OEND), including education to members of patient participants’ 
social networks, and coaches patient participants on communicating their 
needs effectively to their clinical care team. 
3.
Organizational 
(Clinic level) 
Telephone health coach suggests clinic resources and proactively links 
patients to the Nurse Care Manager for referrals when patients 
spontaneously raise barriers to reducing opioid misuse (e.g., physical or 
mental health problems). 
Nurse Care Manager evaluates patients for OUD and opioid-related risk 
behaviors and provides ongoing monitoring that is communicated back to 
the clinical team; makes referrals to specialty care services patients may 
require (e.g., mental health or substance use disorder treatment), and links 
patients who develop OUD to treatment (office-based buprenorphine or 
referral to opioid treatment program). 
4.
Community
Telephone health coach recommends community and/or online resources 
and proactively links patients to the Nurse Care Manager and/or clinic social 
workers for assistance when patients spontaneously raise barriers to 
reducing opioid misuse (e.g., social determinants of health, family/friend 
factors, community/neighborhood factors). 
 
Nurse Care Manager makes referrals to community services that may 
benefit patients such as physical activity programs for pain (e.g., yoga, Tai 
Chi), peer support for substance use (e.g., 12-step and other groups), and 
addiction treatment resources. 

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5.0
OBJECTIVES
5.1
Primary Objective
The primary objective (Aim 1) of the STOP trial is to determine the efficacy of the STOP 
collaborative care intervention, in comparison to enhanced usual care (EUC), for reducing risky 
opioid use in adult primary care patients, over 12 months of follow-up. Risky opioid use is defined 
for the primary outcome measure as nonmedical use of prescribed opioids (taking a higher dose 
or taking an opioid more frequently than prescribed; taking pharmaceutical opioids that were not 
prescribed to the individual taking them), or any use of illicit opioids. Our primary hypothesis (H1.1) 
is that patient participants with primary care providers assigned to the STOP intervention will have 
fewer days of risky opioid use, measured at 6 months from baseline (primary outcome), and at 3, 
9, and 12 months from baseline (secondary outcome (H1.2)), in comparison to patient participants 
with primary care providers assigned to EUC. Because the most intensive intervention period is 
during the initial 3-4 months, the primary outcome is measured at 6 months in order to capture 
the main intervention effect. The 3-month secondary outcome measure will assess early 
intervention effects, while the 9- and 12-month secondary outcome measures will assess the 
durability of intervention effects (which may be maintained, increased, or decreased) over time. 
5.2
Secondary Objectives 
The trial has two secondary objectives, which capture patient participant-level and provider-level 
impacts of the STOP intervention. 
The patient-level secondary objective (Aim 2) is to examine the impact of STOP on important 
patient-level outcomes of substance use that increases opioid-related overdose risk (binge 
alcohol use, benzodiazepine and stimulant use), other drug use, OUD and other drug and alcohol 
use disorders, overdose risk behaviors and nonfatal overdose events, pain symptoms and related 
functioning, mental health symptoms (depression, anxiety, suicidality), sleep, health-related 
quality of life, and acute health care utilization. We hypothesize that patient participants in the 
STOP condition, in comparison to participants in the EUC condition, will have: 
H2.1 
Fewer days of binge alcohol use. 
H2.2 
Fewer days of benzodiazepine use. 
H2.3 
Fewer days of stimulant use (cocaine and amphetamine-type stimulants). 
H2.4 
Fewer days of marijuana use. 
H2.5 
Fewer days of other drug use (not including opioids, benzodiazepines, 
stimulants, and marijuana). 
H2.6 
Lower proportion of individuals having increased days of illicit or nonmedical 
opioid use. 
H2.7 
Reduced prescription opioid misuse behaviors, among patients receiving 
prescribed opioids. 
H2.8 
Lower incidence of moderate-severe OUD. 
H2.9 
Lower rates of non-opioid drug use disorder or alcohol use disorder. 

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H2.10 Lower rates of self-reported overdose risk behavior and nonfatal opioid-related 
overdose events. 
H2.11 No worsening of pain symptoms and pain-related functioning. 
H2.12 Fewer symptoms of depression (including suicidality) and anxiety. 
H2.13 Better sleep quality  
H2.14 Better health-related quality of life. 
H2.15 Lower rates of acute health care utilization (ED and hospital visits). 
The provider-level secondary objective (Aim 3) is to characterize the impact of STOP on primary 
care provider behaviors, including medications prescribed, lab tests, diagnosis of OUD, and 
frequency of medical visits. Our hypothesis is that providers assigned to the STOP condition, in 
comparison to providers in EUC, will have, over 12 months of follow-up: 
H3.1 
Lower rates of prescribing of high-dose opioids (defined as prescriptions totaling 
>90 morphine milligram equivalents) to patients with risky opioid use. 
H3.2 
Fewer patients with risky opioid use who are prescribed benzodiazepines. 
H3.3 
Higher proportion of patients with risky opioid use receiving at least one 
prescription for a naloxone kit. 
H3.4 
Increased monitoring of patients with risky opioid use, defined as urine drug 
screen, diagnosis of OUD, and higher visit frequency. 
5.3
Exploratory Objectives 
The study has the following exploratory objectives: 
Exploratory Objective 1 is to assess the impact of STOP on patient participants’ engagement in 
primary care. There is potential for the intervention to disrupt the patient-PCP relationship, 
particularly if it leads to a dose reduction or cessation of opioid prescribing by the PCP. In the 
TOPCARE study, a post-hoc analysis indicated that patients in the intervention arm whose opioids 
were discontinued were less likely to follow up with their PCP. We believe that the multicomponent 
STOP intervention, which also includes telephone health coaches and PCP brief advice to support 
patient participants in reducing their opioid use, will not lead to decreased primary care 
engagement. However, this could be an important unintended consequence of the intervention. 
We will assess primary care engagement by measuring the frequency of kept appointments and 
missed appointments in each arm. 
Exploratory Objective 2 is to examine the time to development of moderate-severe OUD or 
opioid-related overdose for patient participants in both treatment conditions. We anticipate a low 
rate of these events in our 12-month trial. However, given the lack of knowledge regarding opioid 
use trajectories among individuals with subthreshold OUD, our study may contribute valuable 
descriptive data to inform future interventions. 
Exploratory Objective 3 is to measure the rate of fatal opioid-related overdose deaths. We 
anticipate very low rates, and potentially no overdose deaths, during the 12-month trial. However, 

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given the importance of this outcome, it will be measured for participants in both treatment 
conditions. Where information about cause of death is available, we will seek to identify opioid-
related overdose deaths, other substance overdose deaths, and other causes of death. 
Exploratory Objective 4 is to examine the receipt of addiction treatment (including MOUD) and 
harm reduction services. Individuals with subthreshold OUD (as opposed to those with moderate-
severe OUD) are expected to have little or no involvement with addiction services, but some 
participants (particularly those who develop moderate-severe OUD during the course of the study 
or have a co-occurring non-opioid substance use disorder) may utilize such services. Through 
the involvement of telephone health coaches and a NCM that can recommend and facilitate 
treatment and harm reduction referrals, the STOP intervention could result in higher engagement 
in addiction services in the intervention group. We will use self-reported and EHR data to track 
addiction service utilization in both groups. 
Exploratory Objective 5 is to measure days of substance use as captured by 90-day timeline 
follow-back (TLFB). Like the monthly assessments, the TLFB will assess days of risky opioid use, 
binge alcohol use, and other drug use (benzodiazepines, cocaine, stimulants, marijuana, and 
other drugs). The TLFB results may be examined alongside the days of substance use reported 
in the monthly assessments, in order to describe the consistency of results with these two 
measurement approaches for the purpose of informing future research. 
Exploratory Objective 6 is to measure the rate of PCP counseling on risks of opioid use 
(including overdose, addiction, impact on health conditions). For patient participants who have a 
PCP encounter integrated with the baseline research visit, counseling is measured with the 
baseline exit survey. For all patient participants, information on any discussion or counseling 
provided during follow-up PCP encounters will be assessed with a quarterly patient experience 
questionnaire. 

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6.0
STUDY DESIGN
6.1
Overview of Study Design
This cluster randomized trial, conducted in primary care clinics and randomized at the level of the 
PCP, will compare the STOP intervention to enhanced usual care (EUC) for 12 months. Patients 
who are eligible and enroll will receive the intervention according to the assignment of their PCP. 
In the EUC arm, PCPs conduct primary care as usual, without support of the nurse care manager. 
Patient participants receive an educational pamphlet about overdose prevention and watch a brief 
video on “healthy living” that is not specific to substance use. In the STOP arm, PCPs and their 
enrolled patient participants can receive the STOP intervention, consisting of a NCM, brief advice 
(delivered by PCP and/or video doctor) about health risks of opioid misuse, and telephone health 
coaching via phone and/or HIPAA compliant video chat software (2 sessions conducted 
approximately 2 and 4 weeks after the baseline visit; 4 additional sessions utilizing MI/CBT if 
clinically indicated). Patient participants in either arm who are found by clinical providers to have 
developed a moderate-severe OUD (DSM-5 criteria) at any time during the study can be offered 
medication for OUD (MOUD) and linked to treatment by clinical staff in the EUC arm, and the 
NCM in the STOP arm, to formal assessment and MOUD treatment.
Patients will be recruited to participate in a “healthy living study” and informed that the purpose of 
the study is to improve health behaviors including but not limited to changes in substance use. To 
reduce assessment reactivity, all assessments of substance use will also include questions about 
other health behaviors (e.g., exercise and diet). This strategy was used in the QUIT trial, which 
was portrayed to participants as a ‘living well study’ to promote healthy lifestyles.[21] 
Patient participants will be asked to complete an electronic questionnaire (“healthy living survey” 
that asks about exercise, diet, and drug/alcohol use) once every 30 days, for 12 months, to assess 
opioid and other substance use. Additionally, more detailed assessments of health status, 
symptoms, and behaviors will be completed at baseline and quarterly (every 3 months), for 12 
months. Urine Drug Screens, collected at baseline and at 6 and 12 months, are used to verify the 
self-reported drug use data. Assessments of secondary outcome measures, including mental 
health/suicide risk and SUD symptoms, prescription opioid misuse behaviors, health-related 
quality of life, sleep and pain, will be completed at baseline and re-administered no more 
frequently than once every 3 months to decrease participant burden (see Assessment schedule 
in Section 11). Prescribed medications (opioids, other controlled substances, naloxone) and PCP 
behaviors (prescribing of opioids, benzodiazepines, and naloxone kits, OUD diagnosis, visit 
frequency, toxicology testing) are extracted from the electronic health record (EHR) to measure 
PCP participant outcomes. PCP counseling on opioid use will be obtained via patient self-report. 
The outcome measures must use self-reported information about substance use because 
routinely collected biological measures do not reliably detect intermittent and low-level drug use, 
which may have extinguished days prior to the collection of the sample. Further, biological 
measures are unable to provide information about misuse of prescribed medication (i.e., taking 
the prescribed medication more frequently than instructed). To reduce social desirability bias, all 
substance use assessments will be self-administered using electronic questionnaires. 

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Rationale for the cluster randomized design: The proposed trial will randomize PCPs to either 
STOP or EUC. Randomizing clusters that are smaller than the practice level introduces potential 
for contamination that may reduce the observed intervention effect size. However, this strategy 
was used in the study team’s previous trials (TOPCARE and TEACH randomized PCPs within 
clinics; QUIT randomized patients within clinics) that nonetheless had significant findings.[21, 33] 
Randomization at the clinic level would reduce contamination, but would require a much larger 
number of practice sites and would not be feasible with the resources available for this study. 
Randomizing at the patient level for this collaborative care intervention would increase 
contamination, as PCPs would find it challenging, and may be unwilling, to follow a study protocol 
that requires them to deliver different treatments to patients who have the same condition of 
subthreshold OUD. 
6.2
Duration of Study and Visit Schedule 
PCPs are enrolled just before the start of patient recruitment (approximately 1-2 months prior to 
intervention initiation), in order to allow time to randomize PCPs, and participate in training and 
study preparation activities. PCPs continue participation until the last patient participant completes 
12 months of follow-up. Therefore, the total duration of participation for PCPs is up to 37 months 
[approximately 1 month prior to recruitment; approximately 24 months of recruitment; 12 months 
following enrollment of the last patient]. 
Patients deemed eligible will provide consent and enroll. During their baseline visit, they will view 
the Video Doctor and complete baseline assessments. Intervention patient participants may 
receive brief advice from their PCP either during a PCP visit that is integrated with the baseline 
visit, or within 10 business days after the baseline visit. Intervention patient participants may also 
meet with the Nurse Care Manager. The target dates for the first and second telephone health 
coaching sessions will be within approximately 2 weeks and 4 weeks of the baseline visit, 
respectively. If initial attempts to conduct either of these coaching sessions are unsuccessful, 
attempts to complete these calls will continue for approximately 3 weeks after the intended date 
of the session. Patient participants complete an electronic self-administered “healthy living 
survey” (including substance use and other health behavior) once every 30 days, for 12 months. 
Quarterly follow-up assessments are conducted online and by phone at 3, 6, 9, and 12 months. 
Therefore, the total duration of patient participation in the study is 12 months. 
 
 

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EUC
STOP
6.3
Figure 3: Study Design
All adult patients ( 18 y.o.) of participating PCPs
Prescreening. All patients complete the TAPS Tool and ‘healthy living survey’. Patients who are 
prescribed chronic opioids also complete the COMM (+ TAPS). If prescreen eligible, additional 
questions are given on current substance use and readiness to change.
Screening for study eligibility – RC/RA administers CIDI opioid items and completes inclusion/exclusion 
If eligible, the RC/RA obtains consent for Study Enrollment (online or in-person)
Brief Advice and/or Video Doctor
Nurse Care Manager
Intro to Telephone Health Coach
Educational Materials
Video
Educational Materials
Baseline Assessment
(Urine Drug Screening)
Monthly Healthy Living Survey
Months 1-12
3-month Assessment
6-month Assessment (Urine Drug Screening)
9-month Assessment
12-month Assessment (Urine Drug Screening)
Telephone coaching (2 sessions) 
2 and 4 weeks after Baseline
Participants can receive additional 
telephone MI/CBT weekly for 4 weeks.
(4 sessions)
PCP randomization into EUC or STOP intervention

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7.0
OUTCOME MEASURES
7.1
Primary Outcome Measure
The primary outcome (H1.1) measure is self-reported number of days of risky (illicit or 
nonmedical) opioid use in the past 180 days, assessed at 6 months after the baseline visit using 
single items based on questions used in the Addiction Severity Index, and the COMM.[40, 41]
Collecting data on self-reported days of use in the past 30 days is aligned with timeline follow-
back methodology, and was used in the QUIT trial.[21] Participants are asked to specify the 
number of days of illicit opioid use and of nonmedical opioid use in the past 30 days (range is 0-
30 days). Illicit opioid use includes use of heroin or synthetic opioids. Nonmedical opioid use 
includes using prescribed opioids more than prescribed (e.g., taking 2 tablets when the 
prescription indicates a dose of 1 tablet) or taking pharmaceutical opioids that were not prescribed 
to the individual taking them. Prescription opioids may be prescribed by the participating PCP or 
by another medical provider. The measure is calculated as the sum of all days of use reported on 
the assessments of past 30-day drug use for the first 6 months (i.e., the sum of days of use from 
the measures collected on day 30, day 60, day 90, day 120, day 150, and day 180).
7.2
Secondary Outcome Measure(s)
Measures of Patient-Level Outcomes
1.
Days of substance use: Self-reported days of substance use are collected at baseline
and once every 30 days. Patient participants are asked to specify the number of days of 
use in the past 30 days (range is 0-30 days, value =0 for substances that were not 
used). For binge alcohol use, the measure defines the cutoff as 5+ drinks (for men under 
age 65), and 4+ drinks (for women and men age 65 and over). Measures of substance 
use are calculated as the sum of consecutive assessments of days of use in the past 30 
days. For example, days of use in the past 90 days is calculated as the sum of three 
consecutive assessments of days of use in the past 30 days.
a.
H1.2. Days of risky opioid use at specified time points:
i.
In the past 30 days, measured at baseline and monthly for 12 months.
ii.
In the past 90 days, assessed at 3, 9, and 12 months.
iii.
In the past 180 days, assessed at 12 months.
b.
H2.1. Days of binge alcohol use:
i.
In the past 30 days, measured at baseline and monthly for 12 months.
ii.
In the past 90 days, assessed at 3, 6, 9, and 12 months.
iii.
In the past 180 days, assessed at 6 and 12 months.
c.
H2.2. Days of benzodiazepine use:
i.
In the past 30 days, measured at baseline and monthly for 12 months.
ii.
In the past 90 days, assessed at 3, 6, 9, and 12 months.
iii.
In the past 180 days, assessed at 6 and 12 months.

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d. H2.3. Days of stimulant use (cocaine and amphetamine-type stimulants): 
i. 
In the past 30 days, measured at baseline and monthly for 12 months. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 6 and 12 months.  
e. H2.4. Days of marijuana use: 
i. 
In the past 30 days, measured at baseline and monthly. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 6 and 12 months. 
f. 
H2.5. Days of other drug use (not including opioids, benzodiazepines, stimulants, 
and marijuana). 
i. 
In the past 30 days, assessed at 3, 6, 9, and 12 months 
g. H2.6. Increase in number of days of risky opioid use from baseline to follow-up at 
6 and 12 months: 
i. 
Days of opioid use in the past 30 days, measured at baseline and 
monthly for 12 months 
ii. 
Days of opioid use in the past 180 days, assessed at 6 and 12 months. 
h. H2.7. Prescription opioid misuse behaviors, among participants receiving 
prescribed opioids: 
i. 
Days of taking prescribed opioids for symptoms other than for pain, 
measured at baseline and monthly for 12 months. 
ii. 
Days of taking pain medication belonging to someone else, measured at 
baseline and monthly for 12 months. 
iii. 
COMM score, assessed at screening and at 6 and 12 months. 
Urine Drug Screens are used to verify self-reported drug use. Urine Drug Screens are conducted 
at baseline and at 6 and 12 months. 
2. Substance use disorder: Opioid use disorder is assessed at baseline and at 6 and 12 
months using the modified World Mental Health Composite International Diagnostic 
Interview (CIDI). Drug (other than opioid) and alcohol use disorder measures are 
collected using the PDSQ at baseline and at 6 and 12 months. The PDSQ is used rather 
than the CIDI for these measures because it is brief and self-administered, which makes 
it more feasible for these follow-up assessments. 
a. H2.8. Moderate-severe opioid use disorder (CIDI opioid items) 
b. H2.9. Drug use disorder (PDSQ drug items) 
c. H2.9. Alcohol use disorder (PDSQ alcohol items) 

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3.
Overdose risk behaviors and events
a.
H2.10. Overdose risk behavior and behavioral intention to reduce risk is 
measured at baseline and at 6 and 12 months (Overdose Risk Behavior 
Questionnaire)
b.
H2.10. Episodes of non-fatal overdose are measured at baseline and at 6 and 12 
months (Non-Fatal Overdose Questionnaire)
c.
Exploratory Objective 3. Overdose death is expected to be a rare event in this 
population and will be assessed from the EHR and from other administrative data 
kept by the health system or government entities, for participants who cannot be 
reached at the time of the 12-month study visit.
4.
Pain symptoms and pain-related functioning
a.
H2.11. Pain symptoms (severity, impact on functioning) are measured at 
baseline and at 3, 6, 9, and 12 months using the BPI short form (items #3-6 for 
pain symptoms and items #9A-9G for functioning).
5.
Mental health
a.
H2.12. Anxiety symptoms are measured at baseline and 6 and 12 months 
(PROMIS short form)
b.
H2.12. Depression symptoms and suicidality are measured at baseline and at 6 
and 12 months (PHQ-8 and PSS)
c.
H2.13 Sleep quality is measured at baseline and at 6 and 12 months (PROMIS 
Sleep 4a)
6.
Health-related quality of life and acute health care utilization
a.
H2.14. Health-related quality of life is measured at baseline and at 6 and 12 
months (SF-12)
b.
H2.15. ED and hospital utilization are measured using patient participant self-
report of acute care events (ED visits, hospitalizations for medical reasons, 
hospitalizations for detoxification), collected at baseline and at 6 and 12 months.
Measures of Provider-Level Outcomes
Measures of provider treatment practices are collected from the EHR at baseline and 12 months, 
for patient participants. The data extracted will be for the period beginning 12 months prior to start 
of the intervention, through 12 months after the last patient participant is enrolled.
a.
H3.1. Prescriptions for opioids: number of patient participants receiving prescriptions for 
high-dose opioids (>90 MME); moderate-dose opioids (50-90 MME); and any opioids:
number of prescriptions; daily prescribed dose; and total number of days prescribed.
b.
H3.2. Prescriptions for benzodiazepines: number of patient participants receiving 
benzodiazepine prescriptions and number receiving both chronic opioid and 
benzodiazepine prescriptions: number of prescriptions; daily prescribed dose, and total 
number of days prescribed

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c. H3.3. Prescriptions for naloxone: number of patient participants receiving at least 1 
prescription 
d. H3.4. Urine Drug Screens: number ordered and completed for each patient participant 
e. H3.4. Diagnosis of OUD: number of patient participants receiving a new diagnosis of 
OUD during the study period. 
f. 
H3.4. Primary care visits: number of scheduled visits per patient participant 
7.3
Other Outcome Measures
The following additional measures will be collected to assess exploratory outcomes, characterize 
domains from our conceptual model, and may be used to adjust models of the primary and 
secondary outcomes. These measures are collected at the baseline study visit and at the study 
visits specified in Tables 5 and 6 (schedule of assessments). 
a. Demographic characteristics and insurance status.  
b. Patient participants’ self-assessments of readiness to change risky opioid use and other 
substance use will be measured using two items that query self-reported readiness and 
confidence to change, rated on a 10-point scale. 
c. Social support will be assessed using the PROMIS instrumental and emotional health 
short forms. 
d. Patient engagement in primary care (Exploratory Objective 1): Number and frequency of 
kept appointments and missed appointments for primary care visits. 
e. Addiction treatment and harm reduction program utilization (Exploratory Objective 4): 
Self-reported number of weeks of addiction treatment or harm reduction program 
services, and self-reported number of weeks receiving MOUD is assessed at baseline 
and at 6 and 12 months. Prescriptions for MOUD received in the primary care clinic are 
additionally assessed from the EHR from at 12 months. 
f. 
PCP knowledge and attitudes regarding substance use, subthreshold OUD, and opioid 
management, assessed at baseline and at the end of the intervention period. 
g. TLFB measure of substance use in the past 90 days (Exploratory Objective 5): A 90-day 
TLFB administered at the 3- and 6-month quarterly assessments, will capture days of 
risky opioid use, days of binge alcohol use, and other drug use including 
benzodiazepines, cocaine, stimulants, marijuana, and other drugs. For any prescription 
opioids, benzodiazepines, and amphetamine-type stimulants, the TLFB will measure 
non-medical use. 
h. Patient participant-completed assessments will measure PCP counseling on opioid use 
(Exploratory Objective 6). For patient participants who have a PCP encounter integrated 
with the baseline research visit, counseling is measured with the baseline exit survey. 
For all patient participants, information on any discussion or counseling provided during 
follow-up PCP encounters will be assessed with a quarterly patient experience 
questionnaire. 

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7.4
Study Timeline
Due to delays encountered during the COVID-19 pandemic, after receiving CCTN approval of the 
protocol, approximately 16 months of trial preparation activities will elapse prior to commencing 
PCP enrollment in the main study (see Estimated Project Timeline, Table 2). Trial preparation will 
include obtaining Institutional Review Board (IRB) approval, developing the data collection 
systems, conducting a pilot study (described below), developing the Manual of Procedures
(MOP), conducting all staff training, and endorsing sites. Recruitment of patient participants was 
originally expected to take approximately 12 months; however, due to the recruitment challenges 
posed by the COVID-19 pandemic, up to 12 additional months of recruitment at selected sites 
may be added to the original study timeline to provide sites additional time for recruitment. Follow-
up assessments will be conducted for approximately 12 months after completion of the 
recruitment phase. Two months will be allowed for database lock after the last patient’s final visit; 
therefore, database lock is projected to occur at approximately month 67.
Pilot Study
A pilot study will be conducted at one study site and is further described in Section 10.5. The 
purpose of the pilot is to refine study procedures for recruitment, enrollment, and baseline 
assessments, and it will primarily focus on evaluating the feasibility and acceptability of screening, 
enrollment, and assessment procedures. There is no randomization of PCPs for the pilot study. 
The pilot is expected to begin approximately 4 months following CCTN approval of the protocol,
and to be completed in approximately 15 weeks. In addition to the formal pilot study, we will 
conduct telephone health coaching only with up to 10 patients at the pilot site in order to inform 
the training of health coaches for the main study.

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Study Month
1-3
4-6
7-9 10-12 13-15
16-18 19-21 22-24
25-27 28-30 31-33 34-36 37-39 40-42
43-45 46-48 49-51
52-54
55-57
58-60
61-63
64-67
Patient 
participant 
enrollment  
 
 
 
 
 
 
 
Intervention
Patient 
participant 
follow up
Data cleaning 
and data lock 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.0
STUDY POPULATION
The sample consists of PCPs and their patients. We anticipate that approximately 100 PCPs and 
approximately 300 patient participants will participate. The unit of randomization is the PCP, and 
randomization will be stratified by site. The study population includes patients who are receiving 
prescribed opioids for pain and those who are using illicit opioids; there are no predetermined 
targets for the number of patients enrolled from each of these groups. Each site will continue 
enrolling patient participants until approximately 300 patient participants have been enrolled 
across all sites. PCPs are only offered study participation if they plan to remain in the practice 
until the study is completed. 
8.1
Inclusion and Exclusion Criteria
Participants include both PCPs and their patients. Individuals must meet all of the group-specific 
(PCP or patient participant) inclusion criteria at screening in order to be eligible to participate. 
Individuals meeting any of the exclusion criteria at screening will be excluded from study 
participation. Participant characteristics are anticipated to reflect the characteristics of PCPs and 
their adult patients in the participating sites. Patient participants will include a diversity of racial 
and ethnic groups, males and females and all will be at least 18 years of age.
PCP Inclusion and Exclusion Criteria
PCP Inclusion Criteria
1.
Licensed medical professional (MD, DO, PA, NP).
2.
Currently providing care to approximately 4 or more adult patients (18 years or older)
who are receiving chronic opioid treatment and/or have risky opioid use. Chronic opioid 
treatment is defined as having at least three opioid prescriptions, at least 21 days apart, 
in the past six months, with EHR documentation of active opioid prescription within the 
60 days prior to screening. For PCPs who practice in a team, the care of patients 
receiving chronic opioid treatment may be shared with other team members who also 
meet criteria for participation in the study. 
3.
Total patient volume is approximately 40 or more adult patients (18 years or older) per 
week on a typical week (excluding vacation and inpatient rounding weeks).
4.
Willing to be randomized to either of the two study conditions.
PCP Exclusion Criteria
1.
Planning to resign from the clinic in the next 24 months, per PCP self-report.
2.
Planning to change their schedule in the next 24 months such that they would no longer 
meet the inclusion criteria for patient volume, per PCP self-report.

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Patient Participant Inclusion and Exclusion Criteria
Patient Participant Inclusion Criteria
1.
PCP is enrolled in the study.
2.
Age 18 years or older at time of prescreening.
3.
Proficient in spoken and written English, as determined by patient self-report and research 
staff evaluation. 
4.
Risky opioid use in the past 90 days from date of prescreening, as determined by a TAPS 
score >1 for heroin and/or prescription opioids, and/or a positive response (>Never) to any 
of the three COMM items indicating taking more opioid medication than prescribeda. 
5.
Access to phone that can receive text messages, and access to internet (via smartphone, 
tablet, or computer), per patient self-report.
6.
Able to provide sufficient contact information (minimum of 1 reliable locator).
7.
Able to provide informed consent.
a.COMM items used for determining eligibility:
Item 9: In the PAST 30 DAYS, how often have you needed to take pain medications 
belonging to someone else?
Item 14: In the PAST 30 DAYS, how often have you had to take more of your medication 
than prescribed?
Item 15: In the PAST 30 DAYS, how often have you borrowed pain medication from 
someone else?
Patient Participant Exclusion Criteria
1.
Patients with moderate-severe OUD, defined as meeting 4 or more DSM-5 criteria for 
OUD at screening, as assessed by research staff using the modified-CIDI opioid items.
2. Receiving MOUD or engaged in an opioid treatment program in the past 30 days from 
screening date, per patient self-report. 
3. Receiving opioids for end of life care, per patient self-report.
4.
Pregnancy (females age 18-50), as determined by patient self-report at the time of 
screening. 
5.
Are currently in jail, prison, or other overnight facility as required by court of law or have 
pending legal action that could prevent participation in study activities.
6.
Plan to leave the area or the clinical practice within the next 12 months, per patient self-
report. 
7.
Other factors that may cause harm or increased risk to the participant or close contacts or
preclude the patient’s full adherence with or completion of the study. 

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Patient Participant Inclusion and Exclusion Criteria for 
Additional Pilot Telephone Health Coaching for Training 
Purposes Only
Patient Participant Inclusion Criteria
1.
Received prescription opioids in the past six months and/or are known to have risky 
opioid use or OUD
2.
Age 18 years or older at time of screening
3.
Proficient in spoken and written English, as determined by patient self-report and 
research staff evaluation
4.
Access to phone, per patient self-report
5.
Willing and able to provide informed consent
Patient Participant Exclusion Criteria
1.
Are currently in jail, prison, or other overnight facility as required by court of law or have 
pending legal action that could prevent participation in study activities.
Patients will not need to meet the other inclusion or exclusion criteria listed above in Section 8.1.2 
in order to qualify for the additional pilot health coaching sessions.
8.2
Strategies for Recruitment and Retention
Recruitment of PCPs
The Site PI and/or Clinical Champions will work with clinic staff to identify potentially eligible PCPs. 
EHR data may be used to produce a list, organized by PCP, of patients who have been on chronic 
opioid treatment. All potentially eligible PCPs will be approached by the Site PI or other study 
affiliated personnel to assess their interest in study participation. All interested and potentially 
eligible PCPs will be invited to a meeting at the practice site, which may include a meal (breakfast 
or lunch) to increase the likelihood of attendance.
Study affiliated personnel will attend the meeting to describe the study in detail, answer questions,
and ascertain interest in the study. PCPs who are interested in participating will complete the 
Screening survey to make a final determination of eligibility for enrollment. If eligible, PCPs will 
continue with consent, (see Informed Consent Procedures, Section 10.2.2) and the Baseline 
survey. PCPs who are unable to attend the group meeting will meet individually with study 
affiliated personnel to replicate the same process as in the group. PCPs will be enrolled in the 
study just before the start of the patient recruitment and/or after the intervention begins to allow 
for PCPs who are eligible after the first group of PCPs are enrolled. Sites will be able to continue 
enrolling eligible PCPs until approximately 6 months before the end of patient recruitment.
Recruitment of Patients
Recruitment procedures are further detailed in Section 10. Research staff will attempt to contact 
all adult patients of participating PCPs. Recruitment materials will direct participants to an online 
site where they may complete an initial eligibility prescreening survey to assess minimum eligibility 

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criteria. Patients will be provided information on how to access the online site, which may be 
accessed directly or through electronic links provided in correspondence and/or a study specific 
website. Patients receiving COT as well as patients with conditions such as alcohol use, tobacco 
use and benzodiazepine use will be prioritized for prescreening throughout the study. These 
patients will be identified through review of EHR data and/or by clinical staff. 
Both males and females will be recruited. Based on our prior studies in primary care, we anticipate 
that at least one-third of patient participants will be female, and that their race and ethnicity will 
reflect the demographic characteristics of English-speaking patients from the participating clinics. 
This study does not to seek to enroll prisoners. If a participant later meets the Office for Human 
Research Protections (OHRP) definition of a prisoner (as stated in 46 Subpart C) after baseline 
enrollment, sites may keep such individuals in the study and collect follow-up data only if they 
have IRB and OHRP approval to do so. Data may be collected either in person or by electronic 
means, provided that data collection follows the procedures approved by OHRP and the local 
IRB. 
Anticipated number of patients screened: The study will enroll approximately 100 PCPs from a 
total of 5 sites. We estimate, however, that 30-40% of the enrolled PCPs will have no participating 
patients (because we will not identify patients who meet the eligibility criteria in their panel), 
leaving approximately 60 PCPs who will have patients that will enroll into the study. Each of these 
PCPs is expected to have approximately 5 patient participants participating in the study (see 
Table 3). 
We expect that approximately 15-20% of the sample will be comprised of patient participants who 
are receiving prescribed opioids. Based on urine toxicology data collected in the TOPCARE study, 
we anticipate that approximately 30% of patients who are receiving prescribed opioids will have 
unhealthy opioid use. Participating PCPs are expected, on average, to have approximately 8 long-
term opioid patients, and so we anticipate that 1-2 of these patients will be eligible. PCPs with 
more than 8 patients on long-term opioids will contribute more from this group (risky opioid use of 
prescribed opioids). Patients with illicit/non-prescribed opioid use are anticipated to constitute the 
remainder of the sample. In our prior studies, between 3.9% and 6.6% of adult primary care 
patients screened positive for illicit opioid use.[12, 21] 
In the general patient population (not limited to those patients on prescribed long-term opioids), 
we anticipate that PCPs will have approximately 1100 patients in total (this panel size is slightly 
lower than the national average (1200-1900/PCP), to accommodate some less than full-time 
providers [42]). Approximately 42% of patients are expected to be screened for the study. Of the 
approximately 460 general patients who we anticipate being able to screen, we conservatively 
estimate that 1% (total of 5 patients) will be eligible. We expect to enroll approximately 75% of 
those deemed eligible (a conservative estimate, given that in our prior trials the rate of enrollment 
of eligible patients was 81-84%[21, 37]). Thus, in total, each PCP is anticipated to have 
approximately 1 patient on prescribed opioids, and 4 patients with risky use of illicit/non-
prescribed opioids, participating in the study. 
 
 

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Table 3: Anticipated Patient Participant Screening and 
Enrollment for each of the 60 PCPs Having Patients in the 
Study 
PCP Panel Size ~ 1100 patients
Prescribed Opioids
(N=8)
General Patient Population
(N=1100)
Number Screened
(42% of panel) 
5
460
Percent Eligible
30%
1%
Number Eligible
1-2
5
Agree to Enroll 
(75% of eligible)
1
4
Anticipated Enrollees
1 + 4 = 5
Procedures for study retention: Patient participants will provide detailed contact information in a 
locator form at the baseline visit, which will be updated by research staff whenever the information 
changes and reviewed and updated at each quarterly assessment. Patient participants will be 
informed that if their contact information changes between study visits, they will receive an 
incentive if they contact the research team and provide the updated information. Research staff 
will attempt to contact patient participants approximately once/month during the study period. 
Patient participants will receive electronic notifications and reminders to complete questionnaires. 
In addition, research staff may contact patient participants by phone, text, email, letter, and/or in 
person to ask them to complete assessments. The dates of follow-up assessments that are to be 
conducted by phone will be scheduled at the time of the current study visit. 
To lower potential barriers to participating in study visits, assessments may be completed 
remotely (electronically by text/online and by phone). Because of the expected difficulty of 
maintaining high follow-up rates in the study population, adequate compensation for time and 
inconvenience is critical. Monetary incentives will be provided for each post-visit study activity, 
including for completing the baseline and quarterly assessments, monthly questionnaires, and 
urine drug screens. During the first 6 months of study participation, patient participants will also 
receive a bonus for completing consecutive assessments, paid monthly. For example, if a patient 
participant has completed their Month 1 assessment, and they go on to complete their Month 2 
assessment, they will receive a bonus payment in addition to the standard incentive for completing 
the Month 2 assessment. If they do not complete their Month 1 assessment, then in Month 2 they 
are not eligible for the bonus payment. Patient participants who miss a monthly assessment will 
be notified that they can still receive the incentive if they complete the assessment in the 
subsequent month. Incentives will be paid in the form of either a debit card or gift card. The 
amount of each incentive payment will be specified on the informed consent documents and
reviewed with patients as part of the consent process.

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9.0
SITE SELECTION
9.1
Number of Sites
Approximately 5 sites will be selected to participate in the study. Each site will have approximately
5 primary care clinics serving adult patients. For sites with more than 1 participating clinic, the 
clinics must share the same administrative infrastructure and be geographically proximal 
(approximately 1 hour or less on average to travel between sites).
A site survey designed specifically for this study, followed by interviews and site visits, will be 
used to arrive at the final site selection. Sites will be selected based on the capacity and patient 
volume to support enrollment of the target population. Research experience and successful 
participation in prior studies is desirable as it provides evidence of the feasibility of study 
implementation. Participating clinics must be primary care clinics serving adult patients. Each site 
is expected to have approximately 7-30 eligible primary care providers who will meet eligibility 
criteria and agree to participate. Across 5 sites, each site will have approximately 16 PCPs. Sites 
need to have capacity to provide referrals to opioid treatment program(s), and have a fully 
functional electronic health record system, including clinical notes, laboratory tests, and 
prescribed medications. Sites will need to provide a clinical champion to facilitate the 
implementation of the intervention and conduct of the research and provide space for the NCM. 
To ensure that there is sufficient contrast between the STOP and EUC conditions, the 
participating clinics should not be currently using a collaborative care model dedicated to 
managing primary care patients receiving opioid prescriptions.
Additional characteristics that will make sites desirable for this study are as follows:
Located in an area with higher than average prevalence of opioid use, to ensure a 
sufficient pool of eligible patients for recruitment. We use rates of opioid overdose 
deaths and opioid prescribing as markers of opioid prevalence.
Capacity to provide office-based buprenorphine treatment.
Able to provide space in or near the clinic for recruitment, consent, and research 
activities.
A diverse, representative sample of participants is desirable to enhance the external 
validity of the findings. However, it will only be feasible to conduct assessments and the 
intervention in English.
Rationale for Site Selection
The selection of study sites is based on the applicability of the expected findings to patients in the 
community, as well as cost and feasibility. Study participants will be recruited from primary care 
sites. We will seek to select sites that serve a diverse group of patients with a mix of race/ethnicity 
and socio-economic status. Primary care sites will be selected based on the site characteristics 
delineated above.

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10.0 STUDY PROCEDURES
10.1
Screening and Informed Consent Procedures
Prescreening
Patients aged 18 or older of participating PCPs will be asked to complete prescreening 
questionnaires. The prescreening questionnaire is electronic and self-administered. The following 
modes of contacting patients for prescreening and screening may be used: 1) messages through 
the clinic’s EMR/patient portal, email, text message, fliers and posters, and/or mailed letters; 2) 
research staff outreach in-person or by telephone; 3) clinical staff referring patients to the research 
staff. Patients can be recruited before, during or after any type of clinic visit, and/or without an 
upcoming appointment. Details of the RC/RA interaction with the patient participant will be 
specified in the Manual of Procedures (MOP). Figure 4 describes the prescreening and enrollment 
process.
Before initiating the prescreening questionnaire, patients will view written information online that 
briefly describes the study and informs them that participation is voluntary. There is no incentive 
provided for prescreening. Individuals will be informed that if they are eligible and choose to enroll 
in the study, they will receive incentives for participation.
Prescreening is anonymous and confidential; therefore, a waiver of consent will be obtained from 
the IRB. Patients with prescreening results indicating that they may be eligible for the study will 
be guided to complete the Healthy Living Monthly and Readiness to Change assessments, and, 
if still eligible, provide contact information and construct a unique identifier that can be used to 
retrieve their prescreening responses. Patients who are eligible after these initial surveys will be 
contacted by the RC/RA for further screening (CIDI, and eligibility review) and consent. A modest
incentive may be offered to patients who prescreen eligible if the RC/RA is able to reach them for 
screening, in order to increase the chance that screening will be completed. For patients who 
have an upcoming PCP appointment that will be integrated with the baseline visit, the RC/RA
should attempt to screen and consent them prior to this appointment. If a patient is participating 
in a telehealth visit with their PCP, the RC/RA will attempt to contact the patient prior to their 
telehealth visit to determine study eligibility.
Methods for Remote Screening and Enrollment
1.
Individuals who are prescreened online and provide contact information will be contacted 
by a RC/RA within approximately one week of completing prescreening. At this contact, 
the RC/RA will explain the next steps for screening and enrollment. At this time, the 
RC/RA will also inquire about whether the patient has an upcoming scheduled 
appointment with their participating PCP. Refusals and inability to participate will be 
recorded by the RC/RA in the Participant Tracking Log.
a.
The patient agrees to continue screening over the phone:
i.
If the patient does not have an upcoming PCP appointment, the RC/RA
will conduct screening, and if eligible, will request permission to obtain 
electronic consent from the participant for participation. After enrollment, 

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the RC/RA can continue with baseline activities, including the video 
doctor and RC/RA-administered assessments, as time allows. The PCP 
will be asked to follow-up with the patient participant within 10 business 
days after the baseline to deliver the brief advice. All baseline activities 
should be completed as soon as possible, preferably within 30 days of 
prescreening. 
ii. If the patient does have an upcoming PCP appointment in the next 30 
days, the RC/RA will conduct screening, and if eligible, will request 
permission to obtain electronic consent from the participant for 
participation prior to their PCP appointment. The RC/RA should wait to 
enroll the participant and conduct the rest of the baseline activities until 
after the PCP appointment. If the patient misses or reschedules their PCP 
appointment, then the RC/RA can complete baseline activities and ask 
the PCP to follow-up to provide brief advice within 10 business days of 
the baseline visit. 
b. The patient does not want to continue with remote screening and provide 
consent: 
i. If the patient does not have an upcoming PCP appointment in the next 30 
days, the RC/RA will schedule another time within the 30 day screening 
window (either in-person or remote) to continue screening and if eligible, 
complete enrollment procedures. Once enrolled, the RC/RA can continue 
with the baseline activities (video doctor and RC/RA-administered 
assessments). The PCP will be asked to follow-up with the patient 
participant within 10 business days after the baseline to deliver the brief 
advice. 
ii. If the patient does have an upcoming PCP appointment in the next 30 
days, the patient will be instructed to arrive to their appointment 30 
minutes early to conduct screening, and if eligible, provide consent for 
participation before seeing their provider. The RC/RA should wait to enroll 
the participant and conduct the rest of the baseline activities until after the 
PCP appointment. If the patient misses or reschedules their PCP 
appointment, then the RC/RA can complete baseline activities and ask 
the PCP to follow-up to provide brief advice within 10 business days of 
the baseline visit. 
c. Patients who prescreen eligible, but screen ineligible are not eligible to 
participate in the study. If they screen ineligible due to moderate or severe OUD 
or receipt of MOUD, the RC/RA will provide the patient with overdose prevention 
information (including printed and/or electronic materials); a list of community 
and/or clinic resources for OUD treatment; contact information for a social worker 
or behavioral health staff in the patients clinic, if available; an ineligible patient 
letter patients can provide to their PCP (for moderate to severe OUD patients 
only); and will suggest that patients speak with their primary care provider. 

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2.
Individuals who prescreen eligible and contact the RC/RA themselves will follow the 
same process outlined above for a) remote screening and consent, b) in-clinic screening 
and consent, or c) ineligible status.
3.
If a prescreened eligible patient has an upcoming PCP appointment, but is not reached 
by the RC/RA prior to their PCP appointment, the patient can complete screening and
consent any time within 30 days of prescreening.
4.
Individuals who prescreen eligible but are not screened by the RC/RA within 30 days,
will need to begin the process for determining eligibility again after the 30 day window.
Please refer to the MOP for additional details and Section 10.2.2 for consent 
procedures.
Methods for In-Person Prescreening, Screening and Enrollment
1.
RC/RAs will approach patients in the clinic and follow the RC/RA in-clinic recruitment 
script. They will then offer patients the prescreening questionnaire on a tablet if they 
have not already completed it (in the past 30 days). Assistance may be provided by the 
RC/RA if this is requested by the patient. If the patient is not able or willing to use the 
tablet, paper CRFs will be available. All paper assessments will be stored as source 
documentation. Patients with prescreening results indicating that they may be eligible for 
participation in the study will be informed of this by the RA, who will meet with them in a 
private area to conduct screening, and if eligible obtain consent. Enrollment procedures 
and baseline activities can continue after the PCP appointment, as needed, or preferably 
within 30 days of prescreening.
2.
If an individual screens ineligible due to moderate or severe OUD or receipt of MOUD 
the RC/RA will provide the patient with overdose prevention information (including 
printed and/or electronic materials); a list of community and/or clinic resources for OUD 
treatment; contact information for a social worker or behavioral health staff in the 
patients clinic, if available; an ineligible patient letter patients can provide to their PCP
(for moderate to severe OUD patients only); and will suggest that patients speak with 
their primary care provider.
Methods for Telehealth Prescreening, Screening and Enrollment
1.
If a patient completes the prescreener prior to a telehealth visit, the RC/RA will attempt 
to reach out to them prior to the telehealth visit and conduct screening and consent. If 
eligible and the patient enrolls in the study, the RC/RA will provide the patient’s PCP with 
the patient’s screening results as indicated in the local SOP.
2.
If a patient does not complete the prescreener prior to their telehealth visit, the RC/RA 
may call the patient prior to their scheduled telehealth visit to inquire about their interest 
in participating. If a patient is interested, the RC/RA will text or email the prescreener 
survey to the patient, and either stay on the phone with the patient as they complete it or 
have the patient call them back when finished. 
a.
If the patient is ineligible, the RC/RA will thank them for their time using an IRB 
approved script.

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b. If the patient’s prescreening results indicate that they may be eligible, the RC/RA 
will conduct screening, and if eligible obtain consent. 
c. If an individual screens ineligible due to moderate or severe OUD or receipt of 
MOUD, the RC/RA will provide the patient with overdose prevention information 
(including printed and/or electronic materials); a list of community and/or clinic 
resources for OUD treatment; contact information for a social worker or 
behavioral health staff in the patients clinic, if available; an ineligible patient letter 
patients can provide to their PCP (for moderate to severe OUD patients only); 
and will suggest that patients speak with their primary care provider. 
 
 

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Figure 4: Patient Prescreening and Enrollment
*If a patient has a PCP appointment and there is not enough time to read the full study consent before their PCP 
visit, the RC/RA may obtain verbal consent instead using a brief IRB approved consent script. In such cases, 
patients will read and sign the full consent after their PCP visit.
**Research staff are encouraged to complete the baseline visit as soon as possible after enrollment, preferably 
within 30 days of prescreening. 
Remote screening
Pre-screen eligible
Provides contact info
RA establishes contact
Screening and consent* 
Baseline visit** 
Incentive, Exit
In-person screening
Pre-screen eligible
Screening and consent*
Baseline visit
Incentive, Exit

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10.2
Prescreening and Assessment of Study Eligibility
The prescreener will include tools to assess study eligibility and a general health behavior 
questionnaire called the “healthy living survey,” which includes questions about general health 
behavior (exercise, diet) as well as substance use. The purpose of including questions that are 
not about substance use is to partially mask the topic of the study for potential participants, and 
those questions will not be used to determine eligibility. For all patients, the prescreening tool 
includes the Tobacco, Alcohol, Prescription medication, and other Substance Screening Tool 
(TAPS Tool). The TAPS Tool is a brief screening and assessment instrument that was developed 
and validated in CTN-0059. For patients who have received a prescription for opioid medication 
in the 6 months prior to date of prescreening, based on patient self-report, the prescreening tool 
will additionally include the Current Opioid Misuse Measure (COMM).[43, 44] The study will utilize 
three items from the COMM, items 9, 14, and 15, to determine eligibility. Prior to each of these 
three questions, there will be an instruction line informing patients that the questions are only 
asking about their opioid pain medications.
Prescreening is considered positive if the patient has a TAPS score >1 for heroin and/or 
prescription opioids, and/or a positive response to COMM items 9, 14, or 15. The TAPS Tool 
requires at least 1 day of unhealthy opioid use in the past 90 days to achieve a score of >1, and 
the COMM requires opioid misuse behaviors to have occurred in the past 30 days.
Individuals with a positive prescreen for risky opioid use, but do not meet the other eligibility 
criteria, will receive from the RC/RA additional information about overdose prevention and OUD 
treatment. This may include specific information about linkage to clinic resources that can assist 
them with initiating MOUD treatment, as detailed in the MOP and site specific standard operating 
procedures (SOPs).
Prescreening forms will not include identifying information for those who are ineligible; however, 
if a patient prescreens eligible, they will be asked to create a unique ID (referred to as ‘study ID’ 
in patient participant facing materials) and leave their contact information for the RC/RA to reach 
them. Individuals who are interested and screen eligible will undergo the informed consent 
process described below. Patients who do not qualify for the study will receive no further 
intervention, but the anonymous prescreening data will be kept to allow comparison to those who 
do qualify.
Because the prescreener is anonymous, the research staff will not know who has already 
completed it. Therefore, patients may receive an invitation to take the prescreener more than 
once, but they will be instructed to not complete it more than once in a 30 day period.
Screening for Eligibility
Patients who are interested in enrolling and have prescreening results suggesting study eligibility 
will meet with research staff by phone or in-person in a private area of the clinic, to complete the 
information needed for assessment of eligibility. Research staff will administer the CIDI opioid 
items and complete a checklist of inclusion/exclusion criteria to make a final determination of 
eligibility for enrollment. If the screener assesses that the patient is eligible, they can move onto 
informed consent and enrollment.

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Patients who prescreen eligible but screen ineligible, may receive another invitation to reinitiate 
the prescreening and screening process, but should be encouraged not to take the prescreener 
more than once every 30 days.
Informed Consent Procedures
The study includes PCPs and patients as participants. All participants will give informed consent 
for study participation.
Informed Consent for PCP Participants
PCPs will be recruited and enrolled prior to the enrollment of patients (see recruitment of PCPs, 
Section 8.2.1). Those who are eligible will be provided with an IRB-approved informed consent 
form on paper and/or electronically and will be asked to sign this document. The study 
investigators will not inform personnel outside of the study whether providers have chosen to 
participate and if so, to which group they have been randomized. PCPs will be allowed to inform 
others about their participation, if they choose to.
Informed Consent for Patient Participants
Patients are not informed of the PCP’s study intervention assignment prior to enrollment. They 
are informed that their PCP is participating in a healthy living study and that they will receive either 
the STOP intervention elements (including nurse care manager, telephone health coaching) or 
EUC. Screening, enrollment, and consent can be completed any time within 30 days of 
prescreening eligible. 
Informed consent will be obtained from patients before their baseline visit using an IRB-approved 
informed consent form on paper and/or electronically. A brief verbal consent will be available as 
a backup for patients enrolling before a PCP appointment who do not have time to read and 
discuss the full consent form before their PCP appointment. In such cases, patients will be read 
an IRB-approved verbal consent script and will be asked to provide verbal consent for 
participation in all study activities that take place during the PCP appointment (PCP brief advice
and/or video doctor). Following the PCP appointment, and prior to completion of the baseline 
assessments, these individuals will sign the full consent which covers participation in all study 
activities. Consent forms will be in compliance with the pertinent sections of 45 CFR 46. Because 
of the low risks associated with the study, the consent form will be as brief as possible within the 
constraints of adequate human subjects protections. The consent form will include a description 
of all significant elements of the study. We also will obtain permission to audio record some 
telephone health coaching sessions for intervention fidelity monitoring purposes. Given the multi-
site nature of the trial, it is possible that ancillary studies will be proposed before or after the study 
begins recruitment. For this reason, during the informed consent process, we also will seek 
permission to contact the participant in the future about other study opportunities.
Research staff will be available to answer questions about the consent form while patients are 
reviewing the document. Patients will read the  informed consent document (or have it read to 
them, if this is preferred) and express verbally their understanding of the key elements of the study 
(e.g., description of the treatment condition, duration of follow-up). They then indicate their 

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consent to participate in the study by signing (either written or electronic) the informed consent 
form.
HIPAA Authorization and Medical Record Release Forms
Health records may be used preparatory to research, to identify individuals who are potentially 
eligible for study participation and to determine the timing of a potential participant’s next PCP 
visit. For patient participants, a HIPAA disclosure will allow the study to access protected health 
information in the patient’s medical record. Health records will be used for the collection of some 
study outcome measures (e.g., prescriptions and care received in the study clinic). This study will 
have a single IRB. Sites will be responsible for communicating with their local IRBs or Privacy 
Boards and obtaining the appropriate approvals or waivers to be in regulatory compliance.
10.3
Randomization
After providing written/electronic informed consent, PCPs will be randomly assigned in a 1:1 ratio 
to (1) STOP Intervention, or (2) Enhanced Usual Care (EUC). In study sites where PCPs practice 
in teams, randomization will be at the team level (for example, if PCPs practice in teams of two, 
the two PCPs will be treated as one cluster in the randomization). Randomization will be stratified 
by site and will occur at each site prior to the intervention start date. The randomization procedure 
will be conducted through a process set up by the CTN Data and Statistics Center (DSC), and 
the randomization sequence will be unknown to staff. The DSC statistician will review the 
randomization data on a regular basis to ensure that the scheme is being implemented according 
to plan.
Patient participants receive the intervention to which their PCP is assigned. While randomizing at 
the PCP level introduces the possibility of contamination that has the potential to reduce the 
observed intervention effect size, this strategy is similar to our study team’s previous studies 
(TOPCARE randomized PCPs, QUIT randomized patients) that had significant findings.
Contamination could arise if patient participants change PCPs or make appointments with PCPs 
in the opposite treatment arm, or if PCPs drop out of the study (which would force a change in 
PCP upon their patients). These instances of contamination will be recorded, and the 
contamination data may be summarized with the study findings.
After the baseline PCP encounter, differences in clinical care received by the patient participant
are driven primarily by the NCM, who interacts directly with the patient participant and provides 
advice to the PCP about the patient participant’s management. To guard against contamination,
NCMs will be instructed to communicate only with PCP and patient participants who are in the 
intervention condition. To facilitate this, NCMs will have a list of patients who are enrolled in the 
study and have a PCP assigned to the intervention condition. In the relatively unlikely event that 
a patient participant in the EUC group has a visit with STOP intervention PCP after the baseline 
visit (for example, if the intervention PCP is covering for the patient’s regular provider), the NCM 
will not interact with the patient participant.
10.4
Baseline Assessment
PCP participants complete self-administered (SA) questionnaires at baseline. These are 
completed as paper or electronic questionnaires prior to the beginning of the intervention period.

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For patient participants, the baseline assessments are broken up into two parts: 1) a few baseline 
assessments are administered as part of the prescreener survey, for participants who prescreen 
eligible and 2) the remaining baseline assessments are administered during the baseline visit. 
The specific assessments are detailed in Table 6. Details regarding all assessments are in 
Section 11. Assessments are electronically self-administered or RA-administered as indicated; 
those that are RA-administered will be given in a private area of the clinic or may be done by 
phone. 
Assessments that are most sensitive to change based on the brief advice delivered by the video 
doctor and/or PCP are included at the end of the prescreener survey for patients who prescreen 
eligible. So as not to interfere with time-pressured clinical workflows, patient participants can 
complete assessments that are less sensitive to change after the baseline visit. These 
assessments may be completed up to three weeks after the baseline visit, but most often will be 
done on the same day or within one week. The assessments administered after the baseline visit 
include questionnaires on demographics, mental health, sleep, social supports and health-related 
quality of life, and health services utilization. If possible, a urine sample will also be collected 
(either in-person or remotely) at the baseline visit.  
10.5 Pilot Study 
A pilot study will be conducted in 1 study site prior to initiation of the trial. The pilot site may 
participate in the main study, following completion of the pilot. The purpose of the pilot is to assess 
whether any adaptations are needed to facilitate patient recruitment, enrollment, or the collection 
of the baseline assessment, and only patient participants are enrolled in the pilot study. Eligibility 
requirements for patient participation are the same as for the main study, with the exception of 
the requirement that patients have a PCP who is participating in the study. The study procedures 
for patient recruitment and enrollment in the pilot will be the same as those detailed above for the 
main study. 
Procedures for enrolled patient participants in the pilot will be the same as those used for the 
main study, except that pilot study activities will be limited to no more than four coaching sessions 
and two follow-up assessments, conducted at approximately 2- and 4-weeks post-baseline. Pilot 
study patient participants will not receive the full EUC or STOP intervention. Four telephone health 
coaching sessions (one per week after the baseline visit) may be conducted in order to test the 
mechanics of carrying out the sessions. Pilot patient participants may also be asked to participate 
in interviews, which may include cognitive interviews and question testing techniques that are 
intended to gather information about the feasibility and acceptability of the study procedures, 
assessments, and the STOP intervention. Interviews may also include assessing the acceptability 
of assessment procedures, and incentive payments for patient participants. The NCM and PCP 
brief advice components of the intervention will not be piloted, because introducing these 
practices into the clinic prior to the intervention start date is likely to contaminate the study (i.e., 
the NCM and PCPs would begin using their skills to manage opioid use with their other patients, 
who have not yet been enrolled). Given that both the PCP and NCM components have been 
tested in prior large trials (QUIT and TOPCARE), little new information is likely to be gained from 
a pilot. Instead, training of the NCMs will include role plays of clinical scenarios that will serve to 
build provider skills, while simultaneously refining the content and delivery of the clinical 
intervention. Training sessions, which are described in Section 12 and further detailed in a training 

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plan, will be led by members of the research team who have experience teaching and 
implementing these protocols with clinical staff.
The informed consent document used in the pilot will reflect the limited study activities for these 
participants. Individuals participating in the pilot will receive a monetary incentive for participation. 
The research team may enroll up to a limit of 50 patient participants. The higher number of pilot 
patient participants will be used if there is a need to adapt and test alternative approaches to the 
recruitment, enrollment, and assessment procedures, or if additional interviews are needed to 
inform feasibility and acceptability.
Additional Telephone Health Coaching for Training Purposes
In addition to the pilot activities described above, the pilot site will also recruit up to ten patients 
to participate only in the telephone health coaching component of the pilot study. The purpose of 
this activity is to collect additional information and feedback on the coaching sessions, in order to 
better inform training activities for the health coaches in the main study. Patients will be offered a
total incentive of $50 to participate in this activity. Participants will receive up to four coaching
sessions and the content and structure of the sessions will be the same as what is described in 
Section 10.6. No data will be entered into eClinical for this activity. Patients will be asked to
verbally consent to recording of the coaching sessions, and research staff will document consent 
at the bottom of the script. The inclusion criteria for this activity are listed in Section 8.1.2.
Patients may be referred to participate in this activity by their PCP or other clinical staff at the pilot 
site. Research staff may also invite participants who prescreen eligible for the pilot study, but are 
not eligible (i.e., screen ineligible) for the pilot study, or those who screen eligible but do not wish 
to enroll. Participants receiving telephone health coaching only will provide verbal consent to 
participate in the coaching sessions using an IRB approved verbal consent script. They will not 
complete any self-administered forms or surveys; they will be contacted by the RC/RA
approximately two weeks after completing their last coaching session in order to participate in a 
brief feedback interview over the phone.
10.6
Study Treatments
Interventions used in the study are described below. Training, supervision, and fidelity monitoring 
procedures for the interventions are described in Section 12, and in more detail in the Training 
Plan.
Patient participants in either arm who develop a moderate-severe OUD, based on the clinical 
judgment of the PCP, NCM, or telephone health coach at any time during the study can be offered 
clinical care to address OUD. This care may include office-based treatment using medication for 
OUD (MOUD) and referrals to addiction treatment. In the EUC arm, clinical care for OUD is 
facilitated by clinical staff (for example, PCPs, behavioral health providers, or social workers), 
while in the STOP arm clinical care for OUD is facilitated by the NCM or other clinical staff. Clinical 
guidelines for identifying OUD will be provided in the study MOP, and procedures for linking 
patients to OUD treatment will be included in the site operating procedures (SOP).

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Enhanced Usual Care (EUC)
In the EUC arm, PCPs will conduct primary care as usual, without the support of the NCM. At the 
baseline visit, patient participants receive educational materials and view a short video. The 
educational materials include information about preventing opioid-related overdose, including 
how to obtain a naloxone kit; and a handout on cancer prevention. The video content will feature 
information on cancer prevention. It will be viewed on a tablet or desktop computer and will be 
approximately 2 minutes long. All EUC patient participants receive the same video, which is not 
tailored to the responses given on their questionnaires. There is no study intervention after the 
baseline visit.
There are no limitations placed on primary care treatment as usual. The EUC condition enhances 
usual care by providing patient participants with an OD prevention educational handout. This is 
done for safety reasons, because the current standard of care in most primary care clinics is to 
offer no universal screening for opioid use or OD prevention interventions in primary care. The 
local research teams at each site will ensure that information on naloxone is detailed and specific, 
and that the pamphlet gives clear guidance on how to access naloxone. The content will be further 
detailed in the manual of procedures and/or site standard operating procedures.
STOP Intervention
In the STOP arm, enrolled patient participants will receive the intervention components of brief 
advice from their PCP and/or a video doctor, printed educational materials, and will be asked to 
interact with the NCM and receive telephone health coaching. The roles of the intervention team 
members are summarized in Table 4 and further detailed below.
Telephone Health Coaches, Nurse Care Managers and research staff will use a HIPAA compliant 
communication software called QliqSOFT to coordinate care for STOP intervention patient 
participants.
Baseline primary care visit
Patient participants in the STOP arm will receive brief advice, consisting of PCP-delivered 
counseling and/or viewing a “video doctor.” For in-person visits, the video doctor can be 
completed either in-person or remotely. For telehealth visits, the video doctor will be sent via email 
or text to the patient participant. They will additionally receive an educational pamphlet about 
opioid overdose prevention and an introduction to the role of the NCM and telephone health
coaches.
PCP brief advice
Brief advice can be delivered by the patient participant’s PCP as part of the baseline visit or within 
10 business days. Before providing the patient participant with the brief advice, PCPs will receive 
a printed summary report from the RC/RA or clinical staff. The summary advises the PCP that 
their patient participant screened positive for risky opioid use, lists the patient participant’s 
screening results (TAPS Tool +/- COMM) and gives a suggested counseling script. The 
counseling script will include specific advice on opioid-related risks, (e.g., developing addiction, 
physiologic dependence, and overdose prevention), will inform patient participants of resources 

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to help them reduce their risk (NCM and telephone health coaching), and will include a 
recommendation to reduce their risk behavior. PCPs will be trained in using this script to deliver 
counseling, which is intended to last approximately 3 minutes. In the QUIT trial, two-thirds of the 
interventions lasted at most 3-4 minutes; only three (1.5%) required more than 10 minutes. PCPs 
will not be incentivized for delivering this counseling. 
Video Doctor: The video doctor should be completed as part of the baseline visit. If the patient 
participant sees their PCP during the baseline visit, they will view the Video Doctor after they see 
their PCP and before they complete the baseline assessments. If the patient participant does not 
see their PCP as part of the baseline visit, the RC/RA will show them the Video Doctor after 
consent and enrollment. For telehealth or remote visits, the video link may be sent via email or 
text to the patient participants. The video is a recording of a provider delivering brief advice about 
opioid use that includes the same elements covered in the summary report outlined above, and 
will be specific to use of illicit or prescribed opioids. The video may also include an introductory 
message from the site NCM and the telephone health coach(es). 
Patient participants in the STOP intervention will receive an educational pamphlet, which includes 
information about preventing opioid-related overdose, including how to obtain a naloxone kit. 
Patient participants will also receive a printed handout with information about the NCM and 
telephone health coaching sessions, including the benefits and expectations of their participation, 
schedule of research visits and telephone health coaching sessions, and contact information. 
When possible, the NCM will introduce themselves to the patient participant in-person during the 
course of the baseline visit. The NCM may reach out to the patient participant following the 
baseline visit (by phone, email, text message, or via the patient portal) to introduce themselves. 

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Nurse Care Manager 
The Nurse Care Manager (NCM) is a central element of the intervention, as the nurse works 
closely with the PCP to assess, educate, and manage patient participants with risky opioid use. 
For all patient participants in the STOP condition, it will include facilitating linkage to needed 
specialty care, including pain (e.g., physical therapy), mental health (pharmacotherapy) and 
addiction, as indicated. NCMs will provide health education and counseling on risk reduction, 
overdose prevention and self-management skills. For patient participants on COT, the role will 
include monitoring opioid prescribing and risks. Details of the NCM intervention are outlined in 
Table 5 below. Patient participants will be asked to participate in an initial visit with the NCM, 
which will occur on the same day as the baseline visit if possible. The NCM continues working 
with patients in the STOP condition throughout their 12 months of study participation. Following 
the initial visit with the NCM, the frequency of visits depends on patient participant needs. For all 
patients of intervention PCPs, the NCM can provide care management and usual nursing care. 
For all patients of PCPs in the EUC arm, the NCM cannot provide any care management. They 
can perform nursing activities distinct from what they do for enrolled intervention patients. For 
example, they can assist with clinic-wide initiatives such as immunization clinic (e.g., flu shots), 
or other nursing care (triage, wound dressing, etc.). The NCM may also work with all patients of 
the clinic who are receiving medication for OUD, as these patients are not eligible for our study. 
 
 

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Table 5: Nurse Care Manager Intervention 
Nurse: Patient Participant ratio1
 
Approximately 50 patient participants/1.0 FTE NCM (panel will increase over the course of the 
study, as patient participants are enrolled). 
Roles/Duties
 
Integrating into work flow: Prior to the start of the study, NCM will coordinate with existing 
practice staff to ensure smooth transition of duties and integration into usual work flow for 
patients of intervention PCPs. 
Reviewing panel of patient participants with risky opioid use, including those on COT: Meet 
with PCP to review patient participant panel to identify high risk or problem patient 
participants; and as patient participants are enrolled into the study, to review with PCP before 
or after PCP visit.
 
Review charts and prescription drug monitoring program (PDMP) for presence of treatment 
agreements, urine drug screens and risk factors. 
Engage and assess patient participants: Conduct initial and ongoing evaluations for substance 
use and opioid use disorder, pain, mental health symptoms, social supports, overdose risk, 
suicidality, and barriers to treatment engagement and adherence.  
Conduct urine drug testing and pill counts (for patient participants on COT). 
 
Educate and counsel patient participants: Provide health education on substance use and 
disease or symptom self-management, including the relationship of opioid use to pain.  
 
Provide opioid risk reduction and overdose prevention counseling, ensure that patient 
participant is offered naloxone kit and training. Teach self-management skills for pain and 
other triggers for opioid use. 
 
Support engagement in care: Outreach to patients in between scheduled PCP visits or if 
patient cancels/no shows to visits to offer counseling and support. 
 
Refer patient participants to appropriate clinic and community resources, support ongoing 
engagement in primary care. 
 
Meet with PCPs: Review patient participants, help interpret urine drug screen results. 
Track prescriptions for patient participants and when appropriate, prepare prescriptions for 
PCPs to sign for naloxone and/or COT. 
Management of patient participants with substance use disorder: Refer patient participants 
with any active substance use disorder to treatment within or outside of the practice, as 
appropriate. 
 
Documentation: the NCM will document all patient participant interactions, changes to care 
and incidents in the EHR as a progress note.  
 
Provide care management and usual nursing care to all patients of intervention PCPs. 
Patient Participant Tracking 
 
Each practice will choose an approach to track patient participants with subthreshold OUD. 
Templates of recommended fields will be supplied by the study. Options include: 1) Use EHR 
if possible, 2) local database (Excel, Access, etc.), or 3) develop a clinic registry. 
1  In addition to study participants, nurses may manage up to 50 patients who are receiving COT or MOUD and have 
a PCP in the STOP intervention condition but are not participating in the study. 
 

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Telephone Health Coaching 
The STOP protocol includes one-on-one telephone behavioral coaching targeting risky opioid 
use. Patient-facing interventions based on Motivational Interviewing (MI) and Cognitive 
Behavioral Therapy (CBT) will utilize phone follow-ups to improve patient participant motivation 
and self-efficacy to change health behavior [45-47] and behavioral outcomes.[45, 48] MI and CBT 
are evidence-based treatments for behavioral health conditions, including opioid and other 
substance use, and can effectively be delivered via telephone and in as few as 2 sessions, with 
increased efficacy when up to 4 sessions are delivered. They are commonly integrated to optimize 
potency. 
Consistent with our Social Ecological Framework of Unhealthy Opioid Use, telephone health 
coaching will target multiple levels that impact subthreshold OUD. These include individual patient 
factors (knowledge, motivation, self-efficacy, behavioral skills), interpersonal factors (education 
on communication skills and limit setting), organizational factors (within clinic resource referral), 
and community factors (community and/or on-line resource referral). 
All patient participants in the STOP arm will be offered telephonic health coaching sessions with 
or without video at approximately 2- and 4-weeks post-baseline. Patient participants who may 
benefit from additional coaching (for example, those who do not improve or who experience 
clinical worsening of unhealthy opioid use) may receive up to 4 additional coaching sessions from 
the telephone health coach. Coaching is delivered from a centralized call center, by staff that 
receive standardized training and supervision. To the extent possible, calls will be scheduled at 
the patient participant’s convenience (e.g., evenings, weekends). Patients may chose not to 
participate in health coaching. 
Basic Coaching (Step 1): 
All patient participants in the STOP arm will be offered the Step 1 coaching, which is conducted 
by telephone health coaches, who are trained health professionals. The coaches will assess the 
patient participant’s current opioid use and other needs and provide appropriate referrals and 
resource links. The coaching approach is supportive and informed by MI techniques, which seek 
to increase the patient participant’s motivation and self-efficacy to improve health behaviors. 
The content of the Step 1 coaching focuses on the domain areas of substance use behavior, 
stress/mood management, and quality of life issues, with a particular emphasis on risky opioid 
use and overdose prevention. Sessions will be tailored to address risky use of other substances 
and provide brief recommendation to quit/reduce risky opioid use. For patient participants who 
endorse readiness to change, coaching will address behavioral skills acquisition, as well as 
behavior change plan development and implementation. Telephone health coaches will make 
referrals to clinic social work/behavioral health or other clinic services, or referrals to 
clinic/community resources, in response to barriers to opioid use reduction raised by patient 
participants or need for additional services. Timing of coaching sessions will be based at the 
patient participant’s convenience, including evenings and weekends. Patient participants will be 
given approximately $3 per completed call for reimbursement of cell phone costs. 

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Step 1 coaching will include 2 sessions, each 20 to 30 minutes in length. The first will occur 
approximately 2 weeks post-baseline and the second will occur approximately 4 weeks post-
baseline. While these are ideal windows, if initial attempts to complete the counseling sessions 
are unsuccessful, further attempts to engage patient participants will be made for up to 3 weeks 
after the target date for each call.
Enhanced Coaching (Step 2):
Patient participants who may benefit from additional coaching following the Step 1 sessions will 
be offered up to 4 additional sessions with a telephone health coach. Patient participants will be 
referred for these coaching sessions by the NCM or PCP, or at the discretion of the telephone
health coach, based on clinical criteria which may include ongoing or escalating nonmedical or 
illicit opioid use, overdose risk behavior, symptoms of OUD, OD episodes, and/or consequences 
of opioid and other substance use. This determination will typically be made during or after the 
first or second Step 1 coaching session. These criteria will be further detailed in the MOP, and 
training on their application will be provided as specified in the training plan.
The telephone health coach will provide patient participants with approximately 4 sessions of 
coaching over the telephone for Step 2. Calls with or without video will occur approximately weekly 
and each call will be approximately 30-40 minutes in length. An assessment of motivation to 
reduce risky opioid use will be conducted by the clinician using MI-based “rulers” (e.g., “On a 
scale of 0 to 10, how motivated are you to reduce your risky opioid use right now?”). For patient
participants with low motivation to change current unhealthy behaviors, the coach will conduct 
additional MI to increase motivation and self-efficacy. As patient participants increase readiness 
to change, specific behavioral strategies for relapse prevention and pain self-management will be 
presented by the coach within a CBT framework. These coaching sessions will ideally start within 
two weeks of the patient participant’s referral into Step 2 and occur once a week for four 
consecutive weeks. Circumstances in which a participant may receive more or less than 4 
sessions (for example, the participant refuses further coaching, or is unable to fully complete one 
of the sessions and wants to schedule a make-up to receive the intended content) will be detailed 
in the manual of procedures. If initial attempts to initiate the telephone health coaching sessions 
are unsuccessful, further attempts to engage participants will be made for up to 10 weeks after 
the referral. This time period reflects usual care practices in terms of being able to re-engage with 
care at a later time, balanced against the need to deliver the treatment prior to assessing 
outcomes in the study. Following the initial session, the subsequent 3 coaching sessions will 
ideally be completed weekly (one session/week). If one of these sessions is missed or delayed, 
further attempts to re-engage the patient participant will be made for up to 3 weeks after the target 
date for each session. Timing of calls will be based at the patient participant’s convenience, 
including evenings and weekends. Patient participants will receive approximately $3 per call for 
reimbursement of cell phone costs.
10.7
Premature Withdrawal of PCP or Patient Participants
Withdrawal of PCP Participants
All PCP participants will be followed for the duration of the study unless they withdraw consent,
or the investigator or sponsor decides to discontinue their enrollment for any reason. PCP 

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participants may withdraw voluntarily from the study at any time. Reasons for the investigator or 
sponsor terminating a PCP participant from the study may include, but are not limited to, the PCP 
breaking the study blind, lack of funding, or DSMB early termination of the study for safety or 
effectiveness reasons.
Withdrawal of Patient Participants
All patient participants will be followed for the duration of the study unless they withdraw consent, 
die, or the investigator or sponsor decides to discontinue their enrollment for any reason. Patient 
participants may withdraw voluntarily from the study at any time. Reasons for the investigator or 
sponsor terminating a participant from the study may include, but are not limited to, the patient 
participant becoming a threat to self or others, lack of funding, or DSMB early termination of the 
study for safety or effectiveness reasons. Treatment will be discontinued if there is evidence that 
continuing in the study would be harmful to the patient participant. Patient participants who 
withdraw or discontinue early may be replaced with other eligible individuals, if the site is still in 
the enrollment phase.
10.8
PCP Participant Follow-Up
PCP participant follow up will occur until the last patient participant completes 12 months of follow-
up. Therefore, the total duration of participation for PCPs is up to 37 months [approximately 1 
month prior to recruitment; 24 months of recruitment; 12 months following enrollment of the last 
patient]. Approximately six months after the last patient participant is enrolled in the study, PCPs 
will be asked to complete a second set of assessments, for which they will be compensated. If a 
PCP participant withdraws from the study early, the PCP will be asked to complete the end of 
study survey prior to their departure.
Provider behavior, including prescriptions for opioids and other controlled substances are 
assessed from the electronic health record (EHR). Provider counseling will be assessed from 
medical chart review and from patient exit interviews conducted at quarterly assessments. 
Research staff will conduct a structured chart review to collect data from the EHR for patient 
participants who are enrolled in the study. To provide data on the baseline provider behavior as 
well as any changes during the course of the study, the chart review will span the 12 months prior 
to study participation and the 12 months following enrollment.
10.9
Patient Participant Follow-Up
Follow-up assessments will be conducted for approximately 12 months following the baseline 
visit.
Most follow-up assessments will be self-completed electronically by participants. 
Assessments that require an interviewer will typically be done by phone but may be done in
person. The full list of assessments and assessment schedule is detailed in Section 11. Patient 
participants will receive a monetary incentive for the completion of each follow-up visit, the 
amounts of which are specified in the MOP and consent documents. All assessments are 
confidential, and collected using the patient participant’s unique study ID.
Once per month, patient participants will receive an electronic message (by text and/or email) 
instructing them to fill out a brief survey. The survey questions will consist of general health 
behaviors (for example, exercise frequency, duration, and diet), followed by assessment of the 

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days of risky opioid use (use of illegal or non-prescribed opioids or use of prescribed opioids at a 
higher dose or frequency than prescribed) and days of other substance use. Surveys can be 
completed by text message and/or online. Patient participants have a one-month window to 
complete each monthly survey. This means the prior month’s survey can be completed at the time 
of the current month’s survey if the prior month’s survey was missed.
On a quarterly basis, (at approximately 3, 6, 9, and 12 months post-baseline), patient participants 
will be contacted by the RC/RA to complete additional assessments. These assessments include 
both self-administered (usually completed online, but may be done on paper), and interviewer-
administered (completed by phone) questionnaires which may be completed by participants 
remotely (i.e., no required travel to the research site). If a patient participant has missed the prior 
follow-up assessment, the RC/RA will only complete the assessment items that are currently due 
(e.g., if a patient participates in their 6-month follow-up after skipping the 3-month follow-up, they 
will complete the 6-month assessment items only).
Patient participants will submit a biologic sample (urine) for urine drug screening at 3 times during 
the study period, if possible. These samples will be requested as part of baseline, 6-month, and 
12-month assessments. The location and processes for sample collection will be specified in the 
MOP and the site standard operating procedures. The results of the urine drug screen will not be 
shared with the participant’s medical providers.
Follow-up with Prisoners (as defined by OHRP)
Prisoners will not be enrolled in this study. If a participant later meets the OHRP definition of a 
prisoner as stated in 45 CFR 46 Subpart C after baseline enrollment, sites may keep such 
individuals in the study and collect follow-up data only if they have IRB and OHRP approval to do 
so. These procedures must be compliant with 45 CFR 46 Subpart C. Data may be collected either 
in person or by electronic means, provided that data collection follows the procedures approved 
by OHRP and the IRB of record.
10.10 Blinding
Type of Blinding
Randomization is at the level of the PCP, and PCPs will be aware of their assignment to the STOP 
vs. EUC condition. NCMs and telephone health coaches will only interact with patient participants 
in the intervention condition and will not be informed about patient participants who are enrolled 
in the EUC condition or who are not participating in the study. Patient participants are blinded to 
the treatment condition of their PCP and will be informed that the purpose of the research is to 
study health behaviors, not limited to opioid use.
Maintenance of the Blind
Most assessments are self-administered (SA) by patient participants. It is not feasible to blind 
research staff because the delivery of some intervention components require their involvement
(e.g., showing educational video vs. video doctor to the participant, intervention specific CRFs). 
Patient participants may be able to deduce the assignment of their PCP, (e.g., through 
conversation with other patient participants in the study), but this information will not be 

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volunteered by clinical or research staff. To assess the success of the blind, patient participants 
will be asked at the end of the study what they considered to be the goal of the research.
Breaking the Blind
We do not anticipate any situations that would require unblinding patient participants. The patient 
participant’s PCP will be aware of their study condition and will be able to administer any 
emergency medical treatment as needed without specifically informing the patient participant of 
their assignment.
10.11 Patient Participant Compensation
Incentives will be paid in the form of a debit card (e.g., ClinCard) or gift card for each of the 
following study activities:
Baseline visit (compensation may be given in two parts: 1) following completion of RA-
administered assessments and 2) following completion of the participant self-
administered assessments).
Monthly surveys (12 total).
Quarterly assessment visits (phone or in-person) at 3, 6, 9, and 12 months (4 total)
Urine drug screen that occurs after the baseline visit (2 total), if collected.
Bonuses for completing consecutive assessments will be paid monthly over the first 6 months.
Patient participants will additionally receive a small payment (approximately $3) for each 
telephone health coaching session, to cover the potential cost of using a cell phone for the call. 
Patient participants will receive an incentive each time they contact the research team to inform 
them of any changes to their contact information (patient participants may receive this incentive 
no more than four times during the study period), the details of which will be described in the 
MOP.

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11.0 STUDY ASSESSMENTS
The selected assessment battery attempts to balance the value of comprehensive data against 
the costs of data collection in terms of staff time, feasibility of completion in the context of primary 
care practice, financial cost, and assessment reactivity. The study is testing the efficacy of a 
relatively low-intensity behavioral intervention, and so assessment reactivity (i.e., the therapeutic 
effects of assessment) must be balanced against the need to collect detailed information about 
opioid use. Therefore, assessments have been limited to those that contribute directly to the 
objectives of the study.
To partially mask the purpose of the study and further minimize the impact of assessments on 
substance use behavior, questionnaires about substance use will be accompanied by 
questionnaires about other health behaviors, specifically exercise and diet. This strategy was 
used in the QUIT trial, which was conveyed to patients as a “healthy living study.” Information that 
is most likely to be impacted by stigma or social desirability bias, such as substance use and 
overdose behavior, will be participant self-administered to decrease the potential for biased 
reporting. Self-administered assessments will be delivered electronically, and audio guidance 
may be made available to assist individuals with lower literacy to complete them without 
assistance.
11.1
Table of Assessments
Table 6 (patient participants) and Table 7 (PCP participants) list assessments and the schedule 
on which they are administered.
Patient Participant Assessments
Table 6 indicates those assessments that are self-administered (SA) versus administered by 
research staff (RA). To increase the feasibility of collecting baseline data, the baseline 
assessments are divided into those that must be completed prior to the baseline visit, and those 
that may be completed after the baseline visit. Assessments that must be gathered prior to the 
baseline visit are those that are most likely to change based on the brief advice delivered by the 
PCP and/or video doctor. SA assessments are typically self-completed by patient participants but
may in some cases be RA-administered if the patient participant is unable or unwilling to self-
complete.

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11.2 Table 6: Schedule of Patient Participant Assessments 
Assessment/Activity
Done By3
Screening 
for 
Eligibility 
Baseline
Monthly 
(1-12)
3 
Months
6 
Months
9 
Months
12 
Months
As 
Needed
Visit
Window
 
 
 
Pre-PCP 
Encounter 
Post-PCP 
Encounter 
 
 
 
 
 
 
 
Enrollment
Master Enrollment Log++ 
RA 
 
X 
 
 
 
 
N/A 
Informed Consent/HIPAA 
RA 
 
X** 
 
 
 
 
N/A 
Inclusion/Exclusion Checklist
RA
X**
N/A
Demographics  
RA 
 
X 
 
 
 
 
N/A 
Locator Information Form
RA
X
(-) 1 / (+) 3 weeks
Screening Assessments 
Healthy Living Eligibility Screener
SA
X*
(-) / (+) 1 week
TAPS Tool 
SA 
X*
 
 
 
 
X 
 
X 
(-) 1 / (+) 3 weeks 
COMM2
SA
X*
X
X
(-) 1 / (+) 3 weeks
CIDI for opioids 
RA
X
X
X
(-) 1 / (+) 3 weeks
Measures of Primary and Secondary Outcomes 
Days of opioid use in past 30 days (Healthy 
Living Monthly Survey)
SA 
X1
X 
(-) / (+) 4 weeks 
Days of non-opioid substance use in past 30 
days (Healthy Living Monthly Survey)
SA 
X1 
X 
(-) / (+) 4 weeks 
PDSQ - drug and alcohol sections 
SA 
 
 
X 
 
 
X 
 
X 
 
(-) 1 / (+) 3 weeks 
Overdose Risk Behavior Questionnaire 
SA
X
X
X
(-) 1 / (+) 3 weeks
Non-Fatal OD Questionnaire
SA
X
X
X
(-) 1 / (+) 3 weeks
Brief Pain Inventory (BPI)-short form
SA
X
X
X
X
X
(-) 1 / (+) 3 weeks
PROMIS anxiety short form
SA
X
X
X
(-) 1 / (+) 3 weeks
Patient Health Questionnaire (PHQ-8)
RA
X
X
X
(-) 1 / (+) 3 weeks
Patient Safety Screener (PSS)
RA
X
X
X
(-) 1 / (+) 3 weeks
Short Form 12 (SF-12) Measure
SA
X
X
X
(-) 1 / (+) 3 weeks
Patient Reported ED visits and 
hospitalizations 
SA 
X 
X 
X 
(-) 1 / (+) 3 weeks
Days of non-opioid substance use in past 90 
days (TLFB) binge alcohol, benzodiazepine, 
stimulants, marijuana, other drug
RA
X 
X 
(+) 3 weeks
Days of opioid use in past 90 days (TLFB)
RA
X
X
(+) 3 weeks
Exit survey on PCP-Delivered Opioid 
Counseling***
RA
X 
(+) 1 week
Chart Abstraction
RA
X
N/A
Marijuana Use Assessment
SA
X
X
(-) 1 / (+) 3 weeks
E-Cigarette and Vaping
SA
X
X
X
(-) 1 / (+) 3 weeks

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Assessment/Activity
Done By3
Screening 
for 
Eligibility
Baseline
Monthly 
(1-12)
3 
Months
6 
Months
9 
Months
12 
Months
As 
Needed
Visit 
Window
Pre-PCP 
Encounter
Post-PCP 
Encounter
PROMIS Sleep 4a 
SA 
 
 
X 
 
 
X 
 
X 
(-) 1 / (+) 3 weeks 
Other Measures
Patient Experience Questionnaire 
SA 
 
 
 
 
X 
X 
X 
X 
 
(-) 1 / (+) 3 weeks 
Readiness to change 
SA 
 
X1 
 
 
X 
X 
 
 
 
(-) 1 / (+) 3 weeks 
PROMIS instrumental and emotional health 
short forms
SA 
X 
X 
X 
(-) 1 / (+) 3 weeks
Addiction treatment and harm reduction 
program utilization
SA 
 
 
X 
 
 
X 
 
X 
 
(-) 1 / (+) 3 weeks 
Urine Drug Screen 
RA 
 
 
X 
 
 
X 
 
X 
 
(-) 1 / (+) 3 weeks 
Assessment of blinding
RA
X
N/A
Study Administration 
Inventory – Supplies Form
RA
X
N/A
Recruitment Log
RA 
 
 
 
 
 
 
 
 
X 
N/A 
Missed Visit and Visit Documentation Form
RA
X
X
X
X
X
X
(-) 1 / (+) 3 weeks
Monthly Survey Link 
RA 
 
 
 
 
 
 
 
 
X 
N/A 
Progress Note Checklist++
RA
X
N/A
Protocol Deviation 
RA
X
N/A
Visit Compensation Log++ 
RA 
 
 
 
 
 
 
 
 
X 
N/A 
RA recorded ED visits and hospitalizations
RA
X
N/A
Mental Health Follow-Up Assessment 
RA 
 
 
 
 
 
 
 
 
X 
N/A 
Study Completion Form
RA
X
N/A
Death Form
RA
X
N/A
1 Assessment completed within the prescreener survey but is considered a baseline assessment if the participant screens eligible and is enrolled into the study.
2 Adapted COMM provided to individuals receiving any opioid therapy in the past 6 months.
3 RA – Research Assistant or Research Coordinator Administered; SA – Self Administered++ = Not captured in eClinical
* = Completed as part of pre-screening for study eligibility
** = May be done after the baseline visit, if there is not enough time to complete before. 
*** = Survey is only given to patients who have an integrated PCP and baseline visit
Note – TLFB at 3 and 6 months cannot be completed earlier than or on the target visit date. 
Note – All participant-facing documents will be reviewed/approved by the IRB. Minor edits may be made to assessments (e.g., grammar, punctuation, directions, system programming, etc.) as 
needed. Assessments will only be submitted for re-review if information to be collected is changed (e.g., addition of new questions.).

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PCP Participant Assessments
PCP participants in both arms will self-administer questionnaires at baseline and the end of the 
intervention period (approximately 6-10 months after the last patient is enrolled unless PCP 
withdraws early). These assessments are adapted from the TOPCARE and TEACH studies.[33, 
49] 
Table 7: PCP Participant Assessments
Topic
Description
Screening
Baseline
End of 
Intervention
RC/RA Only:
Provider Eligibility 
Review
To document PCP inclusion criteria that the RC/RA extracts 
from the clinic data. To be completed prior to the PCP 
completing their Baseline Assessment package
X 
Inclusion/Exclusion 
Checklist
To document eligibility of PCPs
X 
x 
Demographics
Age, gender, race, ethnicity
x
Education
Years since completing training, addiction training, pain 
training, certification, licensures
x 
Individual PCP Practice 
characteristics
Current position, number of patients seen for visits per month
x 
Organizational function
PCP views on organizational leadership, change capacity, 
management, resources
Instrument: ORCA Context items
x 
Assessment and 
treatment of pain, COT 
management
Confidence in assessing and treating pain, identifying 
substance use disorder, negotiating medication agreements, 
urine toxicology interpretation, clinical practices for managing 
patients on opioid therapy, barriers to pain treatment.
Instrument: Modified TOPCARE survey
x 
x 
Substance use and 
misuse in patients: 
knowledge and attitudes
Estimate number (%) of patients on opioids, number (%) of 
patients with substance misuse (incl. opioid, tobacco, 
alcohol, other). 
Rate concern about misuse of prescribed opioids and impact 
of substance use on prescription of opioids, beliefs about 
substance use problems in community, attitudes toward 
patients with substance use and addiction treatment. 
Instrument: Modified ASIP survey
x 
x 
Management of risky 
opioid use, OUD, 
overdose prevention 
Views on interventions to reduce risky opioid use and risk 
behavior, clinical practices for managing patients on opioid 
therapy, availability and effectiveness of specialists (pain, 
addiction, mental health, palliative care) and non-
pharmacological therapies, knowledge about opioid overdose 
risks. 
Instrument: Adapted items from TOPCARE survey; OEND 
questionnaire
x 
x 
Feedback on intervention
(Intervention PCPs only)
Acceptability, value, feasibility of STOP intervention in 
practice 
Instrument: Adapted items from QUIT
x 

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11.3
Patient Participant Assessments
General Measures
Inclusion/Exclusion Checklist
This form lists each inclusion and exclusion criterion to document eligibility and is completed by 
research staff. Eligibility is assessed continually as appropriate. Only participants who continue 
to meet study eligibility criteria are allowed to continue with the screening process, and 
randomization (for PCPs only). Because presence of a moderate-severe OUD is an exclusion 
criterion in this study, as part of screening for eligibility research staff will administer the CIDI 
opioid items (details on the CIDI are given below). Individuals with a CIDI opioid score of 4+ 
(indicating moderate-severe OUD using DSM-5 criteria) will not be eligible to enroll in the study.
Locator Form
A locator form is used to obtain information to assist in finding participants during the study. This 
form collects the participant’s current address, email address, and phone numbers. In order to 
facilitate locating participants if direct contact efforts are unsuccessful, addresses and phone 
numbers of others such as friends and family who may know how to reach the participant are 
collected. To facilitate contacting individuals who cannot be reached by phone or email, the form 
will also collect information on other locations that are frequented by the participant (for example,
programs, clinics, shelters, drop-in spaces), as well as professionals who are involved with their 
care (for example, case managers, clinicians, outreach workers). This information will be collected 
at screening and will be updated at each study visit. Participants will be asked to notify the 
research team if there are any changes in their contact information between study visits and will 
receive a modest incentive for doing so. Individuals are eligible to receive this incentive up to 4
times during their study participation. No information from the locator form is used in data 
analyses, nor is this information captured in the database that includes information from the study 
assessments.
Demographics Form
The Demographics form collects information about demographic characteristics of the participant, 
including biological sex, date of birth, ethnicity, race, education, employment status, and marital 
status. Self-reported information on insurance status will also be collected. To minimize 
assessment reactivity, only those substance use assessments that are required to inform primary 
and secondary outcome measures are collected. We will adopt PhenX toolkit items for collecting 
these measures to the extent possible, but will not include the full battery of the Substance Abuse 
and Addiction Collection of the PhenX Toolkit (http://www.phenxtoolkit.org/).
Study Completion Form
This form tracks the participant’s status in the study. It is completed at the month 12 follow-up 
visit, or once the month 12 follow-up visit window lapses for participants who do not complete this 
final follow-up. If the participant withdraws consent, dies or is removed from the study per 
judgement of study staff, this form will be completed at the time of termination from the study. This 
form is used in data analyses to address variables such as treatment retention and completion. 
This form also provides a location for the site PI attestation of review of all study data.

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11.4
Protocol Specific Assessments
Healthy Living Eligibility Screener
A brief self-administered questionnaire about health behaviors, not including substance use, will 
be administered along with substance use screening and assessment questionnaires. This 
questionnaire, called the “healthy living survey,” is used to partially mask the primary focus of the 
study from participants, and does not contribute to our outcome measures. This strategy was 
used in the QUIT intervention study to reduce assessment reactivity and social desirability bias 
on self-reported substance use measures.[21, 23] The healthy living survey includes questions 
about nutrition and frequency of exercise in the past 30 days.
Tobacco, Alcohol, Prescription Medication, and Other 
Substance Use (TAPS) Tool
The TAPS Tool consists of a 4-item screen for tobacco, alcohol, illicit drugs, and nonmedical use 
of prescription drugs, followed by a substance-specific assessment of risk level for individuals 
who screen positive. The TAPS Tool was developed and validated, in self-administered and 
interviewer-administered versions, in 2,000 adult primary care patients in CTN-0059. In that study, 
the TAPS demonstrated good sensitivity and specificity for detecting problem use of tobacco, 
alcohol, and 5 classes of drugs, including heroin and prescription opioids.[50] At a score of 1+, 
the self-administered TAPS had 85% sensitivity and 97% specificity for detecting any past-month 
opioid use (heroin and/or nonmedical use of prescription opioids, measured by 30-day timeline 
follow-back).[51]
Modified World Mental Health Composite International 
Diagnostic Interview (CIDI)
The CIDI has been used widely in epidemiologic and clinical research to assess substance use 
disorders, including opioid use disorder (OUD) based on the Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition (DSM-4).[52-56] The CIDI items for opioid use will be used as 
the measure of OUD severity. As in prior studies, (including CTN-0059),[50, 57] the CIDI will be 
adapted for DSM-5 so that only the existing CIDI items that map onto the DSM-5 OUD 
classifications will be administered (omitting the item on legal problems and including the one on 
craving). Classification of the severity of OUD are based on the standard diagnostic thresholds: 
2-3 criteria signifies mild OUD, 4-5 signifies moderate OUD, and 6+ signifies severe OUD. The 
CIDI opioid items are administered during screening for study eligibility, and at the 6-month and 
12-month study visit. Only individuals with fewer than 4 criteria at the time of screening are eligible 
for enrollment.
Current Opioid Misuse Measure (COMM)
The COMM is a 17-item self-administered questionnaire that is widely used to monitor pain 
patients receiving opioid therapy.[43, 44] The COMM is designed to detect aberrant behavior 
associated with misuse of opioid medications, and has been validated in approximately 500 
chronic pain patients receiving opioid therapy. We will be adapting the COMM to include an 
instruction line at the beginning of the survey and before items 9, 14, 15, and 16 to clarify the 
questions are asking about opioid pain medications. Because the COMM is only intended for use 

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in individuals who are taking prescription opioids, in our study it will be administered only to 
individuals who self-report being prescribed opioid medications.
11.5
Measures of Primary and Secondary Outcomes
Days of Opioid Use (Healthy Living Monthly Survey)
The primary outcome of days of risky opioid use will be measured at baseline and every 30 days 
using items based on the Addiction Severity Index [40,41] and the COMM: “During the past 30 
days, on how many days did you use [drug name]?” The question will be asked separately for 
heroin/illicit opioids and for nonmedical use of prescribed opioids. For patients with a current 
opioid prescription, items from the COMM will also be asked. To inform the primary outcome: a) 
“During the PAST 30 DAYS, on how many days did you need to take pain medications belonging 
to someone else?” and b) “During the PAST 30 DAYS, on how many days have you had to take 
more of your medication than prescribed?” The extent of overlap between these different types of 
risky use will also be measured, when applicable. The number of days of risky use for an individual 
will be the sum of days for each of these questions minus the overlap. Overlap between illicit use 
and nonmedical use will be calculated so that every individual will have a calculated number of 
days of risky use. To inform secondary outcomes, the following items, adapted from the COMM, 
will also be administered: c) “During the PAST 30 DAYS, on how many days did you borrow pain 
medication from someone else?” and d) “During the PAST 30 DAYS, on how many days did you 
use your pain medication for symptoms other than for pain (e.g., to help you sleep, improve your 
mood, or relieve stress)?”. The assessment is self-administered using a computerized form. This 
approach to measuring days of drug use was used for assessing the primary outcome in the QUIT 
trial, where it demonstrated feasibility and sensitivity to change, including for opioid use.[21]
Days of Non-Opioid Substance Use (Healthy Living Monthly 
Survey)
Days of non-opioid substance use are measured using the same approach as days of opioid use, 
with one question asking about the use of each substance type in the past 30 days. Substances 
queried include alcohol (binge drinking; 4+ drinks/day for women, 5+ drinks/day for men), 
benzodiazepines, illicit stimulants (cocaine or methamphetamine), prescription stimulants 
(amphetamines), marijuana, and other drugs.
Timeline Follow-Back (TLFB)
The Timeline Follow-Back procedure (Sobell et al., 1988) will be used to elicit the patient 
participant’s self-reported use of substances (opioids and other drugs, binge alcohol), diet and 
exercise (>20 min) in the past 90 days.[58] The TLFB will be administered by the RC/RA by phone 
or in person as part of the 3-month and 6-month assessment battery, to document the patient 
participant’s self-reported use of substances for each day since the previous TLFB assessment.
Psychiatric Diagnostic Screening Questionnaire (PDSQ)
The PDSQ is a brief self-administered instrument to assess DSM-4 Axis I disorders, including 
alcohol use disorder (AUD) and drug use disorder (DUD). It is the only brief questionnaire 
assessing DSM-4 substance use disorder that has been validated for self-administration. The 
PDSQ was validated in more than 3,000 in both medical and mental health outpatient settings.[59-

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61] There are 6 items assessing AUD and 6 items for DUD, all using a yes/no response format 
and a 2-week timeframe. The PDSQ is used for baseline and follow-up assessments of AUD, 
DUD, and depression. Because the PDSQ does not specify drug class (for example, it does not 
distinguish between cocaine vs. opioid use disorder) the CIDI, rather than the PDSQ, is used to 
measure DSM-5 OUD. The drawbacks to the PDSQ—namely, that it assesses DSM-IV rather 
than DSM-V SUDs, and is not specific to drug class—are counterbalanced in this study by the 
benefits of having a brief instrument that has been validated for self-administration.
Overdose Risk Behavior Questionnaire
Overdose risk behavior is assessed using a 9-item self-administered questionnaire that was 
developed by a group of opioid researchers based on knowledge of overdose behavioral risk 
factors, [62] and used in 3 prior studies to capture overdose risk behavior.[62-64] These questions 
measure the frequency, in the past 6 months, at which individuals used alone; used in a new 
place/environment; used other substances (alcohol, benzodiazepines, stimulants) within 2 hours 
of opioids; used more than one opioid; used more than the usual amount; and used inhaled or 
injected opioids. The total risk score is an aggregation of responses to the individual questions. 
The overdose risk behavior questionnaire is self-administered.
Non-Fatal Overdose Questionnaire
Non-fatal overdose is assessed using a single-item question developed and used in prior 
research.[65] The questionnaire is self-administered using the timeframe of the past 6 months.
Brief Pain Inventory Short Form (BPI)
The BPI is a self-administered questionnaire that measures the “sensory” dimension of pain 
(intensity, or severity) and the “reactive” dimension of pain (interference with daily function) 
experienced in the past 24 hours. The form asks a series of questions to measure the intensity of 
pain, and the rate at which pain interferes with daily activities, using a 0 to 10 scale. The BPI short 
form has been validated as a tool to assess the severity of pain and the impact pain has on an 
individual’s quality of life. Participants will complete the 4 items addressing pain symptoms (#3-6 
of the short BPI instrument) and the 7 items on pain-related functioning (#9 A-G of the short BPI 
instrument).
Depression and Suicidality (PHQ-8 and PSS)
Assessment of depression symptoms and suicidality is accomplished with the Patient Health 
Questionnaire (PHQ-8) depression screening tool, and the Patient Safety Screener (PSS). The 
ninth item of the PHQ-9 is about suicidal ideation, which is queried separately in our study as part 
of the PSS. The PHQ-8 has been validated as a measure of depression, independent of the PHQ-
9.[66] The PSS is a validated screening instrument that was used in the ED-SAFE study. It 
consists of one item about suicidal ideation in the past two weeks, followed by one item about 
lifetime suicide attempts, in a yes/no format. Individuals reporting a suicide attempt are asked 
when this last occurred. The PSS is administered by research staff for safety reasons, to allow 
for rapid assessment and response for patients with suicidality (following safety procedures 
specified in the site’s standard operating procedures).

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PROMIS Anxiety Short Form
The PROMIS anxiety short form (8a) is an 8-item self-assessment of anxiety symptoms in the 
past 7 days.[67] The tool assesses the severity of symptoms on a Likert scale. The PROMIS 
anxiety short form has been validated in adults with multiple sclerosis, and found to perform 
similarly to more lengthy anxiety assessments.[68]
Health-Related Quality of Life (SF-12)
The Short Form 12 (SF-12) Measure is broadly used in clinical research and is part of the CTN 
DSC recommended assessment battery that measures overall functional health and well-being. 
The questionnaire begins by asking to rate one’s overall health on a scale of 1 to 5, followed by 
two items on daily living activities. Additional questions address physical and emotional health as 
well as pain interference during the past 4 weeks. The SF-12 is a validated tool for measuring 
health-related quality of life.
Participant Reported ED Visits and Hospitalizations
Acute care admissions (hospital, emergency department) are a meaningful outcome for health 
systems and policymakers and will be measured using a self-administered questionnaire. Patient 
participants will report the number of ED visits and number of hospitalizations (detox admissions 
and non-detox admissions) in the past 6 months.
Chart Review
A structured chart review will be conducted by research staff to assess the following secondary 
outcome measures. Each measure is extracted for the period 12 months prior to the baseline 
visit, and 12 months after the baseline visit. Patient participants give consent for gathering this 
information when they enroll in the study.
Prescription of opioid medications, including medication name, dose, frequency, and 
number of pills to be dispensed. This will be converted into MME by day (assuming 
maximum medication used) over the 12-month period.
High-dose opioids (defined as >90 MME daily).
Prescriptions for benzodiazepines, converted into standard medication (e.g., diazepam) 
equivalent dose, and converted into daily doses. It will also allow calculation of overlap 
of opioids and benzodiazepines.
Prescription of naloxone kits: date of prescription.
Monitoring of patient participants with opioid use: toxicology testing, diagnosis of OUD.
Primary care visits and missed appointments at the study clinic.
Number of visits to a study PCP randomized to the opposite treatment arm
Exit Survey on PCP-Delivered Opioid Counseling
Patient participants will complete a brief RC-administered exit survey at the baseline visit only if
the patient had a PCP appointment integrated with their baseline visit. The exit survey asks patient 
participants about the substance use counseling elements they received from their PCP and is 

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based on a questionnaire that was used in a prior study (Trial Registration ClinicalTrials.gov ID 
NCT02893514, Protocol ID DA040830, (McNeely, PI)) to assess delivery of drug use brief 
intervention by PCPs.
Marijuana Use Assessment
This survey assesses participants' recreational and medical cannabis/marijuana use frequency 
over the past 12 months, including reasons for use (e.g., to address medical/psychological 
concerns, to replace other substances or medications), method of administration, and perceived 
harm or benefit associated with use.
E-Cigarette and Vaping Assessment
This survey will determine how often in the previous six months a participant vapes, and if so, did 
the device contain either nicotine or marijuana/THC.
PROMIS Sleep 4a Assessment
Patient participants will complete this assessment (PROMIS Item Bank v1.0, Sleep Disturbance 
Short Form 4a) to provide information on sleep quality over the past seven days. 
11.6
Measures of Readiness to Change
Readiness to change substance use behavior is frequently measured in behavioral intervention 
trials with patients who are not treatment-seeking. While studies have not shown consistent 
effects, readiness appears to be associated with higher consequences of substance use, while 
confidence to change is associated with future reductions in consumption.[69] Participants will 
complete two related items; one item asks about readiness, another asks about confidence to 
change opioid, other drug, and alcohol use behavior. These items are self-reported on a scale of 
1-10, where 1 indicates lowest and 10 indicates highest readiness.
PROMIS Instrumental and Emotional Health Measures
Two PROMIS forms are selected to measure the social support domains of emotional and 
instrumental support that participants receive. The measure of instrumental support (PROMIS 
Item Bank v2.0, Instrumental Support Short Form 4a) is 4 items that ask about the availability of 
someone to help if the participant is confined to bed, needs to be taken to the doctor, is sick and 
needs assistance with daily chores, and running errands if needed. The emotional support 
instrument (PROMIS Item Bank v2.0, Emotional Support Short Form 4a) asks about the frequency 
with which the participant is available to listen to them when they need to talk, to confide in, to 
make them feel appreciated, and to talk with them when they have a bad day.
Addiction Treatment and Harm Reduction Services Utilization
A self-reported questionnaire will collect information on the number of weeks of participation in 
any addiction treatment program or in any harm reduction program, and number of weeks taking 
MOUD (buprenorphine, methadone, naltrexone). MOUD received in the study clinic is additionally 
assessed through chart review, as indicated above.

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Patient Experience Questionnaire
A self-reported questionnaire will collect information from patient participants about their 
interactions with care providers in the past 3 months. Individuals assigned to the STOP 
intervention will complete all items of the questionnaire (pertaining to PCP, nurse care manager, 
and telephone health coach), while individuals assigned to EUC will complete only the PCP 
section. The questionnaire addresses the ‘individual’ level of influence in our conceptual model 
by assessing patient satisfaction and comfort with the patient-facing intervention components. For 
participants who report receipt of opioid counseling, they will complete additional items about how 
they perceived the counseling in relation to the reason they sought care, how helpful it was to 
them, what they learned, and if it made them think about changing their opioid use behavior. The 
questionnaire is administered with the quarterly assessments at months 3, 6, 9, and 12. Because 
the telephone health coaching intervention ends by month 6, the telephone health coach-specific 
items are not administered in the month 9 and month 12 assessments.
11.7
Fidelity Measures
Fidelity monitoring is discussed in Section 12. Only the fidelity assessment that is completed by 
study participants is presented here. The remaining fidelity assessments are completed by study 
staff (NCMs, telephone health coaches, research staff) or PCPs, and are discussed in the fidelity 
monitoring section.
Exit Survey on PCP-Delivered Opioid Counseling
For fidelity monitoring of the PCP brief advice, which can be provided at the baseline visit for 
patient participants who have an integrated PCP and baseline visit, patient participants will 
complete a RC-administered exit survey.
Assessment of Blinding
At the end of the 12-month study visit, or at the patient participants last study visit if they withdraw 
early, the RC/RA will ask patient participants what they considered to be the primary objective of 
the study and record the verbatim and categorical response. The response categories include:
opioid study; drug/alcohol study; exercise study; weight loss study; healthy lifestyle study; other.
Qualitative Interviews
A designated interviewer(s), who is qualified and appropriately trained, will conduct qualitative 
interviews with up to 30 participating patients assigned to the STOP intervention to understand 
how they engaged with the NCM, health coach, and PCP. Approximately 6 patient participants 
will be interviewed at each site. A purposeful sampling approach will be used to select patient
participants in the following categories: a) patient participants who utilized both the NCM and 
health coach; b) patient participants who utilized the NCM but not the health coach; c) patient
participants who utilized the health coach but not the NCM; d) patients who received brief advice
within the 10 business day window; and e) patients who did not receive brief advice within the 10 
business day window. Interviews will be approximately 30-45 minutes in length, and will be audio 

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recorded. Individuals invited to participate in interviews will complete a separate informed consent 
for this activity, and will receive an additional incentive payment for their participation.
11.8
Clinical and Safety Assessments
The study is of a behavioral intervention embedded in primary care. Each of the research sites 
have established practices for managing medical and psychiatric emergencies, and the study staff 
will utilize these procedures. Patient participants’ medical providers will be responsible for 
monitoring participants for possible clinical deterioration or other problems, and for implementing 
appropriate courses of action. Pregnancy is an exclusion criterion for study enrollment.
Mental Health Follow-Up Assessment 
This CRF/eCRF must be completed by the RC/RA if the patient participant endorses suicidal 
thoughts on the PSS at the 6-month and 12-month assessments to document that the appropriate 
actions were taken as guided by site-specific SOPs.
Death Form 
This form will be used to capture patient participant deaths that occur during the study. This form 
will document when and where the death had occurred, the primary and secondary causes of 
death, the source for the cause of death, and any additional supplementary narrative on the 
circumstances surrounding the death of the patient participant. The RC/RA entering the form will 
also be instructed to upload any supporting documentation, such as an autopsy, death, or 
discharge note.
RA-recorded ED Visits and Hospitalizations
This form will be used to capture information regarding a participant’s ED visit or hospitalization 
during the course of the study post baseline. The form will document the admission dates of ED 
visits or hospitalization, the dates that the RC/RA was notified of these visits, diagnoses, 
outcomes, and discharge dates. The RC/RA is expected to submit this form for every ED visit and 
hospitalization that they become aware of after the baseline visit.
11.9
Drug Use Measures
Urine Drug Screen 
Urine drug screens are conducted at baseline and at the 6- and 12-month assessments. The drug 
screens conducted for the study are for verification of self-report, and results will not be shared 
with the clinical team. Urine samples may be collected on-site or off-site. For urine samples that 
are collected off-site they must be sent to the research site for testing. If research staff are not 
allowed on site due to COVID-19 restrictions, the NCM may conduct the urine drug screen testing
or it may be skipped.
Study personnel will ship or give patient participants urine specimen cups labeled with study ID 
and prepaid packaging to ship back to the research site. All urine specimens are tested using an 
FDA-approved dip card following all the manufacturer's recommended procedures. Fentanyl 
dipsticks are not FDA cleared; therefore, results cannot be used for clinical care. Results can only 
be used to add to the data system to characterize a study population. The urine drug screen 

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includes the following drugs: opioids, oxycodone, fentanyl, barbiturates, benzodiazepines, 
cocaine, 
amphetamine, 
methamphetamine, 
marijuana, 
methadone, 
buprenorphine, 
phencyclidine (PCP) and ecstasy (MDMA). 
11.10 Administrative Forms
Missed Visit and Visit Documentation Form: This form is designed to capture whether or not a 
visit occurred, reasons for any visit that is missed, and specific information regarding the details 
of a visit that is completed (e.g., where did the visit occur). This assessment will be completed 
directly in the electronic data capture system at every protocol-specific visit. Submission of this 
form indicating the visit did not occur will remove the requirement for all assessments scheduled 
for that visit. Active tracking and follow-up should be performed for all missed visits. 
Monthly Survey Link Form: This form is used as needed in instances where the RC/RA needs to 
retrieve a Healthy Living Monthly survey link for a specific participant and time point, in the case 
a participant no longer has access to the survey link (e.g., participant deleted the text message 
and/or email they received to complete the monthly survey). 
Protocol Deviation: This form should be entered into the electronic data capture system whenever 
a protocol deviation occurs. This form will document a description of the deviation, how it occurred, 
the corrective action taken to resolve the specific deviation, as well as a description of the plan 
implemented to prevent future occurrences of similar deviations.
11.11 Out-of-Window and Missed Assessments
Research staff are expected to make all reasonable efforts to obtain survey and UDS 
assessments from participants within the windows outlined in Tables 6 and 7 above. However, 
given that all study assessments can be collected remotely, research staff have limited control 
over whether and when participants complete assessments. Therefore, if research staff make 
reasonable and timely efforts to collect assessments within window, but participants choose to 
skip an assessment or complete it late, the study team would not consider this to be a deviation 
from the procedures outlined in this protocol. 

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12.0 TRAINING, SUPERVISION, AND FIDELITY MONITORING
12.1 Research Staff Training
Research staff will be trained as specified in a comprehensive Study Training Plan developed by 
the Lead Node, CCC, DSC, and Protocol Development team. Additional details and guidance for 
study procedures will be provided in a Manual of Procedures (MOP) and in local site SOPs. The 
Investigative Team is also responsible for the development of instructional material and delivery 
of the training. 
CTN-0101 research staff training will be primarily conducted via webinar and/or telephone 
conferences. Additional details on training for the Primary Care Providers, Clinical Champions, 
Nurse Care Managers and Telephone Health Coaches can be found below. Required training for 
all study staff will include Human Subjects Protection (HSP) and Good Clinical Practice (GCP), 
as well as protocol-specific training as needed (e.g., assessments, study visits and procedures, 
safety and Safety Event reporting, data management and collection, and quality assurance). 
Research staff collecting and entering data in the Electronic Data Capture (EDC) system will 
complete training on electronic case report form (eCRF) data entry and data management and 
integrity. All study staff will be required to complete the study-specific training plan for their 
assigned study role as well as satisfy any training requirements per local institutions. Tracking of 
training completion for individual staff as prescribed for assigned study role(s) will be documented, 
endorsed by the site PI and LN, and audited by the CCC. As changes occur in the prescribed 
training, the Training Plan and training documentation tracking forms will be amended to reflect 
these adjustments. 
The Lead Node is primarily responsible for development and delivery of study-specific training 
related to the study intervention(s) and procedures. The CCC is responsible for the development 
and delivery of non-intervention training, including regulatory and laboratory procedures, safety 
and Safety Event reporting, quality assurance and monitoring, etc. The DSC is responsible for 
training related to data management (DM), the EDC system, and good data management 
practices. Other parties will contribute as needed based on the subject matter and material to be 
covered. The various sub-teams will collaborate to deliver quality instructional material designed 
to prepare research staff to fully perform study procedures based on the assigned research roles 
and responsibilities. 
12.2 Primary Care Provider Training 
PCPs randomized into the STOP Intervention will attend remote trainings conducted online, via 
webinar, or in person. The Clinical Champion will play a leading role in training PCPs at their clinic 
and may provide additional coaching and support. Trainings will focus on the PCP role in 
delivering brief advice and collaborating with the Nurse Care Manager to counsel and manage 
the care of patient participants with subthreshold OUD. Training will include discussion and 
demonstration of common scenario(s) encountered by PCPs who are caring for patient 
participants with subthreshold OUD. PCPs will also be provided documentation guidance for 
entering opioid information and counseling into patient charts. 

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12.3
Clinical Champion Training
PCP clinical champions (approximately one per site) will be invited to a training led by members 
of the investigative team. The primary goal of clinical champion training is to prepare them to be 
a well-informed resource who can further educate and provide guidance to their PCP colleagues. 
The training will educate Clinical Champions about the study, including the roles of PCPs and all 
members of the research team. It will include content on delivering brief advice to patients with 
substance use, management and monitoring of patients receiving prescription opioids, identifying 
and assessing OUD, treatment of OUD, and overdose prevention. Additional remote trainings for 
clinical champions may be conducted to address areas of need that are identified by members of 
the research team, participants, or clinical staff throughout the study period.
12.4
Nurse Care Manager Training
The NCMs will undergo training initially and receive ongoing support. Training will emphasize the 
NCM role with patient participants who are using illicit opioids, as well as their role in the 
management of patient participants who are receiving prescription opioids from their PCP. The 
details are noted in Table 8 below.
Table 8: Outline of NCM Training
Initial Training
Prior to live training, the NCMs will receive online training, including SCOPE of Pain 
(http://www.scopeofpain.org/) or a similar free continuing education activity on managing pain 
medications, as well as motivational interviewing such as SAMHSA-endorsed free on-line 
program https://attcnetwork.org/node/2892. They will be assigned readings on managing 
patients with opioid and other substance use, overdose prevention, non-pharmacologic pain 
modalities and pain management in primary care. 
All NCMs will be invited to a live training conducted either in-person or remotely. For example, 
the training may include the following activities:
8 hours didactic on subthreshold OUD, overdose prevention and risk reduction, motivational 
interviewing, pain management treatments, the relationship between pain and opioid use, and 
identifying OUD. 
 
4-8 hours of interactive workshops on study protocol and potential scenarios, focused on 
strategies for engaging and motivating behavior change in patients with subthreshold OUD. 
Ongoing Technical Assistance and Clinic Site Visits
Technical assistance will occur with co-investigators and nurse consultants
o
Approximately weekly phone calls with each site (together or separately depending on 
scheduling) for 6 months, then every other week until study end. 
Local clinic site visit by a technical assistance team nurse or physician trainer early after start 
of the NCM with:
o 
Any staff who work with intervention PCP
o
Admin/leadership meeting. 
o
One on one with NCM, walk through details. 
o
One on one with clinical champion and site PI. 

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12.5
Telephone Health Coach Training
Telephone health coaches will have an approximate 4-day in-person or virtual training in the 
content and procedures involved in the behavior change coaching, with special focus on building 
competence in MI and CBT techniques. Special emphasis will be paid to education about opioids 
and opioid use (including subthreshold OUD, OUD), assessing patient participants’ readiness to 
change risky opioid use behaviors, and determining treatment foci (e.g., additional MI vs. CBT 
focused on risky opioid use vs. CBT focused on pain management). Telephone health coaches 
will be trained to refer patient participants to clinic and local community resources or to provide 
local information and referral hotlines if needed. In addition, they will be trained to assess patient 
participants for continued unhealthy opioid use or clinical worsening of symptoms that would result 
in initiation of enhanced (i.e., Step 2) coaching. Training activities will include didactic 
presentations, group discussions, and experiential learning through role play and use of practice 
patients. Following the training, telephone health coaches will conduct mock sessions with each 
other, which may be digitally audio recorded and coded for fidelity by the trainers. Health coaches 
who meet performance criteria will be cleared to conduct sessions with patient participants. Those 
who require additional training, practice, and supervision will continue to conduct mock sessions 
and have all recordings reviewed and coded by the trainers until cleared. In-person learning 
community sessions will be held every 2-4 weeks to debrief jointly, problem-solve challenging 
patient participants, and monitor and provide supervision on every patient participant. 
All telephone health coaches will complete suicide assessment and triage training. Solicitations 
of patient participant discomfort and suicidal ideation will be made by telephone health coaches 
when indicated during telephone sessions. 
12.6 Fidelity Monitoring
PCP brief advice: In the STOP arm, at the baseline visit or within 10 business days, PCP 
participants will be asked to complete an Intervention Checklist that indicates the content of their 
counseling and any referrals made. Patient participants will complete a post-baseline visit exit 
survey that asks them about the substance use counseling elements they may have received 
from their PCP. These instruments are based on tools that have been used in prior NIDA-funded 
studies (Trial Registration ClinicalTrials.gov ID NCT02893514, Protocol ID DA040830, 
http://www.clinicaltrials.gov, (McNeely, PI); Trial Registration ClinicalTrials.gov ID NCT01942876, 
Protocol ID DESPR DA022445, http://www.clinicaltrials.gov (Gelberg, PI)) to assess delivery of 
drug use brief intervention by PCPs. 
NCM: The NCM will document the delivery of intervention components on a fidelity checklist, and 
track interactions with patient participants, PCPs, and telephone health coaches (THCs). 
Monitoring may include: 
 
Number of interactions with PCP and route (in-person, phone, electronically). 
 
Number of interactions with THC. 
 
Number of new patient visits. 
 
Number of follow up patient participant visits. 
 
Number of contacts via phone or electronically, and whether contact was successful 

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Duration and content area(s) covered in each patient session. 
Health coaching: To facilitate fidelity monitoring, all health coaching sessions will be recorded by 
the research staff providing the coaching, with oral permission from participants during each call. 
Additionally, health coaches will track, for each patient participant, the number of contacts 
attempted, number of successful contacts, and the duration of each coaching session. They may 
also complete a checklist of content area(s) covered in each coaching session. 
Given the content and the relatively brief course of coaching sessions, the focus of fidelity 
monitoring for adherence to the chosen therapeutic style will be on the use of motivational 
interviewing (MI) skills, rather than cognitive behavioral therapy (CBT). The primary source of the 
rating scale is the Motivational Interviewing Treatment Integrity (MITI) Scale 4.1. We will follow 
the strategy of Haddock and colleagues to integrate elements of CBT techniques into the fidelity 
monitoring.[70] Additionally, we will use a study-specific rating tool for the content of the sessions, 
based on the treatment manual, to ensure that the core domains/topics are covered during the 
session. 
 
Coders: The study team will include individuals responsible for coding sessions. The 
coders will be trained by the investigators. The coders will all code the same recordings 
until sufficient inter-rater agreement (>80%) is achieved. 
 
Frequency of Sessions Coded. For the first 3 months of intervention delivery, all 
sessions will be reviewed and MITI coded in real time. Coders will provide results of 
coding to the investigator responsible for supervising the telephone health coaching 
intervention, who can integrate them into 1:1 supervision. Once a level of consistency 
has been achieved for each telephone health coach, we will continue with bi-weekly in-
person supervision but may only code a random 10% of the sessions for independent 
ratings of adherence to the intervention. 
 
Use of Coding for Improving Session Delivery. Individuals delivering the coaching, along 
with members of the investigator team will participate in weekly learning community calls 
to debrief on and jointly problem solve challenging cases, and monitor/provide 
supervision on every intervention case. 

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13.0 CONCOMITANT THERAPY/INTERVENTION
13.1 General 
Patients must meet the inclusion and exclusion criteria at the time of enrollment, including the 
requirements that they are not currently taking medication for treatment of opioid use disorder or 
enrolled in an opioid treatment program. Participation in the trial does not prohibit initiating any 
medications or treatments. 

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14.0 STATISTICAL DESIGN AND ANALYSES
14.1
General Design
Study Hypothesis
The primary objective (Aim 1) of the STOP trial is to determine the efficacy of the STOP 
collaborative care intervention, in comparison to enhanced usual care (EUC), for reducing risky 
opioid use in adult primary care patients, over 12 months of follow-up. Risky opioid use includes 
nonmedical use of prescribed opioids (taking a higher dose or taking an opioid more frequently 
than prescribed; taking pharmaceutical opioids that were not prescribed to the individual taking 
them), or any use of illicit opioids. Our primary hypothesis (H1.1) is that patient participants with 
primary care providers assigned to the STOP intervention will have fewer days of risky opioid use, 
measured at 6 months from baseline (primary outcome), and at 3, 9, and 12 months from baseline 
(secondary outcome (H1.2)), in comparison to patient participants with primary care providers 
assigned to EUC. Because the most intensive intervention period is during the initial 3-4 months, 
the primary outcome is measured at 6 months in order to capture the main intervention effect. 
The 3-month secondary outcome measure will assess early intervention effects, while the 9- and 
12-month secondary outcome measures will assess the durability of intervention effects (which 
may be maintained, increased, or decreased) over time.
Secondary Objectives
The trial has two secondary objectives, which capture patient-level and provider-level impacts of 
the STOP intervention.
The patient-level secondary objective (Aim 2) is to examine the impact of STOP on the important 
patient participant outcomes of moderate-severe OUD, overdose risk behavior and overdose 
events, alcohol and other drug use, health-related quality of life, mental health, pain symptoms 
and functioning, sleep, and acute health care utilization. We hypothesize that participants in the 
STOP condition, in comparison to participants in the EUC condition, will have:
H2.1
Fewer days of binge alcohol use.
H2.2
Fewer days of benzodiazepine use.
H2.3
Fewer days of stimulant use (cocaine and amphetamine-type stimulants).
H2.4.
Fewer days of marijuana use.
H2.5
Fewer days of other drug use (not including opioids, benzodiazepines, 
stimulants, and marijuana).
H2.6
Lower proportion of individuals having increased days of illicit or nonmedical 
opioid use.
H2.7.
Lower prescription opioid misuse behaviors, among participants receiving 
prescribed opioids.
H2.8
Lower incidence of moderate-severe OUD.
H2.9
Lower rates of non-opioid drug use disorder and alcohol use disorder.

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H2.10 Lower rates of self-reported overdose risk behavior and nonfatal opioid-related 
overdose events.
H2.11 No worsening of pain symptoms and pain-related functioning.
H2.12 Fewer symptoms of depression (including suicidality) and anxiety.
H2.13 Better sleep quality 
H2.14 Better health-related quality of life.
H2.15 Lower rates of acute health care utilization (ED and hospital visits).
The provider-level secondary objective (Aim 3) is to characterize the impact of STOP on primary 
care provider behaviors, including prescribing practices and monitoring of patient participants with 
subthreshold OUD. Our hypothesis is that providers assigned to the STOP condition, in 
comparison to providers in EUC, will have over 12 months of follow-up:
H3.1
Lower rates of prescribing of high-dose opioids (defined as prescriptions totaling 
>90 morphine milligram equivalents).
H3.2
Fewer patients with risky opioid use who are prescribed benzodiazepines.
H3.3
Higher proportion of patients with risky opioid use receiving at least one 
prescription for a naloxone kit.
H3.4
Increased monitoring of patients with risky opioid use, defined as: toxicology 
testing, diagnosis of OUD, and higher visit frequency.
Exploratory Objectives
The study has the following exploratory objectives:
Exploratory Objective 1 is to assess the impact of STOP on patient participants’ engagement in 
primary care. There is potential for the intervention to disrupt the patient-PCP relationship, 
particularly if it leads to a dose reduction or cessation of opioid prescribing by the PCP. In the 
TOPCARE study, a post-hoc analysis indicated that patients in the intervention arm whose opioids 
were discontinued were less likely to follow up with their PCP. We believe that the multicomponent 
STOP intervention, which also includes counseling to support patients in reducing their opioid 
use, will not lead to decreased primary care engagement. However, this could be an important 
unintended consequence of the intervention. We will assess primary care engagement by 
measuring the frequency of kept appointments and missed appointments in each arm.
Exploratory Objective 2 is to examine the time to development of moderate-severe OUD or 
opioid-related overdose for participants in both treatment conditions. We anticipate a low rate of 
these events in our 12-month trial. However, given the lack of knowledge regarding opioid use 
trajectories among individuals with subthreshold OUD, our study may contribute valuable 
descriptive data to inform future interventions.
Exploratory Objective 3 is to measure the rate of fatal opioid-related overdose deaths. We 
anticipate very low rates, and potentially no overdose deaths, during the 12-month trial. However, 
given the importance of this outcome, it will be measured for participants in both treatment 
conditions. Data on deaths of study participants will be obtained from the EHR and from other 

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administrative data kept by the health system or government entities. Where information about 
cause of death is available, we will seek to identify opioid-related overdose deaths, other 
substance overdose deaths, and other causes of death.
Exploratory Objective 4 is to examine the receipt of addiction treatment (including MOUD) and 
harm reduction services. Individuals with subthreshold OUD (as opposed to those with moderate-
severe OUD) are expected to have little or no involvement with addiction services, but some
participants (particularly those who develop moderate-severe OUD during the course of the study) 
may utilize these services. Through the involvement of health coaches and a NCM that can 
recommend and facilitate treatment and harm reduction referrals, the STOP intervention could 
result in higher engagement in addiction services in the intervention group. We will use self-
reported and EHR data to track addiction service utilization in both groups.
Exploratory Objective 5 is to measure days of substance use as captured by 90-day timeline 
follow-back (TLFB). Like the monthly assessments, the TLFB will assess days of risky opioid use, 
binge alcohol use, and other drug use (benzodiazepines, cocaine, stimulants, marijuana, and 
other drugs). The TLFB results may be examined alongside the days of substance use reported 
in the monthly assessments, in order to describe the consistency of results with these two 
measurement approaches for the purpose of informing future research.
Exploratory Objective 6 is to measure the rate of PCP counseling on risks of opioid use 
(including overdose, addiction, impact on health conditions). For patient participants who have a 
PCP encounter integrated with the baseline research visit, counseling is measured with the 
baseline exit survey. For all patient participants, information on any discussion or counseling 
provided during follow-up PCP encounters will be assessed with a quarterly patient experience 
questionnaire.
14.2
Primary and Secondary Outcomes (Endpoints)
Primary Outcome Measure
The primary outcome (H1.1) measure is self-reported number of days of risky (illicit or 
nonmedical) opioid use in the past 180 days, assessed at 6 months after the baseline visit using
single items based on the Addiction Severity Index and COMM.[40, 41] Collecting data on self-
reported days of use in the past 30 days is aligned with timeline follow-back methodology, and 
was used in the QUIT trial.[21] Participants are asked to specify the number of days of illicit opioid 
use and of nonmedical opioid use in the past 30 days (range is 0-30 days). Illicit opioid use 
includes use of heroin or synthetic opioids. Nonmedical opioid use includes using prescribed 
opioids more frequently or at higher doses than instructed on the prescription (e.g., taking 2 tablets 
when the prescription indicates a dose of 1 tablet), or taking pharmaceutical opioids that were not 
prescribed to them. Prescribed opioids may be prescribed by the participating PCP or by another 
medical provider. The measure is calculated as the sum of all days of use reported on the 
assessments of past 30-day drug use for the first 6 months (i.e., the sum of days of use from the 
measures collected on day 30, day 60, day 90, day 120, day 150, and day 180).
Secondary Outcome Measure(s)
Measures of Patient-Level Outcomes

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1. Days of substance use: Self-reported days of substance use are collected at baseline 
and once every 30 days. Patient participants are asked to specify the number of days of 
use in the past 30 days (range is 0-30 days, value =0 for substances that were not 
used). For binge alcohol use, the measure defines the cutoff as 5+ drinks (for men under 
age 65), and 4+ drinks (for women and men age 65 and over). Measures of substance 
use are calculated as the sum of consecutive assessments of days of use in the past 30 
days. For example, days of use in the past 90 days is calculated as the sum of three 
consecutive assessments of days of use in the past 30 days. 
a. H1.2. Days of risky opioid use: 
i. 
In the past 30 days, measured at baseline and monthly for 12 months. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 12 months. 
b. H2.1. Days of binge alcohol use:  
i. 
In the past 30 days, measured at baseline and monthly for 12 months. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 6 and 12 months. 
c. H2.2. Days of benzodiazepine use: 
i. 
In the past 30 days, measured at baseline and monthly for 12 months. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 6 and 12 months. 
d. H2.3. Days of stimulant drug use (cocaine and amphetamine-type stimulants): 
i. 
In the past 30 days, measured at baseline and monthly for 12 months. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 6 and 12 months. 
e. H2.4. Days of marijuana use. 
i. 
In the past 30 days, measured at baseline and monthly for 12 months. 
ii. 
In the past 90 days, assessed at 3, 6, 9, and 12 months. 
iii. 
In the past 180 days, assessed at 6 and 12 months. 
f. 
H2.5. Days of other drug use (not including opioids, benzodiazepines, stimulants 
and marijuana). 
i. 
In the past 30 days, measured at 3, 6, 9, and 12 months 
g. H2.6. Increase in number of days of risky opioid use from baseline to follow-up at 
6 and 12 months: 
i. 
Days of opioid use in the past 30 days, measured at baseline and monthly 
for 12 months. 

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ii. 
Days of opioid use in the past 180 days, assessed at 6 and 12 months. 
h. H2.7. Prescription opioid misuse behaviors, among participants receiving 
prescribed opioids: 
i. 
Days of taking prescribed opioids for symptoms other than for pain, or for 
taking pain medication belonging to someone else, measured at baseline 
and monthly for 12 months. 
ii. 
COMM score, assessed at screening and at 6 and 12 months. 
i. 
Urine Drug Screens are used to verify self-reported drug use. Urine drug screens 
are conducted at baseline and at 6 and 12 months. 
j. 
For participants receiving prescribed opioids, the COMM provides an additional 
measure of prescription opioid misuse, collected at baseline and at 6 and 12 
months. 
2. Substance use disorder: Opioid use disorder is assessed at baseline and at 6 and 12 
months using the modified World Mental Health Composite International Diagnostic 
Interview (CIDI). Drug (other than opioid) and alcohol use disorder measures are 
collected using the PDSQ at baseline and at 6 and 12 months. The PDSQ is used rather 
than the CIDI for these measures because it is brief and self-administered, which makes 
it more feasible for these follow-up assessments. 
a. H2.8. Moderate-severe opioid use disorder (CIDI opioid items) 
b. H2.9. Drug use disorder (PDSQ drug items) 
c. H2.9. Alcohol use disorder (PDSQ alcohol items) 
3. Overdose risk behaviors and events 
a. H2.10. Overdose risk behavior and behavioral intention to reduce risk is 
measured at baseline and at 6 and 12 months (Overdose Risk Behavior 
Questionnaire) 
b. H2.10. Episodes of non-fatal overdose are measured at baseline and at 6 and 12 
months (Non-Fatal Overdose Questionnaire) 
c. Exploratory Objective 3. Overdose death is expected to be a rare event in this 
population and will be assessed from the EHR and from other administrative data 
kept by the health system or government entities, for participants who cannot be 
reached at the time of the 12-month study visit. 
4. Pain symptoms and pain-related functioning 
a. H2.11. Pain symptoms (severity, impact on functioning) are measured at 
baseline and at 3, 6, 9, and 12 months using the BPI short form (items #3-6 for 
pain symptoms and items #9A-9G for functioning). 
5. Mental health 
a. H2.12. Anxiety symptoms are measured at baseline and 6 and 12 months 
(PROMIS short form) 

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b. H2.12. Depression symptoms and suicidality are measured at baseline and at 6 
and 12 months (PHQ-8 and PSS) 
c. H2.13. Sleep quality is measured at baseline and at 6 and 12 months (PROMIS 
Sleep 4a) 
6. Health-related quality of life and acute health care utilization 
a. H2.14. Health-related quality of life is measured at baseline and at 6 and 12 
months (SF-12) 
b. H2.15. ED and hospital utilization is measured using participant self-report of 
acute care events (ED visits, hospitalizations for medical reasons, 
hospitalizations for detoxification), collected at baseline and at 6 and 12 months. 
Measures of provider-level outcomes. 
Measures of provider treatment practices are collected from the EHR at baseline and 12 months, 
for patient participants. The data extracted will be for the period beginning 12 months prior to start 
of the intervention, through 12 months after the last patient participant is enrolled. 
1. H3.1. Prescriptions for opioids: number of patient participants receiving prescriptions for 
high-dose opioids (>90 MME); moderate-dose opioids (50-90 MME); and any opioids: 
number of prescriptions; daily prescribed dose; and total number of days prescribed.  
2. H3.2. Prescriptions for benzodiazepines: number of patient participants receiving 
benzodiazepine prescriptions and number receiving both chronic opioid and 
benzodiazepine prescriptions: number of prescriptions; daily prescribed dose, and total 
number of days prescribed 
3. H3.3. Prescriptions for naloxone: number of patient participants receiving at least 1 
prescription 
4. H3.4. Urine Drug Screens: number ordered and completed for each patient participant 
5. H3.4. Diagnosis of OUD: number of patient participants receiving a new diagnosis of 
OUD during the study period 
6. H3.4. Primary care visits: number of scheduled visits per patient participant 
Other outcome measures. 
The following additional measures will be collected to assess exploratory outcomes, characterize 
domains from our conceptual model, and may be used to adjust models of the primary and 
secondary outcomes. These measures are collected at the baseline study visit and at the study 
visits specified in Tables 5 and 6 (schedule of assessments). 
1. Demographic characteristics and insurance status.  
2. Patient participants’ self-assessments of readiness to change risky opioid use and other 
substance use will be measured using two items that query self-reported readiness and 
confidence to change, rated on a 10-point scale. 

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3. Social support will be assessed using the PROMIS instrumental and emotional health 
short forms. 
4. Patient engagement in primary care (Exploratory Objective 1): Number and frequency of 
kept appointments and missed appointments for primary care visits. 
5. Addiction treatment and harm reduction program utilization (Exploratory Objective 4): 
Self-reported number of weeks of addiction treatment or harm reduction program 
services, and self-reported number of weeks receiving MOUD is assessed at baseline 
and at 6 and 12 months. Prescriptions for MOUD received in the primary care clinic are 
additionally assessed from the EHR from at 12 months. 
6. PCP knowledge and attitudes regarding substance use, subthreshold OUD, and opioid 
management, assessed at baseline and at the end of the intervention period. 
7. TLFB measure of substance use in the past 90 days. A 90-day TLFB administered at the 
3- and 6-month quarterly assessments, will capture days of risky opioid use, binge 
alcohol use, and other drug use including benzodiazepines, cocaine, stimulants, 
marijuana, and other drugs. For any prescription opioids, benzodiazepines, and 
amphetamine-type stimulants, the TLFB will measure non-medical use. 
8. Frequency of PCP counseling on opioid use (Exploratory Objective 6): For patient 
participants who have a PCP encounter integrated with the baseline research visit, 
counseling is measured with the baseline exit survey. For all patient participants, 
information on any discussion or counseling provided during follow-up PCP encounters 
will be assessed with a quarterly patient experience questionnaire. 
14.3 Recruitment 
The study will enroll approximately 100 PCPs from a total of 5 sites. We estimate, however, that 
30-40% of the enrolled PCPs will have no participating patients, (because we may not identify 
any eligible patients within their panel), leaving approximately 60 PCPs who will have patients 
that will enroll into the study. 
Enrolled patients with risky opioid use fall into two groups: (1) those using prescribed opioids and 
(2) those in the general population. We expect that approximately 15-20% of enrolled patients will 
be those receiving prescribed opioids. Based on urine toxicology data collected in the TOPCARE 
study, we anticipate that approximately 30% of patients who are receiving prescribed opioids will 
have subthreshold opioid use disorder, so we expect that for a PCP with 8 long-term opioid 
patients, 1-2 of these will be eligible. (PCPs with more than 8 long-term opioid patients are likely 
to have more eligible patients in this category, but we emphasize the lower bound in order to 
conservatively estimate screening numbers). In addition, we expect that at least 1% of adult 
primary care patients in the general population will screen positive for illicit opioid use. This is a 
conservative estimate, as our prior studies found that between 3.9% and 6.6% of adult primary 
care patients screened positive for illicit opioid use.[12, 21] Therefore, screening approximately 
460 patients for a PCP should yield approximately 5 patients engaged in illicit use. Therefore, 
each PCP will have approximately 6-7 eligible patients in total. Assuming that 75% of eligible 
patients are enrolled, we expect each PCP to have approximately 5 patients participating in the 
study. 

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This results in a total of 300 patients among the 60 PCPs who have patients participating in the 
study, although the study can achieve patient recruitment in a variety of ways, e.g., 60 PCPs may 
have 5 patients enrolled each; OR 50 PCPs may have 4 patients, 5 PCPs may have 6 patients, 
and 7 PCPs may have 10 patients.  
As described in section 2.1.2, original recruitment targets were based on 5 sites recruiting for the 
duration of the study. In October 2021, one site stopped recruiting, leaving 4 sites to continue. 
The sample of approximately 300 patients is thus comprised of recruitment from 5 sites for the 
initial 6 months, and from 4 sites for the remainder of the study.  
14.4 Randomization and Factors for Stratification 
This is a cluster-randomized trial in which PCPs are the clusters. PCPs will be randomized, 
stratified by site, in a 1:1 ratio to either the intervention or control condition. 
14.5 Rationale for Sample Size and Statistical Power
Power was based on simulations exploring four possible scenarios to consider different time 
trends of the intervention effect as well as possible assessment impact in the control group. 
Assessment impact means that the repeated monthly assessments alone could lead to a 
decrease in the control group in the response variable. The four scenarios are depicted in Figure 
5. This figure shows the mean values of unhealthy days (within the past 90 days) assumed in 
each arm at 0, 3, and 6 months. The mean in the control arm is expected to be between 10 and 
20, and 20 was selected for simulations because it is the most conservative (i.e., gives the lowest 
power), assuming that the additive effect size does not change as the control group mean 
changes. Scenario 1 has a 6-day constant difference between groups at both time points; in 
scenario 2 the intervention effect wanes to a 5-day difference during months 4-6. Scenarios 3 and 
4 are the same as 1 and 2, but with assessment impact included, decreasing the mean by an 
additional 1 day per 90 days in each arm. 

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Figure 5: Mean Values in Treatment and Control Groups for 
Four Different Simulation Scenarios
Numbers of days of risky opioid use for each patient participant are drawn from binomial 
distributions for the two 90-day time intervals. The size parameter of the binomial distribution is 
90. The probability parameter is the specified mean number of days divided by 90, but also 
includes a PCP intercept (randomly drawn from a normal distribution with mean zero and variance 
0.15) and an individual intercept (randomly drawn from a normal distribution with mean zero and 
variance 0.25). The PCP intercepts induce within-PCP correlation of simulated responses. The 
individual intercepts create overdispersion to more realistically reflect individual variability. The 
overdispersed distribution may be more appropriately modelled with a negative binomial 
distribution than a binomial or poisson distribution. The variance parameters were selected to be 
conservative and to generate data with most values less than 30 and few values over 45 (per 90 
days). The PCP variance parameter describes how much the PCP-specific mean values tend to 
vary from each other (which is a reflection of the Intra Class Correlation (ICC)). With the specified 
parameters, the middle 50% of the PCP-specific means in the control arm lie between 17 and 25. 
The true within-PCP correlation is not known for this outcome, but this is expected to be an upper 
limit on the expected variability of the PCP-specific means so should provide a conservative 
power estimate. For each simulated data set, a negative binomial model was fit with random PCP 
intercepts and a fixed treatment effect. One thousand iterations were performed per scenario. 

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effect estimates based on a two-sided test.
The original protocol planned to enroll 60 PCPs with approximately 8 participants per PCP. As of 
November 2021, recruitment challenges led to our re-evaluating whether a reduced sample size 
was possible with minimal impact to power.  Additional simulations were run to examine various 
conditions of number of PCPs and patient participants per PCP, with 20% participant dropout
assumed for all simulations. The original power estimates are provided for completeness and to 
show there is minimal loss of power when modifying the assumptions related to number of PCP 
and patient participants. 
Table 9 shows power for the two outcomes in the four simulated scenarios described above, 
under four conditions (A-D) of number of PCPs and patient participants per PCP.  
Condition A shows the power for the original situation of 60 PCPs and 8 participants per PCP, 
with Conditions B and C illustrating the impact to power when keeping the number of PCPs at 60 
but reducing the number of participants per PCP to 4 or 5.  As a sensitivity analysis, we also 
examined the situation in which 50 PCPs had 4 participants each (Condition D), which we believe 
is a worst case scenario in which less than 60 PCPs are contributing patients and those that do 
have participants enrolled from their panel have fewer than the expected 5.  
Effect of time trends of the intervention effect and possible assessment impact in the control 
group: The additive treatment effect for the 180-day period is the sum of the 90-day additive 
effects for the two 3-month time intervals. For example, Scenario 1 indicates 90-day means of 20 
and 14 in the two groups at both the 3- and 6-month time points, which translate into 180 day 
means of 40 and 28 in the two groups, so a treatment effect of -12 days. In scenarios 2 and 4, 
the waning of the effect causes this outcome to lose power. The scenarios with assessment 
impact have more power because there is higher power for lower control group mean values due 
to lower variability of the binomial distribution for a lower probability parameter (and because we 
are assuming equal assessment impact between the two groups). If the impact were higher in the 
control group, the treatment effect would be reduced, reducing power.
Table 9: Power Estimates Based on 1000 Simulations
Condi-
tion
No. of 
PCPs
No. of 
pts per 
PCP
Scenario
Group means
(3-mo, 6-mo)
Power
Control
Treatment
A 
60
8 
1: Constant effect, no assessment impact
20, 20
14, 14
0.98
2: Waning effect, no assessment impact
20, 20
14, 15
0.95
3: Constant effect, assessment impact
19, 18
13, 12
0.99
4: Waning effect, assessment impact
19, 18
13, 13
0.97
B 
60
4 
1: Constant effect, no assessment impact
20, 20
14, 14
0.97
2: Waning effect, no assessment impact
20, 20
14, 15
0.93
3: Constant effect, assessment impact
19, 18
13, 12
0.97
4: Waning effect, assessment impact
19, 18
13, 13
0.95

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Condi-
tion
No. of 
PCPs
No. of 
pts per 
PCP
Scenario
Group means
(3-mo, 6-mo)
Power
Control
Treatment
C 
60
5 
1: Constant effect, no assessment impact
20, 20
14, 14
0.97
2: Waning effect, no assessment impact
20, 20
14, 15
0.93
3: Constant effect, assessment impact
19, 18
13, 12
0.99
4: Waning effect, assessment impact
19, 18
13, 13
0.97
D 
50
4 
1: Constant effect, no assessment impact
20, 20
14, 14
0.93
2: Waning effect, no assessment impact
20, 20
14, 15
0.89
3: Constant effect, assessment impact
19, 18
13, 12
0.94
4: Waning effect, assessment impact
19, 18
13, 13
0.91
Note: All simulations assume 20% dropout.
Within the anticipated range of mean values (10-20 days per 90), power increases as the control 
group mean decreases. Therefore, power would be even higher if the control group mean is 10 
or 15 instead of 20, as long as the additive decrease remains the same (-6 days per 90). 
Additionally, power will be higher if the additive decrease is higher than planned.
Effect of Reducing Number of PCPs and patient participants per PCP:  All scenarios and 
conditions presented have power in the range of 89% - 99%, allowing us to conclude that 1) 
reducing number of patient participants for each of 60 PCPs has minimal impact to power; and 2) 
even if 50 PCPs enrolled 4 participants each for a total of 200 participants, power is still in the 
acceptable range across all scenarios of time trends of the intervention effect and assessment 
impact in the control group. 
Projected Number of Sites
Five sites have enrolled patient participants. Starting October 2021, four sites are still actively
recruiting patients.
Projected Number of Participants per Site
This is a cluster-randomized trial in which PCPs are the clusters. The study aims to enroll 
approximately 100 PCPs. We estimate, however, that 30-40% of the enrolled PCPs will have no 
participating patients because we will not identify any eligible patients in their panel, leaving 
approximately 60 PCPs who will have patients that will enroll into the study. Each of these PCPs 
is expected to have approximately 5 patient participants. This results in a total of approximately 
300 patient participants enrolled in the study.  
As of November 2021, there are 85 patient participants enrolled, requiring that another 215 patient 
participants need to be enrolled during the remaining 12 months of enrollment. Original 
recruitment targets were based on 5 sites recruiting for the duration of the study. In October 2021, 
one site stopped recruiting, leaving 4 sites to continue. The sample of approximately 300 patients 
is thus comprised of recruitment from 5 sites for the initial 6 months, and from 4 sites for the 
remainder of the study (12 months), with an enrollment target of on average 15-20 patients per 

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month across the 4 sites. For the 4 sites recruiting until the end of the study, each site is 
anticipated to enroll on average 4-5 patients per month.  
14.6 Statistical Methods for Primary and Secondary Outcomes
The primary outcome is the number of days of risky opioid use within the first 180 days following 
the baseline assessment. A mixed effects negative binomial model with a log link will be fit to 
estimate the difference in means between treatment and control groups. The model will include 
random PCP intercepts to account for within-PCP correlation of participant response values, fixed 
site effects to account for within-site correlation of responses, a fixed treatment effect, and the 
baseline value of the response variable (days of use within 30 days prior to the baseline 
assessment timepoint), which may improve precision. Letting Yjk denote the response variable of 
a participant in site j with PCP k, treatment denote a binary treatment indicator variable, and 
baseline denote the baseline value, the formula for the log-transformed expectation of Yjk is below: 
log[E(Yjk)] = 
0
1
2
j 
k, 
j is the fixed effect for site j 
k is normally distributed with mean zero and standard 
deviation 
. The negative binomial model allows for potential overdispersion of the response 
variable, so is more flexible than a Poisson distribution which would require the mean to be equal 
to the variance. If 2 or more PCPs are randomized as a single cluster because they share patients 
regularly, they will be analyzed as a single cluster.  
1, is different 
from zero. This is equivalent to testing whether the control mean is different from the intervention 
mean. 
Example R code for the primary analysis is below: 
library(lme4) 
mod = glmer.nb(daysin180 ~ rx + baseline + (1|PCP) + factor(site), data = dat) 
The primary analysis will be performed on the Intention-to-Treat (ITT) Population, analyzing 
participants according to their randomization assignment regardless of potential exposure to the 
opposite assignment. The primary analysis will use multiple imputation to account for missingness 
of the primary outcome variable. See Section 14.10, Missing Data, for further details. A secondary 
analysis will be performed on the Per Protocol (PP) population. This population will exclude 
participants who had appointments with PCPs in the opposite treatment arm. A secondary 
analysis will adjust for individual-level covariates which may be associated with the response, 
such as demographic variables, baseline measures of risk behaviors, substance use, presence 
of alcohol or drug use disorder, pain ratings, mental health symptoms or conditions, and health-
related quality of life. Details regarding selection of covariates for inclusion and potential 
transformations will be specified in the Statistical Analysis Plan (SAP). 
A secondary analysis will fit the same model to the 180-day outcome measured at the 12-month 
timepoint in order to assess durability. Further secondary analyses will explore temporal patterns 
of number of days of risky opioid use. The 3-month (days of use in the first 90 days post-baseline) 
and 6-month (days of use in days 91-180 post-baseline) secondary outcome measures will 

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assess early intervention effects. The measures at 9 and 12 months will assess the durability of 
intervention effects (which may be maintained, increased, or decreased) over time. 
Time trends of the mean number of days of use per 90 days will be visualized over the course of 
the year by treatment group with 95% confidence intervals. In addition, a mixed effects negative 
binomial model will be fit including treatment by time interactions for each timepoint. The model 
will include participant random intercepts to account for correlation in responses arising from 
multiple observations for each participant. Further details, including specification of the 
distributions of the random terms and possible inclusion of participant random slopes, will be 
specified in the SAP. 
As month-to-month variability and temporal trends in the response are not known, this time trend 
analysis will be repeated for monthly observations of the 30-day sum of unhealthy days in order 
to further understand and describe temporal patterns. 
A secondary aim is to evaluate the impact of the STOP intervention on days of alcohol and drug 
use that increases risk of overdose. For this aim, three variables will be analyzed separately: 
number of days of binge alcohol use, number of days of benzodiazepine use, and number of days 
of stimulant use. The analyses will be executed in the same way as the above analyses for days 
of risky opioid use. Time trend analyses will be executed as described above. Analogous analyses 
will be performed for another secondary aim, which is to assess impact of STOP on the number 
of days of marijuana and other drug use (also analyzed separately as two distinct variables), and 
on the number of days of taking prescribed opioids for symptoms other than for pain and the 
number of days of taking pain medication belonging to someone else. 
Analyses for several Aim 2 secondary outcomes are outlined below. In general, mixed effects 
regression models with treatment by time interactions (analogous to those described above for 
the primary outcome) or generalized linear models with generalized estimating equations (GEE) 
to account for correlation of responses, will be fit. Further details for these models, including 
distributional assumptions and covariance structure, will be specified in the SAP. 
 
The incidence of moderate to severe OUD (defined as a score of at least 4 on the CIDI) 
within 12 months of follow-up will be compared between treatment groups and may be 
compared for shorter time intervals. 
 
The proportions of individuals whose average number of days (within 30 days) of illicit or 
nonmedical opioid use during 180 days of follow-up increased relative to their baseline 
measure (days of use in the 30 days before the baseline assessment) will be compared 
between groups at 6 and 12 months. 
 
Self-reported overdose risk behavior will be measured by the overdose risk behavior 
questionnaire (which gives a numeric score) at baseline, 6, and 12 months. Mean scores 
will be compared between groups at 6 and 12 months with regression models. 
 
The total number of non-fatal opioid-related overdose events in the past 3 months will be 
measured at baseline, 6, and 12 months. Mean numbers of opioid-related overdose 
events will be compared between groups. 

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Changes in pain-related symptoms and functioning from baseline as measured by the 
BPI (which calculates a numeric score) will be compared between treatment groups. As 
the scientific goal is to demonstrate no worsening of pain, a noninferiority test will 
compare changes in BPI score between treatment and control groups with a minimal 
clinically important difference of 1 based on the IMMPACT recommendations. A 
secondary analysis will distinguish between the effect of STOP on the change in pain-
related symptoms for participants with opioid prescriptions at baseline to the effect for 
those who were enrolled solely due to illicit use. 
 
Symptoms of depression, suicidality, anxiety, and poor sleep in the past two weeks will 
be measured at baseline and quarterly (PHQ-8) and at baseline, 6, and 12 months 
(PROMIS anxiety and sleep measures and PSS), which provide numeric measures. 
Mean values will be compared between treatment groups. 
 
Mean values for health-related quality of life scores and COMM scores will be compared 
between groups. 
Similar models will be fit for the Aim 3 objectives, but these will use provider rather than patient 
as the unit of observation, so will not need a PCP effect to adjust for within-PCP correlation. 
Regression models will be used to compare number of prescriptions of high-dose opioids within 
12 months of follow-up between treatment groups as well as number of days prescribed during 
12 months follow-up. Similar analyses will be done for number of prescriptions for any opioids or 
benzodiazepines, numbers of naloxone kits prescribed, numbers of urine toxicology tests ordered 
and completed, and number of patient participants receiving a new diagnosis of OUD. 
14.7 Significance Testing
The primary outcome will be evaluated using a two-sided test with a type I error rate of 5%. There 
are several secondary outcomes; however, adjustments for multiple comparisons will not be 
performed since these are not part of the study’s primary objective. The resulting p values will be 
interpreted appropriately in the context of the multiple tests being performed. Effect estimates will 
be presented with confidence intervals, and interpretation of hypothesis tests for multiple 
secondary outcomes will take into consideration the number of tests that were performed. 
Reporting of results will be transparent, with null as well as significant findings reported. 
14.8 Interim Analysis
No interim analyses are planned. 
14.9 Exploratory Analysis 
For the exploratory objectives, regression models with PCP as the unit of observation will 
compare the mean number of primary care visits attended and number of scheduled visits missed 
between treatment arms over the 12-month follow-up period. Time-to-event analysis will be used 
to compare time to development of moderate to severe OUD between treatment groups. 
Proportions of fatal overdose deaths will be presented by treatment group with 95% confidence 
intervals. TLFB results will be described and examined alongside the days of substance use 
reported in the monthly assessments, in order to describe the consistency of results with these 
two measurement approaches. Proportions of PCP visits with counseling on risks of opioid use 
will be compared between groups. 

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14.10 Missing Data and Dropouts
The primary outcome, number of days of risky opioid use within the first 180 days since baseline, 
is measured by repeated monthly assessments. For each monthly assessment, participants will 
record the number of days of risky use within the previous 30 days. We consider two types of 
missing data for this outcome: 
 
Missingness due to dropout: participants may withdraw early from the study and miss all 
subsequent monthly measurements. 
 
Intermittent missingness: participants may miss one or more monthly surveys while 
remaining enrolled in the study. 
It is anticipated that up to 20% of participants may be missing data for the primary endpoint due 
to dropout and/or nonresponse. It is possible that participants who drop out will have higher use 
after their dropout date than those who remain in the study. For example, it is possible that days 
of use after the withdrawal timepoint for dropouts in the treatment arm may more closely resemble 
that of controls than that of other treated participants. In this case it is possible that a complete 
case analysis could overestimate the treatment effect if there is a high level of missing data (and 
if control dropouts do not have an analogous increase). Multiple imputation will be performed for 
the primary analysis to account for missingness of the primary outcome variable. A repeated 
measures model with treatment by time interactions will be created for the imputation in order to 
take full advantage of information from partial reports by participants with intermittent 
missingness. Information on days of risky use assessed by TLFB will be included in the imputation 
model. Further details of the imputation models will be specified in the SAP. If multiple imputation 
is performed, a complete-case analysis will be performed as a secondary analysis. In either case, 
sensitivity analyses will be performed to assess robustness of the treatment effect estimate to 
different patterns of responses for the missing values. 
14.11 Demographic and Baseline Characteristics 
Baseline demographic variables (including sex and race/ethnicity) and all covariates included as 
potential confounders in the adjusted model will be summarized for participants enrolled and 
randomized. Descriptive summaries, such as mean, median, standard deviation, minimum, 
maximum, and quartiles of the distribution of continuous baseline variables will be presented. 
Categorical variables will be summarized in terms of frequencies and percentages. Subgroup 
analyses by sex and minority status will be performed. 
14.12 Safety Analysis 
All Safety Events will be presented as: (1) the number and proportion of participants experiencing 
at least one incidence of each event overall and by intervention group; and (2) a table displaying 
the total number of each event overall and by intervention group. Safety Events that are 
associated with participant death will be summarized by body system and preferred term using 
MedDRA codes (per The Medical Dictionary for Regulatory Activities). Listings of death events 
will be sorted by system organ class (SOC) and preferred term (PT). Concomitant medications of 
interest will be coded using the World Health Organization Drug Dictionaries (WHO DD) and 
presented by preferred drug name and WHO Anatomical Therapeutic Chemical (ATC) 
classification analogous to Safety Event reporting. 

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15.0 REGULATORY COMPLIANCE, REPORTING AND MONITORING
15.1 Statement of Compliance
This trial 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 Protection of Human Subjects 
described in the International Council for Harmonisation Good Clinical Practice (GCP) Guidelines, 
applicable United States (U.S.) Code of Federal Regulations (CFR), the NIDA Terms and 
Conditions of Award, and all other applicable state, local, and federal regulatory requirements. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Sponsor and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. An Operations Manual will be provided as a reference guide and study quality 
assurance tool. 
15.2
Institutional Review Board Approval
The Biomedical Research Alliance of New York (BRANY) will be the IRB of record for the protocol 
and will provide study oversight in accordance with 45 CFR 46. Participating institutions will agree 
to rely on BRANY and will enter into reliance/authorization agreements for Protocol CTN-0101. 
BRANY will follow written procedures for reporting its findings and actions to appropriate officials 
at each participating institution. 
Prior to initiating the study, participating site investigators will obtain written IRB approval from 
BRANY to conduct the study at their respective site, which will include approval of the study 
protocol. If changes to the study protocol become necessary, protocol amendments will be 
submitted in writing by the Lead Node for IRB approval prior to implementation. In addition, the 
IRB will approve all consent forms, recruitment materials, any materials given to the participant, 
and any changes made to these documents throughout study implementation. Approval of both 
the protocol and the consent form(s) must be obtained before any participant is consented. For 
changes to the consent form, a decision will be made regarding whether previously consented 
participants need to be re-consented. IRB continuing review will be performed annually, or at a 
greater frequency contingent upon the complexity and risk of the study. Each site principal 
investigator (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 Lead investigators prior to the initiation of research activities at the site and 
must be available at any time for audit. Unanticipated problems involving risk to study participants 
will be promptly reported to and reviewed by the IRB of record, according to its usual procedures. 
15.3 Informed Consent
The informed consent process is a means of providing study information to each prospective 
participant and allows for an informed decision about participation in the study. Informed consent 
continues throughout the individual’s study participation. 
The informed consent forms for the pilot participants, provider participants, and patient 
participants will include all of the required elements of informed consent and may contain 
additional relevant consent elements and NIDA CCTN specific additional elements. Each study 

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site must have the study informed consent forms approved by the Single IRB (sIRB). Prior to initial 
submission to the IRB and with each subsequent consent revision, the consent form(s) must be 
sent to the Clinical Coordinating Center (CCC) and the Lead Node (LN) to confirm that each 
consent form contains the required elements of informed consent as delineated in 45 CFR 
46.116(b), as well as pertinent additional elements detailed in 45 CFR 46.116(c) and any 
applicable CCTN requirements. Every study participant is required to sign a valid, IRB-approved 
current version of the study informed consent form prior to the initiation of any study related 
procedures, except where documentation of informed consent is waived. The site must maintain 
the original signed informed consent for every participant in a locked, secure location that is in 
compliance with all applicable IRB and institutional policies and that is accessible to the study 
monitors. Every study participant must be given a copy of the signed consent form. 
Electronic consent (eConsent) will be obtained in accordance with IRB and institutional policies, 
including 21 CFR Part 11 compliance, as applicable. All signed eConsent forms will be saved as 
a PDF on a secure sever. Site staff will download the completed and electronically signed 
eConsent PDF and save it in the electronic patient participant PHI file located in the site’s secure 
server.  
During the informed consent process, research staff will explain the study to the potential 
participant and provide the potential participant with a copy of the consent form to read and keep 
for reference. All participants will receive a verbal explanation in English of the purposes, 
procedures, and potential risks of the study and their rights as research participants. Extensive 
discussion of risks and possible benefits will be provided to the participants. Participants will have 
the opportunity to carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their family and close 
friends or think about it prior to agreeing to participate. If the participant is interested in 
participating in the study, a qualified staff member will review each section of the IRB-approved 
informed consent form in detail and answer any questions the participant may pose. The 
participant will consent by signing and dating the consent document. The person obtaining 
consent and a witness, if required by the IRB of record, will also sign and date the consent 
document. It is strongly recommended that another research staff member review the consent 
after it is signed to ensure that the consent is properly executed and complete. Staff members 
delegated by the PI to obtain informed consent must be listed on the Delegation of Responsibility 
and Staff Signature Log and must be approved by the IRB, if required. All persons obtaining 
consent must have completed appropriate GCP and HSP training, as mandated by NIDA standard 
operating procedures. 
The informed consent form(s) must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect participants’ 
participation in the trial. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. The participant will be informed that their participation is voluntary, and 
they may withdraw from the study at any time, for any reason without penalty. Individuals who 
refuse to participate or who withdraw from the study will be treated without prejudice. Study sites 
will be responsible for maintaining signed consent forms as source documents for quality 
assurance review and regulatory compliance. 

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15.4
Quality Assurance Monitoring
In accordance with federal regulations, the study sponsor is responsible for ensuring proper 
monitoring of an investigation and ensuring that the investigation is conducted in accordance with 
the protocol. Qualified monitors will oversee aspects of site conformity to make certain the site 
staff is operating within the confines of the protocol, and in accordance with GCP. This includes 
but is not limited to protocol compliance, documentation auditing, and ensuring the informed 
consent process is being correctly followed and documented. Non-conformity with protocol and 
federal regulations will be reported as a protocol deviation and submitted to the study sponsor 
and IRB of record (as applicable) for further review.
15.5
Participant and Data Confidentiality
Participant confidentiality and privacy are strictly held in trust by the participating investigators, 
their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency, and will 
be maintained in accordance with all applicable federal regulations and/or state/Commonwealth 
law and regulations. This confidentiality is extended to the data being collected as part of this 
study. Data that could be used to identify a specific study participant will be held in strict 
confidence within the research team. No personally identifiable information from the study will be 
released to any unauthorized third party without prior written approval of the sponsor/funding 
agency. All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), and regulatory agencies may inspect all 
documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) for the participants in this study. The clinical study site 
will permit access to such records.
Participant records will be held confidential by the use of study codes for identifying participants 
on CRFs, secure storage of any documents that have participant identifiers, and secure 
computing procedures for entering and transferring electronic data. The study participant’s 
contact information will be securely stored at each clinical site for internal use during the study. 
At the end of the study, all records will continue to be kept in a secure location for as long a period 
as denoted in Section 15.11, Records Retention and Requirements.
By signing the protocol signature page, the investigator affirms that information furnished to the 
investigator by NIDA will be maintained in confidence and such information will be divulged to the 
IRB/Privacy Board, Ethical Review Committee, or similar expert committee; affiliated institution; 
and employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees.
Certificate of Confidentiality
To further protect the privacy of study participants, the Secretary, Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, 
behavioral, clinical or other human subjects research funded wholly or in part by the federal 
government. Recipients of NIH funding for human subjects research are required to protect 
identifiable research information from forced disclosure per the terms of the NIH Policy (see 
https://humansubjects.nih.gov/coc/index). This protects participants from disclosure of sensitive

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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 Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
Health Insurance Portability Accountability Act (HIPAA)
Study sites will be required by their institutions to obtain authorization from participants for use of 
protected health information. Sites will be responsible for communicating with the sIRB or Privacy 
Boards of record and obtaining the appropriate approvals to be in regulatory compliance. 
Releases of participant identifying information that are permitted by the HIPAA regulations, but 
which are prohibited by other applicable federal regulations and/or state/Commonwealth law and 
regulation, are prohibited.
15.6
Investigator Assurances
Each site must file (or have previously filed) a Federalwide Assurance (FWA) with the HHS Office 
for Human Research Protection setting forth the commitment of the organization to establish 
appropriate policies and procedures for the protection of human research subjects, with 
documentation sent to NIDA or its designee. Research covered by these regulations cannot 
proceed in any manner prior to NIDA receipt of certification that the research has been reviewed 
and approved by the IRB provided for in the assurance (45 CFR 46.103). Prior to initiating the 
study, the principal investigator at each study site will sign a protocol signature page, providing 
assurances that the study will be performed according to the standards stipulated therein.
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.
15.7
Clinical Monitoring
Investigators will host periodic visits by NIDA contract monitors who will examine whether study 
procedures are conducted appropriately, and that study data are generated, documented and 
reported in compliance with the protocol, GCP, and applicable regulations. These monitors will 
audit, at mutually agreed upon times, regulatory documents, CRFs, informed consent forms and 
corresponding source documents for each participant. Monitors will have the opportunity and 
ability to review any study-associated document or file.
NIDA-contracted monitors will assess whether submitted data are accurate and in agreement with 
source documentation and will also review regulatory/essential documents such as 
correspondence with the sIRB. Areas of particular concern will be participant informed consent 

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forms, protocol adherence, reported Safety Events and corresponding assessments, and 
principal investigator oversight and involvement in the trial. Reports will be prepared following the 
visit and forwarded to the site principal investigator, the lead investigator and NIDA CCTN. 
Qualified node personnel (Node QA monitors) or other designated party(ies) will provide site 
management for each site during the trial. Node QA staff or other designated party(ies) will audit 
source documentation, including informed consent forms and HIPAA forms. This will take place 
as specified by the local protocol team, node PI or lead team and will occur as often as needed 
to help prevent, detect, and correct problems at the study sites. Node QA personnel will verify 
that study procedures are properly followed and that site personnel are trained and able to 
conduct the protocol appropriately. If the node personnel’s review of study documentation 
indicates that additional training of site study personnel is needed, node QA personnel will 
undertake or arrange for that training. Details of the contract, node QA and data monitoring are 
found in the study QA monitoring plan. 
15.8 Inclusion of Women and Minorities
The study sites should aim and take steps to enroll a diverse study population. Based on prior 
studies in primary care, we anticipate that at least one-third of participants will be female. If 
difficulty is encountered in recruiting an adequate number of women and/or minorities, the 
difficulties involved in recruitment will be discussed in national conference calls and/or face-to-
face meetings. 
15.9 Prisoner Certification
As per 45 CFR 46 Subpart C, there are additional protections pertaining to prisoners as study 
participants. A prisoner is defined as any individual involuntarily confined or detained in a penal 
institution. The term is intended to encompass individuals sentenced to such an institution under 
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment 
procedures which provide alternatives to criminal prosecution or incarceration in a penal 
institution, and individuals detained pending arraignment, trial, or sentencing. In order to meet 
these additional protections, the study team will obtain certification from the Office for Human 
Research Protections (OHRP) to follow-up with participants who become prisoners during the 
course of the study, as necessary. 
If a participant in the study becomes incarcerated or otherwise meets the 45 CFR 46 Part C 
definition of a prisoner during the course of the study, and the relevant research proposal was not 
reviewed and approved by the IRB in accordance with the requirements for research involving 
prisoners under Subpart C of 45 CFR 46, the investigator must promptly notify the IRB. All 
research interactions and interventions with, and obtaining identifiable private information about, 
the participant must be suspended immediately. The lone exception to this regulation is if the 
investigator asserts that it is in the best interests of the prisoner-participant to remain in the study. 
The investigator must promptly notify the IRB of this occurrence. 
15.10 Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be checked at each participating site for 

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regulatory document compliance prior to study initiation, throughout the study, as well as at study 
closure. 
15.11 Records Retention and Requirements 
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, audio and video recordings, and regulatory files) 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 sIRB, state and federal requirements, 
whichever is longest. The sponsor and Lead Investigator must be notified in writing and 
acknowledgment must be received by the site prior to the destruction or relocation of research 
records. 
15.12 Reporting to Sponsor 
The site principal investigator agrees to submit accurate, complete, legible and timely reports to 
the Sponsor, as required. These include, but are not limited to, reports of any changes that 
significantly affect the conduct or outcome of the trial or increase risk to study participants. Safety 
reporting will occur as previously described. At the completion of the trial, the Lead Investigator 
will provide a final report to the Sponsor. 
15.13 Audits
The Sponsor has an obligation to ensure that this trial is conducted according to good clinical 
research practice guidelines and may perform quality assurance audits for protocol compliance. 
The Lead Investigator and authorized staff from the National Lead Study Team; the National 
Institute on Drug Abuse Clinical Trials Network (NIDA CTN, the study sponsor); NIDA’s contracted 
agents, monitors or auditors; and other agencies such as the Department of Health and Human 
Services (HHS), the Office for Human Research Protection (OHRP) and the Institutional Review 
Board of record may inspect research records for verification of data, compliance with federal 
guidelines on human participant research, and to assess participant safety. 
15.14 Study Documentation
Each participating site will maintain appropriate study documentation (including medical and 
research records) for this trial, in compliance with ICH E6(R2) and regulatory and institutional 
requirements for the protection of confidentiality of participants. Study documentation includes all 
case report forms, workbooks, source documents, monitoring logs and appointment schedules, 
sponsor-investigator correspondence, signed protocol and amendments, Institutional Review 
Board correspondence and approved consent forms, and signed participant consent forms. As 
part of participating in a NIDA-sponsored study, each site will permit authorized representatives 
from NIDA and regulatory agencies to examine (and when permitted by law, to copy) clinical 
records for the purposes of quality assurance reviews, audits, and evaluation of the study safety, 
progress, and data validity. 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Whenever possible, the original recording of an observation should be retained as the source 

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document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
15.15 Protocol Deviations 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol. 
The noncompliance may be either on the part of the participant, the investigator, or the study site 
staff. As a result of deviations, corrective actions will be developed by the site and implemented 
promptly. 
These practices are consistent with ICH GCP: 
 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3 
 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1 
 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2 
Any departure from procedures and requirements outlined in the protocol will be classified as 
either a major or minor protocol deviation. The difference between a major and minor protocol 
deviation has to do with the seriousness of the event and the corrective action required. A minor 
protocol deviation is considered an action (or inaction) that by itself is not likely to affect the 
scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a study 
participant. Major protocol deviations are departures that may compromise the participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and could be cause for 
corrective actions if not rectified or prevented from re-occurrence. Sites will be responsible for 
developing corrective action plans for both major and minor deviations as appropriate. Those 
corrective action plans may be reviewed/approved by the Lead Node and the CCC with overall 
approval by the IRB of record as needed. All protocol deviations will be monitored at each site for 
(1) significance, (2) frequency, and (3) impact on the study objectives, to ensure that site 
performance does not compromise the integrity of the trial. 
All protocol deviations will be recorded in the Electronic Data Capture (EDC) system via the 
Protocol Deviation CRF. The CCC, DSC and the Lead Investigator must be contacted 
immediately if an unqualified or ineligible participant is randomized into the study. 
Additionally, each site is responsible for reviewing the sIRB of record’s definition of a protocol 
deviation or violation and understanding which events need to be reported. Sites must recognize 
that the CTN and IRB definition of a reportable event may differ and act accordingly in following 
all reporting requirements for both entities. 
15.16 Safety Monitoring 
Because this is a minimal risk study with no pharmacological intervention, causally related 
Adverse and Serious Adverse events are not anticipated for this study. 
Safety reporting will be limited to reporting the following Safety Events: Emergency Department 
(ED) visits, hospitalizations, overdose events, suicidal ideation, and deaths. Any Safety Event that 
occurs will be recorded on a designated form through the Advantage eClinical data system. As 
there is no medication intervention, pregnancy will not be followed within the context of this study. 

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Each of the sites has established practices for managing medical and psychiatric emergencies
including Suicidality, 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.
Data and Safety Monitoring Board (DSMB)
An independent CTN DSMB will examine accumulating data to assure protection of participants’ 
safety while the study’s scientific goals are being met. The CTN DSMB is responsible for 
conducting periodic reviews of accumulating safety and efficacy data. It will determine whether 
there is support for continuation of the trial, or evidence that study procedures should be changed, 
or if the trial should be halted, for reasons relating to the safety of the study participants, the 
efficacy of the treatment under study, or inadequate trial performance (e.g., poor recruitment).
Reports will be generated and presented for Data and Safety Monitoring Board (DSMB) meetings 
at a frequency requested by the DSMB, but at least annually.
Safety Monitor/Medical Monitor
The CCC Safety Monitor/Medical Monitor is responsible for reviewing all Safety Events reported. 
Where further information is needed, the Safety Monitor/Medical Monitor will discuss the Safety 
Event with the site. Reviews of Safety Events will be conducted in the Advantage eClinical data 
system and will be a part of the safety database. All Safety Events are reviewed on a regular 
basis to observe trends or unusual events.
The CCC Safety Monitor/Medical Monitor will in turn report Safety Events to the sponsor and 
regulatory authorities if the event meets the definition of an expedited event. Reports will be 
generated and presented for Data Safety Monitoring Board (DSMB) meetings.
Adverse Events (AEs)
For the purposes of this protocol, the collection and reporting of Adverse Events is not required
in the data system.

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16.0 DATA MANAGEMENT
16.1 Design and Development 
This protocol will utilize a centralized Data and Statistics Center (DSC). The DSC will be 
responsible for development of the electronic case report forms (eCRFs), development and 
validation of the clinical study database, ensuring data integrity, and training site and participating 
node staff on applicable data management procedures. Advantage eClinical and QualtricsXM, 
web-based distributed data entry systems, will be implemented. These systems will be developed 
to ensure that guidelines and regulations surrounding the use of computerized systems used in 
clinical trials are upheld. The remainder of this section provides an overview of the data 
management plan associated with this protocol. 
16.2 Site Responsibilities 
The data management responsibilities of each individual site will be specified by the DSC and 
outlined in the Advantage eClinical User’s Guide and CRF Manual. 
16.3 Data Center Responsibilities
The DSC will 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide final guided Case Report Forms (CRFs) and electronic 
CRFs (eCRFs) for the collection of data required by the study, 3) develop data dictionaries for 
each eCRF that will comprehensively define each data element, 4) prepare instructions for use of 
Advantage eClinical and for completion of CRFs/eCRFs, 5) conduct ongoing data validation and 
cleaning activities on study data from all participating sites, 6) perform data validation and 
cleaning activities prior to any interim analyses and prior to the final study database lock. 
16.4 Data Collection 
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical or will be collected via direct entry into the eCRF. In the event that 
Advantage eClinical is not available, the DSC will provide the sites with a set of CRF paper source 
documents and completion instructions. Data entry into Advantage eClinical should be completed 
according to the instructions provided and project specific training and guidelines established by 
the DSC. The investigator is responsible for maintaining accurate, complete and up-to-date 
records, and for ensuring the completion of the eCRFs for each research participant. Selected 
eCRFs may also require the investigator’s electronic signature. In some situations, data collected 
on source document will not be entered into Advantage eClinical, but when it is entered, it will 
follow the guidelines stated above. 
16.5 Data Editing 
Data will be entered into the DSC automated data acquisition and management system 
(Advantage eClinical) in accordance with the Advantage eClinical User’s Guide. Only authorized 
individuals shall have access to eCRFs. 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and forms are available to sites at all times in Advantage eClinical. These 
reports will be monitored regularly by the DSC. In addition, the DSC will identify inconsistencies 

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within eCRFs and between eCRFs and post data clarification requests or queries in Advantage 
eClinical on a scheduled basis. Sites will resolve data inconsistencies and errors and enter all 
corrections and changes into Advantage eClinical. 
The CCC will conduct regular on-site and monitoring visits, during which audits comparing source 
documents to the data entered on the eCRF will be performed. Any discrepancies identified 
between the source document and the eCRF will be corrected by the site. 
Trial progress and data status reports, which provide information on items such as recruitment, 
availability of primary outcome, treatment exposure, regulatory status, and data quality, will be 
generated daily and posted to a secure website. These reports are available to the site staff, the 
local node staff, the lead node, the coordinating centers, NIDA CCTN and NIDA to monitor study 
progress overall and at each individual participating site. 
16.6
Data Transfer/Lock
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DSC. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by DSC staff will be secured and password protected. 
The DSC will conduct final data cleaning activities and “lock” the study database from further 
modification. The final raw analysis datasets will be transferred to the Lead Investigator or 
designee and to NIDA, as requested, for storage and archive. De-identified versions of these 
datasets will also be provided to the NIDA CCTN-designated party for storage and archiving. 
These datasets may be posted on the NIDA Data Share website. 
16.7 Data Training 
The training plan for site staff includes provisions for training on assessments, eCRF completion 
guidelines, data management procedures, and the use of Advantage eClinical. 
16.8 Data Quality Assurance
To address the issue of data entry quality, the DSC will follow a standard data monitoring plan. 
An acceptable quality level prior to study lock or closeout will be established as a part of the data 
management plan. Data quality summaries will be made available during the course of the 
protocol. 

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

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

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20.0 APPENDIX A: DATA AND SAFETY MONITORING PLAN
1.0 
BRIEF STUDY OVERVIEW 
The Subthreshold Opioid Use Disorder Prevention (STOP) trial is a cluster-randomized clinical 
trial that examines the efficacy of a primary care intervention to reduce opioid use and overdose 
risk, and prevent progression to OUD, in adults with risky opioid use. STOP is a collaborative care 
model consisting of: 
1) A practice-embedded nurse care manager who provides patient participant education 
and supports the primary care provider (PCP) in engaging and monitoring patient 
participants who have risky opioid use, 
2) Brief advice that may be delivered to patient participants by their PCP and/or a video 
doctor, and 
3) Coaching of patient participants by health coaches and mental health providers to 
motivate and support behavior change. 
The STOP trial will be conducted in 5 primary care practices, with approximately 100 PCPs and 
300 adult primary care patients and will test the efficacy of STOP versus enhanced usual care 
(EUC). Patient participants with providers assigned to the intervention condition will receive the 
full STOP intervention, while those with providers assigned to EUC will receive printed educational 
materials on the health risks of opioid use, including overdose. 
The primary objective (Aim 1) is to determine the efficacy of the STOP collaborative care 
intervention, in comparison to EUC, for reducing unhealthy opioid use in adult primary care 
patients. The primary hypothesis is that patient participants with primary care providers assigned 
to the STOP intervention will have fewer days of unhealthy opioid use, measured at 6 months 
(primary outcome), and at 3, 9, and 12 months (secondary outcome), in comparison to patient 
participants with primary care providers assigned to EUC. 
The patient-level secondary objective (Aim 2) is to examine the impact of STOP on patient 
outcomes of progression to moderate-severe OUD, overdose risk behavior and overdose events, 
alcohol and other drug use, pain-related disability, health-related quality of life, sleep and mental 
health. 
The provider-level secondary objective (Aim 3) is to characterize the impact of STOP on primary 
care provider behaviors, including prescribing practices and monitoring of patients with unhealthy 
opioid use. 
2.0 
OVERSIGHT OF CLINICAL RESPONSIBILITIES 
A. Site Principal Investigator 
Each participating site’s Principal Investigator (PI) is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified, trained 
research staff and medical clinicians to assess, report, and monitor adverse events. 

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B. CCC Safety Monitor/Medical Monitor 
The NIDA CTN Clinical Coordinating Center’s (CCC) Safety Monitor/Medical Monitor or designee 
is responsible for reviewing all reported Safety Events. The CCC Safety Monitor/Medical Monitor 
is alerted via email each time a death-related Safety Event is reported in the EDC. All death-
related Safety Events will be reviewed at the time they are reported in the EDC. All other Safety 
Events will be reported to and reviewed by the CCC Safety Monitor/Medical Monitor on a weekly 
basis to observe for trends or unusual events. The Safety Monitor/Medical Monitor or designee 
will also indicate concurrence or not with the details of Safety Event reports provided by the site 
PI. Where further information is needed, the Safety Monitor/Medical Monitor or designee will 
discuss the event with the site staff. Reviews of Safety Events by the CCC Safety Monitor/Medical 
Monitor or designee will be documented in study-specific safety files and will be a part of the 
safety database. 
C. Data and Safety Monitoring Board (DSMB) 
The NIDA CTN DSMB affiliated with this trial will be responsible for conducting periodic reviews 
of accumulating safety, trial performance, and outcome data. Reports will be generated and 
presented for Data and Safety Monitoring Board (DSMB) meetings. The DSMB will receive Safety 
Events at a frequency requested by the DSMB, but at least annually. Furthermore, the DSMB will 
be informed of expedited reports of Safety Events. The DSMB will make recommendations to 
NIDA CCTN as to whether there is sufficient support for continuation of the trial, evidence that 
study procedures should be changed, or evidence that the trial (or a specific site) should be halted 
for reasons relating to safety of the study participants or inadequate trial performance (e.g., poor 
recruitment). 
Following each DSMB meeting, the NIDA CCTN will communicate the outcomes of the meeting, 
based on DSMB recommendations, in writing to the study Lead Investigator. This communication 
summarizing study safety information will be submitted to participating IRBs. 
D. Quality Assurance (QA) Monitoring 
The monitoring of the study site(s) will be conducted on a regular basis using a combination of 
NIDA CCTN CCC monitors and the local Node QA Monitors. Investigators will host periodic visits 
for the monitors. The purpose of these visits is to assess compliance with the protocol, GCP 
requirements, and other applicable regulatory requirements, as well as to document the integrity 
of the trial progress. The investigative site will provide direct access to all trial related sites (e.g., 
research office), source data/documentation, and reports for the purpose of monitoring and 
auditing by the monitors, as well as for inspection by local and regulatory authorities. Areas of 
particular concern will be the review of inclusion/exclusion criteria, participant Informed Consent 
Forms, protocol adherence, safety monitoring, IRB reviews and approvals, regulatory documents, 
participant records, and Principal Investigator supervision and involvement in the trial. The 
monitors will interact with the site staff to identify issues and re-train the site as needed to enhance 
research quality. 
Site Visit Reports will be prepared by the NIDA CCC monitors following each site visit. These 
reports will be sent to the site Principal Investigator, the study Lead Investigator, NIDA CCTN, 
and other parties as designated. 

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Local Node QA site visit reports will be prepared following each site visit, as applicable. These 
reports are sent to those entities required of them by the Lead Investigative team, generally 
including the Lead Investigator, Lead Project Manager, site Principal Investigator, Node PI and a 
CCC representative, usually the protocol specialist for the study. 
E. Management of Risks to Participants 
Confidentiality
Confidentiality of participant records will be secured by the use of study codes for identifying 
participants on CRFs, and secure storage of any documents that have participant identifiers on 
site, as well as secure computing procedures for entering and transferring electronic data. The 
documents or logs linking the study codes with the study participant on site will be kept 
locked/securely stored separately from the study files and the medical records. No identifying 
information will be disclosed in reports, publications or presentations. 
Information That Meets Reporting Requirements 
The consent form will specifically state the types of information that are required for reporting and 
that the information will be reported as required. These include suspected or known sexual or 
physical abuse of a child or elders, or threatened violence to self and/or others. 
Participant Protection 
The site’s study clinician or other designated and qualified individual will evaluate all pertinent 
screening and baseline assessments prior to participant randomization to ensure that the 
participant is eligible and safe to enter the study.  
Pregnancy 
As there is no medication intervention, pregnancy will not be followed within the context of this 
study. 
3.0 
DATA MANAGEMENT PROCEDURES 
This protocol will utilize a centralized Data and Statistics Center (DSC). Advantage eClinical, a 
web-based distributed data entry model will be implemented. This electronic data capture system 
will be developed to ensure that guidelines and regulations surrounding the use of computerized 
systems in clinical trials are upheld. 
4.0 
DATA AND STATISTICS CENTER RESPONSIBILITIES 
The DSC will: 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide final Case Report Forms (CRFs) and electronic Case 
Report Forms (eCRFs) for the collection of all data required by the study, 3) develop data 
dictionaries for each eCRF that will comprehensively define each data element, 4) prepare 
instructions for the use of Advantage eClinical and for the completion of CRFs/eCRFs, 5) conduct 
data validations and cleaning activities on study data collected from all participating sites, and 6) 
perform data cleaning activities prior to the final study database lock. 

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5.0 
DATA COLLECTION AND ENTRY 
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical, or will be collected via direct entry into the eCRF. In the event that 
Advantage eClinical is not available, the DSC will provide the sites with CRF paper source 
documents and completion instructions. Data entry into Advantage eClinical should be completed 
in accordance with the instructions provided during protocol-specific training and guidelines 
established by the DSC. Data entry into the eCRFs is performed by authorized individuals. 
Selected source documents and eCRFs may also require the investigator’s signature (wet or 
electronic). In some situations, data collected on source documents will not be entered into 
Advantage eClinical, but when it is entered, it will follow the guidelines stated above. 
The Principal Investigator at the site is responsible for maintaining accurate, complete and up-to-
date research records. In addition, the Principal Investigator is responsible for ensuring the timely 
completion of eCRFs for each research participant. 
6.0 
DATA MONITORING, CLEANING AND EDITING 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and missing forms are available to sites at all times in Advantage eClinical. 
These reports will be monitored regularly by the DSC. In addition, the DSC will identify 
inconsistencies within eCRFs and between eCRFs and post queries in Advantage eClinical on a 
scheduled basis. Sites will resolve data queries by entering all corrections and changes directly 
into Advantage eClinical or verifying the data are correct as is. 
As described above, the CCC will conduct regular monitoring visits, during which audits 
comparing source documents to the data entered on the eCRF will be performed. Any 
discrepancies identified between the source document and the eCRF will be corrected by the site. 
Trial progress and data status reports, which provide information on items such as recruitment, 
availability of primary outcome, treatment exposure, attendance at long term follow-up visits, 
regulatory status, and data quality, will be generated daily and posted to a secure website. These 
reports are available to the site staff, the local Node staff, the Lead Investigator, the coordinating 
centers, and NIDA CCTN, to monitor each site’s progress on the study. 
7.0 
DATABASE LOCK AND TRANSFER 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DSC. Individual participants and their research 
data will be identified by a unique study identification number; further, some identifiable data may 
be collected in eClinical. The study data entry and study management systems used by clinical 
sites and by DSC staff will be secured and password protected. 
At the conclusion of data collection for the study, the DSC will perform final data cleaning activities 
and will “lock” the study database from further modification. The final raw datasets will be 
transferred to the Lead Investigator or designee and to NIDA as requested. De-identified versions 
of these datasets will also be provided to the NIDA CCTN-designated party for storage and 
archiving. These datasets may be posted on the NIDA Data Share website. 
Reference: http://grants.nih.gov/grants/guide/notice-files/not98-084.html