Opioid Use Disorder in the Emergency Department: Clinical Trials Network-0069
Phase: NA
Conditions: Opioid Use Disorder
Sponsor: Yale University

 
 
 
 
 
 
 
NIDA CTN PROTOCOL 0069 
 
 
Opioid Use Disorder in the  
Emergency Department (ED-HEALTH) 
 
NCT03023930   
 
Version 4.0 
May 22, 2018 
 
 

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Lead Investigator (LI):  
 
Gail D’Onofrio, MD, MS 
New England Consortium Node 
Department of Emergency Medicine,  
Yale School of Medicine 
Co-Lead Investigator (Co-LI): 
David A. Fiellin, MD 
New England Consortium Node  
Department of Internal Medicine 
Yale School of Medicine 
Co-Investigators (CI): 
 
Yale University 
Marek Chawarski, PhD 
Departments of Psychiatry & Emergency Medicine 
E. Jennifer Edelman, MD, MHS 
Department of Internal Medicine 
Kathryn Hawk, MD, MHS  
Department of Emergency Medicine 
Patrick O’Connor, MD 
Department of Internal Medicine 
Michael Pantalon, PhD 
Department of Emergency Medicine 
Susan Busch, PhD 
School of Public Health 
Leslie Curry, PhD 
School of Public Health 
 
Project Director: 
Patricia Hansen Owens, MS 
Department of Emergency Medicine  
Assistant Project Director: 
Shara Martel, MPH  
Department of Emergency Medicine 
CCTN Protocol Coordinators: 
Kristen Huntley, PhD 
David Liu, MD 
NIDA CTN Clinical Coordinating 
Center and Data and Statistics 
Center: 
Eve Jelstrom, CRNA, MBA  
CCC Co-Principal Investigator 
Dagmar Salazar, MS 
CCC Protocol Specialist 
Kayla Chaney 
CCC Protocol Specialist 
Mat Makowski, PhD 
DSC Statistician 
Lauren Yesko 
DSC Project Director 
Casey Nelson, MPH 
DSC Data Manager 

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Executive Committee: 
 
Roger D. Weiss, MD 
New England Consortium Node 
Harvard Medical School 
Kathleen Carroll, PhD 
New England Consortium Node 
Yale School of Medicine  
Dennis Donovan, PhD  
Pacific Northwest Node 
University of Washington  
John Rotrosen, MD 
New York Node 
New York University 
Ryan P. McCormack, MD 
New York Node 
NYU Langone Medical Center  
 
 

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TABLE OF CONTENTS 
 
1.0 
LIST OF ABBREVIATIONS ............................................................................................... 9 
2.0 
STUDY SYNOPSIS .......................................................................................................... 11 
2.1 
Primary Implementation and Effectiveness Aims ......................................................... 12 
3.0 
INTRODUCTION .............................................................................................................. 13 
3.1 
Background and Significance ....................................................................................... 13 
3.2 
Innovation ..................................................................................................................... 13 
3.3 
Public Health Impact ..................................................................................................... 14 
3.4 
Sustainability ................................................................................................................ 14 
4.0 
AIMS, OBJECTIVES & HYPOTHESES .......................................................................... 15 
4.1 
Overview ....................................................................................................................... 15 
4.2 
Primary Aims ................................................................................................................ 15 
4.3 
Secondary Aims and Hypothesis .................................................................................. 15 
4.3.1 
Implementation Aims ............................................................................................. 15 
4.3.2 
Implementation Hypotheses .................................................................................. 16 
4.3.3 
Effectiveness Aims (at 30-day follow-up assessment) .......................................... 17 
4.3.4 
Effectiveness Hypotheses (at 30-day follow-up assessment) ............................... 17 
4.4 
Exploratory Aims .......................................................................................................... 17 
4.4.1 
Study Patient, Emergency Department and Provider Characteristics ................... 17 
4.4.2 
Cost effectiveness ................................................................................................. 18 
5.0 
STUDY DESIGN .............................................................................................................. 19 
5.1 
Figure 1: Overview: Study Activities ............................................................................. 19 
5.2 
Implementation Facilitation Leads to Practice Change ................................................ 20 
5.2.1 
Table 1: Components of Implementation Facilitation ............................................ 21 
5.3 
Duration of Study .......................................................................................................... 21 
5.3.1 
Study Timeline Estimated Dates ........................................................................... 21 
6.0 
STUDY SETTINGS .......................................................................................................... 22 
6.1 
Number of ED Sites ...................................................................................................... 22 
6.2 
ED Characteristics ........................................................................................................ 22 
6.3 
Rationale for ED Criteria ............................................................................................... 23 
6.4 
ED Providers ................................................................................................................ 23 
6.5 
Community Opioid Treatment Providers and Programs ............................................... 23 
6.6 
Rationale for Community Opioid Treatment Providers and Program Criteria ............... 23 

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7.0 
STUDY POPULATION .................................................................................................... 24 
7.1 
Inclusion Criteria ........................................................................................................... 24 
7.2 
Exclusion Criteria .......................................................................................................... 24 
7.3 
Feasibility ...................................................................................................................... 25 
8.0 
OUTCOME MEASURES ................................................................................................. 26 
8.1 
Primary Implementation Outcome Measure ................................................................. 26 
8.2 
Primary Effectiveness Outcome Measure .................................................................... 26 
8.3 
Secondary Implementation Outcome Measures .......................................................... 26 
8.4 
Secondary Effectiveness Outcome Measures .............................................................. 27 
8.5 
Exploratory Outcomes .................................................................................................. 27 
9.0 
STUDY PROCEDURES ................................................................................................... 29 
9.1 
Screening and Informed Consent Procedures Baseline and IF Evaluation Periods ..... 29 
9.1.1 
Screening .............................................................................................................. 29 
9.1.2 
Informed Consent Procedures (Patient Participants) ............................................ 29 
9.1.3 
Eligibility Confirmation and Enrollment .................................................................. 30 
9.2 
Participant Withdrawal .................................................................................................. 30 
9.3 
Participant 30-day Follow-up Assessments .................................................................. 30 
9.4 
Compensation .............................................................................................................. 30 
10.0 
STUDY PATIENT ASSESSMENTS ................................................................................ 31 
10.1 
Baseline Evaluation and IF Evaluation Periods ............................................................ 31 
10.1.1 
Table 2: Schedule of Study Activities and Assessments (Study Patient) by Study 
Time Period ......................................................................................................................... 32 
10.2 
Study Patient Participant Assessments ........................................................................ 33 
10.2.1 
ED Health Quiz ...................................................................................................... 33 
10.2.2 
DSM-5 ................................................................................................................... 33 
10.2.3 
Urine Drug Screen (Toxicology Testing) ............................................................... 33 
10.2.4 
Patient Eligibility Summary and Compound Informed Consent and 
Inclusion/Exclusion .............................................................................................................. 33 
10.2.5 
Demographics and Additional Characteristics ....................................................... 33 
10.2.6 
Locator Information Form ...................................................................................... 33 
10.2.7 
Other Substance Use ............................................................................................ 34 
10.2.8 
Timeline Follow-back (TLFB) ................................................................................ 34 
10.2.9 
Health Services Utilization Inpatient and Health Services Utilization Outpatient 29 34 
10.2.10 
Health Status ..................................................................................................... 34 

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10.2.11 
Overdose Events ............................................................................................... 34 
10.2.12 
EuroQol (EQ-5D) ............................................................................................... 34 
10.2.13 
Crime and Criminal Justice ................................................................................ 34 
10.2.14 
Healthcare Visit Logistics ................................................................................... 35 
10.2.15 
Engagement in Treatment Survey ..................................................................... 35 
10.2.16 
ED Visit Review ................................................................................................. 35 
10.2.17 
Critical Action Checklist ..................................................................................... 35 
10.2.18 
ED Visits and Hospitalizations ........................................................................... 35 
10.2.19 
Study Completion .............................................................................................. 35 
10.2.20 
Adverse Events (AEs) and Serious Adverse Events (SAEs) ............................. 35 
10.2.21 
Protocol Deviation Form .................................................................................... 36 
11.0 
IMPLEMENTATION FACILITATION (IF) STUDY PROCEDURES ................................. 37 
11.1 
Standard Dissemination Practice - Education .............................................................. 37 
11.2 
Implementation Facilitation ........................................................................................... 37 
11.2.1 
Overview of the Implementation Facilitation .......................................................... 37 
11.2.2 
Formative Evaluation ............................................................................................. 37 
11.3 
Quantitative Data Collection and Analysis .................................................................... 38 
11.4 
Qualitative Data Collection and Analysis ...................................................................... 39 
11.5 
Development of Focus Group Questions ..................................................................... 40 
11.6 
Verbal Consent for Focus Group Participants .............................................................. 40 
11.7 
Conduct of Focus Groups ............................................................................................. 40 
11.8 
Administration of BUP During IF Evaluation Period ..................................................... 41 
11.9 
Referral for Continuation of MAT .................................................................................. 41 
11.10 
Additional Components of Implementation Facilitation ............................................. 41 
11.11 
Provider Intervention to Enhance Motivation for Treatment ...................................... 44 
12.0 
STATISTICAL ANALYSES ............................................................................................. 45 
12.1 
Definition of the Primary Effectiveness Outcome ......................................................... 45 
12.2 
Definition of the Primary Implementation Outcome ...................................................... 45 
12.3 
Experimental Design .................................................................................................... 45 
12.4 
Recruitment and Enrollment ......................................................................................... 46 
12.5 
Hypothesized Treatment Effect Sizes .......................................................................... 46 
12.5.1 
Table 3: Hypothesized Probabilities of Success ................................................... 46 
12.6 
Power Analyses to Justify Sample Size ....................................................................... 46 
12.6.1 
Table 4: Scenarios Used to Simulate Power ......................................................... 47 

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12.7 
Potential for Sites to have Baseline Probability of 0 for Primary  Implementation 
Outcome .................................................................................................................................. 47 
12.7.1 
Table 5: List of Figures and their Contents for the Power Analysis ....................... 48 
12.8 
ChangeToOne Approach .............................................................................................. 48 
12.8.1 
Figure 2: ChangeToOne Power Analysis; Alternative Cases ................................ 49 
12.8.2 
Figure 3: ChangeToOne Confidence Intervals for p1, p2; Alternative Cases........ 50 
12.8.3 
Figure 4: “ChangeToOne” test size; Null Cases .................................................... 50 
12.8.4 
Figure 5: “ChangeToOne” Confidence Intervals, p1, p2; Null Cases .................... 51 
12.9 
Bayesian Approach ...................................................................................................... 51 
12.9.1 
Summary of Power Simulations ............................................................................ 51 
12.10 
Missing Data ............................................................................................................. 51 
12.11 
Controlling Type 1 Error in Primary Analyses ........................................................... 52 
12.12 
Interim Monitoring ..................................................................................................... 52 
12.13 
Planned Secondary Analyses ................................................................................... 52 
12.14 
Statistical Methods .................................................................................................... 53 
12.14.1 
Primary Outcome Analysis ................................................................................ 53 
12.14.2 
Effect Modification of Primary Analysis .............................................................. 54 
12.14.3 
Secondary Implementation Outcomes ............................................................... 54 
12.14.4 
Effectiveness Outcomes .................................................................................... 55 
12.15 
Exploratory Analyses ................................................................................................ 56 
13.0 
TRAINING ........................................................................................................................ 58 
14.0 
REPORTING AND MONITORING ................................................................................... 59 
14.1 
Statement of Compliance ............................................................................................. 59 
14.2 
Regulatory Files ............................................................................................................ 59 
14.3 
Research Advisory Panel of California (California sites only)....................................... 59 
14.4 
Informed Consent ......................................................................................................... 59 
14.5 
Health Insurance Portability and Accountability Act (HIPAA) ....................................... 60 
14.6 
Investigator Assurances ............................................................................................... 60 
14.7 
Financial Disclosure ..................................................................................................... 60 
14.8 
Clinical Monitoring ........................................................................................................ 61 
14.8.1 
Data collection and data completeness monitoring ............................................... 61 
14.9 
Study Documentation ................................................................................................... 62 
14.10 
Safety Monitoring ...................................................................................................... 62 
14.10.1 
Data and Safety Monitoring Board (DSMB) ....................................................... 62 

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14.10.2 
Reporting and Management .............................................................................. 62 
14.10.3 
Confidentiality .................................................................................................... 63 
14.11 
Certificate of Confidentiality ...................................................................................... 63 
14.12 
Adverse Events (AEs) and Serious Adverse Events (SAEs) .................................... 64 
15.0 
DATA MANAGEMENT AND PROCEDURES ................................................................. 66 
15.1 
Design and Development ............................................................................................. 66 
15.1.1 
Data Collection ...................................................................................................... 66 
15.1.2 
Data Acquisition and Entry .................................................................................... 66 
15.1.3 
Site Responsibilities .............................................................................................. 66 
15.1.4 
Data Center Responsibilities ................................................................................. 66 
15.1.5 
Data Editing ........................................................................................................... 67 
15.1.6 
Data Transfer/Lock ................................................................................................ 67 
15.2 
Data Training ................................................................................................................ 67 
15.3 
Data Quality Assurance ................................................................................................ 67 
16.0 
STUDY TIMELINE ........................................................................................................... 68 
17.0 
PUBLICATIONS AND OTHER RIGHTS ......................................................................... 69 
18.0 
SIGNATURES .................................................................................................................. 70 
19.0 
APPENDIX: BAYESIAN ANALYSIS ............................................................................... 71 
19.1 
Figure B5: Bayes power; Alternative Cases ................................................................. 72 
19.2 
Figure B6: Bayes Credibility Intervals for p1, p2; Alternative Cases ............................ 72 
19.3 
Figure B7: Bayes Credibility Intervals for p1-p2; Alternative Cases ............................. 73 
19.4 
Figure B8: Bayes Test Size; Null Cases ....................................................................... 74 
19.5 
Figure B9: Bayes Credibility Intervals for P1, P2; Null Cases ...................................... 74 
19.6 
Figure B10: Bayes Credibility Intervals P1-P2; Null Cases .......................................... 75 
20.0 
REFERENCES ................................................................................................................. 76 
 
 

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1.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
BNI 
Brief Negotiation Interview  
BUP 
Buprenorphine or buprenorphine/naloxone 
CCC 
Clinical Coordinating Center 
CCTN  
Center for the Clinical Trials Network 
CoC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CTN 
Clinical Trials Network 
DHHS 
Department of Health and Human Service 
DSC 
Data and Statistics Center 
DSMB  
Data Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
eCRF 
Electronic Case Report Form 
eSVR 
Electronic Site Visit Report 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EDR 
ED Visit Review  
EHR 
Electronic Health Record  
ERC 
Ethics Review Committee 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HSP  
Human Subject Protection  
IF 
Implementation Facilitation  
IRB 
Institutional Review Board 
IV 
Intravenous  
LI 
Lead Investigator 
LN 
Lead Node 
MAT 
Medication Assisted Treatment  
ME 
Medical Examiner  
MI 
Motivational Interviewing 
MM 
Medical Monitoring 
NA 
Narcotic Anonymous  
NIDA 
National Institute on Drug Abuse 
 

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Abbreviation 
Definition 
NMUPO 
Non-Medical Use of Prescription Opioids 
ORCA 
Organizational Readiness to Change Assessment 
OTP 
Opioid Treatment Program 
OUD 
Opioid Use Disorder 
PARiHS 
Promoting Action on Research Implementation in Health Services 
PC 
Primary Care 
PI 
Principal Investigator 
PT 
Patient 
PPT 
Participant/study participant 
QA 
Quality Assurance 
RA 
Research Associate 
RTS 
Regulatory Tracking System 
SAE 
Serious Adverse Event 
SAMHSA 
Substance Abuse and Mental Health Services Administration 
SBIRT 
Screening, Brief Intervention, Referral and Treatment 
SD 
Standard Deviation 
TLFB 
Time-Line Follow-Back 
WIRB 
Western Institutional Review Board 
 

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2.0 
STUDY SYNOPSIS  
AIMS 
The study will evaluate the impact of (1) Implementation Facilitation (IF) on rates of provision of 
Emergency Department (ED)-initiated buprenorphine/naloxone (BUP) treatment with referral for 
ongoing medication-assisted treatment (MAT) and the (2) effectiveness of IF on patient 
engagement in formal addiction treatment at 30 days.  
DESIGN 
The proposed project uses a Hybrid Type 3 Effectiveness-Implementation framework and a 
modified stepped wedge design. In a Hybrid Type 3 Effectiveness-Implementation study the 
primary research question is the implementation strategy’s impact on uptake. In addition, the 
Hybrid Type 3 design allows one to assess the implementation strategy’s impact on related 
effectiveness outcomes. The study will be conducted at four EDs with a high prevalence of 
patients with untreated opioid use disorder (OUD), an existing research infrastructure and a 
potential network of community opioid treatment providers and programs. 
POPULATION 
The study populations will include:  
1) ED providers and staff involved in the treatment of patients with OUD;  
2) Community opioid treatment providers and program staff involved in providing care for 
patients with OUD referred from the ED;  
3) Approximately 960 ED patients with moderate to severe OUD. 
ELIGIBILITY for Participating in Implementation Facilitation  
ED staff: All staff involved in the process of ED initiation of BUP and/or OUD referral.  
Community opioid treatment providers and program staff: Providers and staff involved in the 
provision of office-based BUP and at opioid treatment programs (OTPs). 
ED patients: (Criteria described below)  
PATIENT INCLUSION/EXCLUSION CRITERIA 
Patients 18 years or older who are treated in the ED during study screening hours with DSM-5 
criteria for moderate to severe OUD and provide an opioid positive urine sample will be eligible to 
participate. Note: Patients who test positive for fentanyl only are not eligible. Patients will be 
excluded if they have a medical or psychiatric condition requiring hospitalization at the index ED 
visit, acutely suicidal or severely cognitively impaired precluding informed consent, presents from 
an extended care facility, requires continued prescription opioids for a pain condition, be a 
prisoner or in police custody at time of index ED visit, currently (during the past 30 days) enrolled 
in formal addiction treatment including by court order, inability to provide 2 contact numbers, 
unwilling to follow study procedures, prior enrollment in the current study or non-English speaking.  
 
 

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METHODS 
A Hybrid Type 3 Effectiveness-Implementation design will be used to evaluate the impact of an 
IF strategy (consisting of a bundle of implementation activities) on the provision of ED-initiated 
BUP with referral for ongoing MAT to ED patients with moderate or severe OUD (implementation 
outcome) and patient engagement in treatment at 30 days (effectiveness outcome) compared 
with a baseline evaluation period. The baseline evaluation period occurs after a standard 
educational dissemination activity using a “grand rounds” format. A modified stepped wedge 
design1-4 will be used to randomize the order of the four EDs receipt of IF. IF is a multi-component 
intervention that assesses key stakeholder's need to provide a tailored implementation strategy 
using an external facilitator, local champions, provider education, academic detailing, stakeholder 
engagement, performance monitoring and feedback, formative evaluations, a learning 
collaborative and program marketing to implement ED-initiated BUP with referral for ongoing 
MAT.1,5 The IF strategies are iterative and continue into the IF evaluation period.  
2.1 
Primary Implementation and Effectiveness Aims 
In a Hybrid Type 3 Effectiveness-Implementation study the primary research question tests the 
implementation strategy’s impact on uptake. In addition, the Hybrid Type 3 design allows one to 
assess the implementation strategy’s impact on related effectiveness outcomes. In the current 
study the primary research question is the impact of IF on the provision of ED-initiated BUP with 
referral for ongoing MAT. The effectiveness outcome, in this case patient engagement in formal 
addiction treatment on the 30th day post enrollment, is also assessed but is not considered co-
primary.  
IMPLEMENTATION  
To compare the baseline evaluation and IF evaluation periods on rates of provision of ED-initiated 
BUP with referral for ongoing MAT. This is the main outcome of the study for the purposes of 
analysis. (Section 12.11) 
Hypothesis: There will be higher rates of provision of ED-initiated BUP with referral for ongoing 
MAT in the IF evaluation period compared with the baseline evaluation period  
EFFECTIVENESS  
To compare the baseline evaluation and IF evaluation periods on rates of patient engagement in 
formal addiction treatment on the 30th day post enrollment. 
Hypothesis: There will be a higher proportion of patients in the IF evaluation period engaged in 
formal addiction treatment on the 30th day post study enrollment than the baseline evaluation 
period.  
The rates of engagement in formal addiction treatment on the 30th day post enrollment during the 
baseline and IF evaluation periods will be compared within each site and for the entire study 
cohort. Engagement in formal addiction treatment will be defined as enrollment and receiving 
formal addiction treatment on the 30th day post enrollment, assessed by direct contact with the 
facility and/or treating clinician. Formal addiction treatment will be those treatments consistent 
with the American Society of Addiction Medicine’s levels of care (1-4), and will include a range of 
clinical settings including office-based providers of BUP or naltrexone, OTPs, intensive outpatient, 
inpatient, or residential treatments. Patients do not need to be receiving MAT on the 30th day post 
enrollment to be considered engaged in formal addiction treatment. Participation in a self-help 
program such as Narcotics Anonymous (NA) alone will not be considered as engagement in 
formal addiction treatment.  

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3.0 
INTRODUCTION 
3.1 
Background and Significance  
Untreated opioid use disorder (OUD) remains a major public health problem in the United States 
despite the availability of effective medication assisted treatments (MATs).6 Patients with 
untreated OUD frequently receive care in EDs for treatment of acute and comorbid conditions, 
opioid overdose and withdrawal, and as a conduit to addiction treatment. EDs typically provide 
referrals to community services, including opioid treatment programs (OTPs), for OUD treatment 
rather than directly initiate treatment for this chronic and relapsing condition with medications such 
as buprenorphine (BUP). We recently demonstrated that ED-initiated BUP with referral for 
ongoing MAT was superior to such referrals, resulting in nearly twice the percentage of patients 
who were engaged in formal addiction treatment on the 30th day post enrollment and less illicit 
opioid use.7 We propose to use an Implementation Facilitation strategy to accelerate 
dissemination and promote sustainable implementation of ED-initiated BUP with referral for 
ongoing MAT. We also propose to build upon prior efficacy work and examine effectiveness of 
the approach to improve engagement in formal addiction treatment on the 30th day post 
enrollment. The outstanding unmet need addressed by this project is an urgent public health 
priority to expand access to MAT for patients with untreated OUD by increasing the use of ED-
initiated BUP with referral for ongoing MAT. We hypothesize that this will increase ED provider 
provision of BUP, patient engagement in formal addiction treatment and reduce illicit opioid use. 
Implementation Facilitation,5 an evidence based and reproducible strategy for changing 
healthcare, holds exceptional promise as a way to increase ED-initiated BUP with referral for 
ongoing MAT.  
3.2 
Innovation 
We seek to expand access to MAT through the use of the ED, a setting with a high prevalence of 
untreated OUD traditionally only used as a site for referral rather than initiation of care for this 
chronic disease. We use a novel strategy from Implementation Science, Implementation 
Facilitation (IF), to address site-specific needs and support the adoption of ED-initiated BUP with 
referral for ongoing MAT.8 To rigorously evaluate the effectiveness of the IF approach, we will 
conduct a modified stepped wedge design, in which EDs are randomized to the calendar time of 
receiving the IF and all sites are evaluated repeatedly following a standard dissemination 
intervention (education only) component and following the IF component. The proposed study will 
evaluate both the implementation process and its subsequent effectiveness. Additionally, this 
research will produce training protocols and materials for ED providers to learn and initiate BUP 
treatment, improved patient screening/evaluation and engagement algorithms, including 
innovative use of electronic health record screening and decision support tools and tablet-based 
software programs to facilitate ED diagnosis, evaluation and treatment provision. Upon successful 
completion of the proposed study, the study sites will have improved capabilities to initiate ED 
BUP treatment, and improved tools to engage in further training and dissemination efforts 
regionally and nationally.  
 
 

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3.3 
Public Health Impact 
EDs are often the source of care for patients with OUD including overdose.6 ED-based care can 
impact short-term (e.g., 30 day) engagement in care. Successful completion of this research will 
provide much needed models and resources to support implementation of ED-initiated BUP and 
promote engagement in addiction treatment and help to establish EDs as a standard site for 
initiation of MAT for OUD, paralleling models of treatment for other chronic diseases such as 
diabetes, asthma and hypertension, thus expanding access to MAT. 
3.4 
Sustainability  
We have opted to use an implementation science framework and IF to specifically address the 
issue of sustainability. To the extent possible, we will use the IF process to identify and implement 
real-world and long-term solutions to BUP initiation in the ED with continuing care in the 
community. This will result in processes and procedures that will remain after the research has 
been completed and that can be transferred to other settings not involved in the study. If 
successful the IF strategy would provide a new, reproducible paradigm for clinical experts and 
policy makers to help expand access to MAT. The study will generate processes, procedures, 
and deliverables for dissemination to EDs, office-based physicians and OTPs nationally. Several 
of the CTN nodes and their corresponding EDs are ideally suited for an evaluation of ED-initiated 
BUP with referral for ongoing MAT. This intervention has demonstrated efficacy in a single site 
and is ideal for simultaneous evaluation of implementation and effectiveness in multiple sites. We 
will build on our extensive experience and the current national and state policy momentum for 
increasing access to MAT of OUD. The CTN has long been a venue to evaluate the provision of 
treatment services in clinical settings. This protocol provides a unique opportunity to expand 
access to effective treatment for OUD via ED settings nationally. We will share our products and 
lessons learned with other CTN nodes, and at Emergency Medicine, Addiction Medicine, Primary 
Care and community-based treatment provider professional societies and meetings. 
 

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4.0 
AIMS, OBJECTIVES & HYPOTHESES  
4.1 
Overview 
We have previously demonstrated that ED-initiated BUP with referral for ongoing BUP treatment 
is superior to referral alone for engaging and retaining patients in formal addiction treatment at 30 
days.7 Thus, ED-initiated BUP offers an innovative strategy to expand urgently needed access to 
MAT for patients with moderate/severe OUD.6 Research is needed to develop strategies to 
efficiently disseminate and implement ED-initiated BUP with referral for ongoing MAT in real-world 
ED settings. IF is an evidenced-based strategy that provides a bundle of activities (Table 1) to 
increase the skill set of ED providers and can improve the adoption of effective treatments.8 We 
propose an Effectiveness-Implementation Hybrid Type 3 study using a modified stepped wedge 
design.1-4,9,10 Four sites will receive the same sequence of interventions: the baseline evaluation 
period after the initial education component, the IF phase, and continuation of facilitation into the 
IF evaluation period. Study participants include ED patients with OUD as well as ED and 
community providers. The timing of initiation of the study activities at each site will be randomly 
offset by 3 month increments to accommodate logistical constraints of simultaneous 
implementation at all sites.  
4.2 
Primary Aims 
To compare the baseline evaluation and IF evaluation periods on:  
 
IMPLEMENTATION:  
Rates of provision of ED-initiated BUP with referral for ongoing MAT. 
Hypothesis: There will be higher rates of provision of ED-initiated BUP with referral for ongoing 
MAT in the IF evaluation period compared with the baseline evaluation period. 
 
EFFECTIVENESS:  
Rates of patient engagement in formal addiction treatment on the 30th day post enrollment  
Hypothesis: There will be a higher proportion of patients in the IF evaluation period engaged in 
formal addiction treatment on the 30th day post enrollment than in the baseline evaluation period. 
4.3 
Secondary Aims and Hypothesis 
4.3.1 
Implementation Aims 
To compare the baseline evaluation and IF evaluation periods on: 
 
1. Provider fidelity to a critical action checklist relating to the provision of ED-initiated BUP 
with referral for ongoing MAT  
2. Rates of enrolled patients receiving an appointment for opioid treatment provider/program 
upon ED discharge 
3. Number of ED providers receiving DATA 2000 training  
4. Number of clinicians providing ED-initiated BUP with referral for ongoing MAT 

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5. ED provider readiness and preparedness ruler scores to initiate BUP and provide referral 
for ongoing MAT  
6. ED Organizational Readiness to Change Assessment (ORCA) scores11 relating to ED-
initiated BUP with referral for ongoing MAT 
7. Community opioid treatment provider/program readiness and preparedness ruler scores 
to continue MAT for patients with OUD who have received ED-initiated BUP 
8. Community opioid treatment provider/program Organizational Readiness to Change 
Assessment (ORCA) scores relating to receiving patients with OUD who have received 
ED-initiated BUP 
4.3.2 
Implementation Hypotheses 
1. There will be higher fidelity to the critical action checklist relating to the provision of ED-
initiated BUP with referral for ongoing MAT in the IF evaluation period compared with the 
baseline evaluation period  
2. A greater rate of patients in the IF evaluation period will receive an appointment with an 
opioid provider/program upon ED discharge compared with the baseline evaluation period 
3. A greater number of providers will undergo DATA 2000 training in the IF evaluation period 
compared with the baseline evaluation period 
4. A greater number of clinicians will provide ED-initiated BUP with referral for ongoing MAT 
in the IF evaluation period compared with the baseline evaluation period 
5. ED provider readiness and preparedness ruler scores will reflect a greater readiness and 
preparedness for provision of BUP and referral for ongoing MAT in the IF evaluation period 
compared with the baseline evaluation period 
6. ED ORCA scores will reflect a greater organizational readiness to change with respect to 
provision of ED-initiated BUP in the IF evaluation period compared with the baseline 
evaluation period 
7. Community opioid treatment provider/program provider readiness and preparedness ruler 
scores to continue MAT for patients with OUD who have received ED-initiated BUP will be 
greater in the IF evaluation period compared with the baseline evaluation period 
8. Community opioid treatment provider/program ORCA scores relating to receiving patients 
with OUD who have received ED-initiated BUP will be greater in the IF evaluation period 
compared with the baseline evaluation period.  
 
 

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4.3.3 
Effectiveness Aims (at 30-day follow-up assessment) 
To compare the baseline evaluation and IF evaluation periods on: 
 
1. Self-reported days of illicit opioid use (past 7 days) as measured by Time-Line Follow-
Back (TLFB) methods at 30 days  
2. Overdose events (past 30-days) captured by participant self-report, state medical 
examiner records, National Death Index and review of medical records  
3. HIV risk taking behaviors (past 30 days) as measured by HIV Risk Taking Behavior Scale 
4. Healthcare service utilization (past 30 days)  
5. Rates of illicit opioid negative urines at 30 days 
4.3.4 
Effectiveness Hypotheses (at 30-day follow-up assessment) 
Patients in the IF evaluation period compared with baseline evaluation period will: 
 
1. Report fewer days with illicit opioid use in the past 7 days  
2. Experience fewer overdose events (past 30 days) 
3. Report fewer HIV risk taking behaviors (past 30 days) 
4. Utilize fewer inpatient OUD services (past 30 days) 
5. Have greater rates of illicit opioid negative urine tests at 30 days 
4.4 
Exploratory Aims 
4.4.1 
Study Patient, Emergency Department and Provider Characteristics 
We will evaluate a limited set of study patient, ED and ED provider characteristics for their 
potential effect on the primary outcomes. 
IMPLEMENTATION 
ED characteristics such as size, location, existing addiction treatment services, and follow-up 
resources as well as the range and number of addiction treatment services in the catchment area 
of the ED will be evaluated. Provider characteristics such as age, gender, years and level of 
training will be evaluated. 
 
EFFECTIVENESS  
Study patient characteristics such as type of opioid used (prescription vs. heroin) mode of use 
(IV/PO/intranasal), frequency of use, demographics, pain intensity and interference, and reason 
for ED presentation such as overdose, seeking treatment or visit related to substance use, 
comorbid substance use and referral to office-based versus opioid treatment program will be 
evaluated. The overall effectiveness of ED-initiated BUP compared with other interventions during 
both baseline evaluation and IF evaluation periods will be evaluated.  
 

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4.4.2 
Cost effectiveness 
We will perform an incremental cost effectiveness analyses (CEA) and calculate the incremental 
cost per unit increase in engagement in formal addiction treatment comparing patients in the IF 
evaluation period with those in the baseline evaluation period.  
We will perform incremental cost effectiveness analyses (CEA) to evaluate if effectiveness 
benefits are worth the additional costs.  

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5.0 
STUDY DESIGN 
5.1 
Figure 1: Overview: Study Activities 
Opioid Education
”Grand Rounds”
Baseline Evaluation
N=120
12 months
IF Evaluation
N=120
12 months
IF
6 months
 
We will use a Hybrid Type 3 Effectiveness-Implementation design9 and a modified stepped wedge 
design1-4,10 to evaluate the effect of the IF on ED-initiated BUP with referral for ongoing MAT and 
its effectiveness. A Hybrid Type 3 design is recommended when there is strong face validity and 
strong initial evidence for the clinical and implementation interventions that would support 
generalizability; there is strong “implementation momentum” for adoption of the clinical 
intervention and evidence that the intervention being tested is feasible and supportable. In light 
of our prior work and the emphasis nationally on addressing the opioid epidemic, a Hybrid Type 
3 design is warranted. The advantages of this design include a balanced provision of resources 
and support across all study sites, enrollment of comparable cohorts of participants during 
baseline evaluation and IF evaluation phases across all sites, and the completion of the proposed 
study in a short period of time (48 months). This overall short study time will minimize the potential 
impact of population related time trends and other time related factors such as changes in 
healthcare practice and policy. The randomized order of the timing of the IF at each site, offset 
by 3 month increments, is used to accommodate logistical constraints of a simultaneous 
implementation at all sites. The stepped wedge design is increasingly used to promote the 
implementation of evidence-based practice and is appropriate for evaluating interventions when 
there is evidence that the intervention is likely to be beneficial and when practical considerations 
require a sequential deployment of an intervention.4,10 At each of the four study sites, there will be 
a 12-month baseline evaluation period after the standard dissemination activity via a “grand 
rounds” education session, followed by a 6-month IF phase, followed by a 12-month IF evaluation 
period. A 6-month IF phase is required to allow adequate time to conduct the multiple components 
of the IF (see Table 1). An evaluation period of 12 months is necessary to enroll enough patients 
for adequate sample size. The number of patients should be similar during the baseline evaluation 
and the IF evaluation periods. The strategies included in the IF are iterative and continue 
throughout the IF and IF evaluation periods. The proportion of eligible study participants in each 
time period who are engaged in formal addiction treatment on the 30th day post enrollment will be 
assessed within each site and for the entire study cohort.  
Implementation Science and the Promoting Action on Research Implementation in Health 
Services (PARiHS) framework can guide efforts to promote the uptake of ED-initiated BUP with 
referral for ongoing MAT 

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Implementation Science, defined by the National Institute of Health as the study of methods 
to promote the integration of research findings and evidence into healthcare policy 
and practice,12 provides an organized approach and tools for addressing the gap between the 
need and provision of ED-initiated BUP and ongoing MAT. We will use a proven Implementation 
Science strategy, Implementation Facilitation (sometimes referred to as Practice Facilitation) 
which provides a bundle of interlinked implementation activities. The goal will be to support ED 
providers and to promote uptake of ED-initiated BUP and referral for ongoing MAT among eligible 
patients. We will initially conduct a formative assessment of site-specific organizational, provider, 
and patient factors potentially impacting uptake of provision of ED-initiated BUP to refine the IF.  
The Promoting Action on Research Implementation in Health Services (PARiHS) framework was 
first published in 1998 and refined in 2008.13-16 The recent revisited framework identifies four 
elements for determining successful implementation of an evidence-based practice into clinical 
care:  
1. Nature of the innovation;  
2. Recipients of the facilitation, including people affected by and who influence 
implementation of the innovation;  
3. Qualities of the local and outer (i.e., social, policy, regulatory and political infrastructures) 
context in which the evidence is being introduced and enacted upon; and  
4. Facilitation (i.e., the implementation intervention), the active process of promoting 
implementation by assessing and responding to the recipients and associated context.4,13-
15 Johnson and colleagues expanded the PARiHS domains to allow for a more specific 
application17 and has informed the development of a measure of organizational readiness 
to change, the Organizational Readiness to Change Assessment (ORCA),11 that we use, 
after tailoring the items to address issues related to ED-initiated BUP. 
5.2 
Implementation Facilitation Leads to Practice Change 
IF is defined as a “process of ‘helping individuals and teams to understand what they need to 
change and how they need to change it in order to apply evidence to practice.”18 IF is an effective 
intervention5 that includes a “deliberate process of interactive problem solving and support that 
occurs in the context of a recognized need for improvement and supportive interpersonal 
relationship.”17 A recent systematic review and meta-analysis found that IF has a positive impact 
on guideline adoption in primary care.5 A central aspect of IF includes the active role of the 
facilitator(s) working in partnership with relevant stakeholders, and other implementation 
intervention components.17,18 Importantly, IF involves a “formative evaluation” to identify the 
specific and dynamic needs of stakeholders and the context (i.e., ED) for implementation of 
evidence-based practices.18 This “diagnostic” formative evaluation informs the initial tailoring and 
refinement of the IF, which includes the “bundle” of services18 (Table 1) tailored to meet site-
specific needs. The formative evaluation process is iterative and occurs during the 6 month IF 
period and continues throughout the IF evaluation period.19 Tailored implementation strategies 
have been found to be more effective than non-tailored interventions in changing practice20 and 
have been applied to changing primary care and mental health treatment delivery.8,21 IF has been 
used by large healthcare organizations including the Veterans Health Administration and is 
endorsed by the Agency for Health Care Research and Quality as a way to assist practices in 
becoming Primary Care Medical Homes.22  
 
 

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5.2.1 
Table 1: Components of Implementation Facilitation 
5.3 
Duration of Study  
Each ED site will need 2 months of startup time to hire the research associates and prepare for 
study procedures, and will enroll study patients for 12 months during the baseline evaluation 
period. Study patients will then be evaluated 30 days post enrollment. The initial IF phase will last 
6 months and will be followed by 12 months of study patient enrollment in the IF evaluation period 
and enrolled study patients will be evaluated 30 days post study enrollment. We anticipate 
completing study patient enrollment and follow up by 42 months. We proposed an additional 6 
months for analysis of the data and NIDA CTN presentation (see study timeline section 5.3.1).  
5.3.1 
Study Timeline Estimated Dates 
 
Study Year 1 
Study Year 2 
Study Year 3 
Study Year 4 
M 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 
DATE 
2/17 
3/17 
4/17 
5/17 
6/17 
7/17 
8/17 
9/17 
10/17 
11/17 
12/17 
1/18 
2/18 
3/18 
4/18 
5/18 
6/18 
7/18 
8/18 
9/18 
10/18 
11/18 
12/18 
1/19 
2/19 
3/19 
4/19 
5/19 
6/19 
7/19 
8/19 
9/19 
10/19 
11/19 
12/19 
1/20 
2/20 
3/20 
4/20 
5/20 
6/20 
7/20 
8/20 
9/20 
10/20 
11/20 
12/20 
1/21 
ED1 
Start 
Baseline evaluation period 
IF 
IF evaluation period 
F  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ED2 
 
Start 
Baseline evaluation period 
IF 
IF evaluation period 
F  
 
 
 
 
 
 
 
 
 
 
 
ED3 
 
 
 
 
 
 Start 
Baseline evaluation period 
IF 
IF evaluation period 
F  
 
 
 
 
 
 
 
 
ED4 
 
Start 
Baseline evaluation period 
IF 
IF evaluation period 
F  
 
 
 
 
 
All 
 
Analysis  
KEY:    IF= IMPLEMENTATION FACILITATION Phase, F=FOLLOW-UP ASSESSMENTS, M=MONTH 
Component 
Description 
External Facilitator 
Outside content expert who assists site 
Local Champion 
Local site stakeholder who promotes change 
Provider Education  
and Academic Detailing 
Provision of unbiased peer education 
Stakeholder Engagement 
Aligning goals of implementation and those impacted 
Tailor Program to Site 
Addressing site-specific needs based on formative assessment  
Performance Monitoring 
and Feedback 
Assess implementation of treatment efforts  
and inform site of results 
Formative Evaluation 
Quantitative and qualitative determination of impact 
Establish a Learning 
Collaborative 
Shared learning opportunities tailored to stakeholders 
Program Marketing 
Efforts designed to increase attention to availability 
of ED-initiated BUP  

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6.0 
STUDY SETTINGS 
6.1 
Number of ED Sites 
Four EDs will participate as enrolling sites for the study. This allows for conduct of the study within 
the 48-month time period giving ample time for patient enrollment into the study during the 
baseline evaluation and IF evaluation periods at each site assuming a high prevalence of 
untreated moderate/severe OUD. It also allows for adequate time to initiate and continue a 
meaningful IF at each site. 
6.2 
ED Characteristics 
Participating EDs should have the following characteristics and respond to the Data Call 
regarding: 
• 
Large prevalence of patients with untreated OUD so that the target of 10-12 patients 
enrolled into the study per month can be met. Sites must provide number of ICD 9/10 
codes for the past year related to overdose and opioid dependence, abuse and 
unspecified use/opioid use disorders  
• 
An electronic health record that can be queried daily to weekly 
• 
Wireless internet access as information entered on tablets will be uploaded to a secure 
study server  
• 
Prior clinical research experience (report funded projects, enrollment, retention, etc.) 
• 
An Emergency Physician with experience as Principal Investigator (PI) and with time to 
devote to the project 
• 
No current routine use of ED-initiated BUP 
• 
Ability to have BUP on their formulary and available to the ED 
• 
Ability to present a plan for patient flow and space utilization 
• 
Have or are able to hire appropriate staff to conduct the study  
• 
Have sufficient referral network for patients needing MAT that could potentially 
accommodate referrals in 96 hours  
• 
Be in a state that allows for MAT through its Medicaid program 
• 
Have accessible pharmacies to fill BUP prescriptions 
• 
Have an active state prescription monitoring program  
 

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6.3 
Rationale for ED Criteria 
The volume of patients seen in the ED must be adequate to ensure a steady stream of eligible 
patients for recruitment. A diverse, representative sample of patients and participants is desirable 
to enhance the external validity of the study. Geographical diversity of ED settings are desirable 
and research experience and successful participation in prior studies is essential as it provides 
evidence of the feasibility of study implementation. Patient flow and space utilization are 
challenging in the ED setting. The Research Associates (RAs) will preferably have experience 
working in ED settings, and therefore can be quickly integrated into the ED staffing team. 
6.4 
ED Providers 
We will include all ED providers credentialed to practice in the site ED that are capable of 
prescribing BUP. This includes physicians, nurse practitioners (NPs) and physician assistants 
(PAs).23,24 
6.5 
Community Opioid Treatment Providers and Programs  
Each ED may use multiple locations to refer patients for ongoing MAT. This would include opioid 
treatment programs and office-based providers.  
 
Participating community opioid treatment providers and programs should have the following 
characteristics: 
 
• 
At least one office-based provider of BUP not currently at their limit according to DATA 
2000 provisions, and one OTP without active waiting lists. 
• 
Programs and/or providers with the ability to accept patients with a variety of insurance 
plans (including Medicaid) within 96 hours of ED-initiated BUP. 
• 
Treatment providers and/or programs located within the general vicinity of where ED 
patients reside.  
6.6 
Rationale for Community Opioid Treatment Providers and Program 
Criteria 
These criteria ensure that there will be at least one of each type of provider in the community to 
whom patients who receive ED-initiated BUP can be referred. We will work to engage all office-
based providers of BUP and OTPs in each ED’s catchment area in receipt of patients with ED-
initiated BUP. 

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7.0 
STUDY POPULATION  
Patients with OUD enrolled in effectiveness evaluation 
7.1 
Inclusion Criteria 
All patients enrolled into the study must: 
 
1. Be 18 years or older 
2. Treated in the ED during study screening hours 
3. Meet DSM-5 diagnostic criteria for moderate to severe opioid use disorder  
4. Have a urine toxicology test that is positive for opioids (opiates, oxycodone, 
buprenorphine, or methadone.) For patients with acute pain conditions requiring opioid 
administration, urines will need to be obtained prior to ED opioid medication 
administration. 
7.2 
Exclusion Criteria 
All patients enrolled into the study must not: 
1. Have a medical or psychiatric condition that requires hospitalization at the index ED visit 
2. Be actively suicidal or severely cognitively impaired precluding informed consent 
3. Present from extended care facility (e.g., skilled nursing facility) 
4. Require continued prescription opioids for a pain condition 
5. Be a prisoner or in police custody at the time of index ED visit  
6. Currently have (past 30 days) enrolled in formal addiction treatment, including by court 
order  
7. Inability to provide reliable locator information including 2 contact numbers  
8. Be unwilling to follow study procedures (e.g., unwilling to provide permission to contact 
referral provider/program or return for 30-day assessment)  
9. Have prior enrollment in the current study 
Note: A patient may NOT enroll in both the baseline evaluation and IF evaluation periods. 
10. Not able to speak English sufficiently to understand the study procedures and provide 
written informed consent to participate in the study 
 

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7.3 
Feasibility 
An annual ED visit of 60,000 or greater, should provide an adequate volume of participants 
available for screening and enrollment along with the requisite ≥ 300 unique ICD codes related to 
opioid poisoning and dependence as reported in the site selection data call document. To ensure 
that recruitment and enrollment is done consistently and accurately with sequential patients, 
avoiding convenience sampling, each site is expected to have the equivalent of 3.0 full time 
Research Assistants (RAs) that will provide cross coverage over their assigned shifts. The 
number of patients screened at each site will vary based on the number of overall ED visits at 
each site. Each site will need to document the potential to enroll 10-12 patients into the study per 
month. This will allow the study to enroll approximately 960 patients overall into the study.  

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8.0 
OUTCOME MEASURES 
8.1 
Primary Implementation Outcome Measure  
Aim: To compare the baseline evaluation and IF evaluation periods on rates of provision of ED-
initiated BUP with referral for ongoing MAT. 
Hypothesis: There will be higher rates of provision of ED-initiated BUP with referral for ongoing 
MAT in the IF evaluation period compared with the baseline evaluation period.  
The rates of provision of ED-initiated BUP with referral for ongoing MAT will be based on: 
1. Proportion of enrolled patients who receive ED-initiated BUP with referral for ongoing MAT 
or 
2. Computed from ED data on the numbers of providers and their patients who received ED-
initiated BUP with referral for ongoing MAT 
As estimating a very low frequency outcome by sampling is not reliable, computation will 
be used if #1 results in zeros or small ratios. This entails reviewing existing ED records 
and counting the numbers of ED providers assigned to patients with OUD, and the number 
of patients who received ED-initiated BUP with referral for ongoing MAT during the study 
period. (See analysis section)  
8.2 
Primary Effectiveness Outcome Measure 
Aim: To compare the baseline evaluation and IF evaluation periods on rates of patient 
engagement in formal addiction treatment on the 30th day post study enrollment. 
Hypothesis: There will be a higher proportion of patients in the IF evaluation period engaged in 
formal addiction treatment on the 30th day post study enrollment than in the baseline evaluation 
period.  
The rates of engagement in formal addiction treatment at the 30th day post study enrollment during 
the baseline and IF evaluation periods will be compared within each site and for the entire study 
cohort. Engagement in formal addiction treatment will be defined as enrollment and receiving 
formal addiction treatment on the 30th day post study enrollment, assessed by direct contact with 
the facility and/or treating clinician. Formal addiction treatment will be those treatments consistent 
with the American Society of Addiction Medicine’s levels of care (1-4), and will include a range of 
clinical settings including office-based providers of BUP or naltrexone, OTPs, intensive outpatient, 
inpatient, or residential treatments. Patients do not need to be receiving MAT on the 30th day post 
enrollment to be considered engaged in formal addiction treatment. Participation in a self-help 
program such as NA alone will not be considered as engagement in formal addiction treatment. 
Additional analyses evaluating the effects of patient characteristics will also be conducted. 
8.3 
Secondary Implementation Outcome Measures 
To compare the baseline evaluation and IF evaluation periods on: 
 
1. Provider fidelity to a critical action checklist relating to the provision of ED-initiated BUP 
with referral for ongoing MAT  

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2. Rates of enrolled patients receiving an appointment for opioid treatment provider/program 
upon ED discharge 
3. Number of ED providers receiving DATA 2000 training  
4. Number of clinicians providing ED-initiated BUP with referral for ongoing MAT 
5. ED provider readiness and preparedness ruler scores to initiate BUP and provide 
referral for ongoing MAT  
6. ED Organizational Readiness to Change Assessment (ORCA) scores11 relating to ED-
initiated BUP with referral for ongoing MAT 
7. Community opioid treatment provider/program readiness and preparedness ruler scores 
to continue MAT for patients with OUD who have received ED-initiated BUP 
8. Community opioid treatment provider/program Organizational Readiness to Change 
Assessment (ORCA) scores relating to receiving patients with OUD who have received 
ED-initiated BUP 
8.4 
Secondary Effectiveness Outcome Measures  
To compare the baseline evaluation and IF evaluation periods on: 
1. Self-reported days of illicit opioid use (past 7 days) measured by TLFB methods at 30 
days 
2. Overdose events (past 30 days) captured by participant self-report, state medical 
examiner records, National Death Index and review of medical records  
3. HIV risk taking behaviors (past 30 days) as measured by HIV Risk Taking Behavior Score 
4. Healthcare service utilization (past 30 days) measured by Health Services Utilization Form 
5. Rates of illicit opioid negative urines at 30 days 
8.5 
Exploratory Outcomes  
We will evaluate a limited set of study patient, ED and ED provider characteristics for their 
potential effect on the implementation and effectiveness outcomes. 
IMPLEMENTATION 
ED characteristics such as size, location, existing addiction treatment services and follow up 
resources as well as the range and number of addiction treatment services in the catchment area 
of the ED will be evaluated. Provider characteristics such as age, gender, years and level of 
training will be evaluated . 
EFFECTIVENESS  
Patient characteristics such as type of opioid used (prescription vs. heroin) mode of use 
(IV/PO/intranasal), frequency of use, demographics, pain intensity and interference, and reason 
for ED presentation such as overdose, seeking treatment or visit related to substance use, 
comorbid substance use, and referral to office-based versus opioid treatment program treatment 
will be evaluated. The overall effectiveness of ED-initiated BUP compared with other interventions 
during both baseline and IF evaluation periods will be evaluated.  

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COST EFFECTIVENESS 
We will perform an incremental cost effectiveness analyses (CEA) and calculate the incremental 
cost per unit increase in engagement in formal addiction treatment comparing patients in the IF 
evaluation period with those in the baseline evaluation period.  
We will perform incremental cost effectiveness analyses (CEA) to evaluate if effectiveness 
benefits are worth the additional costs. 
 
 

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9.0 
STUDY PROCEDURES  
9.1 
Screening and Informed Consent Procedures Baseline and IF 
Evaluation Periods  
9.1.1 
Screening 
Patients will be recruited throughout the entire evaluation period at each ED site. Research 
Associates (RAs) assigned to the study will work in shifts to ensure cross coverage to screen all 
ED patients who are potentially eligible for the study. The RA will use the ED log to identify all 
patients seen in the ED and will eliminate patients with obvious exclusions such as under police 
custody. The RA will keep a log of all patients excluded and the reasons for exclusion. Patients 
will be evaluated by an RA for eligibility.  
Patients will be asked for verbal consent to complete a set of screening assessments starting with 
a screener that includes questions about illicit opioid use in the past 30 days embedded in a 
general health and substance use screener that also includes questions about safety, tobacco 
and alcohol use.25,26 We have successfully used this strategy of embedding questions about 
opioid use in a general health survey as a method to screen for drug and alcohol use. Embedded 
questions have also been noted by the World Health Organization to improve the reliability of self-
reported behavior. The screener will contain questions regarding heroin/fentanyl and non-medical 
use of prescription opioids (ED Health Quiz screener).  
Potential study patients who report any opioid use in the past month will complete a 7-day TLFB. 
If opioid use is reported during the past 7 days a brief (10 minute) structured diagnostic interview 
(DSM-5) to evaluate for the presence of moderate/severe OUD is administered. Potential study 
patients who do not meet criteria for moderate/severe OUD will not be asked to participate and 
will be given a handout recommending that they abstain from drug use and a list of local referral 
options at the discretion of their ED providers. Those who meet criteria for moderate/severe OUD 
will be informed that they may qualify for a study if they are willing to produce a urine sample If 
the urine tests are positive for any opioid (fentanyl only are not eligible), the patient indicates 
he/she is able to provide contact information for 2 reliable contacts and the patient meets all 
eligibility criteria on the Patient Participant Eligibility Summary form, patients will be offered 
participation and informed consent will be obtained. 
9.1.2 
Informed Consent Procedures (Patient Participants) 
We will use the Western Institutional Review Board (WIRB) as the IRB of record for the study and 
comply with all necessary requirements at each site. Each site will utilize the IRB-approved 
compound authorization form that serves as a combined informed consent and HIPAA disclosure 
form allowing study access to protected health information in the patient’s ED medical record. 
Because of the time constraints of completing the assessment and intervention in the ED, and 
because of the relatively low risks associated with the study, the informed consent form will be as 
brief as possible within the constraints of adequate human subjects’ protections. The compound 
authorization document will include a description of the following key elements including: the 
assessment interview and questionnaires; the follow-up interviews; risks and benefits of study 
procedures; alternatives to participation in the study; confidentiality; payment for participation; a 
statement that participation is voluntary and that they may freely withdraw participation at any 
time; and information about whom to contact with questions or in case of emergency. The form 
will also include assurances of confidentiality (including a Certificate of Confidentiality) and that 
the decision to participate will in no way influence other aspects of the patient’s treatment.  

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In addition, potential participants will be instructed concerning the importance of telling the truth 
and that compensation and continuation in the study has nothing to do with their drug use or test 
results. Initial screening questions will be asked with verbal consent, however, all eligible study 
patients will be asked for written consent to participate using the IRB-approved compound 
authorization form.  
9.1.3 
Eligibility Confirmation and Enrollment 
Once the eligibility is confirmed and written informed consent (compound authorization) is 
obtained from the study patient, he/she will be considered enrolled in the study. The enrollment 
procedures will be captured through a centralized process managed by the CTN Data and 
Statistics Center (DSC). Study patients who do not complete all screening assessments or who 
are otherwise found to be ineligible for participation in the study will be considered screen failures. 
Section 10.0 describes all study assessments.  
9.2 
Participant Withdrawal 
At any time, participants may decide that they no longer wish to continue to participate in the 
study.    
9.3 
Participant 30-day Follow-up Assessments 
Follow-up assessments are expected to be conducted at 30-days post study enrollment in-person 
by the ED study staff. Assessment of the effectiveness study outcome, enrollment in formal 
addiction treatment on the 30th day post enrollment will be based on direct contact with the 
treatment provider/program provided by the patient. Printed appointments for the follow-up will be 
given to the study patient participant prior to discharge. In addition, the RA will send a reminder 
in the mail/text/email/or social media (based on study participant preference) about 7 days prior 
to the scheduled follow-up visit with an additional reminder phone call the day before the 
scheduled follow-up visit.  
9.4 
Compensation 
Because of the expected difficulty of maintaining high follow-up rates in the study population, 
adequate compensation for time and inconvenience is critical. Compensation of $50 for 
completing the enrollment process at the initial ED visit, and $50 for the 30-day post enrollment 
follow-up visit. Follow up is expected to be conducted in person in the ED or at an offsite research 
location but may be completed as a telephone visit if a participant is unable to attend visit. A urine 
sample will not be collected if the visit is completed via telephone.   

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10.0 STUDY PATIENT ASSESSMENTS  
10.1 Baseline Evaluation and IF Evaluation Periods 
The screening and follow-up assessments for this study are brief balancing the value of 
comprehensive data against feasibility and to minimize assessment reactivity that can obscure 
treatment effects.27 The practical issue is that extensive study patient participant level 
assessments are likely to interfere with the rapid pace of clinical treatment in the ED setting. A 
cumbersome assessment process is also likely to impede the successful completion of the study 
through an adverse effect on recruitment, and would not be part of real world clinical practice. 
Excluding collection of study patient participant characteristics and locator information, the patient 
baseline data will include a brief instrument assessing health status, healthcare utilization, 
overdose events, past 7-day alcohol and drug use including opioids using the Time-line Follow 
Back (TLFB)28 method, use of other substances, the EuroQol (EQ-5D) and other cost data 
necessary to compare costs with the costs and benefits of other funded interventions. Table 2 
provides the schedule of study assessments. The total expected time burden for the screening 
assessments is less than 30 minutes. Assessments collected at 30 days post study enrollment 
will be similar. 
 

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10.1.1 Table 2: Schedule of Study Activities and Assessments (Study 
Patient) by Study Time Period 
Instrument/Activity 
Time 
Done 
by 
Baseline Evaluation Period 
(12 Months) 
IF     
(6 
Months) 
IF Evaluation Period     
(12 Months) 
Screening 
Enroll-
ment 
30 Day 
Follow-up 
Screening 
Enroll- 
ment 
30 Day 
Follow-
up 
(Index ED Visit 1) 
(Visit 2) 
(Index ED Visit 1) 
(Visit 2) 
ED Health Quiz 
2’ 
RA 
X 
 
 
 
X 
 
 
DSM-5 
5’ 
RA 
X 
 
 
 
X 
 
 
Urine Drug Screen  
5’ 
RA 
X 
 
 
 
X 
 
 
Patient Eligibility Summary 
2’ 
RA 
X 
 
 
 
X 
 
 
Written Compound Informed 
Consent  
10’ 
RA 
 
X 
 
 
 
X 
 
Demographics 
1’ 
RA 
 
X 
 
 
 
X 
 
and Additional Characteristics 
Locator Information form 
2’ 
RA 
 
X 
 
 
 
X 
 
Other Substance Use 
1’ 
RA 
 
X 
 
 
 
X 
 
Timeline Follow-Back (TLFB) 
10’ 
RA 
 
X 
X 
 
 
X 
X 
Health Services Utilization 
6’ 
RA 
 
X 
X 
 
 
X 
X 
(Inpatient and Outpatient) 
Health status (HRBS/PHQ9/PEG) 
3’ 
RA 
 
X 
X 
 
 
X 
X 
Overdose 
1’ 
RA 
 
X 
X 
 
 
X 
X 
EuroQol-5D  
2’ 
RA 
 
X 
X 
 
 
X 
X 
Crime and Criminal Justice 
1’ 
RA 
 
X 
X 
 
 
X 
X 
Urine Drug Screen 
5’ 
RA 
 
 
X 
 
 
 
X 
Healthcare Visit Logistics 
1’ 
RA 
 
 
X 
 
 
 
X 
Engagement in Treatment  
5’ 
RA 
 
 
X 
 
 
 
X 
ED Visit Review  
 
RA 
 
X 
 
 
 
X 
 
Critical Action Checklist 
 
RA* 
 
X 
 
 
 
X 
 
ED Visits and Hospitalizations 
 
RA 
 
 
X 
 
 
 
X 
Study Completion 
 
RA 
 
 
X 
 
 
 
X 
Serious Adverse Event (Death) 
 
RA 
As Needed 
 
As Needed 
Protocol Deviations 
 
RA 
As Needed 
 
As Needed 
Total Duration in Minutes for Participant 
Interaction: 
14’ 
37’ 
34’ 
 
14’ 
37’ 
34’ 
* Site staff, with PI input as needed.  
 
 
 

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10.2 Study Patient Participant Assessments  
10.2.1 ED Health Quiz 
Individuals will meet with an RA to be evaluated for study eligibility. This assessment will be 
conducted after verbal consent, and before enrollment into the study. It will include questions 
about illicit opioid use in the past 30 days embedded in a general health and substance use 
screener that also includes questions about safety, tobacco and alcohol use. 
10.2.2 DSM-5  
The DSM-5 criteria are assessed during the screening period to determine a current diagnosis of 
moderate or severe opioid use disorder. This assessment will be completed electronically and will 
be automatically scored.  
10.2.3 Urine Drug Screen (Toxicology Testing) 
Urine testing will be performed for the presence of the following drugs: opioids, oxycodone, 
benzodiazepines, 
cocaine, 
methamphetamine, 
amphetamine, 
3.4-methylenedioxy-
methamphetamine 
(MDMA), 
tetrahydrocannabinol 
(THC), 
barbiturate, 
methadone, 
buprenorphine and fentanyl. The urine drug screen is collected during the screening phase and 
at 30-days post study enrollment along with the other assessments. The fentanyl urine drug 
screen is being used for research purposes only. Urine testing supplies (e.g., dip stick) will be 
provided to the sites. 
10.2.4 Patient Eligibility Summary and Compound Informed Consent and 
Inclusion/Exclusion  
The Patient Eligibility Summary form collects information regarding eligibility during the screening 
phase, before written informed consent is obtained. After written compound informed consent, 
individual inclusion and exclusion criteria listed is assessed to confirm documentation of eligibility. 
Only patients who continue to meet study eligibility criteria will be allowed to continue to the 
enrollment phase.  
10.2.5 Demographics and Additional Characteristics  
The demographics forms collect information about demographic characteristics of the study 
participant, including age, gender, cultural/ethnic group, educational level, marital status, and type 
of insurance. 
10.2.6 Locator Information Form 
A locator form is used to obtain information to assist in finding study participants during the 
baseline evaluation and IF evaluation periods. This form collects contact information including 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 
family/friends who may know how to reach the participant are collected. This information will be 
collected at enrollment and updated at the follow-up visit, or when the participant reports a change 
in locator information. No information from this form will be used in data analyses.  
 

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10.2.7 Other Substance Use 
Selected questions from the ASSIST-lite will be used to assess severity of drug and alcohol 
problems over the past 3 months and will be asked at enrollment only. Questions related to opioid 
use have been eliminated to avoid duplication.  
10.2.8 Timeline Follow-back (TLFB)  
The Timeline Follow-back procedure (Sobell & Sobell, 199228; Fals-Stewart, 200034) will be used 
to elicit the patient participant’s self-reported use, quantity, and route of administration of opioids, 
marijuana, stimulants, benzodiazepines and alcohol. At enrollment, substance use is reported by 
the patient participant for the 7-day period prior to informed consent.28 At the 30 day follow-up 
visit, substance use is reported for the 7 days prior to study day 30. 
10.2.9 Health Services Utilization Inpatient and Health Services Utilization 
Outpatient 29 
A brief, structured interview regarding health care utilization (inpatient and outpatient) will be used, 
which collects information on the type and amount of services received. This includes ED visits, 
hospitalizations, primary medical care visits (excluding those for buprenorphine treatment and 
self-help sources of support (e.g., NA)). It is collected at enrollment and at 30 days post study 
enrollment. 
10.2.10 Health Status 
The Health Status form collects information on HIV and Hepatitis C status, HIV risk (CTN HRBS), 
Pain (PEG), and psychological health (PHQ-9)31 usual care and reason for ED visit. The HIV Risk-
taking Behaviour Scale (HRBS)32 is a brief, 12-item questionnaire measuring the behavior of 
people who inject drugs that puts them at risk of either contracting/transmitting HIV. Also 
embedded within is the Patient Health Questionnaire (PHQ-9)31 used to assess depressive 
symptoms. Health status questions are collected at enrollment and at 30 days post study 
enrollment.  
10.2.11 Overdose Events 
We will ask participants about past 30-day opioid-related overdose events.33 Assessment of past 
30-day overdose events will be completed at enrollment and at 30 days post study enrollment. In 
addition, Site PIs will search the National Death Index, and local electronic medical records for 
overdose events.  
10.2.12 EuroQol (EQ-5D)  
The EuroQol (EQ-5D)30 is a structured interview that collects general health information applicable 
to a wide range of health conditions and treatments, providing a simple descriptive profile and a 
single index value for health status. The EQ-5D is collected at enrollment and at 30 days post 
study enrollment.  
10.2.13 Crime and Criminal Justice 
This form captures data on incarceration, recent crimes, and recent contact with the law and is 
collected at enrollment and at 30 days post study enrollment. 

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10.2.14 Healthcare Visit Logistics 
The Healthcare Visit Logistics form asks cost data questions at 30 days post study enrollment. 
10.2.15 Engagement in Treatment Survey 
At 30 days post enrollment, participants will be asked to report OUD treatment received on their 
30th day post enrollment target date (Day 30, with the ED enrollment visit being Day 0). Data will 
be reported on the Engagement in Treatment: Patient Survey. The effectiveness outcome will be 
confirmed with the addiction treatment provider. Engagement is based on enrollment in treatment 
on the 30th day post enrollment (Enrollment is considered Day 0). The Engagement in Treatment: 
Facility survey includes the type of treatment the participant is receiving, i.e., methadone, 
buprenorphine and/or naltrexone treatment, detoxification, residential or inpatient treatment. Date 
of admission is recorded as well as the level of treatment received according to ASAM Levels of 
care, such as Level I: Outpatient Treatment; Level II: Intensive outpatient treatment (including 
partial hospitalization); Level III: Residential/Inpatient Treatment; Level IV: Medically managed 
intensive inpatient treatment or Other-specified. 
10.2.16 ED Visit Review  
The ED Visit Review (EDR) form collects information about study and clinical processes 
surrounding the index ED visit. It is completed by the Senior RA without patient input, in part by 
performing a medical record abstraction. EDR data may be independently reviewed for accuracy.   
10.2.17 Critical Action Checklist  
The critical action checklist provides documentation of best practices for ED-initiated 
buprenorphine including: urine toxicology and liver function tests obtained; patient participant 
meets criteria for DSM-5 moderate-severe opioid use disorder; urine positive for opioid; formal 
assessment of Clinical Opioid Withdrawal Scale (COWS) score; ED-initiated BUP provided; BUP 
education and induction instructions provided; and referral for ongoing medication assisted 
treatment. Data is acquired for this form by performing a medical record abstraction by a site staff 
member that is blinded to the index visit. 
10.2.18 ED Visits and Hospitalizations 
The ED Visits and Hospitalizations form collects information about the index ED visit and any 
visits or hospitalizations between the index and follow-up. Data is acquired for this form by 
performing a medical record abstraction.  
10.2.19 Study Completion  
The participant’s status with regard to study visits will be recorded at the end of the study, 
providing information on whether the participant completed the follow-up visit at day 30, and 
providing a location to document withdrawal of consent or other reasons for not completing the 
follow-up visit.   
10.2.20 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
All deaths, regardless of cause, will be captured for this study. These events may be identified 
when possible through using state medical examiner records, National Death Index, and review 

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of medical records. Appropriate information surrounding the event will be documented on the 
AE/SAE forms set. Only death events that occur within the 30 day follow-up period will be 
recorded on the AE/SAE form set. 
10.2.21 Protocol Deviation Form 
This form should be entered into the electronic data capture system whenever a protocol deviation 
occurs. This form will document a description of the deviation, how it occurred, the corrective 
action taken to resolve the specific deviation, as well as a description of the plan implemented to 
prevent future occurrences of similar deviations.   
  

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11.0 IMPLEMENTATION FACILITATION (IF) STUDY PROCEDURES  
11.1 Standard Dissemination Practice - Education  
A major goal of the current study is to determine whether an IF strategy increases the provision 
of ED-initiated BUP with referral for ongoing MAT. We will compare the uptake of ED-initiated 
BUP following a standard dissemination practice – provider education using a Grand Rounds-
style educational format provided at the beginning of the baseline evaluation period. 
To achieve this goal, we will arrange for a grand rounds presentation at each participating ED site 
during the institution’s usual Emergency Medicine teaching conference, during the start-up 2 
months at each site. Traditionally this is a 50-minute lecture with time for questions and 
comments. The content of the lecture will cover the scope of the opioid problem, ED specific facts 
related to the epidemic, potential models of intervention including the results of publications 
outlining the efficacy of ED-initiated BUP.7 We will ensure that results are presented regarding 
the 30 day outcomes of various strategies including referral, brief intervention and facilitated 
referral and ED-initiated BUP with referral for ongoing MAT in an office-based primary care 
setting.  
11.2 Implementation Facilitation 
IF activities will begin in the IF period and continue through the IF evaluation period. 
11.2.1 Overview of the Implementation Facilitation  
IF will be based on a manualized program developed by Kirchner and colleagues8 that has had 
significant impact on implementing healthcare practices in clinical settings. The LN will modify the 
Kirchner manual during the conduct of the study based on their facilitation experiences. Building 
on the mixed-methods analysis conducted during the formative evaluation, we will use the 
PARiHS framework to tailor the IF for site-specific needs. The facilitators and barriers identified 
by administrators, providers, and patients and will be characterized according to the PARiHS sub-
elements of patient and clinical experience (communication, knowledgeable and empathetic 
providers), receptive context (resources to provide addiction treatments), and culture (value of 
team-based approach) identified. As described below, PARiHS will be used to further explicate 
and design the IF, guide the ongoing formative evaluation, and revise the strategy in an iterative 
manner to improve implementation success. The individual components (Table 1) of IF are 
described below. 
11.2.2 Formative Evaluation 
We will conduct a three-stage formative evaluation using mixed-methods35 (qualitative and 
quantitative) to identify evidence, context, and facilitation-related factors impacting the 
provision of ED-initiated BUP with referral for ongoing MAT in the community and use these data 
to tailor, refine, monitor and evaluate the effectiveness of the IF. Given that formative evaluation 
techniques will be used during the IF period continuing into the IF evaluation period we will 
describe the methods in detail here and refer back to this section as needed. 
Formative evaluation is a widely accepted implementation assessment approach designed to 
identify influences on the development, progress and effectiveness of implementation efforts.19  

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To increase the rate of provision of ED-initiated BUP and referral for ongoing MAT, we will use 
this formative evaluation to understand:  
1. Site-specific practices  
2. Determinants of these practices  
3. Barriers and facilitators to practice change, and  
4. Perspectives regarding IF. Using the PARiHS framework, we will employ a mixed-methods 
approach with 1) quantitative methods, using the Organizational Readiness to Change 
Assessment modified to focus on ED initiation of BUP (ED ORCA)11 and Provider 
Readiness to Change scales, followed by 2) qualitative methods to develop an 
understanding of evidence, context and facilitation-related factors impacting the practice 
of ED-initiated BUP from the perspectives of diverse stakeholders including ED patients, 
nurses, social workers, physicians, NPs, PAs, pharmacists, and administrative directors 
(physician and nursing), and office-based physicians and OTPs representatives. We will 
provide feedback to all providers regarding the care of patients with OUD during the IF 
period. 
11.3 Quantitative Data Collection and Analysis 
The ORCA11 instrument is based on the PARiHS framework, to evaluate evidence, context and 
facilitation-related factors impacting implementation ED-initiated BUP and referral for ongoing 
MAT. The ORCA has been applied to the evaluation of interventions intended to promote 
evidence-based practices, including addiction treatment, and predicts implementation efforts.36-38 
Baseline ORCA, and provider readiness and preparedness scores will be used to determine 
evidence and context related strengths and weaknesses in organizational readiness to implement 
BUP and referral and to tailor the IF. Other process measurements will include the number of ED 
providers attending the initial educational session, participating in the BUP training courses, 
obtaining a DATA 2000 waiver, proportion of eligible patients receiving ED-initiated BUP, provider 
skill and adherence to critical actions on initiating BUP treatment with referral to ongoing MAT; 
and organization data including integration of materials into EHR and proportion of patients with 
ED-initiated BUP who are successfully linked to office-based BUP providers and/or OTPs. EHRs 
will be queried for each enrolling shift to determine potential ICD 10 codes identifying patients that 
were potentially eligible for ED-initiated treatment and/or referral.  
ED Organizational Readiness: We will use the ORCA with wording to reflect ED-initiated BUP to 
measure factors impacting the rates of ED-initiated BUP. This 5-minute survey is based on the 
PARiHS framework and asks the respondent to rate local factors related to evidence, context and 
facilitation on a 5-point Likert scale from strongly disagree to strongly agree. Facilitation questions 
will be omitted from the baseline assessment since this part of the intervention will not have taken 
place.  
Community Providers Organizational Readiness: We will use the ORCA to measure factors 
impacting the care of the study participants with ED-initiated BUP. This asks the respondent to 
rate local factors related to evidence, context and facilitation on a 5-point Likert scale from strongly 
disagree to strongly agree. Facilitation questions will be omitted from the baseline assessment 
since this part of the intervention will not have taken place. 
ED Provider Readiness and Preparedness: We will use change rulers, among appropriate 
providers, to assess readiness and preparedness to provide ED-initiated BUP.39 Stage of change 

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assessments have been validated and have been used in the field of addiction and mental health 
to assess readiness to adopt evidence-based treatments.40-43 
The change rulers will independently assess, on a 0-10 scale each provider’s:  
1. Readiness to provide the intervention  
2. Preparedness to provide the intervention  
Community Treatment Provider Readiness: We will use change rulers, among appropriate 
providers, to assess readiness and preparedness to provide care for study participants who have 
received ED-initiated BUP among office-based providers of BUP and representatives of OTPs.39  
The change rulers will independently assess, on a 0-10 scale each provider’s:  
1. Readiness to provide the intervention  
2. Preparedness to provide the intervention 
Readiness rulers will be completed at the beginning and end of the IF period and after the 12 
month IF evaluation period. ED and community provider ORCA assessments, including parts 1 
and 2 (evidence and context assessment), will be completed at the beginning of the IF period. An 
ORCA that includes a facilitation assessment will be administered at the end of the IF period and 
at the end of the IF evaluation period, 12 months later. All readiness rulers and ORCA documents 
will be administered as survey instruments to ED and community providers and staff.  
11.4 Qualitative Data Collection and Analysis  
At each of the four ED study sites, we will conduct focus groups with a purposeful sample of key 
stakeholders at multiple distinct stages of our project: during the first month of the IF period, 
approximately at the 4th-5th months of the IF period and nearing completion of the IF evaluation 
period. However, data collected during focus groups and during the formative evaluation is part 
of an iterative process, and therefore additional focus groups, one-on-one phone interviews and 
email correspondence take place as needed. Purposeful sampling is a well-established method 
in qualitative studies and is designed to identify study participants who have direct experience 
with or knowledge of the phenomenon of interest, in this case OUDs and ED-initiation of BUP with 
referral for ongoing MAT. We have chosen to use focus groups given their suitability for generating 
data from multiple perspectives regarding the organizational and individual level factors impacting 
complex processes whereby the group interaction is anticipated to stimulate unique ideas.35 We 
will enroll a variety of participants including ED patients, nurses, social workers, physicians, NPs, 
PAs, pharmacists, physician and nursing directors at each ED site and office-based BUP 
providers and representatives from OTPs to allow for evaluation of processes from multiple 
perspectives (triangulation). Focus groups will be conducted with approximately 4-8 study 
participants and representation from each of the stakeholder categories.44 We will conduct focus 
groups and utilize the Rapid Assessment Process,44 a type of participatory action research using 
intensive, team interaction and multiple cycles of data collection followed by data review and 
analysis. It is estimated that approximately 8-10 events will occur until themes begin to repeat. 
This process allows for results to be used for planning, monitoring and evaluating activities when 
prolonged fieldwork usually associated with traditional qualitative research is not possible. 
Recognizing our aggressive time schedule we will have ample time to schedule times early so 
that we are ready to conduct them immediately upon entry into the IF period.  

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11.5 Development of Focus Group Questions 
The focus group guides will be informed by the PARiHS framework and include “grand tour” 
questions designed to establish rapport and elicit open-ended responses. Probes will be used to 
understand specific details of those experiences and allow for clarification of ideas. We will design 
and pilot test these guides with study participants and key informants from the participating NIDA 
CTN nodes and refine as indicated. 
11.6 Verbal Consent for Focus Group Participants 
Focus group participants comprised of ED and Community providers, staff, and patient s will be 
provided with an IRB-approved verbal consent including all significant elements of the study. We 
will work with the EDs to provide staff assurances that their participation in the research will in no 
way affect their employment status either positively or negatively. Focus groups will be voluntary 
and information collected for research purposes will not become part of staff’s personnel records. 
The verbal consent for the ED and Community staff will outline these assurances. For the 
recording of the focus group sessions, participants will be made aware during the verbal consent 
process that the sessions will be digitally recorded and, for patient s, that the nature of these sessions 
will involve participants speaking about information regarding their health status and opioid use.  
Focus group participants will also be made aware that they will complete a brief demographic survey.   
11.7 Conduct of Focus Groups 
Trained and qualified personnel will conduct focus groups at each ED site during the IF period 
and the IF evaluation period. The focus groups will be recorded and professionally transcribed for 
qualitative analysis. Study participants will also complete a brief demographic survey. Using 
directed content analysis49, we will analyze the data with a multi-disciplinary group with 
experience in qualitative methods, which will include Addiction Medicine physicians, ED 
Physician, and a health service researcher. Data will be entered into and organized using Atlas.ti 
software, or something comparable.  
We will share our results with study participants (participant confirmation) to ensure that we have 
accurately understood and represented stakeholder’s perspectives and experiences. Consistent 
with prior studies, we will plan to generate a summary of the findings to share with participants 
via email and conference calls for their feedback. We will use data reduction strategies to sharpen, 
sort, focus, discard and organize data in a way to draw inferences regarding the implementation 
interventions in place at each ED site. These data will directly inform the site-specific IF and be 
used to evaluate the facilitation process and outcomes. This will be an iterative process. We will 
develop a template summary of data at each ED organized by evidence, context and facilitation-
related factors. At the completion of all 4 ED sites IF periods we will create a matrix across all 
sites and respondents to understand the major issues with regard to implementation across sites 
that can be disseminated to the Emergency Medicine community.  

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11.8 Administration of BUP During IF Evaluation Period  
The following procedures will be incorporated into the training of ED providers during the IF period. 
We will assess fidelity to the procedures (adherence) using a critical action checklist. The checklist 
will include confirmation of documentation of: urine toxicology and liver function tests obtained; 
patient participant meets criteria for DSM-5 moderate-severe opioid use disorder; urine positive 
for opioid; formal assessment of Clinical Opioid Withdrawal Scale (COWS); ED-initiated BUP 
provided; BUP education and induction instructions provided; and referral for ongoing medication 
assisted treatment. Education regarding BUP and Induction is provided; and Appointment for 
ongoing MAT provided. Providers will be instructed to induce patients onto BUP using an 
induction and stabilization protocol that has been well tolerated by patients in our previous study.7 
Buprenorphine induction will take place in the ED or unobserved, and should be based on the 
study patient’s level of opioid withdrawal as measured by the COWS. Depending on the study 
patient’s level of physical dependence, the goal of the induction will be 8mg on the first day and 
16mg on subsequent days. Study patients will receive a dose in the ED if they exhibit moderate 
to severe withdrawal on the COWS and will leave with a prescription for the daily doses needed 
prior to their scheduled follow-up appointment, and their significant others, will be provided with 
instructions for unobserved induction if their COWS score indicates less than mild withdrawal 
(Mild 5-12) at the time of the ED visit. Unobserved induction has become common practice50 and 
was used successfully in our prior study of ED-initiated BUP. Unobserved induction will also have 
a goal of 8mg on the first day. In an effort to maximize retention and abstinence achievement 
during the induction we will instruct ED providers to provide study patients with a scheduled 
appointment for follow up with an office-based BUP provider or an OTP within 96 hours of their 
ED visit.  
11.9 Referral for Continuation of MAT 
1. Baseline evaluation period: participants will be referred based on existing clinical practice 
at each site. The study will not inform practice. 
2. IF and IF evaluation period: During the IF, linkages will be established with all community 
stakeholders offering MAT including office-based providers of BUP and OTPs. Referral 
options will be offered according to insurance status, study patient preferences and 
availability.  
11.10 Additional Components of Implementation Facilitation 
EXTERNAL FACILITATORS 
IF involves external facilitators working with local champions to facilitate multiple inter-related 
interventions designed to promote implementation of the evidence-based clinical practice tailored 
to the clinic specific needs and applied as needed over the course of the study protocol. The 
external facilitators in the current study assisted by trained and qualified personnel are expected 
to be a content experts who possesses superior communication and interpersonal skills and 
flexibility who will provide training, coach and mentor local champions, and encourage the 
exchange of ideas within and among sites.  
LOCAL CHAMPIONS 
The external facilitators in collaboration with trained and qualified personnel will spend the 
baseline phase of the project working with the local site PIs to identify local champions related to 
the ED and to community opioid treatment providers and programs. It is essential that local ED 

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champions work clinically in the ED and are seen as opinion leaders by the staff. The local 
champion(s) will be a respected physician(s) with a self-declared interest in treatment of OUD 
who expresses interest in promoting ED-initiated BUP with referral for ongoing MAT.51 Following 
an in-person orientation and trainings the external facilitators in collaboration with trained and 
qualified personnel will provide external facilitation including bimonthly phone meetings for the 
duration of the IF. The Project Director or designee will take notes during these meetings, 
capturing information on challenges, barriers, facilitators and strategies. This information will be 
integrated into the formative evaluation, described in section 11.0. 
PROVIDER EDUCATION AND ACADEMIC DETAILING  
Academic detailing involves trained clinician consultants visiting other clinicians to share unbiased 
information about patient assessment and treatment with the goal of improving quality of care.8 
All providers involved in the implementation will be offered dedicated educational sessions on 
OUD and provision of BUP training, specifically tailored to each provider’s tasks based on the 
initial formative evaluation and potentially modify, remove or add strategies to enhance 
implementation.  
We will address practical issues such as efficient use of the electronic medical record for prompts, 
easily available procedures and check lists such as DSM-5 criteria for moderate/severe 
dependence, the COWS to determine whether BUP can be administered at the time of visit or as 
a take home, follow up procedures for appointments and patient monitoring strategies by ED 
follow up nurses, etc. We will share protocols for integration that have been developed at the 
Yale-New Haven Hospital and elsewhere. The external facilitators in collaboration with trained 
and qualified personnel will be primarily responsible for providing the content or identifying local 
site content experts who can deliver interactive training sessions. Training strategies will be based 
on adult learning theory and include didactic presentations on the effectiveness and safety of 
prescribing BUP and skill’s based practice sessions. These sessions will focus on small group 
activities to promote the education of providers regarding the use of Motivational Interviewing 
(MI), brief interventions, and medication.  
We will focus on frequent brief presentations at regular scheduled provider meetings and 
educational offerings such as faculty meetings, during the routine weekly educational lectures, 
simulation sessions and retreats. We will provide meals/refreshments at trainings and tools and 
web-based resources such as pcssmat.org. We will offer opportunities and facilitate completing 
the DATA 2000 waiver for BUP prescribing. In addition, we will use the faculty/other provider list 
serves to provide continual information and feedback.  
STAKEHOLDER ENGAGEMENT 
Stakeholder Engagement will take place at the administrative, provider, and patient levels. Efforts 
at increasing engagement will be informed by the focus groups conducted during the initial 
formative evaluation and supported by the efforts of the local champions. This work will be 
informed by the Normalization Process Model52 whereby the external facilitators will work to have 
the screening, diagnosis and practices associated with OUDs embedded into the everyday ED 
processes. Thus, normalizing the care into everyday real world practice.  
TAILORING THE PROGRAM TO LOCAL SITE 
Tailoring the Program to Local Site will occur as a result of the formative evaluations and will be 
informed by local site PIs and local champions. 

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PERFORMANCE MONITORING AND FEEDBACK 
This will involve regular assessment of individual clinician performance and providing information 
about that performance.8 We will work with ED directors and other members of the ED staff to 
identify the optimal outcomes to be tracked as well as how often and in what format feedback will 
be provided based on ED and provider-level data. Outcomes will include the rate of BUP 
prescribed for eligible patients and follow up information regarding the patient’s enrollment in 
treatment as well as individual provider adherence to critical actions on a checklist for prescribing 
BUP. These continual improvement activities will be integrated into the department’s continuous 
quality improvement and feedback initiatives, similar to other clinical quality and safety measures 
such as door to balloon times used for patients who present to the ED with acute coronary 
syndromes. Emergency providers are accustomed to receiving daily operating reports such as 
patient length of stay, door to doctor and time to decision making. It is part of their world, and this 
will be integrated into their processes. The external facilitators in collaboration with trained and 
qualified personnel will provide additional training or educational booster sessions for sites with 
low implementation and those requesting such services. 
FORMATIVE EVALUATION  
a) Implementation-focused formative evaluation will occur during the implementation and 
focus on the discrepancies between the implementation plan and its operationalization. 
Examples of processes that will be examined include: 1) number and types of educational 
training sessions attended by staff, 2) number of staff who view the audit and feedback 
reports, and 3) number of champions that attend facilitation meetings. 
b) Progress-focused formative evaluation meetings, led by trained and qualified 
personnel, will monitor achievement of implementation goals and performance targets to 
identify blocked progress, allowing steps to be taken to optimize the intervention. These 
meetings will focus on barriers and strategies to address identified barriers. Non-
attendance of site participants will be documented and outreach through individual 
facilitation meetings, calls or emails will be initiated to assess for stalled progress and offer 
assistance.  
c) Interpretive formative evaluation uses the data collected from the other formative 
evaluations and information collected at the end of the project regarding the participant 
experiences to clarify the meaning of successful or failed implementation and to enhance 
understanding of IF’s impact. At the conclusion of the IF evaluation period (12 months), 
we will conduct an interpretive evaluation that will assess stakeholder views regarding (a) 
value of ED-initiated BUP with referral for ongoing MAT, (b) satisfaction or dissatisfaction 
with various aspects of IF, (c) reasons for ED level action or inaction with respect to ED-
initiated BUP with referral for ongoing MAT, (d) additional barriers and facilitators, and (e) 
recommendations for further refinements. Information will also assess stakeholders’ 
beliefs regarding IF’s success and overall ‘‘worth’’.19  
LEARNING COLLABORATIVE 
A Learning Collaborative will be formed by inviting each of the sites’ local champions, and other 
key stakeholders, to participate in monthly calls to promote shared learning regarding issues 
promoting and hindering implementation of addiction treatment. The local champions and key 
stakeholders will set the agenda and the calls will be facilitated by the external facilitators, in 
collaboration with trained and qualified personnel,  and provide a dedicated time to discuss site-
specific updates, challenges and possible solutions for implementation of addiction services. In 
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developed for use by all sites starting at the beginning of their IF phase. The external facilitators 
will make resources, protocol templates, materials and presentations available through the CTNs 
and ED professional organizations and other websites so they will be widely accessible at the end 
of the project.  
PROGRAM MARKETING 
Program Marketing will be conducted to promote awareness of the ED-initiated BUP clinical 
practice among all emergency providers and other ED providers, patients and community 
physician ED referrals, once we have completed the IF period in each site. The goal of the 
marketing will be to promote ED-initiated BUP with referral for ongoing MAT, and designed to 
initiate a motivational discussion between patients and providers. The ultimate marketing 
approach will be tailored to the needs of the stakeholders and include direct (e.g., “in-services” to 
discuss the treatment services and referral processes, flyers) and indirect (e.g., informal 
conversation) approaches. We will work with ED leaders and community based providers and 
programs to sustain all projects and spread the learning to other spokes related to the institutions, 
including newsletters, etc.  
11.11 Provider Intervention to Enhance Motivation for Treatment 
We will conduct skills based workshops open to all providers in the ED in an effort to motivate 
patients to accept a referral using our previous published brief intervention for severe opioid use 
disorder.54 This intervention uses the principles of MI and is adapted from our work with hazardous 
and harmful alcohol use.55,56 The active components involve: (1) Establishing rapport by asking 
permission to discuss the patient’s opioid use (2) Providing feedback, including stating concern 
for their drug use, and offering education regarding the use of medication-assisted treatment, 
such as BUP, and any harm reduction strategies; (3) Enhancing motivation by asking the patient 
how ready he/she is to accept a referral on a scale from 1-10, 1 being not ready at all and 10 
being completely ready. If the patient chooses a number between 2-10, then we ask why he/she 
did not choose a lower number which in essence asks them why he/she wants to change. We 
then use reflective listening to elicit motivational statements for acceptance of a referral to a 
treatment program. During the training, we will use real case scenarios that were collected from 
our previous study. In addition to the skills based workshop we will provide access to our web-
based, training program www.yale.edu/sbirt, Coach Vicky, which provides case-based practice of 
this 4-step brief intervention with a virtual patient with alcohol problems.54 

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12.0 STATISTICAL ANALYSES 
This study aims to test two complementary hypotheses: 
1. Implementation outcome: Across the entire study cohort, there will be a higher proportion 
of patients receiving ED-initiated BUP with referral for ongoing MAT in the IF evaluation 
period than in the baseline evaluation period. 
2. Effectiveness outcome: Across the entire study cohort, there will be a higher proportion of 
patients engaged in formal addiction treatment on the 30th day post enrollment in the IF 
evaluation period than in the baseline evaluation period. 
12.1 Definition of the Primary Effectiveness Outcome 
The primary effectiveness outcome measure is based on a binary variable reflecting engagement 
in addiction treatment on the 30th day post enrollment. Engagement in addiction treatment will be 
defined as enrollment and receiving formal addiction treatment on the 30th day post enrolment, 
assessed by direct contact with the facility and/or treating clinician. Formal addiction treatment 
will be those treatments consistent with the American Society of Addiction Medicine’s levels of 
care (1-4), and will include a range of clinical settings including office-based providers of BUP or 
naltrexone, OTPs, intensive outpatient, inpatient, or residential treatments.  
12.2 Definition of the Primary Implementation Outcome 
The primary implementation measure is based on a binary variable reflecting ED provider 
documentation of ED-initiated BUP with referral for ongoing MAT in the EHR as accessed by the 
RA.  
12.3 Experimental Design 
The experimental design will be a modified stepped wedge, as shown in Figure 2. The proposed 
study will be conducted at 4 ED sites, with a randomized order of when each site starts the 
protocol. Resource limitations preclude the use of more than 4 sites. At each of the study sites, 
approximately 25-30 of diverse ED providers will be engaged in the IF activities and evaluation 
research. The proposed sequence of baseline evaluation, IF and subsequent IF evaluation 
activities will take approximately 30-33 months at each site. Site selection criteria (e.g., a large 
prevalence of patients with OUD, population representative of US population, with sufficient 
referral networks for patients needing formal addiction treatment) will ensure the feasibility of 
providing the planned implementation research and generalizability of the study findings.  
We plan to enroll a minimum of 240 (~120 during both the baseline evaluation period and IF 
evaluation periods = 240) patients with moderate/severe OUD at each of the 4 study sites, or 
approximately 960 patients total. The adequacy of this sample size to grant sufficient power for 
the two alternative hypotheses is discussed below. Enrollment will be monitored to ensure 
balance between the two enrollment periods at each site. 

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12.4 Recruitment and Enrollment  
Patients with untreated moderate/severe OUD comprise in general less than 2% of the overall 
ED patient population. In our prior work conducted at a large inner city ED (Yale-New Haven 
Hospital), within 39 months we screened 71,742 patients to identify approximately 1200 patients 
with recent illicit opioid use. We estimate that each of the study sites will have an approximate 
volume of 5000 to 7000 ED patients per month, and will be able to enroll 10-12 study participants 
with moderate/severe OUD per month during the two 12-month enrollment periods.  
12.5 Hypothesized Treatment Effect Sizes 
We anticipate that during the baseline evaluation period, the rates of ED-initiated BUP treatment 
for OUD (primary implementation outcome) will be very low at each of the study sites (less than 
15% of all eligible patients). Based on our prior work and other published research, we estimate 
that the rates of participation in a formal addiction treatment on the 30th day post enrollment 
(effectiveness outcome) will be approximately 25% for patients with OUD enrolled in the baseline 
evaluation period.  
We anticipate that during the IF evaluation period, at each of the study sites, at least 25% of all 
eligible patients with OUD will receive ED-initiated BUP with referral for ongoing MAT. Based on 
our prior research, we also anticipate that approximately 40-50% of patients with OUD enrolled 
during the IF evaluation period will be engaged in formal addiction treatments at 30 days. The 
expected treatment effects of this section are summarized in Table 3 below. 
12.5.1 Table 3: Hypothesized Probabilities of Success 
Outcome 
Baseline Evaluation Period 
IF Evaluation Period 
Implementation 
< 15% 
25% 
Effectiveness 
25% 
40-50% 
12.6 Power Analyses to Justify Sample Size 
The power simulation to assess the adequacy of the sample size followed the method of Parzen57 
to simulate many vectors of (0,1) random variates with specified probabilities, a specified positive 
intraclass correlation (ICC) 𝜌𝜌, and assuming 240 patients enrolled at each of the 4 sites. The first 
120 elements of each vector all had a common probability 𝑝𝑝1, while the second 120 elements had 
a common probability 𝑝𝑝2, where (𝑝𝑝1, 𝑝𝑝2) are assumed probabilities of success in the baseline and 
IF evaluation periods, respectively. Each vector thus specifies in its first half a site’s outcomes in 
the baseline evaluation period, while in the second half it specifies outcomes in the IF evaluation 
period. Four such vectors (one for each site) comprised the data for a single iteration of the 
simulation. Each element in each vector was assigned a month using the Study Timeline, shown 
in Figure 21. (However, month by itself played no role in determining the probability of success of 
 
1 Treatment assignment is partially confounded with time of enrollment in the proposed design. If scheduling does not 
go the way it is supposed to (e.g., if site 1 IF period onset is delayed by 3 weeks), confounding will be complete. 

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any vector elements.) For each setting of the parameters (𝑝𝑝1, 𝑝𝑝2, 𝜌𝜌), we generated 10,000 
replicates (that is, 40,000 vectors) for simulation analysis. 
The Stepped-Wedge model described in section 12.14.1 was used to analyze simulated data. 
Simulated power was taken to be the proportion of the 10,000 glimmix runs that had a significant 
type 3 p-value for arm (in this document the baseline and IF evaluation periods are referred to as 
“arms”) at level 0.05, one-tailed. There is no attempt to control for type I error across these two 
outcomes. 
We simulated power for four parameter sets (scenarios), under both alternative and null 
hypotheses as indicated in Table 4. 
12.6.1 Table 4: Scenarios Used to Simulate Power 
Scenario 
Hypothesis 
P1 (Baseline) 
P2 (IF) 
Implementation outcome with low p1 
Alt 
0.05 
0.25 
Implementation outcome with high p1 
Alt 
0.15 
0.25 
Efficacy outcome with low p2 
Alt 
0.25 
0.40 
Efficacy outcome with high p2 
Alt 
0.25 
0.50 
Implementation outcome with low p1 
Null 
0.05 
0.05 
Implementation outcome with high p1 
Null 
0.15 
0.15 
Efficacy outcome  
Null 
0.25 
0.25 
12.7 Potential for Sites to have Baseline Probability of 0 for Primary 
 Implementation Outcome  
We inspected the power under these scenarios in Table 4 as a function of an assumed ICC. 
Except for the “Implementation outcome with low p1” scenario, which had very low baseline 
probability, the power curves (not shown) exhibit the check-mark shape (i.e., power that first 
decreases, then increases as ICC gets larger), typical of Stepped Wedge design power curves2. 
However, the “Implementation outcome with low p1” scenario power curve declines steadily as 
ICC increases. Extensive further simulations (also not shown) suggested that the declining power 
curve of the “Implementation outcome with low p1” was due to the fact that, when ICC is large 
and baseline probability is low, there are many sites with all-zero data at baseline. Although data 
sets with this property generally converge, they often have nonpositive definite estimated G 
matrices. The G matrix contains the estimated covariance parameters. For the simulations under 
discussion, this means that the estimated variance of the site random effect is zero. According to 
SAS documentation, if the G matrix is not positive definite, there is not enough variation in the 
response to attribute any variation to the random effect, while controlling for other factors in the 
model. Although there is nothing inherently wrong with the results when this occurs, one approach 
is to remove the corresponding random effect from the model. One of the advantages of using 
SAS procedures GLIMMIX or PROC MIXED is that the same answers result with or without the 
zeroed term in the RANDOM statement. (We confirmed that removing the site random effect from 
the model when it is estimated to be zero does not change the p-value of the treatment effect.) 
 
2 The check-mark shape is presumably due to the two sources of power in Stepped Wedge designs: across-site 
comparisons and within-site comparisons. The latter contributes more to power when the ICC is high. 

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This issue suggests that low baseline probability, when coupled with high ICC, increases the rate 
of non-positive-definite G matrices in GLIMMIX, and this, while not causing GLIMMIX to actually 
fail, apparently degrades power. 
Because in this study it is likely the implementation outcome will have a low probability in the 
baseline evaluation period coupled with a large ICC, other analytical methods were identified that 
had better power characteristics than the Glimmix approach outlined above. One method is to 
substitute historical data for the relevant site(s) for the data in the “all zeros” arm. Problems with 
this approach are (1) there is no guarantee that the historical data will not be “all zeros”, and (2) 
it is difficult to simulate the effect of this policy beforehand. Below we show two other potential 
solutions: (1) the “ChangeToOne” policy and (2) Bayesian analysis. 
We present graphs showing behavior of proposed analysis methods under various scenarios. For 
the convenience of the reader, Table 5 lists in one place the graphs and their content. Figures 
with a “B” concern Bayesian analyses and are presented and discussed in the Appendix Bayesian 
Analysis. Terms displayed in Table 5 are clarified in the text. 
12.7.1 Table 5: List of Figures and their Contents for the Power Analysis 
Figure 
Method 
Hypothesis 
Measure Displayed 
2 
ChangeToOne 
Alt 
Power 
3 
ChangeToOne 
Alt 
Conf intervals for p1, p2 
4 
ChangeToOne 
Null 
Test size 
5 
ChangeToOne 
Null 
Conf intervals for p1, p2 
B5 
Bayes 
Alt 
Power 
B6 
Bayes 
Alt 
Cred intervals for p1, p2 
B7 
Bayes 
Alt 
Cred intervals for p1-p2 
B8 
Bayes 
Null 
Test size 
B9 
Bayes 
Null 
Cred intervals for p1, p2 
B10 
Bayes 
Null 
Cred intervals for p1-p2 
 
12.8 ChangeToOne Approach 
Under the ChangeToOne policy, if a particular site-arm has "all zeros" data (that is, if all results 
for that site are zero in either the baseline or IF evaluation period), a randomly-chosen one of the 
zeros is turned into a one. It is hoped that moving the data back from the edge of the outcome 
space will spare the analysis method from having to deal with phenomena such as estimated 
variances of zero. Note that, under the alternative that the control arm has a lower success 
probability than the treated arm, this change will tend to move the arms closer together, and thus 
can be considered conservative. This rather naïve approach actually turns out to have a 
surprisingly beneficial effect on “Implementation Outcome with low p1”, without appreciably 

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changing power for the other scenarios (in which the probability of an “all zero” site-arm is very 
low, so the “change” policy has an effect only seldom). 
Figure 2 shows power as a function of ICC for the 4 “Alt” scenarios of Table 4. A horizontal 
reference line at 0.8 (80% power) separates the (0.05, 0.25 – Implementation Outcome with low 
p1) and (0.25, 0.50 – Efficacy Outcome with high p2) scenarios from the other two, which have 
low power. The rate of convergence failure was very low in these simulations: considerably less 
than 1% for each scenario (not shown). Each data point in Figure 1 is labeled with the rate of non-
zero variance estimates. This is low when the ICC = 0 (in which case the variance of the site 
random effect is actually zero), but fairly high elsewhere. 
12.8.1 Figure 2: ChangeToOne Power Analysis; Alternative Cases 
 
We use LSMEANS to aid intuition concerning the precision to expect from these analyses. For 
the current application, the LSMEAN statement estimates, for each arm separately, the probability 
of success at the average time (roughly month 22). More specifically, this is a transform of a linear 
combination of the fixed effects. Random site effects are taken into account (via the variance of 
the estimated betas) when calculating confidence limits. Figure 3 shows the estimated probability, 
with 95% confidence intervals, for the baseline arm (black solid) and the IF arm (red dashed). The 
point estimates and confidence limits are averaged across the iterations of the simulation. 
Increasing ICC widens the confidence intervals considerably. 

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12.8.2 Figure 3: ChangeToOne Confidence Intervals for p1, p2; Alternative 
Cases 
 
Figure 4 gives simulated test size (i.e. under the null hypothesis) at 𝛼𝛼= 0.05, 1-tailed for the last 
3 scenarios of Table 4, calculated on the basis of 10,000 iterations. A horizontal reference line 
marks 0.05, and the Y-axis scale goes from 0 to 0.1. Test sizes are tolerable, if not perfect. 
12.8.3 Figure 4: “ChangeToOne” test size; Null Cases 
 
 
 
Figure 5 gives LSMEAN estimates of the probabilities of success in the “null” scenarios of Table 
4. As expected, the two arms agree as to success probabilities in this case. Again, increasing ICC 
widens the confidence intervals. 

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12.8.4 Figure 5: “ChangeToOne” Confidence Intervals, p1, p2; Null Cases 
 
12.9 Bayesian Approach 
We also considered a Bayesian approach, which has its own attractions and drawbacks. We detail 
these in an Appendix Bayesian Analysis. We propose to use the “ChangeToOne” approach for 
the primary analysis, and relegate the Bayesian approach to a secondary supporting analysis that 
we do not discuss here. 
12.9.1 Summary of Power Simulations 
Under the most optimistic scenarios investigated (Implementation Outcome with low p1 and 
Efficacy Outcome with high p2) and ICC < 0.3 (and perhaps higher), power for the envisioned 
design exceeds 0.8 under the ChangeToOne policy and Bayesian approach. Other scenarios 
featuring less separation between groups have lower power. 
Having sites with “all zeros” in the baseline arm degrades power if you take no corrective action. 
The “ChangeToOne” policy seems a simple and attractive remedy. 
A Bayesian approach with diffuse priors leads to conclusions similar to those from the 
ChangeToOne policy (see Appendix Bayesian Analysis). 
Except for the credibility intervals for 𝑝𝑝2 −𝑝𝑝1, increasing ICC degrades precision. 
12.10 Missing Data 
Patients lost to follow-up will not be counted as successes for either primary outcome, and, 
because counted as failures, will not generate missing data. Accordingly, we ignore the possibility 

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of loss to follow-up in the power calculations, and will assume that losses are failures for the 
purposes of the actual data analysis. 
Several strategies will be implemented to minimize the likelihood and the rate of potential missing 
data in the proposed study. Timely data entry combined with frequent, planned, and scheduled 
evaluation of data completeness reports will trigger protocols for tracking and obtaining missing 
data. In our previous research, we developed patient tracking and communication protocols that 
resulted in very low rates of missing data. These filed tested procedures with proven 
effectiveness, with the necessary site specific adjustments, will be disseminated across all study 
sites. 
12.11 Controlling Type 1 Error in Primary Analyses 
In this study, we have defined two primary aims, one for implementation and one for efficacy. As 
this study is designed as a Hybrid Type 3 Effectiveness-Implementation study, the implementation 
is the main outcome, and so when measuring success of the study, the implementation outcome 
will take precedent over the effectiveness outcome, which will be considered secondary. 
Therefore, considering the effectiveness aim as secondary, it is not necessary to put in 
procedures to control the type 1 error across multiple outcomes. We also do not anticipate 
multiple-comparison adjustments when performing secondary analyses, but instead will be 
mindful of the multiple testing problem, thus report secondary findings as noteworthy hypothesis-
generating results only when their p-values are considerably smaller than 0.05. 
12.12 Interim Monitoring 
No interim looks at primary or secondary outcomes are planned for this study. However, a power 
and sample size recalculation will be performed based on the primary outcome rates and 
enrollment rates observed in the baseline evaluation period. The power and sample size 
recalculation will be done no earlier than the end of the first site’s baseline evaluation period. 
12.13 Planned Secondary Analyses 
We plan to perform the following secondary analyses: 
Implementation Outcomes to compare the baseline evaluation and IF evaluation periods. 
• 
Fidelity to a critical action checklist relating to the provision of ED-initiated BUP with 
referral for ongoing MAT in eligible patients  
• 
Rates of enrolled patients with OUD receiving an appointment for opioid treatment 
provider/program upon ED discharge 
• 
Number of ED providers receiving DATA 2000 training  
• 
Number of clinicians providing ED-initiated BUP with referral for ongoing MAT 
• 
ED provider readiness and preparedness ruler scores to initiate BUP and provide referral 
for ongoing MAT  
• 
ED Organizational Readiness to Change Assessment (ORCA) scores relating to ED-
initiated BUP with referral for ongoing MAT 

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• 
Community opioid treatment provider/program readiness and preparedness ruler scores 
to continue MAT for patients with OUD who have received ED-initiated BUP 
• 
Community opioid treatment provider/program Organizational Readiness to Change 
Assessment (ORCA) scores relating to receiving patients with OUD who have received 
ED-initiated BUP. 
Effectiveness Outcomes to compare the baseline evaluation and IF evaluation periods: 
• 
Self-reported days of illicit opioid use (past 7-days) as measured by TLFB methods at 30 
days  
• 
Overdose events (past 30 days) captured by participant self-report, state medical 
examiner records, National Death Index and review of medical records.  
• 
HIV risk taking behaviors (past 30 days) as measured by HIV Risk Taking Behavior Score 
• 
Healthcare service utilization (past 30 days) measured by Health Services Utilization Form  
• 
Rates of illicit opioid negative urines at 30 days 
Data for the secondary implementation and effectiveness outcomes will be collected by trained 
RAs and using standardized assessment instruments (see Table 2) via face to face interviews 
with ED providers and patients with OUD enrolled in the proposed implementation research. The 
RAs will use tablet based software application to read questions and record responses directly to 
Advantage eClinical. Urine drug screen results will be obtained by testing urine samples using 
instant/rapid tests and entering the test result directly into Advantage eClinical via the tablet 
software application.  
12.14 Statistical Methods 
12.14.1 Primary Outcome Analysis 
The study primary outcome is the implementation outcome. This outcome is defined as the rate 
of ED-initiated BUP with referral for ongoing MAT. The following base model will be used to 
compare the IF evaluation period to the baseline evaluation period in regards to the rates of ED-
initiated BUP with referral for ongoing MAT. 
logit(𝒑𝒑𝒔𝒔𝒔𝒔) = 𝜶𝜶+ 𝜷𝜷𝒕𝒕𝒔𝒔𝒔𝒔+ 𝜸𝜸𝒇𝒇𝒔𝒔𝒔𝒔+ 𝒓𝒓𝒔𝒔 

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where: 
𝑝𝑝𝑠𝑠𝑠𝑠 is the probability of success of patient i at site s. 
𝑡𝑡𝑠𝑠𝑠𝑠 is the calendar time of enrollment of patient i at site s. In the simulations reported below, 
t is expressed in integer months. 
𝑓𝑓𝑠𝑠𝑠𝑠 is the indicator of whether patient i at site s is in the baseline (f=0) or IF (f=1) periods 
𝑟𝑟𝑠𝑠 is the random effect of site s, where 𝑟𝑟𝑠𝑠~𝑁𝑁(0, 𝜎𝜎) 
The following SAS code fragment estimates this model: 
proc glimmix data = simul method = quad; 
class arm (ref=”1”); 
model z / trials = arm month / dist = binomial link = logit solution; 
random intercept / subject = site; 
estimate "trt effect" arm 1 -1 / cl; 
lsmeans arm / cl ilink; 
run; 
 
In this model the γ estimate represents the estimated difference in the logit of the probability of 
success. The model will test a one-tailed hypothesis at a 0.05 level. The null and alternative 
hypotheses are: 
𝐻𝐻0: 𝛾𝛾= 0 
𝐻𝐻𝑎𝑎: 𝛾𝛾> 0. 
12.14.2 Effect Modification of Primary Analysis 
Several covariates may have an effect on the primary outcome. At a minimum, sex, race and 
ethnicity will be considered as covariates in the model. They will be entered into the model in a 
stepwise manner using a p-value cutoff of 0.05. The most complicated model with the three 
minimal covariates would be: 
logit(𝒑𝒑𝒔𝒔𝒔𝒔) = 𝜶𝜶+ 𝜷𝜷𝒕𝒕𝒔𝒔𝒔𝒔+ 𝜸𝜸𝒇𝒇𝒔𝒔𝒔𝒔+ 𝜽𝜽𝟏𝟏∗𝒔𝒔𝒔𝒔𝒔𝒔𝒔𝒔𝒔𝒔+ 𝜽𝜽𝟐𝟐∗𝒓𝒓𝒓𝒓𝒓𝒓𝒓𝒓𝒔𝒔𝒔𝒔+ 𝜽𝜽𝟑𝟑∗𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒔𝒔𝒔𝒔 
+ 𝜽𝜽𝟒𝟒∗𝒇𝒇𝒔𝒔𝒔𝒔∗𝒔𝒔𝒔𝒔𝒔𝒔𝒔𝒔𝒔𝒔+ 𝜽𝜽𝟓𝟓∗𝒇𝒇𝒔𝒔𝒔𝒔∗𝒓𝒓𝒓𝒓𝒓𝒓𝒓𝒓𝒔𝒔𝒔𝒔+ 𝜽𝜽𝟔𝟔∗𝒇𝒇𝒔𝒔𝒔𝒔∗𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒆𝒔𝒔𝒔𝒔+𝒓𝒓𝒔𝒔 
where sex, race and ethnicity are indicators for their respective variables. Additional appropriate 
covariates and parameters may also be considered in the above model. 
12.14.3 Secondary Implementation Outcomes 
• 
Fidelity (as measured by the check list score) to a critical action checklist relating to the 
provision of ED-initiated BUP with referral for ongoing MAT in eligible patients will be 
compared in the IF evaluation period to the baseline evaluation period. This will be done 
using standard models including mixed models, or other appropriate methodology. 

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• 
Rates of enrolled patients with OUD receiving an appointment for opioid treatment 
provider/program upon ED discharge. The IF evaluation period will be compared to the 
baseline evaluation period using the model described for the primary analysis in section 
12.14.1. 
• 
Number of ED providers receiving DATA 2000 training will be compared between IF 
evaluation period and baseline evaluation period using appropriate methodology. 
Permutation tests will be considered for this analysis.  
• 
Number of clinicians providing ED-initiated BUP with referral for ongoing MAT will be 
compared in the IF evaluation period to the baseline evaluation period using count models. 
Models considered will be Poisson, zero-inflated Poisson, negative binomial and zero-
inflated negative binomial. An offset will be considered for how long the provider has been 
trained.  
• 
ED provider readiness and preparedness ruler scores to initiate BUP and provide referral 
for ongoing MAT will be compared between IF evaluation period and baseline evaluation 
period. This will be done using standard models including mixed models or other 
appropriate methodology. If the data do not follow a Gaussian distribution a modified 
Wilcoxon test 58 will be used. 
• 
ED Organizational Readiness to Change Assessment (ORCA) scores relating to ED-
initiated BUP with referral for ongoing MAT will be compared between IF evaluation period 
and baseline evaluation period. This will be done using standard models including mixed 
models or other appropriate methodology. If the data do not follow a Gaussian distribution 
a modified Wilcoxon test will be used. 
• 
Community opioid treatment provider/program readiness and preparedness ruler scores 
to continue MAT for patients with OUD who have received ED-initiated BUP will be 
compared between IF evaluation period and baseline evaluation period. This will be done 
using standard models including mixed models or other appropriate methodology. If the 
data do not follow a Gaussian distribution a modified Wilcoxon test will be used. 
• 
Community opioid treatment provider/program Organizational Readiness to Change 
Assessment (ORCA) scores relating to receiving patients with OUD who have received 
ED-initiated Bup will be compared between IF evaluation period and baseline evaluation 
period. This will be done using standard models including mixed models or other 
appropriate methodology. If the data do not follow a Gaussian distribution a modified 
Wilcoxon test will be used. 
12.14.4 Effectiveness Outcomes 
• 
The primary effectiveness outcome is defined as the rates of patient engagement in formal 
addiction treatment on the 30th day post enrollment. The model described in section 
12.14.1 and 12.14.2 will be used to analyze this outcome. 
• 
Self-reported days of illicit opioid use (past 7-days) as measured by TLFB methods at 30 
days will be compared between IF evaluation period and baseline evaluation period using 
count models. Models considered will be Poisson, zero-inflated Poisson, negative 
binomial and zero-inflated negative binomial. 

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• 
Overdose events (past 30 days) captured by participant self-report, state medical 
examiner records, National Death Index and review of medical records will be compared 
using count models. Models considered will be Poisson, zero-inflated Poisson, negative 
binomial and zero-inflated negative binomial. An offset will be considered for how long a 
participant was in a given period if less than 30 days. 
• 
HIV risk taking behaviors (past 30 days) as measured by HIV Risk Taking Behavior Score 
will be compared between IF evaluation period and baseline evaluation period. This will 
be done using standard models such as mixed models or other appropriate methodology. 
If the data do not follow a Gaussian distribution a modified Wilcoxon test will be used. 
• 
Healthcare service utilization (past 30 days) measured by Health Services Utilization Form 
will be compared using count models. Models considered will be Poisson, zero-inflated 
Poisson, negative binomial and zero-inflated negative binomial. An offset will be 
considered for how long a participant was in a given period if less than 30 days. 
• 
Rates of illicit opioid negative urines at 30 days. The IF evaluation period will be compared 
to the baseline evaluation period using the model described for the primary analysis in 
section 12.14.1. 
For all secondary analyses, covariates such as sex, race and ethnicity will be considered if 
appropriate and feasible. Specifically, if model based approaches are used covariates will be 
considered. If non-parametric methods are used then the tests may be done at different covariate 
levels. 
12.15 Exploratory Analyses 
We will also evaluate a limited set of patient and provider characteristics for their potential effect 
on successful implementation and effectiveness outcomes. Study participant characteristics to be 
evaluated are: 
• 
Gender 
• 
Race/Ethnicity 
• 
Health insurance status 
• 
Age 
• 
Primary drug (heroin vs prescription opioids) 
• 
Reason for presentation such as seeking treatment for OUD or overdose 
• 
Referral to office-based BUP provider versus OTP 
• 
Pain Intensity and Interference (PEG scale)  
ED characteristics such as size, location, existing substance abuse services and follow up 
resources as well as the range and number of addiction treatment services in the catchment area 
of the ED will be described, as well as ED provider characteristics such as age, gender, years, 
and level of training will be evaluated.  

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These analyses will utilize similar models as for the primary analysis, the MIXED models 
procedure repeated measures and generalized estimating equations (GEE), or other appropriate 
regression, clustering, and factor analytical tools to evaluate potential impact of site factors and 
patient characteristics on the primary implementation outcome and effectiveness outcome.  
For cost effectiveness analyses, resource costs will include intervention costs incurred in the ED 
related to the studied intervention, (e.g., cost to provide ED-initiated BUP with referral for ongoing 
MAT, cost of buprenorphine), downstream medical costs and patient costs of treatment (e.g., 
time, transportation). Where relevant, we will convert duration of an activity to monetary values 
by multiplying by provider labor costs. The costs of all addiction and medical treatment (e.g., 
inpatient, outpatient, treatment center, medication) received by participants will be included in the 
cost calculations. This information will be collected by self-report through a health service 
utilization survey. Unit costs of substance abuse and medical treatment will come from the facility 
surveys or other published estimates.59 Medication costs will be calculated from the average 
wholesale price plus the dispensing fee. We will collect Medicare reimbursement rather than 
Medicaid or commercial insurance amounts for relevant services in the facility surveys because 
Medicare reimbursement is most likely to reflect marginal costs of service provision. Incremental 
cost effectiveness ratios will be calculated, defined as ΔC/ΔE, where ΔC is the difference in costs 
and ΔE is the difference in effectiveness between the baseline evaluation period and IF evaluation 
period. Effectiveness is narrowly defined to the primary outcome – engagement in formal 
addiction treatment. The drawback of incremental CEA is that because no outcome is 
comprehensive, analyses do not allow one to directly compare interventions with different 
outcome measures. Yet, policymakers may still value this information when choosing among 
competing programs. Researchers often use the outcome Quality Adjusted Life Years (QALYs) 
to enable comparisons across interventions. In the case of OUD, many of the benefits accrue to 
individuals other than the individual being treated and would not be captured in this metric making 
this outcome less appealing. Because health care costs are typically highly skewed, we will 
consider several cost estimation models. We will not include monetized values of societal 
outcomes (i.e., reduced criminal activity) because inclusion of these monetized values of these 
outcomes in the numerator of the cost effectiveness ratio would lead to double counting of these 
outcomes (e.g., their monetized value would be counted in the numerator and then counted again 
as the value of being abstinent in the denominator of the cost effectiveness ratios). We will not 
include training or research costs because these costs would not be incurred in standard care. 
Our primary outcome will be cost effectiveness acceptability curves, which indicate the probability 
different implementation strategies are cost effectiveness at different willingness to pay threshold 
values of the studied outcome. For cost estimates which are subject to debate either because of 
known imprecision in the estimation procedures or lack of adequate information, we will conduct 
sensitivity analyses with the goal of explaining the ways in which different assumptions would 
impact study results. 
We will use appropriate non-parametric, parametric, and analysis of variance statistical 
procedures to descriptively evaluate the key characteristics of each study site (e.g., patient flow 
indicators such as length of stay of treated and released patients, and demographic and drug use 
characteristics of patients with OUD presenting at each ED site, indicators of organizational level 
differences between the sites (e.g., the number ED providers, number/ratio ED providers DEA 
waivered to prescribe BUP), and to evaluate comparability of baseline characteristics among 
patient cohorts enrolled at each of the study sites and overall during baseline evaluation period 
and the IF evaluation periods across all sites.   

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13.0 TRAINING 
Study RAs: A detailed training plan will be developed as part of the study Manual of Operations 
(MOP). Training in study-specific procedures and assessments will be provided by the Yale 
Project Director and affiliated staff members. The training will be conducted via web based, and 
in-person training sessions.  
Provider: Qualified and trained personnel will provide training regarding ED-initiated BUP and 
ongoing community-based treatment for patient participants who have received ED-initiated BUP. 
Non-Study specific training: Training will cover standard NIDA training for all CTN studies (e.g., 
Good Clinical Practices (GCP) and Human Subject Protection (HSP)), as well as protocol specific 
training as needed (e.g., safety procedures, data management and collection). All site staff will 
complete required Human Subjects Protection and Good Clinical Practices (GCP) training. 
The training will include modules targeting all research team members conducted via web, 
telephone and in-person training sessions. All study staff will be required to complete any local 
training requirements per study site and IRBs. Further details are presented in the study Manual 
of Operations (MOP). 
 

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14.0 REPORTING AND MONITORING 
14.1 Statement of Compliance 
This study will be conducted in compliance with the appropriate protocol, current GCP, the 
principles of the Declaration of Helsinki, and all other applicable regulatory requirements. 
Participating sites must obtain written approval of the study protocol, consent form, other 
supporting documents, and any advertising for participant recruitment from the IRB of record for 
the study in order to participate in the study. Any amendments to the protocol or consent materials 
must be IRB approved before they are implemented. Annual progress reports and local Serious 
Adverse Event (SAE) reports will be submitted to the IRB of record for the study, according to its 
usual procedures. 
14.2 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 
the regulatory documents compliance prior to study initiation, throughout the study, as well as at 
the study closure. The CCC will collaborate with the sites to be sure that all sponsor required 
regulatory documents have been uploaded into the Regulatory Tracking System (RTS). 
14.3 Research Advisory Panel of California (California sites only)  
Prior to initiating the study, the sponsor will obtain written approval from the Research Advisory 
Panel of California (RAP-C). Any planned research project to be conducted in California requiring 
the use of a Schedule I or Schedule II Controlled Substance as its main study drug as well as 
research for the treatment of controlled substance addiction or abuse utilizing any drug, scheduled 
or not (SAT) must be submitted to RAP-C for review and approval prior to study start-up. Study 
approval is based on review of the study protocol, consent form, and other pertinent study 
documents. Yearly reports will be provided to the RAP-C in order to obtain continuing study 
approval. 
14.4 Informed Consent 
An IRB waiver for written consent and instead elicit verbal consent to conduct all screening 
procedures to determine eligibility was approved by the IRB of record.  
An IRB waiver for written consent and instead elicit verbal consent for the conduct of the focus 
groups was approved by the IRB of record. 
The informed consent form is a means of providing information regarding the study to a 
prospective patient participant and allows for an informed decision about participation in the study. 
Given the now established safety and efficacy of the current ED-initiated BUP in our prior work, 
we do not view the proposed study as high risk. The consent form will include all of the required 
elements of informed consent. Each study site must have the study informed consent approved 
by the IRB of record for the study. A copy of the IRB-approved consent, along with the IRB study 
approval, must be sent to the Yale PI prior to the site initiation visit. Every patient participant to be 
included in the implementation or effectiveness outcomes is required to sign a valid, IRB-
approved current version of the study informed consent form prior to enrollment into the study. 
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secure location that is in compliance with their IRB and institutional policies and that is accessible 
to the study monitors. Every participant should be given a copy of their signed consent form. 
Once eligibility is determined, the RA, who is knowledgeable about the study will explain the 
significant elements of the study to the potential participant. Included in the consent will be 
language allowing the ED RA to contact community-based providers and programs to determine 
the patient’s engagement in formal addiction treatment status on the 30th day post enrollment. If 
the patient is able to converse and alert to person, place and time, the RA obtains signed, dated 
consent. A copy of the signed consent will be left with the participant. All persons obtaining 
consent must have completed appropriate training. 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. 
The informed consent form must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect participants’ 
participation in the study.  
14.5 Health Insurance Portability and Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. Sites will be responsible for communicating with their IRBs or 
Privacy Boards and obtaining the appropriate approvals or waivers to be in regulatory compliance. 
14.6 Investigator Assurances 
Each study site must file (or have previously filed) a Federal Wide Assurance (FWA) with the 
DHHS 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(b) and (f)). 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. 
14.7 Financial Disclosure 
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. Everyone with decision-making responsibilities regarding the protocol as well as all listed 
on the Investigator Agreements will be verified on an annual basis with the CCC that they are in 
compliance with their institutional reporting requirements. 

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14.8 Clinical Monitoring 
14.8.1 Data collection and data completeness monitoring 
The primary implementation outcomes at each study site will be based on ED provider 
documentation of ED-initiated BUP with referral for ongoing MAT in the EHR. Medical records will 
be accessed by an RA blinded from the index visit. The data will be entered into Advantage 
eClinical and accessed at each site by the RA.  
The effectiveness data will be obtained by study RAs at each site by conducting the 30-day follow 
up assessment. All study patient participant-reported treatment engagement information will then 
be verified directly with the provider/program. Loss of follow up will be mitigated by having the RA 
schedule a 30-day post enrollment follow-up appointment prior to ED discharge and provide a 
printed appointment card.  
At baseline we will collect information on provider wages and space costs to perform interventions 
to use in cost analysis. Unit process for other health care treatments will come from published 
national data. 
Data completeness will be monitored weekly by review of aggregates/summaries of data 
completeness reports. The DSC will produce completeness summaries for DSMB meetings and 
for Trial Progress Reports, which are posted daily on the internet for perusal by study leadership. 
The Lead Team (LT) comprised of the Lead Investigators (LI), Project Directors, and Site PI team 
will provide oversight for the study at all sites, with input from the Local Node PIs, Lead Node PIs 
and NIDA CCTN Scientific Officers and the DSC and CCC when required. Emmes will support 
study activities related to logistics (e.g., provision of study supplies and quality control) and data 
management. As the primary goal of this project is implementation, these monitoring efforts will 
focus on research (data collection) procedures of the research staff and not on implementation 
procedures, processes or outcomes of other entities. Qualified research personnel from the Local 
Node may assist the Lead Investigators with site management during the study to encourage and 
assess compliance with the study protocol, GCP guidelines, and to ensure the integrity of the 
study progress. This will take place as specified by the Lead Investigators and will occur as often 
as needed to help prevent, detect, and correct research problems at the study sites. The Lead 
Team will verify that study research procedures are properly followed and that site research staff 
members are trained and able to conduct the research protocol appropriately. If review of study 
documentation indicates that additional training of study personnel is needed, the Lead 
Investigators and/or Local Node will see that it is done.  
Protection of the rights and welfare of study participants will be a vigilant process conducted by 
the research teams at all sites, at the Lead Node and by the sponsors of the research. Monitoring 
of the study sites will be conducted on a regular basis using a combination of NIDA-contracted 
monitors, local node monitors, and Lead Investigators staff. Site investigators will host periodic 
visits by monitors who will ensure all study procedures are appropriately conducted, and that 
study data are generated, documented and reported in compliance with the protocol, GCP, and 
applicable regulations. These monitors will audit at mutually agreed upon times, regulatory 
documents, case report forms (CRFs), and corresponding source documents for each participant. 
NIDA-contracted monitors will assure that submitted data are accurate and in agreement with 
source documentation where applicable and will also review regulatory/essential documents such 
as correspondence with the IRB. Areas of particular concern will be participant signed/dated 
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and approvals, regulatory documents, participant records, and principal investigator supervision 
and involvement in the study. Reports will be prepared following the visits and forwarded to the 
Lead Investigators and Site PIs the Lead Node, local node and NIDA CCTN. 
Local QA monitor visits will take place as specified by the Lead Investigators and visits will occur 
as often as needed to help prevent, detect, and correct problems at the study sites. The Lead 
Investigator's team will work in collaboration with the local node staff to ensure that study 
procedures are properly followed and that site staff are trained and able to conduct the protocol 
appropriately. If the Lead Investigator's team review of study documentation indicates that 
additional training of study personnel is needed, node staff will communicate with the Lead 
Investigators to determine course of action. 
14.9 Study Documentation 
Study documentation includes but is not limited to, all case report forms, data correction forms, 
workbooks, source documents, monitoring logs and appointment schedules, sponsor-investigator 
correspondence, and signed protocol and amendments, Ethics Review Committee or IRB 
correspondence and approved consent form and signed participant consent forms. 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the study. All study 
information should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. Whenever possible, the original recording of an observation should 
be retained as the source document; however, a photocopy is acceptable provided that it is a 
clear, legible, and exact duplication of the original document. 
14.10 Safety Monitoring 
As buprenorphine, a marketed medication with prior known and labeled adverse reactions, is 
being used for its labeled indication in this study and is not being provided as a study medication 
but being used as a standard of care for treatment of opioid use disorder, the collection and 
reporting of safety events will be limited to those concerning hospitalization for all medical 
(including psychiatric) indications, Emergency Department visits, overdoses, and death of any 
participant enrolled in this study. All safety events, including designated SAEs will be presented 
to the DSMB. 
14.10.1 Data and Safety Monitoring Board (DSMB) 
An independent CTN DSMB will assure protection of study 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 study, or evidence that study procedures should be changed, or if the study should be 
halted, for reasons relating to the safety of the study participants, the efficacy of the treatment 
under study, or inadequate study performance (e.g., poor recruitment). 
14.10.2 Reporting and Management 
Any divergence from procedures and requirements outlined in the protocol will be classified a 
protocol deviation. A protocol deviation is an action (or inaction) that alone may or may not affect 
the scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a 
study participant. In some cases, a protocol deviation may compromise participant safety, 

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participant rights, inclusion/exclusion criteria or the integrity of study data and is cause for 
corrective action to resolve the deviation and to prevent re-occurrence. 
Protocol deviations will be monitored at each site for (1) significance, (2) frequency, and (3) impact 
on the study objectives, to ensure that site performance does not compromise the integrity of the 
study. The decision about whether a departure from the protocol will be designated as major or 
minor will be made by the Clinical Coordinating Center (CCC) and the protocol’s Lead 
Investigators. The consequences will be specified, re-training or resolution conducted and 
participating sites should be informed as well as reviewed anonymously with all sites so similar 
deviations do not occur at other research sites  
All protocol deviations will be recorded in the Advantage eClinical data entry system via the 
Protocol Deviation eCRF. Additionally, each site is responsible for tracking and reporting protocol 
deviations the IRB of record for the study, as required. The Data and Statistics Center (DSC) and 
the Lead Investigators must be contacted immediately if an unqualified/ ineligible study participant 
is enrolled into the study. 
14.10.3 Confidentiality 
By signing the protocol signature page, the investigator affirms that information furnished to the 
investigator by NIDA will be maintained in confidence and such information will be divulged to the 
IRB, Ethical Review Committee, or similar expert committee; affiliated institution; and employees 
only under an appropriate understanding of confidentiality with such board or committee, affiliated 
institution and employees.  
14.11 Certificate of Confidentiality 
The Lead Investigator will obtain a federal Certificate of Confidentiality (CoC) and will distribute it 
to all sites when received. No patients will be enrolled prior to receipt of the COC. A CoC helps 
researchers protect the privacy of human research participants enrolled in biomedical, behavioral, 
clinical and other forms of sensitive health-related research (e.g., drug use). Certificates protect 
against compulsory legal demands, such as court orders and subpoenas, for identifying 
information or identifying characteristics of a research participant. The department that issues the 
CoC will be advised of any changes in the CoC application information that may occur during the 
study, as required. Participating sites will be notified if CoC revision is necessary. 
Participant records will be kept confidential by the use of study codes for identifying participants 
on CRFs, secure separate storage of any documents that have participant identifiers, and secure 
computing procedures for entering and transferring electronic data. All laboratory specimens, 
eCRFs, reports, and other data records will be identified by the participant identification study 
code that includes the site number, protocol number, and participant number. Research records 
will be stored in a locked cabinet. Only authorized individuals will have access to the study 
records. Participant information will not be released without written permission, except as 
necessary for monitoring by the NIDA-contracted monitors, local node monitors, lead node staff, 
or NIDA. By signing the protocol signature page, the investigator agrees that within local 
regulatory restrictions and ethical considerations, NIDA or any regulatory agency may consult 
and/or copy study documents in order to verify eCRF data. 

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14.12 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
For the purposes of this protocol, the collection and reporting of safety events will be limited to 
hospitalization for all medical (including psychiatric) indications, Emergency Department visits, 
overdoses, and death of any participant enrolled in this study. The study staff will be trained to 
monitor for and report all protocol-defined safety events including Serious Adverse Events. All 
safety events, including designated SAEs will be presented to the DSMB. SAEs that are specified 
for reporting will be reported to the IRB of record per the IRB’s guidelines.  
Reportable AEs will include:  
 
• 
None 
 
Reportable SAEs will include: 
 
• 
Any death for any reason 
 
All deaths, regardless of cause, will be captured for this study. These events will be identified 
through the participants’ locator information or when possible through using state medical 
examiner records, National Death Index, and review of medical records. Deaths will be reported 
using the Adverse Event/Serious Adverse Event form set so that appropriate information 
surrounding the event can be gathered. It is the expectation that all *deaths will be reported in the 
EDC within 24 hours of site awareness. *Note: only death events that occur within the 30-day 
follow-up period will be recorded on the AE/SAE form set. 
OTHER SAFETY EVENTS OF INTEREST 
Hospitalization for all medical (including psychiatric) indications, Emergency Department visits 
and overdose events will not be captured as AEs or SAEs, but instead will be reported on study 
specific form(s). 
All hospitalization events (including psychiatric indications) as well as Emergency Department 
visits will be captured for this study using self-report as well as review of medical records. These 
hospitalizations will be reported on the Health Services Utilization and ED Visits and 
Hospitalization CRFs. When possible, these forms will confirm the diagnosis for the hospital or 
ED visit and the information will be verified by study staff. The completion of these forms will 
indicate whether the information was gathered via self-report or medical record abstraction. This 
information will be collected at enrollment and at the 30-day follow up visit. 
All overdose events will be captured for this study. Non-fatal overdose events will be captured 
through participant self-report on the Overdose CRF. This information will be collected at the 
enrollment visit as well as all follow-up visits for the study. Fatal overdose events will be captured 
through state medical examiner records, National Death Index, and review of medical records. 
*Fatal overdose events also qualify as a reportable SAE and will, therefore, be additionally 
reported on the AE/SAE CRF form set. *Note: only death events that occur within the 30-day 
follow-up period will be recorded on the AE/SAE form set. 
OTHER EVENTS 
Pregnancy is not exclusionary and will not be captured as the procedures for prescribing 
medication is per standard of care. 

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Incarceration that occurs on study will be reported on the Crime and Criminal Justice case report 
form but will not be considered an adverse or serious adverse event. 
Loss of confidentiality related to participation in this study will be monitored at the site and will be 
reported on the Protocol Deviation eCRF as well as reported to the IRB of record per IRB 
requirements. 

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15.0 DATA MANAGEMENT AND PROCEDURES  
15.1 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) for tablet use, 
development and validation of the clinical study database, ensuring data integrity, and along with 
the Project Director will assist in training site investigators and staff on applicable data 
management procedures. Advantage eClinical, a web-based distributed data entry system will be 
implemented. This system will be developed to ensure that guidelines and regulations 
surrounding the use of computerized systems used in clinical research are upheld. The remainder 
of this section provides an overview of the data management plan associated with this protocol. 
15.1.1 Data Collection  
Data is collected at the study sites either through direct data entry at the study sites into 
Advantage eClinical or on source documents, which are entered at the study site into Advantage 
eClinical. In the event that Advantage eClinical is not available, the DSC will provide the sites with 
a final set of guided source documents and completion instructions. Data entry into the source 
documents and electronic Case Report Forms (eCRFs) should be completed according to the 
instructions provided and project specific training. 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.  
15.1.2 Data Acquisition and Entry 
Data entry into eCRFs shall be performed by authorized individuals and shall be entered into the 
Advantage eClinical system in accordance with the Advantage eClinical User’s Guide. Selected 
eCRFs may also require the Site Principal Investigator’s written signature or electronic signature, 
as appropriate. Electronic CRFs will be monitored for completeness, accuracy, and attention to 
detail throughout the study. 
15.1.3 Site Responsibilities 
The data management responsibilities of each individual site will be specified by the DSC and 
outlined in the Advantage eClinical User’s Guide. 
15.1.4 Data Center Responsibilities 
The DSC will 1) develop a data management plan and will conduct data management activities 
in accordance with that plan guide, 2) provide final guided source documents and eCRFs for the 
collection of all data required by the study, 3) develop data dictionaries for each eCRF that will 
comprehensively define each data element, 4) conduct ongoing data monitoring activities on 
study data from all participating sites, 5) monitor any preliminary analysis data cleaning activities 
as needed, and 6) rigorously monitor final study data cleaning. 

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15.1.5 Data Editing 
Completed data will be entered into Advantage eClinical. If incomplete or inaccurate data are 
found, a data clarification request will be generated to the sites for a response. Sites will resolve 
data inconsistencies and errors and enter all corrections and changes into Advantage eClinical in 
accordance with the Advantage eClinical User’s Guide. 
15.1.6 Data Transfer/Lock 
Data will be transmitted by the DSC to the NIDA central data repository as requested by NIDA. 
The DSC will conduct final data quality assurance checks and “lock” the study database from 
further modification. The final analysis dataset will be returned to NIDA, as requested, for storage 
and archive. 
15.2 Data Training 
The training plan for RA staff includes provisions for training on assessments, eCRF completion 
guidelines, data management procedures, the use of Advantage eClinical and the use of other 
computerized systems, as required. 
15.3 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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16.0 STUDY TIMELINE  
From time of approval of the final version of the protocol, the study team launched the study within 
approximately 6 months. The pre-launch activities included submitting and obtaining IRB 
approval, obtaining a Certificate of Confidentiality, data system development, site selection and 
preparation, initial investigator meeting and training, and completion of the Manual of Operations 
(see Study Timeline diagram in Section 5.3.1).  

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17.0 PUBLICATIONS AND OTHER RIGHTS  
Per NIH Policy, the results of the proposed study are to be made available to the research 
community and the public at large. The planning, preparation, and submission of publications will 
follow the policies of the Publications Committee of the CTN. 

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18.0 SIGNATURES  
SPONSOR’S REPRESENTATIVE (CCTN DESIGNEE) 
 
 
 
 
 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
• 
I am in receipt of version 4.0 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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19.0 APPENDIX: BAYESIAN ANALYSIS 
To construct a Frequentist confidence interval for a parameter, one follows a recipe that generates 
from the data a region that, with specified probability, encloses the parameter. One tests at level 
0.05 whether a parameter is or is not equal 0 by determining whether the 95% confidence interval 
for the parameter does or does not enclose 0.  
In Bayesian statistics, the parameter is associated with a probability distribution. This distribution 
describes one’s belief that the parameter could equal various numeric values. Credibility intervals, 
the Bayesian analogues to Frequentist confidence limits, are regions of the distribution that 
integrate to specific probabilities. A Bayesian analogue to testing whether a parameter is or is not 
equal 0 involves discovering whether the 95% credibility interval for the parameter does or does 
not enclose 0. A Bayesian analogue to power is the proportion of simulated data sets in which the 
0.95-level credibility interval for the treatment effect does not enclose zero. (Equivalently for 1-
tailed tests, the parameter differs from 0 if the integral of its distribution from 0 to infinity exceeds 
0.95).  
Figures B5 and B8 show the Bayesian power curves in the alternative and null cases we have 
been considering. These figures, based on simulations of 1000 iterations per scenario (the 
Bayesian method takes much longer – 8 hours for 250 iterations per scenario -- than the 
Frequentist approach – 4 hours for 10,000 iterations per scenario), are comparable to Figures 1 
and 3, respectively. They indicate that the Bayesian approach may be a useful secondary analysis 
method for the primary hypotheses under discussion. Note, however, that although 
autocorrelation was a problem in only a fraction of a percent of the alternative-case iterations, 
about 27% of the null-case iterations generated SAS warnings that there was still significant 
autocorrelation after 500 lags. 
The Bayesian approach undertaken here uses diffuse priors. Perhaps using historical data to 
estimate priors could lead to an increase in power, but this is not investigated here. 
Figures B6-B7 show Bayes estimates for 𝑝𝑝1, 𝑝𝑝2, and 𝑝𝑝1 −𝑝𝑝2. The average credibility intervals for 
𝑝𝑝1and 𝑝𝑝2 are somewhat wider than corresponding confidence intervals. The reason for this is 
unclear. Although the treatment effect is an odds ratio, i.e. 𝑝𝑝2(1 −𝑝𝑝1)/[𝑝𝑝1(1 −𝑝𝑝2)] in both 
approaches, an attractive aspect of the Bayes MCMC method is that it is easy to get the posterior 
distribution of the simple treatment difference 𝑝𝑝2 −𝑝𝑝1, as shown in Figure B7. The credibility 
interval for 𝑝𝑝2 −𝑝𝑝1 seems less sensitive to ICC than other interval estimates investigated. 

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19.1 Figure B5: Bayes power; Alternative Cases 
 
19.2 Figure B6: Bayes Credibility Intervals for p1, p2; Alternative Cases 
 
 
 
 

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19.3 Figure B7: Bayes Credibility Intervals for p1-p2; Alternative Cases 
 
 
Figures B8-B10 give test size and credibility intervals under the “Null” scenarios of Table 4. 
Figures B8-B9 are comparable to their Frequentist analogues (Figures 4.-5, sections 11.8.3-
11.8.4). As in Figure B7, the credibility interval for 𝑝𝑝2 −𝑝𝑝1 (Figure B10) seems less sensitive to 
ICC than other interval estimates investigated. 

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19.4 Figure B8: Bayes Test Size; Null Cases 
 
19.5 Figure B9: Bayes Credibility Intervals for P1, P2; Null Cases 
 

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19.6 Figure B10: Bayes Credibility Intervals P1-P2; Null Cases 
 
 
We document here the SAS code for the Bayesian approach, which employs the Markov Chain 
Monte Carlo method. 
proc mcmc data = summsimul nbi = 1000 nmc = 10000 thin = 2 seed = 159  
monitor = (beta0-beta2 beta2_gt_0 p1 p2 pdiff) statistics = (summary intervals); 
parms beta0-beta2 0; 
parms sigma2 1; 
prior beta0-beta2 ~ normal(mean = 0, var = 1000); 
prior sigma2 ~ igamma(shape = 0.001, scale = 0.001); 
random b0 ~ normal(mean = 0, var = sigma2) subject = site; 
array p[2]; 
p[treat+1] = logistic(beta0 + beta1 * 22 + beta2 * treat); 
pdiff = p2 – p1; 
eta = beta0 + beta1 * month + beta2 * treat + b0; 
pi = logistic(eta); 
model z ~ binomial(n = trials, p = pi); 
beta2_gt_0 = beta2 > 0; 
run; 

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