Substance Use Treatment and Recovery Team
Phase: NA
Conditions: Opioid-use Disorder, Opioid-Related Disorders
Sponsor: Cedars-Sinai Medical Center

 
 
Official Grant Title: Collaborative Care Teams for 
Hospitalized Patients with Opioid Use Disorders 
Study/Intervention Title: Substance Use Treatment and Recovery 
Team (START) 
National Clinical Trial (NCT) Identified Number: 
  NCT05086796 
Principal Investigators:  
Itai Danovitch, MD, Cedars-Sinai Medical Center (MPI) 
Allison J. Ober, PhD, RAND (MPI) 
 
Peter D. Friedmann, MD, MPH, Baystate Health (Site PI) 
Kimberly Page, PhD, MPH, University of New Mexico (Site PI) 
Sponsor: Cedars-Sinai Medical Center 
Grant Number: 1U01TR002756-01A1 
Funded by: National Center for Advancing Translational Sciences, National 
Institute on Drug Abuse 
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ii 
 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein will be published or disclosed without 
prior approval of the Principal Investigators or other participating study leadership and as consistent 
with the NIH terms of award.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................ 6 
INVESTIGATORS’ SIGNATURES .......................................................................................................... 7 
1 
PROTOCOL SUMMARY ............................................................................................................... 9 
1.1 
Synopsis ................................................................................................................................. 9 
1.2 
Schema ................................................................................................................................. 12 
1.3 
Schedule of Activities ......................................................................................................... 13 
2 
INTRODUCTION .......................................................................................................................... 14 
2.1 
Study Rationale ................................................................................................................... 14 
2.2 
Background .......................................................................................................................... 14 
2.3 
Risk/Benefit Assessment ................................................................................................... 18 
2.3.1 
Known Potential Risks ...................................................................................... 18 
2.3.2 
Known Potential Benefits ................................................................................. 18 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 19 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................. 21 
4 
STUDY DESIGN ........................................................................................................................... 22 
4.1 
Overall Design ..................................................................................................................... 22 
4.2 
Scientific Rationale for Study Design ............................................................................... 24 
4.3 
Justification for Intervention ............................................................................................... 25 
4.4 
End-of-Study Definition ...................................................................................................... 25 
5 
STUDY POPULATION ................................................................................................................. 25 
5.1 
Inclusion Criteria.................................................................................................................. 25 
5.2 
Exclusion Criteria ................................................................................................................ 26 
5.3 
Lifestyle Considerations ..................................................................................................... 26 
5.4 
Screen Failures ................................................................................................................... 26 
5.5 
Strategies for Recruitment and Retention ....................................................................... 26 
5.5.1 
Patient Identification and Recruitment ........................................................... 26 
5.5.2 
Consent AND Enrollment ................................................................................. 27 
5.5.3 
Retention ............................................................................................................ 27 
5.5.4 
Incentives ........................................................................................................... 27 
5.5.5 
anticipated enrollment ...................................................................................... 28 
6 
STUDY INTERVENTIONS .......................................................................................................... 30 
6.1 
Study Intervention Administration ..................................................................................... 30 
6.1.1 
Study Intervention Description ........................................................................ 30 
6.1.2 
Usual Care Description .................................................................................... 31 
6.1.3 
Administration and/or Dosing .......................................................................... 31 
6.2 
Fidelity ................................................................................................................................... 32 
6.2.1 
Interventionist Training ..................................................................................... 32 
6.2.2 
Fidelity measures .............................................................................................. 32 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 33 
6.4 
Study Intervention/Experimental Manipulation Adherence ........................................... 34 
6.5 
Concomitant Therapy ......................................................................................................... 34 

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6.5.1 
Rescue Therapy ................................................................................................ 34 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ........................................................................ 34 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation .............................. 34 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 35 
7.3 
Lost to Follow-Up ................................................................................................................ 35 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 35 
8.1 
Endpoint and Other Non-Safety Assessments ............................................................... 35 
8.1.1 
Eligibility Screening ........................................................................................... 36 
8.1.2 
Baseline Interview ............................................................................................. 36 
8.1.3 
1-Month Follow-Up Interview ........................................................................... 36 
8.1.4 
Procedural Flow................................................................................................. 36 
8.1.5 
Variables Collected ........................................................................................... 37 
8.2 
Safety Assessments ........................................................................................................... 41 
8.3 
Adverse Events and Serious Adverse Events ................................................................ 41 
8.3.1 
Definition of Adverse Events ........................................................................... 41 
8.3.2 
Definition of Serious Adverse Events ............................................................. 41 
8.3.3 
Classification of an Adverse Event ................................................................. 42 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ......... 43 
8.3.5 
Adverse Event Reporting ................................................................................. 44 
8.3.6 
Serious Adverse Event Reporting .................................................................. 45 
8.3.7 
Reporting Events to Participants .................................................................... 46 
8.3.8 
Events of Special Interest ................................................................................ 46 
8.3.9 
Reporting of Pregnancy ................................................................................... 46 
8.4 
Unanticipated Problems ..................................................................................................... 51 
8.4.1 
Definition of Unanticipated Problems ............................................................. 51 
8.4.2 
Unanticipated Problems Reporting ................................................................. 51 
8.4.3 
Reporting Unanticipated Problems to Participants ...................................... 52 
9 
STATISTICAL CONSIDERATIONS ........................................................................................... 52 
9.1 
Statistical Hypotheses ........................................................................................................ 52 
9.2 
Sample Size Determination ............................................................................................... 53 
9.3 
Populations for Analyses ................................................................................................... 54 
9.4 
Statistical Analyses ............................................................................................................. 54 
9.4.1 
General Approach ............................................................................................. 54 
9.4.2 
Analysis of Primary and Secondary Endpoints ............................................ 54 
9.4.3 
Safety Analyses ................................................................................................. 55 
9.4.4 
Baseline Descriptive Statistics ........................................................................ 55 
9.4.5 
Planned Interim Analyses ................................................................................ 56 
9.4.6 
Sub-Group Analyses......................................................................................... 56 
9.4.7 
Tabulation of Individual Participant Data ....................................................... 56 
9.4.8 
Exploratory Analyses ........................................................................................ 56 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 57 

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10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 57 
10.1.1 
Informed Consent Process .............................................................................. 57 
10.1.2 
Study Discontinuation and Closure ................................................................ 57 
10.1.3 
Confidentiality and Privacy .............................................................................. 58 
10.1.4 
Future Use of Stored Specimens and Data .................................................. 59 
10.1.5 
Key Roles and Study Governance ................................................................. 59 
10.1.6 
Safety Oversight ................................................................................................ 60 
10.1.7 
Clinical Monitoring ............................................................................................. 61 
10.1.8 
Quality Assurance and Quality Control .......................................................... 61 
10.1.9 
Data Handling and Record Keeping ............................................................... 61 
10.1.10 
Protocol Deviations ........................................................................................... 64 
10.1.11 
Publication and Data Sharing Policy .............................................................. 65 
10.1.12 
Conflict of Interest Policy ................................................................................. 65 
10.2 
Additional Considerations .................................................................................................. 66 
10.3 
Abbreviations and Special Terms ..................................................................................... 66 
10.4 
Protocol Amendment History ............................................................................................ 67 
11 
APPENDICES ............................................................................................................................... 67 
11.1 
Recruitment and Enrollment .............................................................................................. 67 
11.2 
Evaluation ............................................................................................................................. 68 
11.3 
Data Safety And Monitoring .............................................................................................. 68 
12 
REFERENCES .............................................................................................................................. 69 

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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the National 
Center for Advancing Translational Sciences Terms and Conditions of Award. The Principal Investigators 
will assure that no deviation from, or changes to the protocol will take place without prior agreement 
from the funding agency and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) will 
be obtained before any participant is consented. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form(s) 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 

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INVESTIGATORS’ SIGNATURES 
The signatures below constitute the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
1 April 2021 
 
Name: Itai Danovitch, MD 
 
Title: 
MPI 
Investigator Contact Information 
Affiliation: Cedars-Sinai Medical Center 
Address: 8730 Alden Drive, Suite E-135, Los Angeles, CA 90048 
Telephone: 310.423.2600 
Email: itai.danovitch@cshs.org 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
4/5/21 
 
Name: Allison Ober, MSW, PhD 
 
Title: 
MPI 
Investigator Contact Information 
Affiliation: RAND Corporation 
Address: 1776 Main Street, Santa Monica, CA 90407 
Telephone: 310-393-0411 ext. 6639 
Email: ober@rand.org 
 
 
 

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Signature of the clinical site investigators who are responsible for the day-to-day study implementation 
at the specific clinical sites. 
Signed: 
 
Date: 
1 April 2021 
 
Name: Peter Friedmann, MD 
 
Title: 
Co-I 
 
Affiliation: Baystate Health 
Signed: 
 
Date: 
29 March 2021 
 
Name: Kimberly Page, MPH, PhD 
 
Title: 
Co-I 
 
Affiliation: University of New Mexico 
 
 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Collaborative care teams for hospitalized patients with opioid use 
disorders: Translating evidence into practice 
Grant Number: 
1U01TR002756-01A1 
Study Description: 
The purpose of this study is to evaluate whether an intervention by an 
interdisciplinary collaborative care team compared with usual care for 
hospitalized patients with opioid use disorders (OUD) can increase 
initiation of medication for opioid use disorder (MOUD) and improve 
linkage to OUD-focused follow-up care. If the aims of the research are 
achieved, we hope to improve MOUD initiation and linkage to follow-
up care as well as clinical outcomes, and, ultimately, create a 
generalizable, sustainable model of care to increase OUD treatment 
delivery and decrease the downstream effects of untreated OUD. If 
effective, this translational model also can be used to increase uptake 
of evidence-based practices for other substance use and associated 
behavioral health disorders.  
Objectives: 
 
Primary Objectives: 
1. To test the effectiveness of the START intervention on MOUD 
initiation relative to usual care.  
2. To test the effectiveness of the START intervention on linkage with 
post-discharge OUD treatment relative to usual care.  
Secondary Objectives: 
1. To test the effectiveness of the START intervention on addiction-
focused discharge planning. 
2. To test the effectiveness of the START intervention on MOUD 
engagement relative to usual care.  
3. To test the effectiveness of the START intervention on linkage to 
medical care relative to usual care.  
4. To test the effectiveness of the START intervention on self-reported 
days of opioid use relative to usual care. 
Endpoints: 
Primary Endpoints: 
1. Proportion of patients in each arm who initiate MOUD prior to 
discharge, defined as use of any FDA-approved pharmacotherapy 
for OUD, including buprenorphine, naltrexone and methadone. 
2. Proportion of patients in each arm who attend at least one OUD-
related care visit within 30 days of hospital discharge. 
Secondary Endpoints: 
1. Proportion of patients in each arm with an after-hospital care plan 
that specifies a date and time for a post-discharge addiction care 
appointment.  
2. Proportion of patients in each arm who initiate MOUD or continue 
MOUD treatment within 30 days following hospital discharge. 

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3. Proportion of patients in each arm who complete at least one visit 
to an outpatient medical provider within 30 days of hospital 
discharge.  
4. Days of opioid use in the past 30 days. 
Study Population: 
Inpatients* at three medical hospitals in California, Massachusetts, and 
New Mexico who are 18 or older, admitted for any reason, and screen 
positive for moderate to severe OUD using the ASSIST 
Phase or Stage: 
Pragmatic Clinical Trial   
Description of 
Sites/Facilities Enrolling 
Participants: 
Cedars-Sinai Medical Center: Cedars-Sinai is a nonprofit academic 
healthcare organization serving the diverse Los Angeles community 
and beyond. Cedars-Sinai is one of the largest nonprofit academic 
medical centers in the U.S., with 886 licensed beds, 2,100 physicians, 
2,800 nurses and thousands of other healthcare professionals and 
staff. Cedars-Sinai serves more than 1 million people each year in over 
40 locations, with more than 4,500 physicians and nurses and 1,500 
research projects in motion. 
 
Baystate Medical Center: Baystate Health (BH) is a not-for-profit, 
integrated healthcare system serving over 800,000 people in Western 
New England.  Headquartered in Springfield, MA, Baystate Health is 
comprised of the flagship Baystate Medical Center (713 beds) Baystate 
Children’s Hospital, and three community hospitals: Baystate Franklin 
Medical Center (89 beds), Baystate Noble Hospital (97 beds), and 
Baystate Wing Hospital (74 beds). Baystate Health is also comprised of 
Baystate home care and hospice, Health New England (a local health 
insurer with approximately 150,000 members), Baystate Reference 
Laboratories, and Baystate Medical Practices which includes more than 
950 primary and specialty care providers spread across more than 85 
practice locations throughout Western and Central Massachusetts, 
including three community health centers.  Baystate provides care for 
approximately 45,000 inpatients, 197,000 emergency care patients, 
and 1.8 million outpatient visits annually. Participants for this study will 
be primarily recruited from the inpatient units at Baystate Medical 
Center. Recruitment may expand to the three community hospitals if 
needed. 
 
University of New Mexico Hospital: The University of New Mexico 
(UNM) Health system provides the highest quality of care for more 
than 200,000 New Mexicans each year. UNM Health providers 
specialize in over 150 areas of medicine and employ over 7,000 
professionals. UNM Health operates more than 30 clinics around the 
state of New Mexico through the UNM Medical Group and 
encompasses six hospitals and medical centers. Together, these 
facilities receive 900,000 outpatient visits, 22,000 surgical cases and 
100,0000 emergency room visits each year. Participants in this study 

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will be recruited at UNM Hospital, a 550 inpatient, urban, safety net 
hospital and New Mexico’s only Level 1 Trauma Center.     
Description of Study 
Intervention/Experimental 
Manipulation: 
The intervention is a collaborative care team called the Substance Use 
Treatment and Recovery Team (START). START is comprised of an 
Addiction Medicine Specialist (AMS) and a Care Manager (CM). The 
AMS and CM work closely together to treat patients. The CM assesses 
readiness, discusses treatment options, assists with linkage to follow-
up care, and tracks patient progress in a registry. The AMS assists 
patients with initiating MOUD, when indicated. The study intervention 
is initiated in the hospital and lasts a total of 4-6 hours, with various 
components delivered at different time points during the hospital stay.  
(Intervention periods must be flexible to work around medical care and 
patient wellbeing.) The intervention will be conducted in-person or via 
telehealth (telephone or televideo) depending on COVID-19 protocols. 
After discharge, the CM will continue the intervention with follow-up 
calls with patients once a week for one month, or more often if 
needed, to provide ongoing support and continue to facilitate 
treatment. Follow-up calls will last approximately 15-20 minutes each. 
Study Duration: 
11 months 
Participant Duration: 
Participant will complete study-related tasks over 4-6 hours during the 
course of their hospitalization. Weekly phone calls of approximately 
15-20 minutes each will be conducted for up to one month after 
discharge. A 30-40 minute 1-month follow-up interview will be 
conducted. 
Research Procedures 
 
The primary research visits are as follows:  
• 
Eligibility screening: A member of the research team conducts 
eligibility screening with the patient. Responses are entered into 
the REDCap database.  
• 
Consent: A member of the research team provides the consent 
form to the patient, explains it, and ensures the study is 
understood. 
• 
Baseline interview (30-40 minutes): A member of the research 
team conducts the baseline interview either in-person, by 
telephone, or by televideo. Responses are entered into the REDCap 
database.  
• 
1-month follow-up interview (30-40 minutes): A member of the 
research team will conduct the follow-up interview by telephone 
Responses are entered into the REDCap database.  
*The term ”inpatient” throughout this document refers to those either admitted to an inpatient bed or 
for observation. 
 
 

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1.2 
SCHEMA 
Figure 1. Flow Diagram 
 
 
 
 
 
Research staff screens participants for eligibility 
Screening  
(After admission) 
Visit 1: Consent  
(During hospital stay) 
Research staff conducts informed consent; informs interviewers of 
consent 
Visit 2: Baseline 
Interview (During 
hospital stay)
Research staff conducts baseline interview; randomizes 
Arm 2  
(Usual Care) 
N = 207  
Arm 1 
(Intervention) 
N = 207  
Visits 3-6+: 
Intervention (During 
hospital stay) 
Intervention staff conducts 
intervention in the hospital 
Visits 7-11: 
Intervention follow-
up (Post-discharge)    
Intervention staff conducts post-
discharge follow-up calls with 
patient 1x per week 
Visit 12: Outcomes 
data collection (1-mo 
post-discharge)  
Research staff conducts 1-month follow-up interview (+60 days) 
Randomize 

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1.3 
SCHEDULE OF ACTIVITIES  
 
Table 1. Schedule of Activities 
 
Screening 
(Pre-consent) 
Visit 1: Consent 
(During hospital 
stay) 
Visit 2: Baseline 
(During hospital 
stay) 
Visit 3-6+: 
Intervention 
(During hospital 
stay) 
Visit 7-11: 
Intervention 
Follow-Up 
(Post-
discharge) 
Visit 12: Follow-
up Interview 
(30-90 days 
post- discharge) 
ASSIST 
X 
 
 
 
 
 
Current MAT Utilization 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Intervention Visits 
 
 
 
X 
 
 
Post-Discharge Follow-Up Calls 
 
 
 
 
X 
 
Adverse Events Reporting 
 
X 
X 
X 
X 
X 
Outcome Evaluation 
 
 
 
 
 
 
Pain Intensity & Frequency (PEG) 
 
 
X 
 
 
X 
Depression (PHQ-9) 
 
 
X 
 
 
X 
Anxiety (GAD-7) 
 
 
X 
 
 
X 
30-Day Opioid (and other 
substance) Use (adapted from 
NSDUH) 
 
 
X 
 
 
X 
SUD Treatment Utilization 
(adapted from NSDUH) 
 
 
X 
 
 
X 
SUD Healthcare and Mental 
Health Utilization (adapted from 
GAIN) 
 
 
X 
 
 
X 
Opinions about MAT 
 
 
X 
 
 
 
Employment 
 
 
X 
 
 
X 
Severity of Substance Use 
(PROMIS) 
 
 
X 
 
 
X 
Overdoses 
 
 
X 
 
 
X 
Patient Experience of Stigma 
 
 
X 
 
 
 
Social Support (MSPSS) 
 
 
X 
 
 
 
Significant Other with OUD 
 
 
X 
 
 
 
Criminal Justice Involvement 
 
 
X 
 
 
 
Demographics 
 
 
X 
 
 
 
MAT Utilization 
 
 
 
 
 
X 
Patient Experience of Chronic 
Illness Care (PACIC) 
 
 
 
 
 
X 
Therapeutic Alliance (CAHPS)* 
 
 
 
 
 
X 
Satisfaction with START* 
 
 
 
 
 
X 

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*START group only 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
Problem/question. In the past decade, hospitalizations for OUD nearly doubled, from 301,707 in 2002 to 
520,275 in 2012, with inpatient charges for these hospitalizations nearly quadrupling.1 Patients admitted 
to the hospital with an underlying OUD rarely receive treatment for the OUD while hospitalized.2,3 
Medication for OUD (MOUD), is rarely initiated in the hospital, and patients are seldom linked to 
outpatient treatment after discharge.4 Hospitalized patients with OUD who do not initiate MOUD or 
receive linkage to post-discharge treatment are at high-risk of continued misuse, delays in care, future 
overdose and costly readmission.4-9 This study identifies the inpatient hospital stay as a new opportunity 
to initiate MOUD and link patients with follow-up care for their OUD. Hospitalization is an opportune 
time to initiate MOUD and provide linkage to follow-up care for patients with an OUD.10  
Rationale for the clinical trial and intervention. Collaborative care is a team-based treatment approach 
that uses multi-faceted interventions (care management, pharmacotherapy and psychotherapy), 
measurement-based care, and patient registries to increase delivery of evidence-based care. A 
collaborative care team (CCT) in the hospital offers specialist expertise, an organized system of care, and 
opportunities for patient education. A hospital-based CCT has the potential to facilitate initiation of 
MOUD during the inpatient stay and linkage to post-discharge care.11 Prior studies have demonstrated 
the effectiveness of collaborative care in outpatient settings for patients with opioid and alcohol use 
disorders.12-16 To our knowledge, however, no experimental studies to date have focused on testing a 
hospital-based collaborative care team to help patients initiate MOUD and to provide focused discharge 
planning and follow-up monitoring for hospitalized patients with an OUD. Our study is a multi-site, 
randomized trial at three diverse sites to evaluate whether a CCT, called the Substance Use Treatment 
and Recovery Team (START), increases the use of evidence-based interventions for OUD (i.e., MOUD and 
OUD-focused discharge planning) and improves linkage to follow-up care among hospitalized patients 
with OUD. 
2.2 
BACKGROUND  
The underuse of effective treatments for behavioral health conditions in the hospital setting is an 
important translational problem.17 Patients with behavioral health conditions are often hospitalized for 
emergent medical and surgical treatment,18-23 and the clinical conditions that prompt hospitalization 
often are related to undertreatment of the behavioral health condition.24 However, despite the 
prevalence of co-morbidity, few patients receive evidence-based treatments, or are successfully linked 
to treatment after discharge.2-4,25 This has critical consequences: patients with mental health and 
substance use comorbidities have longer length of stay, higher readmission rates, and worse 

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outcomes,4,6,8,26 and the inpatient hospitalization becomes a missed opportunity to address suffering 
and long-term health care costs.20,27  
There are multiple scientific and operational reasons for this translational science problem. Inpatient 
physicians frequently treat acute overdose, withdrawal, and suicidality, but they lack knowledge and 
skills for addressing behavioral health disorders, such as how to choose and adjust medication therapy, 
or when to refer for psychotherapy.28 Given pressures to minimize length of stay, the inpatient team is 
primarily focused on addressing the acute reason for admission and may defer addressing chronic 
conditions to outpatient providers. Moreover, few hospitals have the organizational infrastructure 
needed to treat behavioral health conditions effectively, such as dedicated teams, evidence-based 
protocols, or the ability to coordinate care transitions, such that patients can be linked to community 
resources.29 Separate funding streams, stringent federal privacy regulations, and long waiting lists for 
publicly-funded treatment, create additional barriers.30,31 Finally, patients with behavioral health 
conditions often experience stigma, even from health care professionals, a known barrier to 
treatment.32,33 
Opioid use disorders (OUD) are an exemplar of this problem.31,34 Patients with OUD experience high 
burden of disease from medical comorbidities,35 and are increasingly hospitalized with medical 
complications related to OUD.1,7 In the past decade, hospitalizations for OUD nearly doubled, from 
301,707 in 2002 to 520,275 in 2012, with inpatient charges for these hospitalizations nearly 
quadrupling.1 Although treatment for OUD is highly effective,36-38 patients admitted to the hospital with 
an underlying OUD rarely receive treatment for the root cause of their hospitalization—the OUD2,3 – or 
are linked with outpatient treatment.4,39 High rates of discharges against medical advice (~15%) suggest 
failed care transitions.9 While the acute manifestations of an OUD (such as opioid intoxication and 
withdrawal) may be addressed, effective treatment for the underlying disease itself, medication for OUD 
(MOUD), is rarely initiated during the inpatient stay, and patients are seldom linked to post-discharge 
treatment.4 This missed opportunity leaves patients at high-risk of continued misuse, delays in care, 
future overdose and costly readmission.4-9 
Starting treatment in the hospital and linking patients with post-discharge care addresses the 
treatment gap and could lower readmissions and costs. Despite being in the midst of an opioid 
epidemic of unprecedented scale, in 2015 only 20% of those with a drug use problem received any 
treatment.40,41 And, among Medicaid enrollees, only 25% of those hospitalized with a substance use 
disorder were linked with post-discharge treatment.4 MOUD (buprenorphine/naloxone, methadone and 
injectable naltrexone) cuts overdose rates, reduces criminal behavior and infectious disease, and lowers 
mortality.36,37,42 When started in the hospital, MOUD increases outpatient treatment and reduces opioid 
use. Among hospitalized Medicaid enrollees with substance use disorders, patients who were linked to 
care within 14 days were less likely to be readmitted.4 Studies suggest that the inpatient hospitalization 
is a teachable moment, and that patients are willing to engage with treatment, if barriers can be 
reduced.43-47 Rapid-access pathways to treatment after discharge address systemic problems with care 
transitions and low community capacity. 

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Inpatient health care providers face structural and functional barriers to the delivery of coordinated, 
evidence-based treatment for OUD. Within the hospital, efficiency pressures to reduce costs drive 
hospitalist services to stabilize acute symptoms and defer treatment of OUD to the ambulatory setting. 
Most providers in hospital settings are not trained to assess or manage patients with OUD, contributing 
to low rates of OUD identification or treatment initiation.28 Patient ambivalence requires targeted 
motivational interventions, which hospitalists are not typically trained to provide. Stigmatization of OUD 
and untreated withdrawal may contribute to high rates of discharge against medical advice (~15%), 
which can truncate treatment for the condition that prompted the hospitalization.7,48,49 Barriers 
impeding linkage to post-discharge OUD care include the lack of outpatient providers (which requires 
persistence to find an opening for treatment) and federal privacy regulations that effectively segregate 
medical and substance use care.30,31 Insurance coverage for addiction aftercare services is frequently 
inadequate, and even insurers with benefits may not have an easily accessible network of community 
providers. Further, medical comorbidities may limit patient aftercare options.  
There is a debate about how best to increase access to behavioral health treatment in the hospital.29 
There are three service delivery models that have been used to address the behavioral health conditions 
of hospitalized patients; all are limited in that all of them are provided by a single individual and are 
focused on addressing the acute problem. In the traditional consultation-liaison psychiatry model, a 
primary medical or surgical team requests a consultation for a recognized problem and is responsible for 
implementing the consultant’s recommendations. In the proactive model,50,51 case-finding strategies 
identify patients early in their hospitalization and the consultant provides recommendations to the 
primary team. The co-management model52 is characterized by an embedded behavioral health provider 
on a medical or surgical service, who has a direct role in case finding and management, rather than 
standard consultative recommendation. We chose to test a collaborative care model because it 
addresses the limitations of the three previous models. Most service delivery models51,52 used to 
address behavioral health conditions among hospitalized patients are limited by being implemented by a 
single individual. A team-based approach can capitalize on the different skills available from team 
members, execute tasks more efficiently, and address a range of patient needs.53 Recently, a team-
based model was experimentally tested for patients with co-morbid trauma and alcohol abuse, with the 
goal of preventing PTSD,54-58 but treatment was not provided until 3 months after discharge. While 
hospitals have started to develop addiction consultation services—suggesting feasibility and readiness—
research on these services has been observational rather than experimental.5,11,43,46,59,60 The single study 
with a randomized design occurred at one site and was a buprenorphine effectiveness study rather than 
a translational study.61 Given ongoing pressures to demonstrate the value of service delivery 
interventions, there is a pressing need to experimentally test whether an inpatient collaborative care 
team (CCT) approach to increasing treatment delivery can improve outcomes. 
There is a strong scientific premise for testing the effectiveness of an interdisciplinary, collaborative 
care team (CCT) as a translational approach to the problem of OUD treatment underuse. Substantial 
evidence supports the use of collaborative care for behavioral health disorders,62 and for behavioral 
health conditions co-morbid with medical illnesses.11,63-65 Significantly, collaborative care programs are 

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highly effective for safety-net patients and can reduce health disparities in access.66-71 Work by our team 
demonstrated the effectiveness of collaborative care in outpatient settings for patients with opioid and 
alcohol use disorders.12-16 Collaborative care is a service delivery approach that uses multi-faceted 
interventions (care management, pharmacotherapy and psychotherapy), clinical measures, systematic 
patient registries, and a team orientation to increase delivery of evidence-based care. By offering 
expertise that most hospital-based physicians lack, creating an organized system of care, providing 
patient education with a focus on self-management and harm reduction (e.g., giving patients 
prescriptions for naloxone), and addressing barriers to follow-up care, a hospital-based CCT could 
overcome the translational roadblocks to initiating MOUD during the inpatient stay and linking patients 
with post-discharge care.11 If CCTs work, they could be a new and highly significant translational 
approach to addressing the problem of OUD treatment underuse. 
The study offers a new model—a consultation service-based collaborative care team—for improving 
care processes for hospitalized patients with OUD. Hospitals have extensive experience using care 
managers to improve in-hospital and follow-up care for several patient populations at high risk of 
readmission,72,73 including acute medical patients,74 and many have a consultation service to support the 
medical team with patients in need of behavioral health care. However, to date, we have not seen any 
cross-site experimental studies of collaborative care models to improve outcomes for inpatients with 
OUD. Further, leveraging the existing consultation service is an innovative and generalizable approach to 
managing the large number of hospital inpatients with untreated OUD without burdening inpatient 
physicians and unit case managers who may not have the expertise or time to prescribe medications or 
resolve barriers to OUD-focused discharge and follow-up. The consultation service-based CCT is a novel, 
comprehensive program for facilitating MOUD initiation in the hospital and linking patients to follow-up 
care for one of the most common SUDs among inpatients. 
Our study is a multi-site, randomized pragmatic trial in being conducted in three diverse sites. The study, 
called the Substance Use Treatment and Recovery Team (START), will evaluate whether a CCT increases 
the use of two interventions—MOUD with buprenorphine, methadone or injectable naltrexone, and 
OUD-focused discharge planning—among hospitalized patients with OUD and improves linkage to 
follow-up care relative to usual care. The START consists of an addiction medicine specialist and a care 
manager who will use evidence-based tools to decrease barriers to MOUD and engage patients with 
post-discharge OUD care. We will randomize 414 patients total from Cedars-Sinai Medical Center in Los 
Angeles, the University of New Mexico Hospital in Albuquerque, and Baystate Health in Springfield, 
Massachusetts to receive either START or usual care, stratifying by prior MOUD exposure.   
This project has potential for high impact because it both improves public health and advances 
translational science. Our study simultaneously addresses a critical public health problem – the opioid 
crisis – and advances translational science. The undertreatment of OUD is arguably the most important 
translational science problem related to the opioid crisis. In 2015, 11.5 million individuals reported 
misusing opioids and 1.9 million reported being addicted to opioids,75 yet fewer than 20% receive any 
treatment.40,41 By experimentally testing a new translational approach – the CCT on treatment 
translation – and assessing implementation factors such as context and cost, this study could both 

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improve public health by identifying an efficient and generalizable model to increase OUD treatment 
delivery and decrease the downstream effects of untreated OUD, and it could also advance translational 
science by identifying an effective and generalizable approach to address translational roadblocks that 
result in the undertreatment of behavioral health conditions. Our findings on cost and sustainability will 
be highly relevant to hospital administrators and policy makers considering operational and financial 
implications of adopting and implementing similar services.  
The study builds from a small pilot RCT (N=80) now being conducted at Cedars-Sinai by testing the 
intervention at three diverse locations, thus increasing generalizability. We also examine whether and 
how context influences outcomes. By addressing context, cost and sustainability along with a diverse 
range of traditional patient-level outcomes, we go beyond the usual scope of clinical trials. Diffusion of 
innovation theory emphasizes that factors related to context influence implementation.76 This 
innovative approach to study design can generate more rapid translational gains, more effective 
downstream implementation and dissemination strategies, and more practical information for decision-
makers. 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
The study procedures involve the following potential risks: (1) unauthorized disclosures of sensitive 
information, (2) psychological distress, and (3) financial costs associated with treatment. See Protection 
of Human Subjects.   
1. Disclosures of Sensitive Information: Potential risks include transmission of protected health 
information without using encryption, without password protection, or to an unintended 
member of the research team, and transmission of protected health information outside of the 
study team. A breach of confidentiality could cause psychological or other harm to patients due 
to disclosure of sensitive study information.  
2. Psychological Distress:  Patients could experience psychological distress from discussing their 
substance use and mental health during data collection or the intervention.   
3. Financial Costs of Treatment: Patients could experience distress over costs of treatment. 
Note that patients could experience some expected side effects of OUD medication, however, this 
study is not testing the efficacy of medications. Medications, which are optional, are FDA-approved 
and considered the standard of care for treatment of OUD.  
2.3.2 KNOWN POTENTIAL BENEFITS  
The study may benefit individual participants by helping participants receive evidence-based FDA 
approved OUD medication as well as behavioral treatment while hospitalized and after discharge. The 
study will also have long-term benefits for society by improving public health and advancing 
translational science. This study will provide several types of new knowledge: 

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1. Whether START compared with usual care improves care for hospitalized patients with an 
OUD. That is, whether START leads to improved initiation of medication and linkage to follow-
up care for patients who are admitted to the hospital, either for a problem related to their 
OUD or for another medical issue.   
2. Whether START compared with usual care reduces substance use. 
3. Whether START, implemented in hospitals with different contexts, is cost-effective and is 
sustainable.  
These knowledge gains will provide invaluable, preliminary information on how to improve the quality 
of care for hospitalized patients with OUD and on how to address an unmet need that has severe 
individual and societal consequences. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Because the purpose of this study is to increase the use of FDA-approved, evidence-based treatments 
for OUD, for each individual patient enrolled, the potential benefits of participation are likely to 
outweigh risks. Untreated OUD puts patients at risk for fatal and non-fatal overdose as well as other 
acute and chronic harms. In addition, the study is intended to inform hospitals’ and national 
policymakers’ responses to the current crisis in the overuse of opioid medications, with its attendant 
high fatality rates. Thus, the research offers substantial potential benefit to both subjects and society 
with little risk to patients.  
We will minimize risks in the following ways: 
Disclosure of Sensitive Information: We will protect against unauthorized disclosures of information 
through a robust data safeguarding plan. Site PIs will be responsible for serving as local data 
safeguarding officers, assuring adherence to the study data safeguarding plan and training in human 
subjects protections. Standard procedures will include storing data on secure institutional password-
protected servers, using password-protection and encryption when transmitting any data (including 
within a hospital), limiting access to patient identifiers to the smallest number of individuals possible, 
ensuring that datasets do not have sensitive information in them unless necessary, assigning patients 
study ID numbers at random to enable removal of other direct HIPAA identifiers from datasets, and 
ensuring that all individuals who handle study data and study staff are trained in human subjects 
protections, HIPAA, and study procedures. Individuals who handle data on potential or actual study 
subjects will be required to avoid any unplanned disclosures of information beyond the study team, and 
will be required to report any unplanned disclosures.  
Per Section 2012 of the 21st Century Cures Act as implemented in the 2017 NIH Certificates of 
Confidentiality Policy, all ongoing or new research funded by NIH as of December 13, 2016 that is 
collecting or using identifiable, sensitive information is automatically issued a Certificate of 
Confidentiality. Researchers with a Certificate of Confidentiality may ONLY disclose identifiable, sensitive 
information in the following circumstances: if required by other Federal, State, or local laws, such as for 

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reporting of communicable diseases; if the subject consents; or for the purposes of scientific research 
that is compliant with human subjects regulations.  
Psychological Distress: To reduce the potential for psychological risks, study coordinators and members 
of the START will undergo training to ensure that they approach patients in a manner that is empathetic 
and non-judgmental, based on principles of motivational interviewing. If patients exhibit mild to 
moderate discomfort with study eligibility or survey questions, the study coordinator will ask the patient 
whether he/she prefers to complete the activity later. If patients exhibit severe distress, this will be 
interpreted as an inability to consent. If a patient volunteers that they are having thoughts about 
harming themselves or others, they will be referred to a psychiatrist immediately. If the participant 
reports any thoughts of suicide during the baseline interview (i.e. scored anything other than never—
1,2, 3, DK, REF—on  MH1i), upon completion of the interview the interviewer will inform the site PI or 
Co-I, who will ensure that a physician on the primary team is aware and can address in accordance with 
their standard of care as indicated. If the participant reports an thoughts of suicide during the follow-up 
interview (i.e. scored anything other than never—1,2, 3, DK, REF—on  MH1i), the CSSRS (see below) will 
be administered in REDCap.  If the patient is at high-risk of suicide per the CSSRS, the interviewer will 
address this upon completion of the interview. The interviewer will refer the patient to a suicide hotline 
and will inform the study clinician (site PI/Co-I or other). If the participant appears to be experiencing 
emotional distress during the baseline interview, the interviewer will ask the participant if they would 
like the interviewer to make the primary team aware. If the participant appears to be experiencing 
emotional distress during the follow-up interview, the interviewer will ask the participant if they would 
like to receive support after the call.  If so, upon completion of the interview the interviewer will provide 
the number of local mental health resources. Study hospitals have on-staff psychiatrists available at all 
times in case of psychiatric emergencies.   
Adverse Effects of Treatment: The Addiction Medicine Specialist on the START will adhere to clinical 
standards of care for the field. S/he will also adhere to the following the clinical protocols used in the 
study related to initiating, adjusting, discontinuing, or otherwise changing therapies including 
medication. Medications will be monitored clinically, particularly during dose adjustments. If patients 
report any adverse effects of treatment to study staff, these will be immediately reported to the treating 
providers who ordered the treatment. For example, if a patient tells a care manager about medication 
side effects, then the care manager would immediately refer this information to the treating physician. 
The risks of treatment with MOUD are similar to but lower than those associated with untreated OUD.  
Financial Costs to Patients:  The study aims to test whether the START intervention facilitates linkage to 
treatment.  This could result in financial cost to patients who engage in treatment.  As part of the 
intervention group (START), the care manager will  work with patients to try to minimize the costs of any 
medications and follow-up care by helping the patients to understand any insurance benefits that they 
may have and to access available community resources.  Usual care patients could receive assistance in 
minimizing the costs of medications and follow-up care as part of regular discharge planning by the 
medical team.  

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3 
OBJECTIVES AND ENDPOINTS  
 
Table 2. Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary 
 
 
 
To test the effectiveness of the 
START intervention on MOUD 
initiation relative to usual care 
Proportion of patients 
in each arm who 
initiate MOUD prior to 
discharge, defined as 
use of any FDA-
approved 
pharmacotherapy for 
OUD, including 
buprenorphine, 
naltrexone and 
methadone.  
Compared to usual care, START 
will result in a higher 
proportion of patients initiating 
MOUD for OUD in the hospital. 
Improved 
understanding of 
and motivation 
for MOUD 
through addiction 
focused 
motivational 
interviewing and 
discharge 
planning 
To test the effectiveness of the 
START intervention on linkage 
with post-discharge OUD 
treatment relative to usual 
care  
Proportion of patients 
in each arm who attend 
at least one OUD-
related care visit within 
30 days of hospital 
discharge. 
Compared to usual care, 
patients in the START arm will 
have increased linkage to post-
discharge OUD treatment. 
Improved 
understanding of 
and motivation to 
seek post-
discharge care  
Secondary 
 
 
 
To test the effectiveness of the 
START intervention on 
addiction-focused discharge 
planning 
Proportion of patients 
in each arm with an 
after-hospital care plan 
that specifies a date 
and time for a post-
discharge addiction 
care appointment. 
Compared to usual care, START 
will result in a higher 
proportion of patients having a 
post-discharge care 
appointment.  
Facilitated 
discharge 
planning 
To test the effectiveness of the 
START intervention on any 
post-discharge MOUD 
utilization relative to usual care  
Proportion of patients 
in each arm who 
initiate MOUD or 
continue MOUD 
treatment within 30 
days of hospital 
discharge. 
Compared to usual care, START 
will result in a higher 
proportion of patients engaging 
in MOUD treatment after the 
hospital. 
Improved 
understanding of 
and motivation to 
seek post-
discharge care 
To test the effectiveness of the 
START intervention on linkage 
to medical care relative to 
usual care  
Proportion of patients 
in each arm who 
complete at least one 
visit to an outpatient 
medical provider within 
30 days of hospital 
discharge. 
Compared to usual care, START 
will result in a higher 
proportion of patients linking 
to medical care after the 
hospital. 
Improved 
understanding of 
and motivation to 
seek post-
discharge care 
To test the effectiveness of the 
START intervention on self-
Days of opioid use in 
the past 30 days 
Compared to usual care, START 
will result in a higher 
Reduced cravings 
for opioids 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
reported days of opioid use 
relative to usual care 
proportion of patients with 
reduced opioid use. 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Design  
This study is a pragmatic randomized controlled trial (RCT) to evaluate primarily whether the START 
intervention compared to usual care increases initiation of medication for OUD in the hospital—MOUD 
with buprenorphine, methadone or injectable naltrexone, linkage to OUD care post-discharge—among 
hospitalized patients with OUD. The study also will evaluate the effect of the START intervention on 
post-discharge planning, linkage with or continuation of MOUD, utilization of medical care and 
reduction in opioid use after discharge.  
The START intervention consists of an addiction medicine specialist and a care manager who will use 
evidence-based tools such as motivational interviewing and addiction-focused discharge planning to 
decrease barriers to MOUD and engage patients with post-discharge OUD care.  
The trial will be implemented at Cedars-Sinai Medical Center (CSMC) in Los Angeles, the University of 
New Mexico Hospital in Albuquerque, and Baystate Health in Springfield, Massachusetts.  Patients will 
be randomly assigned within each hospital to receive either START or usual care, stratifying by prior 
MOUD exposure. 
Figure 2. Consort Diagram (Anticipated) 

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Hypotheses 
The primary objectives/hypotheses are: 
1. To test the effectiveness of the START intervention on MOUD initiation relative to usual 
care.  
a. Hypothesis: Compared to usual care, START will result in a higher proportion of 
patients initiating MOUD in the hospital. 
1,656 Identified for study (anticipated) 
828 Assessed for eligibility (anticipated) 
207 Allocated to START 
207 Received allocated intervention 
828 Excluded (anticipated) 
 
# Refused screening 
 
# Discharged/AMA 
414 Excluded (anticipated) 
 
# Ineligible 
 
# Declined to participate 
 
# Other reasons 
207 Allocated to usual care 
207 Received allocated intervention 
39 Lost to follow-up (anticipated) 
 
# Refused to follow-up 
 
# Deceased 
 
# Not located 
2 Excluded from analysis 
 
# [reason] 
2 Excluded from analysis 
 
# [reason] 
39 Lost to follow-up (anticipated) 
 
# Refused to follow-up 
 
# Deceased 
 
# Not located 
166 Included in patient outcomes 
analysis 
414 Randomized 
166 Included in patient outcomes 
analysis 

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2. To test the effectiveness of the START intervention on linkage with post-discharge OUD 
treatment relative to usual care.  
a. Hypothesis: Compared to usual care, a higher proportion of patients in the START 
arm will have increased linkage to post-discharge OUD treatment.  
The secondary objectives/hypotheses are:  
1. To test the effectiveness of the START intervention on addiction-focused discharge planning 
a. Hypothesis: Compared to usual care, START will result in a higher proportion of 
patients having a post-discharge care appointment.  
2. To test the effectiveness of the START intervention on any post-discharge MOUD utilization 
relative to usual care.  
a. Hypothesis: Compared to usual care, START will result in a higher proportion of 
patients initiating MOUD or continuing MOUD treatment. 
3. To test the effectiveness of the START intervention on linkage to medical care relative to 
usual care.  
a. Hypothesis: Compared to usual care, START will result in a higher proportion of 
patients linking to medical care after the hospital. 
4. To test the effectiveness of the START intervention on self-reported days of opioid use 
relative to usual care.  
a. Hypothesis: Compared to usual care, START will result in a higher proportion of 
patients with reduced opioid use. 
Phase 
N/A - This is a pragmatic clinical trial.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The study is a randomized controlled trial testing the START intervention compared with usual care. 
Usual care at each hospital consists of the medical team referring patients suspected of having an OUD 
to a psychiatric consultation service with an AMS or directly to an AMS not affiliated with a consultation 
service.  None of the hospitals is currently employing as usual care a collaborative care team that 
consists of an AMS – CM team that uses a set of principles based on collaborative care along with 
evidence-based tools to support the medical team in intervening with patients with OUD and delivering 
for OUD treatment in the hospital and after discharge.  This pragmatic trial intends to measure the 
START intervention’s effectiveness compared with usual care in diverse hospital settings. The RCT design 
allows for this comparison.   

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4.3 
JUSTIFICATION FOR INTERVENTION 
Prior research has shown collaborative care to be an effective model to treat behavioral health 
disorders,62 behavioral health conditions co-morbid with medical illnesses,11,63-65 and substance use 
disorders.12-16 Collaborative care can also reduce health disparities in access.66-71 However, this model 
has not been tested experimentally for hospitalized inpatients with OUD.  Core components of 
collaborative care consist of a collaboration between a behavioral health specialist (care manager) and 
AMS team, the team using evidence-based practices and tools, close collaboration between the AMS 
and CM, and follow-up with the patient.77  Literature on dosage and core components of collaborative 
care in the hospital setting is not yet available, but we have defined fidelity as incorporating elements of 
each core component. Thus, we do not set values on the dosage of the intervention. Rather, we define 
the intervention as interacting with the AMS and CM team, the AMS and CM incorporating evidence-
based tools (brief negotiated interview and addiction-focused discharge planning) and the patient 
receiving follow-up care. Common in pragmatic trials, the study uses an “intent-to-treat” design, thus all 
participants randomized to receive the START intervention will be included in the evaluation regardless 
of whether they receive the intervention. We anticipate it will be rare for participants to receive none of 
the intervention components.  As an exploratory analysis, we will incorporate dosage (number of visits 
with the START) into our statistical models to understand the relationship between amount of 
intervention received and intervention effects.  
4.4 
END-OF-STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed the baseline and 1-
month follow-up assessments.  Ideally, the participant will also receive some or all of the intervention 
but due to the dynamic nature of the hospital stay (unpredictable medical treatments and discharge, 
leaving against medical advice) and post-discharge complexities, participants may not be able to receive 
the whole intervention. Nevertheless, the study is “intent to treat,” so all participants in the intervention 
condition will be included in the analysis.  
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Admitted to an inpatient bed or for observation at Cedars-Sinai Medical Center (CSMC), 
University of New Mexico Hospital (UNM), or Baystate Health (BH) 
2. Age 18 and older 
3. Have a probable OUD diagnosis, defined by scores of >3 on the opioid section of the Alcohol, 
Smoking, and Substance Involvement Screening test (ASSIST)  
4. Speaks English or Spanish as primary language 
5. Able to provide informed consent 

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5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Currently receiving FDA-approved medication treatment for an opioid use disorder* 
2. <6 months life expectancy  
*”Currently receiving medication” is defined as medications on order at the hospital or soon to be 
ordered while in the hospital, as indicated by medication orders in the EMR, or by patient self-report 
on the eligibility screener of taking the medication since their admission or being told by their 
medical team that they will be receiving the medication while in the hospital. 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who do not meet eligibility criteria for participation in this 
trial or who consent to participate in this study but are not subsequently assigned to the study 
intervention (i.e., they are discharged from the hospital or leave against medical advice before 
completing the baseline interview and/or randomization).  
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of meeting 
one or more exclusion criteria that are likely to change over time may be rescreened. Examples include 
if someone reenters the hospital and now meets criteria for an opioid use disorder or is no longer on an 
FDA-approved medication for opioid use disorder, or was discharged or left AMA before being 
randomized. Rescreened participants will be a new participant number as for the initial screening. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.5.1 PATIENT IDENTIFICATION AND RECRUITMENT 
 
1. Approved study staff will prescreen patients for screening and potential enrollment in two ways: 
o A daily electronic medical record (EMR) report of opioid misuse (“Daily Report”) that 
lists potentially eligible subjects (variables include demographics, opioid history, 
diagnoses, and screenings)  
o Clinician referral 
2. Approved study staff will approach patients in two ways:  
o CSMC Only: Potential subjects will be contacted directly by approved study staff for this 
research through the Direct-to-Patient Recruitment Letter. A courtesy notification will 

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be sent to subjects’ treating physicians to notify them of the invitation to participate 
whenever feasible.  
o Baystate and UNM: If the attending physician agrees, the physician, someone from the 
medical team or designated study staff will explain the study to the patient. 
3. The study team will use the following advertising and recruitment materials (Appendix 10.1): 
For physicians: 
o Study Physician Flyer 
o Physician Screening Card 
o Physician Recruitment Letter (Dear Doctor Letter), accompanied by FAQs about START 
For patients: 
o Baystate and UNM: Physician to Patient Letter (Dear Patient Letter) to be provided to 
patients deemed eligible for the study. 
o CSMC: Direct-to-Patient Recruitment Letter (Dear Patient Letter) to be provided by 
study staff to patients deemed eligible for the study. 
5.5.2 CONSENT AND ENROLLMENT 
1. Approved study staff will provide the full consent form and review the consent summary 
(Appendix 10.1) with the patient. 
2. Consent will be obtained in-person either on paper or electronically using an approved platform 
or remotely using an approved platform. 
3. When signing electronically, patients will be offered the option of receiving a copy of the signed 
and dated consent form by encrypted email. Otherwise, they will be given a paper copy. 
4. Approved study staff will enroll consented, eligible patients by assigning a study ID in the 
REDCap project. 
5. All patients will be given patient education materials on opioid use disorder, as well as harm 
reduction materials (Appendix 10.1). If the visit is remote, the research team will give these 
materials to a member of the medical team to deliver to the patient or place them in the 
patient’s room. 
 
5.5.1 – 5.5.2 are shown in Figure 3.  
5.5.3 RETENTION  
Retention during the hospital stay is not expected to be problematic. To improve post-discharge 
retention, at the time of enrollment, study staff will collect multiple forms of contact information from 
participants to increase the chances that we will be able to reach participants after discharge even if 
there are changes in contact information (e.g., new phone number). Participants without a means of 
being contacted during the follow-up period will be provided a pre-paid phone with minutes by the 
study. 
5.5.4 INCENTIVES 

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Participants will receive a $50 incentive after completing the baseline interview and a $50 incentive 
after completing the follow-up interview. Participants who initiate contact with the study team either to 
schedule a follow-up interview or to provide updated contact information, will receive an additional $5 
incentive after completing the follow-up interview. Incentive type (i.e., gift/merchandise card, cash) and 
delivery method will follow standard site-specific procedures.  
5.5.5 ANTICIPATED ENROLLMENT 
Enrollment will be conducted at three hospitals: Cedars-Sinai Medical Center in Los Angeles, CA; 
Baystate Health in Springfield, MA; University of New Mexico Hospital, Albuquerque, NM.  
Table 3. Screening and Potential Enrollment 
Average Monthly OUD pts to be prescreened  
(CSMC 1023; Bay State 1433; UNM 2766) 
5222 
Total possible per month to screen 
435 
Total possible per month to be screened if recruiting 4.5 days/week 
261 
Potential enrollment per month assuming 25% eligible/consenting 
65 (~41.4 needed) 
Total to be enrolled (41.4 X 10 months) 
414 
 
Table 4. Projected Enrollment by Site, 10-months 
 
 
CSMC 
CC 
69 
138 
UC 
69 
Baystate 
CC 
69 
138 
UC 
69 
UNM 
CC 
69 
138 
UC 
69 
Total to be enrolled 
414 

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Figure 3. RCT Recruitment, Enrollment, Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6 
STUDY INTERVENTIONS 
6.1 
STUDY INTERVENTION ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The components of the START intervention are as follows (see the START Intervention Manual for 
details):  
 
1. Triage (Care Manager [CM] and Addiction Medicine Specialist [AMS]):  
o The CM assesses the patient for acute biomedical needs related to the OUD. The AMS 
addresses acute biomedical needs (e.g. facilitates withdrawal management).   
2. Engage, assess, plan (CM and AMS) (conducted in person or remotely based on circumstances): 
3. If there is not an urgent need for medical intervention or after the urgent medical need is 
addressed, the CM and/or AMS:   
o 
engages with the patient (CM and AMS)  
o 
conducts a diagnostic and biopsychosocial assessment (CM)   
o 
conducts a complete biomedical assessment and addresses comorbidities (AMS)  
o 
delivers the START intervention, consisting of elements of the brief negotiated interview 
(BNI) and re-engineered discharge (RED) – two evidence-based interventions to assess 
and increase readiness – and develops a plan for initiating evidence-based treatment for 
OUD (MOUD and/or psychosocial treatment) during and after the hospital stay (CM)  
o 
ensures the patient understands the follow-up plan and addresses barriers (CM). 
4. Treat (AMS):  
o 
The AMS facilitates MOUD initiation. 
o 
The AMS facilitates psychosocial treatment for the substance use disorder, if indicated 
and available.  
5. Communicate and Coordinate (CM, AMS)  
o 
The CM and AMS communicate with each other to continue care through one-month (or 
more) after the patient is discharged.   
o 
The CM and AMS communicate with the patient and medical team, and, when 
appropriate, the patient’s family and outpatient providers.  
6. Follow-up (CM):  
o 
The CM calls the patient at least once a week for 1 month after the patient is discharged 
from the hospital to assess whether the patient is following through with the discharge 
plan.  
o 
The CM may also call outpatient providers to determine if the patient linked to care and 
has encountered barriers.  
7. Monitor (AMS):  

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o The AMS continues to monitor the patient after discharge through the CM’s follow-up 
work. 
6.1.2 USUAL CARE DESCRIPTION 
 
Usual care consists of each hospital’s current practices for managing patients identified with OUD along 
with each patient enrolled in the study receiving MOUD education and referral information.  None of 
the hospitals is currently employing a collaborative care team that consists of an AMS – CM team that 
uses a set of principles based on collaborative care along with evidence-based tools to support the 
medical team in intervening with patients with OUD and delivering OUD treatment in the hospital and 
after discharge.  The AMS at all three hospitals will serve as the AMS for the START study and will not 
see usual care patients. Usual care at each hospital is described below. 
 
At CSMC, patients randomized to the UC study condition may receive a referral to the existing 
consultation liaison (CL) service if the patient’s medical team determines the need for a consult, or they 
will be treated and provided discharge planning directly by the medical team.  The CSMC CL service has 
several psychiatrists and social workers who can discuss opioid use with the patient and help the patient 
initiate medication, if indicated. These providers can also provide consultation to the medical team on 
whether medication initiation in the hospital and treatment after discharge are indicated.  If the START 
AMS or CM receive a referral from a medical team, they will check the electronic medical record to see if 
the patient is in the study and their study condition.  If the patient is in the UC condition, they will pass 
the referral to another psychiatrist and/or CM.  The study AMS and CM will not take any referrals for UC 
patients for the duration of the study. If directly approached by a member of the medical team for 
consultation, the study AMS or CM will refer them to California Bridge Program resources.  
 
At Baystate, patients randomized to the UC study condition can be treated directly with MOUD and 
provided discharge planning by the medical team.  If the START AMS or CM receives a referral from a 
medical team, they will check the electronic medical record to see if the patient is in the study and their 
study condition.  If the patient is in the UC condition, they will refer the referring physician to California 
Bridge Program resources. For patients in the UC study condition, the referring physician will have the 
option to contact the standard Psychiatric Liaison Consult Service, which does not include an AMS or 
CM.  
At UNM, patients randomized to the UC study condition can be treated directly with MOUD and 
provided discharge planning by the medical team. If the AMS is contacted for a consult about a patient 
in the UC condition, the AMS will provide the medical team with an existing wiki page link and/or 
California Bridge Program resources.  When the AMS receives a referral, they will check a study-staff 
maintained registry to determine if referred patients are in the study and their study condition. 
6.1.3 ADMINISTRATION AND/OR DOSING 

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The CM and AMS may meet with the participant as frequently as necessary to provide OUD treatment 
while the patient is hospitalized.  The anticipated in-hospital duration of the intervention is 4-6 hours. 
Every effort will be made to initiate the intervention during the hospital stay for a participant in the 
START condition. If a participant in the START condition leaves the hospital before the intervention can 
be delivered, the intervention will be delivered by phone and the CM will continue to help link the 
participant with outpatient care in accordance with the care manager follow-up call procedures. After 
discharge, the CM will call each participant at least four times to provide follow-up care.  
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING  
The AMS and CM will participate in training on the START intervention as outlined in Table 5: 
Table 5: Intervention Training Modules  
Training Module  
Duration  
Participants 
Motivational Interviewing Basics 
Two hours 
CM, AMS 
START Intervention Overview 
Two hours  
CM, AMS 
START Intervention: Care Manager Role 
Two hours  
CMS 
START Intervention: AMS Role 
Two hours  
AMS 
Role Plays 
Four to six hours 
CM, AMS 
6.2.2 FIDELITY MEASURES 
Fidelity to the intervention key components (collaborative care, the brief negotiated interview and 
addiction-focused discharged planning) as well as fidelity to the spirit of MI will be measured. Fidelity 
measures are described in Table 6.  
 
Table 6. Fidelity Measures  
Domain 
Measure 
Source 
Collaborative Care Processes77 
  
  
CM Visit 
Proportion of patients who saw CM at least one time 
Registry 
AMS Visit 
Proportion of patients who saw AMS at least one time Registry 
CM/AMS Consultation 
Proportion of patients who were discussed at least 
one time by CM and AMS 
Registry 
Follow-up 
Proportion of patients who got at least 1 follow-up 
w/in 4 weeks after discharge 
Registry 
Evidence-based Care: BNI78 
  
  
  
  
 
• Proportion of patients who got pros and cons 
Registry 
• Proportion of patients who got the readiness ruler 
Registry 
• Proportion of patients who got an OUD-focused 
Action Plan 
Registry 
Evidence-based Care: RED79,80 
  
  

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Domain 
Measure 
Source 
  
  
  
  
• Proportion of patients for whom CM reviewed 
Action Plan prior to discharge  
Registry 
• Proportion of patients who reported that CM 
reviewed Action Plan in a way that they 
understood 
Follow-up survey 
• Proportion of patients for whom a follow-up appt 
was made prior to discharge 
Registry 
• Proportion of patients who received a follow-up 
call within one-week of discharge 
Registry 
Competency/Fidelity to Spirit of 
MI 
  
  
Baseline 
• CM & AMS reached “good” fidelity at baseline 
MITI (In-person) 
Midpoint (~5 months) 
• CM & AMS reached “good” fidelity at midpoint 
MITI (Recorded) 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization 
1. Approved study staff will randomize the patient to the START or UC arm in the stratified block 
design using REDCap. 
2. Subjects will be stratified according to prior MOUD exposure (yes/no) and randomized into 
START or UC. 
3. A stratified, block randomization design will be used stratified by site and prior MOUD exposure, 
and using randomly permuted block sizes of 2, 4, and 8. 
4. Research staff will access their site-specific randomization module in REDCap. Staff will enter 
which MOUD stratum the patient is in and the intervention arm assignment will be generated. 
5. Enrollment will be continuous with the goal of reaching the desired sample size, and some sites 
may enroll more or less than the targeted 69 for each arm. 
 
Blinding 
The baseline interview will occur prior to randomization so research staff will be blind to study 
condition. Follow-up interviews will be performed by RAND SRG research staff who initially will be 
blinded to study condition, although such blinding will be broken during the course of the follow-up 
interview due to branching questions for START participants only.  
 
Minimization of Bias 
The START AMS and CM at each site will be designated to the START and will not see non-START patients 
for consultation during the study period once patients have been randomized.  
 
While it is likely (and expected) that medical teams will treat patients in both the experimental and usual 
care (UC) conditions, patients in the START will have an enhanced experience because they (unlike 

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patients in the UC condition) will be receiving START components designed to increase their readiness to 
take the medication and link to follow-up care. Moreover, the support provided by the START to medical 
teams for each START patient is the component that we hypothesize will take the burden off the medical 
team and increase the likelihood of the patient receiving medication. Even as medical teams become 
more aware of MOUD and perhaps increase prescribing, we hypothesize that patients whose medical 
teams receive support for their START patients will still be more likely to receive medication, even if 
medical teams are aware they can prescribe these medications. Thus, over time, while we might see 
increased medication initiation for patients in both study conditions, we still hypothesize statistically 
and clinically significant differences for patients in the START group. Nevertheless, we still plan to 
safeguard against any biases and effects of UC patients receiving the START. The research team will 
review electronic health record data to determine whether the START AMS or CM accidentally treated 
UC patients.  
 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
N/A 
6.5 
CONCOMITANT THERAPY 
N/A 
6.5.1 RESCUE THERAPY 
 
N/A 
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
When a subject discontinues from the START intervention but not from the study, either because they 
decline to participate or leave the hospital, remaining study procedures will be completed as indicated 
by the study protocol.   
 
The data to be documented at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue (e.g., patient declined/refused, patient left AMA, unable to 
contact the patient after discharge) 
 
• 
Patients who discontinue the intervention will still be contacted for their 1-month follow-up 
assessment.  

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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
Participant discontinuation or withdrawal from the study will be recorded on the Case Report Form 
(CRF). Subjects who sign the informed consent form, are randomized and receive the study intervention, 
and subsequently withdraw or are discontinued from the study, will not be replaced. 
 
Investigators will not withdraw a participant from the study unless the participant withdraws consent to 
use data not already collected, as all participants will be included in the analysis whether or not they 
receive the intervention.  
 
Intent-to-Treat. All participants who are randomized are included in the statistical analysis and analyzed 
according to the group they were originally assigned, regardless of what treatment (if any) they 
received. This method allows the investigator (or consumer of the medical literature) to draw accurate 
(unbiased) conclusions regarding the effectiveness of an intervention. This method preserves the 
benefits of randomization, which cannot be assumed when using other methods of analysis. 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up only if they do not complete the follow-up interview 
within 90 days of discharge.   
 
The following actions must be taken if a participant cannot be reached for their follow-up interview: 
 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, up to 20 telephone calls, a 
Lexus/Nexus search, and, if necessary, a certified letter or visit to the participant’s last known 
address or local equivalent methods). These contact attempts will be documented in the 
participant’s study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to be lost to 
follow-up but will not be considered withdrawn from the study. 
• 
Participants who are unable to complete the follow-up interview due to imprisonment will be 
considered to be lost to follow-up but will not be considered withdrawn from the study. 
• 
Participants who are imprisoned and then released while still within the follow-up period will 
still be considered enrolled in the study and will be contacted to complete the follow-up 
interview.  
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 

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8.1.1 ELIGIBILITY SCREENING 
 
1. Approved study staff will conduct screening (Appendix 10.1), including a validated assessment 
(ASSIST) and demographic data.  
2. Screening will be conducted in person or remotely using an approved platform (REDCap). 
3. Screening data will be entered into a REDCap electronic form. 
4. Screening data from patients who do not enroll in the study will be anonymous, i.e., they will 
not be linked to a MRN or any identifying information. 
8.1.2 BASELINE INTERVIEW 
 
1. Approved study staff will conduct an in-person or remote 30-40-minute baseline interview 
(Appendix 10.2). 
2. Interview data will be recorded on a tablet or computer into a web-based survey system 
(REDCap).  
3. Each site will be responsible for remunerating their participants per their institutional practice. 
8.1.3 1-MONTH FOLLOW-UP INTERVIEW 
 
1. Interviewers from the RAND Survey Research Group (SRG) will conduct a 1-month follow-up 
interview (Appendix 10.2) by telephone after the patient is discharged from the hospital. 
2. The Statistics and Data Coordinating Center (SDCC) at UNM will provide contact information to 
RAND SRG through secure file transfer protocol.  
3. The interview will be 30-40 minutes long. 
4. RAND SRG will be responsible for remunerating participants per their institutional practices. 
5. The interview will take place between 30 and 90 days after hospital discharge. 
8.1.4 PROCEDURAL FLOW 
 
Procedural flow and designation of research versus standard of care are shown in Table 7.  
Table 7. RCT Procedure Designation (Research v. Standard of Care) 
Research Procedures  
Baseline 
visit 
During course of 
hospital stay 
1-month post-
discharge 
Eligibility 
R 
 
 
Informed Consent 
R 
 
 
Randomization 
R 
 
 
Sociodemographic Data  
R 
 
 

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LEGEND 
R = Research item/procedure done only for research purposes and covered by the study 
S = Standard of care item/procedure that is part of regular care and billed to the patient/ 
insurance 
Footnotes: 
a. Only for patients randomized to the START intervention arm of the study. 
b. Available to but not required for both groups: Usual Care and START intervention.  
c. The START intervention utilizes established standard-of-care services and procedures (care 
manager, addiction medicine specialist, medication treatment, therapy, etc.) and helps 
integrate them into the patient’s care in a systematic way. It is this planned coordination 
and integration that are the intervention, not the services themselves. The START 
intervention includes Brief Negotiated Interview and addiction focused discharge planning 
and follow-up. 
8.1.5 VARIABLES COLLECTED 
Outcome variables, measures, and sources are shown in Table 8. Covariates and potential 
mediators/moderators are shown in Table 9. 
Interviews (Baseline and follow-up) – Pain 
(PEG), Depression (PHQ-9), Anxiety (GAD-7), 
SUD treatment/substance use (NSDUH), 
Overdose, 
Healthcare utilization (GAIN), Substance 
Use Severity (PROMIS), Employment 
R 
 
R 
Interviews (Baseline only): Experience of 
stigma, Social Support (MSPSS),  Opinions 
about MAT (OAMAT), Significant other 
OUD, criminal justice involvement  
R 
 
 
Interview (Follow-up only): MAT utilization, 
patient experience of chronic illness care 
(PACIC), therapeutic alliance (CAHPS)a, 
Satisfaction with START intervention a 
 
 
R 
Medication for opioid use disorder b 
 
S 
 
Therapy for opioid use disorder b 
 
S 
 
START Intervention 
START Addiction Medicine Specialist (AMS) 
coordinates/delivers team-based carea,c 
 
R 
R 
START Care Manager (CM) 
Coordinates/delivers team-based carea,c 
 
R 
R 

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Table 8. Outcome Variables  
Table 9. Measures (Outcomes, Covariates, Potential Mediators and Moderators) 
 
Variable 
 
Measure 
 
Data Source 
Response 
Values/Scales 
Sociodemographics 
(Covariates; Potential Moderator)  
 
• Age 
 
Eligibility Screener 
Continuous  
• Sex (Assigned at Birth) 
 
 
Eligibility Screener 
Binary 
• Gender Identity 
 
Eligibility Screener  
Categorical (1-4) 
• Hispanic  
 
Eligibility Screener  
Binary 
• Race 
 
Eligibility Screener 
Categorical (1-5) 
• Current homeless status 
 
Eligibility Screener 
Binary 
• Marital status 
 
Baseline Interview 
Categorical (1-6) 
Outcome 
Endpoint 
Data Source 
Primary Outcomes 
In-hospital initiation of 
MOUD therapy  
Proportion of patients in each arm who initiate 
MOUD prior to discharge, defined as use of any FDA-
approved pharmacotherapy for OUD, including 
buprenorphine, naltrexone and methadone   
EMR  
Linkage to follow-up OUD 
care 
Proportion of patients in each arm who attend at least 
one OUD-related care visit within 30 days of hospital 
discharge  
1-month interview; 
optional validation 
through follow-up with 
service provider  
Secondary Outcomes 
 
 
OUD-specific discharge plan 
Proportion of patients in each arm with an after-
hospital care plan that specifies a date and time for a 
post-discharge addiction care appointment 
EMR chart review 
Any post-discharge MOUD 
utilization 
Proportion of patients in each arm who initiate MOUD 
or continue MOUD treatment within 30 days following 
hospital discharge 
1-month interview; 
optional validation 
through follow-up with 
service provider  
Post-discharge outpatient 
medical care 
Proportion of patients in each arm who complete at 
least one visit to an outpatient medical provider within 
30 days of hospital discharge 
1-month interview 
Past 30-day number of days 
with any opioid use 
Mean (or median, depending on distribution) days of 
use in the past 30 days after hospital discharge– 
Adapted National Survey of Drug Use and Health 
(NSDUH)81   
Baseline interview 
1-month interview 

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Variable 
 
Measure 
 
Data Source 
Response 
Values/Scales 
• Income 
 
Baseline Interview 
Continuous  
• Education 
 
Baseline Interview 
Categorical (1-20) 
• Insurance type 
Payer name 
EMR  
Text (code to 
numeric) 
Mental Health Symptoms   
(Covariates; Potential Moderator/ 
Mediator)  
 
 
• Depression (9 items) 
 
PHQ-9 82,83   
 
Baseline Interview 
1-month Follow-up 
Likert-type (1-4) 
• Anxiety (7 items) 
GAD-784-86 
Baseline Interview 
1-month Follow-up 
Likert-type (1-4) 
Social Support Scale 
(Covariate; Potential Moderator) 
 
 
• Social support: Family, 
Friends, Significant Other 
(6 items; 2 each scale) 
Modified Multidimensional Scale 
of Perceived Social Support87 
Baseline Interview 
1-month Follow-up  
Likert-type (1-7) 
Medical Symptoms/Treatment  (Covariates; potential 
mediator/moderator) 
 
 
• Overdoses (lifetime, past 3 
mos) 
N/A 
Baseline Interview 
1-month Follow-up 
Continuous  
• Primary and secondary 
diagnosis (inpatient stay) 
Medical or mental health 
conditions as determined by the 
inpatient physician 
EMR  
Numeric text (ICD 
codes) 
• Pain intensity and duration PEG88   
Baseline Interview 
1-month Follow-up 
0-10 scale 
• Length of hospital stay 
Days in hospital 
EMR  
Continuous  
Substance Use Treatment 
History 
(Covariates; potential moderator)  
 
• Ever used an MOUD   
• Times started an MOUD 
N/A 
Eligibility Screener 
• Binary 
• Continuous 
• Type of MOUD medication  N/A 
Eligibility Screener 
Categorical (1-4) 
• Treatment other than 
MOUD 
• Times had treatment other 
than MOUD 
N/A 
Eligibility Screener  
• Binary 
• Continuous 
Recent Substance Use 
Treatment Utilization; 
Opinions; Consequences; 
(Outcomes*; Covariates) 
 
 

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Variable 
 
Measure 
 
Data Source 
Response 
Values/Scales 
SUD Treatment Utilization* (5 
items) 
• Past 90 days baseline 
• Past 30 days from 
discharge follow-up 
*Linkage outcome  
Adapted from National Survey on 
Drug Use and Health (NSDUH)81 
Baseline Interview  
1-month Follow-up 
(optional validation 
through follow-up 
with service provider) 
Binary 
Healthcare Utilization (ER, 
Inpatient, Outpatient) Related to 
SUD (5 items) 
• Past 90 days baseline 
• Past 30 days follow-up 
Adapted from Global Appraisal of 
Individual Needs (GAIN)89 
Baseline Interview 
1-month Follow-up 
Continuous 
• Familiar with MOUD 
• Opinions about MOUD (3 
items)  
Opinions about MAT (OAMAT)90 
Baseline Interview  
Likert-type (1-5) 
Severity of Substance Use (7-
items) 
 
PROMIS 
Baseline Interview 
1-month follow-up 
 Likert-type (1-5) 
  
Patient Experience of Stigma (5 
items) 
Adapted from Grosso et al. 2019.91 Baseline Interview 
Binary  
Patient Experience of Chronic 
Illness Care (11 items) 
Patient Assessment of Chronic 
Illness Care (PACIC)92 
1-month Follow-up 
Binary 
Criminal Justice Involvement 
• Ever arrested 
• Times arrested past 90 
d
Locally developed 
Baseline Interview 
• Binary 
• Continuous 
Intervention – Related  
(Covariates; Exploratory 
feasibility outcomes) 
 
 
Intervention “dose”; exposure 
 
Amount time spent with patient  
Number of encounters with 
patient 
START Registry 
(Deidentified) 
Continuous 
 
 
 
 
Therapeutic Alliance  
Consumer Assessment of 
Healthcare Providers and Systems 
(CAHPS®)93 
1-month follow-up 
(START only) 
Binary 
Satisfaction with START 
intervention 
• Helpful in addressing OUD 
(1 item) 
• Feedback (5 items) 
Locally developed 
1-month Follow-up 
(START only) 
• Binary 
• Open text 
 
Minimum EMR variables needed for recruitment, as available at each site, are as follows: 

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• 
Demographics: Patient name; MRN; CSN; Sex; DOB 
• 
Hospital encounter data: Hospital admission date and time; Inpatient admission date and 
location; Reason for admission; Admission diagnosis; Admitting physician; Attending provider 
• 
Interpreter needed – exclusion criterion unless Spanish 
• 
Attending/PCP 
• 
DRGs (Diagnosis Related Group): F11 (Opioid Use Disorders); F19 (Other psychoactive substance 
use); Overdose 
• 
Past medication orders: Buprenorphine; Naloxone; Naltrexone 
• 
Social history (if available): Drug usage 
Minimum EMR elements needed to compile outcome variables are:  
• 
Hospital encounter data: Type; Dates; Disposition; Attending provider; PCP; Psychiatry consult; 
• 
Reason for admission  
• 
Diagnoses  
• 
Inpatient medication (listed by generic names): Buprenorphine; Buprenorphine/Naloxone; 
Methadone; Naltrexone; Naloxone. 
• 
Hospital utilization metrics: Length of stay; Inpatient admissions in prior 12 months; ED 
admissions in prior 12 months; Number of 30-day readmissions 
• 
Insurance type 
 
8.2 
SAFETY ASSESSMENTS 
Because MOUD initiation will take place in the hospital and is not considered the intervention, safety 
will be monitored by the medical team as part of usual medical care.  Safety concerns that arise during 
baseline and follow-up interviews will be reported to the PI.   
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
This protocol defines an adverse event (AE) as any unfavorable and unintended symptom or disease that 
an investigator or study staff learns about which occurs during a patient’s enrollment in the study, if it is 
considered by the site study team to be possibly related to a study treatment or procedure (“possibly 
related” means there is a reasonable possibility that AE may have been caused by research procedures). 
All AEs possibly related to a study treatment or procedure learned about during the course of a patient’s 
enrollment in the study (from time of consent through the follow-up interview or close of the follow-up 
window if they do not have their follow-up interview) will be recorded and reviewed by the site PI 
and/or clinician and CSMC PI, and study staff, and reported further per guidelines described in section 
8.3.5 and shown in Figure 4 and in Tables 10 and 11. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 

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This protocol defines a serious adverse event (SAE) as an AE that an investigator or study staff learns 
about that is fatal, life-threatening, prolongs initial hospitalization, requires inpatient rehospitalization, 
or is medically significant and which the investigators and/or clinicians regard as serious based on 
appropriate medical judgment. With the exception of fatalities, other SAEs documented this study are 
considered those is possibly related to the study; other events occurring during the normal of the 
hospital stay will be numerous and thus not documented unless possibly related to the study. 
Classification of SEVERITY AND RELATEDNESS 
8.3.2.1 SEVERITY OF EVENT 
The following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities or prescribed course of hospital treatment.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning or prescribed 
hospital treatment. 
• 
Severe – Events interrupt a participant’s usual daily activity or prescribed hospital treatment 
and may require systemic drug therapy or other treatment beyond what was prescribed for 
their inpatient treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to a “serious adverse 
event”. 
 
Severity will be used as a factor in determining expectedness of an event, and therefore, in determining 
if it requires reporting. Changes in severity will guide the duration an event is followed as well as 
potential changes in reporting requirements for that event. 
8.3.2.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
AEs considered by study staff to be possibly related to the study and all SAEs possibly related to the 
study will have their relationship to study procedures, including the intervention, assessed by an 
appropriately trained clinician based on temporal relationship and his/her clinical judgment. The degree 
of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event occurs in a plausible time relationship to 
study procedures administration and cannot be explained by concurrent disease or other drugs 
or chemicals, or other events. The response to withdrawal of the study procedures should be 
clinically plausible. The event must be pharmacologically or phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event occurs within a reasonable time after administration of the 
study procedures, is unlikely to be attributed to concurrent disease or other drugs or chemicals 
or events, and follows a clinically reasonable response on withdrawal.  
• 
Unlikely to be related – A clinical event whose temporal relationship to study procedures 
administration makes a causal relationship improbable (e.g., the event did not occur within a 

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reasonable time after administration of the study procedures) and in which other drugs or 
chemicals or underlying disease or events provides plausible explanations (e.g., the participant’s 
clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
Because the intervention is randomization to a collaborative care team and MOUD initiation is not 
considered part of the intervention, known adverse reactions to a specific medication will not be 
considered related to the study intervention. And, because of the likelihood of adverse events during 
the inpatient stay due to patients’ illness or injury, most AEs/SAEs likely will not be related to the 
study.  
8.3.2.3 EXPECTEDNESS  
Study clinicians with appropriate expertise in addiction medicine will be responsible for determining 
whether an adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study procedures. 
 
Expected events will not be reported or followed as AEs. Because the study is being conducted among a 
hospitalized population of people with OUD, patients likely will have many comorbid conditions as well 
as a higher likelihood of unexpected complications, death or readmission from disease.  Any medical or 
psychiatric condition that is present at the time that the participant is screened will be considered as 
baseline and not reported or followed as an AE. However, if the study participant’s condition 
deteriorates at any time during the study and is considered by site study staff to be possibly related to 
the study, it will be recorded as an AE. Common side-effects associated with taking MOUD will not be 
reported as AEs (see Appendix 11.3) and will be monitored by the medical team as part of usual medical 
care.  
 
The only expected AEs from the START intervention (and not MOUD) may be psychological distress 
related to discussing OUD and seeking treatment.   
 
8.3.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study encounters either in-person or over the phone – at enrollment, interviews, 
or follow-up calls), or through notification by a clinician or other source. 
 
AEs and SAEs possibly related to the study will be captured on the case report form (CRF) in REDCap 
(Reporting Form) by selecting the appropriate event type, participant's clinical status (including any 
underlying conditions), study ID, gender and age; REDCap will then prompt for the information 

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applicable to the type of event be completed. Information to be collected, as applicable to the event 
type, may include:  
 
• 
protocol title and number, PI’s name, and the IRB project number 
• 
date of enrollment and randomization 
• 
a detailed description of the event, incident, experience, or outcome  
• 
an explanation of the basis for determining that the event, incident, experience, or outcome 
represents an AE/SAE, PD, or UP 
• 
times of awareness and onset 
• 
concomitant medications 
• 
dates and findings of any relevant tests/assessments that have taken place 
• 
clinician’s assessment of expectedness, severity, and relationship to study procedures (assessed 
only by those with the training and authority to make a diagnosis) 
• 
time of resolution/stabilization of the event. 
• 
a description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the event 
All AEs and SAEs learned about by study staff during the patient’s enrollment in the study that are 
possibly related to the study will be documented regardless of expectedness. All AEs and SAEs will be 
followed to adequate resolution. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
The study coordinator or designated staff member at each site will record events with start dates 
occurring any time after informed consent is obtained and end dates occurring up until 7 (for non-
serious AEs) or 30 days (for SAEs) after the last day of study participation (i.e., end of follow-up window).  
Events will be followed for outcome information until resolution or stabilization. 
8.3.4 ADVERSE EVENT REPORTING  
 
When deciding whether an event should be recorded on the reporting form in REDCap, each site’s study 
coordinator or designated staff member will consult with the site PI and/or their designated clinical 
study staff member. Following consultation, AEs and SAEs possibly related to the study will be recorded 
by each site’s study coordinator or designated staff member in the REDCap Reporting Form. Each site PI 
and/or their designated clinical study staff member will review the form and investigate each event 
further to ascertain: (1) nature of the event (disclosure, psychological distress, or physical harm), (2) 
type and degree of actual harm (potential, social/psychological, physical), (3) type and degree of 
potential harm (social/psychological, physical), (4) potential attribution to the research study, (5) 
potential contributing factors, and (6) potential for recurrence. The research team (the site PI or 
designee, with the study PI and staff) will confer on how to handle the events, including discussing them 

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with the IRB, if uncertainty exists. The only exception to this rule is patient death, which always will be 
recorded on the REDCap form regardless of whether it is considered possibly related to the study. 
 
AEs possibly related to the study will be provided to Dr. Danovitch and the CSMC study coordinator in a 
weekly summary report. SAEs will be sent to Dr. Danovitch and the CSMC Study Coordinator upon entry 
into REDCap, but regular AEs will not. 
 
IRB reporting: AEs that are not SAEs do not need to be reported to CS-IRB. See below for SAE reporting. 
 
DSMB reporting: All AEs considered possibly related to the study and all SAEs will be summarized and 
reported to the DSMB at three time points during data collection. 
8.3.5 SERIOUS ADVERSE EVENT REPORTING  
Upon consultation with the site PI or and/or their designated clinical study staff member, SAEs possibly 
related to the study will be recorded by each site’s study coordinator or designated study staff in the 
REDCap Reporting Form. All patient deaths learned about by study staff will be recorded and reported 
regardless of whether they are considered possibly related to the study. Each site PI and/or designated 
clinical study staff member will review the form and investigate each event further to ascertain: (1) 
nature of the event (psychological distress, or physical harm), (2) type and degree of actual harm 
(potential, social/psychological, physical), (3) type and degree of potential harm (social/psychological, 
physical), (4) potential attribution to the research study, (5) potential contributing factors, and (6) 
potential for recurrence. The research team (the site PI or designee, with the study PI and staff) will 
confer on how to handle the events, including discussing them with the IRB, if uncertainty exists.  
SAEs will be sent to Dr. Danovitch and the CSMC Study Coordinator upon entry into REDCap. Dr. 
Danovitch and the CSMC study coordinator who will review the form and notify the CS-IRB and the 
DSMB as required and outlined below.  
 
IRB reporting: SAEs must be reported to the Cedars-Sinai IRB if they are unexpected (e.g., not listed in 
the consent form) and at least probably related to the research (with the exception of patient death, 
which is always reported). Reportable events must be reported to the CSMC study team as soon as 
possible but no later than 10 business days from the relying site’s awareness of the event. The CSMC 
study team must submit the event in CS-IRB as soon as possible but no later than 10 business days from 
the CSMC study team’s awareness of the event, via a Reportable New Information (RNI) form in CS-IRB, 
selecting the most appropriate type of report, and including copies of any relevant documentation.  
 
DSMB reporting: All SAEs possibly related to the study and all patient deaths will be summarized and 
reported to the DSMB at three time points: initial, interim, final.  Ad hoc review may take place if there 
is a study-related SAE.  
Patient deaths that the study team becomes aware of during the follow-up period, regardless of the 
relationship to the study, must be reported to the CSMC study team as soon as possible but within 10 

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business days of the site’s awareness of the event. These events will be reported to the DSMB by email 
within 10 business days of CSMC’s awareness of the event. 
NIH reporting: SAEs possibly related to the study will be reported to the Project Officer by email within 
10 business days of CSMC’s awareness of the event. 
8.3.6 REPORTING EVENTS TO PARTICIPANTS  
N/A 
8.3.7 EVENTS OF SPECIAL INTEREST  
 
N/A 
8.3.8 REPORTING OF PREGNANCY  
 
N/A 
 

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Table 10. Site AE/SAE Reporting  
 
Nature of 
Event 
Examples 
Study-
Related 
Reported By 
Reported To 
Format 
Reporting Timeframe  
(From Awareness) 
ADVERSE EVENTS (Events deemed by site study staff to be at least possibly related to the study) 
 
Expected 
Mild side effects of MOUD 
or the psychosocial 
intervention 
At least 
possibly  
N/A (Expected events are not reportable) 
Unexpected 
Unknown 
At least 
possibly  
Site study 
staff/SDCC 
CSMC PI/study staff 
REDCap (AE) 
Reporting Form  
Weekly summary 
prepared by SDCC 
SERIOUS ADVERSE EVENTS (Events deemed by site study staff to be at least possibly related to the study, except patient death) 
Expected 
Unknown 
At least 
possibly  
N/A (Study does not have any expected SAE) 
Unexpected 
Deteriorating condition 
related to expected side 
effects of MOUD or the 
psychosocial intervention; 
other unexpected side 
effects; readmission  
At least 
possibly   
Site study 
staff 
Site PI, CSMC PI/study 
staff 
REDCap (SAE) 
Reporting Form 
As soon as recorded, 
within 10 business days 
Unexpected 
Patient death 
Unrelated or 
related         
Site study 
staff 
Site PI, CSMC PI/study 
staff 
REDCap (SAE) 
Reporting Form 
As soon as recorded, 
within 10 business days 
UNANTICIPATED PROBLEMS 
 
Breach of 
confidentiality 
or privacy 
PHI shared with another 
site; wrong patient email 
used 
Related 
Site study 
staff 
Site PI, CSMC PI/study 
staff 
REDCap (UP) 
Reporting Form 
As soon as recorded, 
within 10 business days 
Patient 
complaint 
(unresolved) 
Claim of non-payment  
Related 
Incarceration 
Patient incarcerated at any 
point during follow-up 
period (even if released) 
N/A 
New risk 
Recall of MOUD given to 
patient 
Related 

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Nature of 
Event 
Examples 
Study-
Related 
Reported By 
Reported To 
Format 
Reporting Timeframe  
(From Awareness) 
NON-COMPLIANCE 
 
Protocol 
Deviations 
Eligibility or consent 
deviation; HIPAA violation 
Related 
Site study 
staff 
Site PI, CSMC PI/study 
staff 
REDCap (PD) 
Reporting Form 
As soon as recorded, 
within 10 business days 
 
Table 11. CSMC AE/SAE Reporting  
 
Nature of 
Event 
Examples 
Study-
Related 
Reported By 
Reported To 
Format 
Reporting Timeframe  
(From Awareness) 
ADVERSE EVENTS (Events deemed by CSMC PI/study staff to be at least possibly related to the study) 
Expected 
Mild side effects of 
MOUD or the 
psychosocial 
intervention 
At least 
possibly   
N/A (Expected events are not reportable and the study does not have expected SAE) 
Unexpected 
Unknown 
At least 
possibly   
CSMC study staff 
DSMB 
AE Summary  
At three time points during data 
collection: initial, interim, final. Ad 
hoc review may take place if there 
is a study-related SAE. 
SERIOUS ADVERSE EVENTS (Events deemed by CSMC PI/study staff to be at least possibly related to the study, except patient death) 
Expected 
Unknown 
At least 
possibly   
N/A (Expected SAEs are not reportable to IRB) 
Unexpected 
Deteriorating 
condition related to 
expected side 
effects of MOUD or 
the psychosocial 
intervention; other  
unexpected side 
effects; readmission 
Probably or 
Definitely 
CSMC study staff 
CSMC IRB  
/ DSMB, NIH 
RNI Form (IRB) 
/ SAE Form 
(DSMB, NIH) 
Within 10 business days 
Unexpected 
Patient death 
Unrelated or 
related  
CSMC study staff 
CSMC IRB (if 
probably 
related) /  
RNI Form /  
SAE Form 
Within 10 business days 

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Nature of 
Event 
Examples 
Study-
Related 
Reported By 
Reported To 
Format 
Reporting Timeframe  
(From Awareness) 
DSMB (all 
deaths) 
UNANTICIPATED PROBLEMS 
 
Breach of 
confidentiality 
or privacy 
PHI shared with 
another site; wrong 
patient email used 
Related  
CSMC Study Staff 
DSMB  
/ CSMC IRB 
RNI Form (IRB) 
/ Summary 
(DSMB) 
Within 10 business days (IRB); At 
three time points during data 
collection. (DSMB) 
Patient 
complaint 
(Unresolved) 
Claim of non-
payment  
Related 
Incarceration 
Patient incarcerated 
at any point during 
follow-up period 
(even if released) 
N/A 
New risk 
Recall of MOUD 
given to patient 
Related  
NON-COMPLIANCE 
 
Protocol 
Deviations 
Eligibility or consent 
deviation; HIPAA 
violation 
Related  
CSMC Study Staff 
CSMC IRB / 
DSMB, NIH 
RNI Form (IRB) 
/ PD Form 
(DSMB, NIH) 
Within 10 business days 

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8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS  
This protocol uses the definition of Unanticipated Problems (UPs) as defined by the Office for Human 
Research Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or 
others to include, in general, any incident, experience, or outcome that meets all of the following 
criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by 
research procedures); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
UPs may or may not be AEs/SAEs. 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 
Site investigators will report UPs to Dr. Danovitch. Dr. Danovitch will report UPs to the CSMC 
Institutional UPs that do not otherwise meet the definition of an AE/SAE (e.g., breach of confidentiality 
or privacy, unresolved patient complaints, incarceration, new risks) will be recorded by each site’s study 
coordinator in the REDCap Reporting Form. Each site PI and/or clinical designee will review the form and 
investigate each event further to ascertain: (1) nature of the event (disclosure, psychological distress, or 
physical harm), (2) type and degree of actual harm (potential, social/psychological, physical), (3) type 
and degree of potential harm (social/psychological, physical), (4) potential attribution to the research 
study, (5) potential contributing factors, and (6) potential for recurrence. The research team (the site PI 
or designee, with the study PI and staff) will confer on how to handle the events, including discussing 
them with the CSMC IRB, if uncertainty exists. If disclosures of sensitive individually identifiable 
information may have occurred outside the research team, the study will adhere to HIPAA and other 
relevant considerations. 
 
Completed UP Forms will be automatically sent through REDCap to Dr. Danovitch and the CSMC study 
coordinator, who will review and notify the Cedars-Sinai IRB, the DSMB, and the study Project Officer as 
required and outlined below.  
 

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• 
UPs that are adverse events (AEs) or serious adverse events (SAEs) will be reported as described 
in Section 8.3. 
• 
Any other UPs will be reported per the same guidelines as AEs/SAEs.  
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Hypotheses: 
Primary Hypothesis 1: We hypothesize that, compared to patients who receive usual care, patients in 
the START condition will be more likely to initiate MOUD while hospitalized. Alternatively, our null 
hypothesis is that there will be no difference in likelihood of in-hospital MOUD initiation between 
patients in the START and UC conditions. 
Primary Endpoint 1: 
Proportion of patients in each arm who initiate MOUD prior to discharge, 
defined as use of any FDA-approved pharmacotherapy for OUD, including buprenorphine, naltrexone 
and methadone.   
 
Primary Hypothesis 2: We hypothesize that, compared to patients who receive usual care, patients in 
the START condition will be more likely to receive linkage to post-discharge MOUD care (i.e., attend at 
least one OUD-related care visit within 30 days of hospital discharge). Alternatively, our null hypothesis 
is that there will be no difference in linkage to post-discharge MOUD care for patients in the START 
condition compared to those in UC condition. 
Primary Endpoint 2: 
Proportion of patients in each arm who attend at least one OUD-related care 
visit within 30 days of hospital discharge. 
 
Secondary Hypotheses: 
Secondary Hypothesis 1: We hypothesize that, compared to patients who receive usual care, patients in 
the START condition will be more likely to receive addiction-focused discharge planning. Alternatively, 
our null hypothesis is that there will be no difference in likelihood of receiving addiction-focused 
discharge planning between patients in the START and UC conditions. 
Secondary Endpoint 1: Proportion of patients in each arm with an after-hospital care plan that specifies 
a date and time for a post-discharge addiction care appointment. 
 
Secondary Hypothesis 2: We hypothesize that, compared to patients who receive usual care, patients in 
the START condition will be more likely to receive MOUD treatment after discharge (i.e., initiate MOUD 
or continue MOUD treatment within 30 days following hospital discharge). Alternatively, our null 

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hypothesis is that there will be no difference in likelihood of receiving MOUD treatment between 
patients in the START and UC conditions. 
 
Secondary Endpoint 2: Proportion of patients in each arm who initiate MOUD or continue MOUD 
treatment within 30 days following hospital discharge. 
 
Secondary Hypothesis 3: We hypothesize that, compared to patients who receive usual care, patients in 
the START condition will be more likely to receive linkage to post-discharge medical care (i.e., complete 
at least one visit to an outpatient medical provider within 30 days of hospital discharge). Alternatively, 
our null hypothesis is that there will be no difference in linkage to post-discharge medical care for 
patients in the START condition compared to those in UC condition. 
 
Secondary Endpoint 3: Proportion of patients in each arm who complete at least one visit to an 
outpatient medical provider within 30 days of hospital discharge. 
 
Secondary Hypothesis 4: We hypothesize that, compared to patients who receive usual care, patients in 
the START condition will be more likely to significantly reduce opioid use after discharge (i.e., days of 
opioid use in the 30 days between discharge and follow-up). Alternatively, our null hypothesis is that 
there will be no difference in likelihood of reducing opioid use between patients in the START and UC 
conditions. 
 
Secondary Endpoint 4: Mean (or median, depending on distribution) days of use in the past 30 days 
after hospital discharge – Adapted National Survey of Drug Use and Health (NSDUH). 
9.2 
SAMPLE SIZE DETERMINATION 
In-patient MOUD initiation: A sample size of n=414 (allowing for 20% attrition) and adjusted type I error 
rate of 2.5% provides 84% power to detect an OR=2.3 comparing the in-patient MOUD initiation rates in 
the CCT and UC arms, stratified on prior MOUD use. Based on literature, 14% of UC patients who are 
MOUD-naïve initiate MOUD in hospital.5 Assuming the average of MOUD-naïve and MOUD-experienced 
in-patient MOUD initiation rates is 20%, we have an adequate sample size and power to detect this 
increase of in-patient MOUD initiation in the CCT arm (37%) compared to UC.5,59,61  
Linkage to OUD Care: We base the sample size estimate on the linkage to care measure since the 
probabilities of successful linkage are lower than for in-patient MOUD initiation. Linkage to care rates 
reported in the literature range between 10%-17% in usual care settings. To err on the side of caution, 
we estimate linkage to care in UC for MOUD-naïve and MOUD-experienced to be 5% and 10%,5,59,61,94 
respectively, yielding an average of 7.5%. We hypothesize that at least 20% of patients randomized to 
the START arm will link to OUD care (attend at least one OUD-related visit) within 30 days following 
discharge. Assuming a Bonferroni-corrected, two-sided type I error rate of 2.5% to adjust for two 
primary endpoints, we will enroll a minimum of 414 patients (207 in each intervention arm) to have 80% 

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power to detect this difference. This estimate includes an adjustment for up to 20% attrition. This effect 
size corresponds to a clinically meaningful odds ratio of 3.0. Prior studies in different settings have found 
larger effects,61,94,95 supporting our ability to conduct this test. 
Sample size calculations for the primary endpoints were performed in PASS 14 using stratified Mantel-
Haenszel tests for two proportions between two groups,96 with strata defined as 50% MOUD-naïve and 
50% MOUD-experienced.61,94,95,97,98 Due to the short 1-month duration of participation, subject 
withdrawal from the study is not anticipated to be significant. 
9.3 
POPULATIONS FOR ANALYSES 
 
Intention-to-Treat (ITT) Analysis Population (i.e., all randomized participants) will be included in 
analyses. Participants who complete the informed consent or part of the baseline interview but are not 
randomized will be excluded from analysis. 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Baseline characteristics will be summarized with descriptive statistics such as means and standard 
deviations for continuous variables and frequencies and percentages for categorical variables. 
Summaries will be presented overall, by intervention arm, and by previous MOUD use. Continuous 
baseline demographics and characteristics will be compared with t tests or Wilcoxon rank sum tests, as 
appropriate. Categorical variables will be compared with chi-square or Fisher exact tests, as appropriate. 
Corresponding confidence intervals will be reported in addition to p-values. The primary and secondary 
analyses will be performed for the intention-to-treat population, which consists of all randomized 
subjects who meet inclusion and exclusion criteria.  
 
Missing Data: Study endpoints are cross-sectional in time. Every effort will be made to obtain all 
necessary outcome and covariate data. We will use inverse probability weighting and multiple 
imputation (IPW-MI) to adjust for missing covariate data.99 Specifically, we will examine whether 
observable baseline characteristics differ by attrition status, and if so we will adjust our comparisons 
using weights. MI will be used to impute intermittently missing data for study completers. We will not 
impute outcomes, but only covariates.  
9.4.2 ANALYSIS OF PRIMARY AND SECONDARY ENDPOINTS 
Primary Endpoint Analyses: 
Unadjusted point estimates and confidence intervals for proportions and means will be reported by arm 
and by prior MOUD use for endpoints. Primary endpoints will be compared between arms by fitting a 
multivariable logistic regression model to each that includes as independent variables: intervention arm, 

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prior MOUD exposure and site, as well as relevant baseline characteristics as covariates, including age, 
insurance status (as a marker for income), race, and ethnicity. Additional covariates that may be 
included are substance use severity, homelessness and length of index hospitalization, as well as any 
other variables also thought to be associated with outcomes that demonstrated imbalance between 
treatment arms.95 Site will be included as a fixed effect to reflect the study design and to control for 
potential variability in CCT implementation. Odds ratios and their Bonferroni-adjusted 97.5% Wald 
confidence intervals will be reported for the two primary outcomes. 
Secondary Endpoint Analyses:  
Similar analyses as described for the primary endpoints will be performed for these secondary 
proportions outcomes, but instead reporting 95% confidence intervals. For Secondary Endpoint #4, a 
general linearized model to number of days of opioid use will be fitted along with the covariates 
described for the logistic regression models. An appropriate link function will be identified and used 
based on the distribution of the outcome data. 
9.4.3 SAFETY ANALYSES 
N/A 
 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
Intervention groups will be compared on baseline characteristics (e.g., demographics, mental health 
characteristics) using descriptive statistics. Planned comparisons are below. Additional comparisons may 
be added to the statistical analysis plan. 
 
• 
Site 
• 
Age (mean, SD) 
• 
Assigned Sex 
• 
Gender Identity 
• 
Ethnicity (Hispanic/Latino) 
• 
Race 
o Black/African American 
o White 
o Asian/Pacific Islander 
o American Indian/Alaska Native 
o Multiple races 
o Other race 
• 
Insurance status 
• 
Homeless 
• 
Depression (PHQ) and anxiety (GAD) 
 
 

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9.4.5 PLANNED INTERIM ANALYSES  
 
We will conduct an interim analysis on the second primary outcome (linkage to post-discharge care) 
when we have enrolled 288 participants.  288 is the revised analytic sample size needed for the first 
primary outcome - medication initiation.  This revised analytic sample size is based on the actual balance 
between those with and without prior MOUD use (our strata) as well as the actual attrition rate rather 
than our hypothetical pre-study calculations, as well as our desire to minimize participant burden.   
Including 288 patients in the interim analysis allows for approximately n = 288 × 0.70 (actual attrition 
rate) = 202, or ~68%, of our final analytic sample size for the linkage outcome (202/299). We will utilize 
an alpha-spending method100,101 to ensure that, should we continue the study until full enrollment, we 
control the family-wise type I error rate to be 2.5% for each outcome. Using a two-sided test, this 
approach will allow us to assess superiority of the intervention over the control or the control over the 
intervention. If we reject the null hypothesis at the interim analysis, we will discontinue the study. 
Should we fail to reject the null hypothesis at the interim analysis, we will continue to full enrollment 
before conducting the final analysis.  
9.4.6 SUB-GROUP ANALYSES   
Past research suggests that sex or gender does not moderate START effectiveness.102 However, we will 
conduct exploratory analyses to see if patient sex or gender, or race/ethnicity has an effect on primary 
outcomes or retention. Adjusted odds ratios and their 95% confidence intervals will be calculated from 
interaction effects between treatment group and sex or gender from the specified linear models for the 
primary and secondary outcome measures. 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be aggregated and summarized descriptively. Inference will be made on 
the entire study sample and not at the individual participant level. 
9.4.8 EXPLORATORY ANALYSES 
To explore possible mechanisms of how START works, we will conduct the following exploratory 
analyses: (1) Assess the mediating effect of inpatient MOUD initiation on use of MOUD and linkage with 
OUD treatment post-discharge; (2) Assess the mediating effect of completion of an OUD-specific 
discharge plan on linkage with OUD treatment 30 days post-discharge; (3) Assess the moderating effects 
of patient characteristics (e.g., gender, race, ethnicity, insurance status) on post-discharge linkage. We 
will summarize bivariate relationships between site and patient characteristics. To evaluate how these 
relationships may affect endpoints, we will assess the interaction effects between site and these 
covariates from the logistic regression models described for the primary and secondary analyses.  

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Additionally, of interest is time to linkage to care following discharge. A Cox proportional hazards model 
will be fitted to the time to linkage with intervention arm and other relevant baseline characteristics as 
covariates, including age, insurance status (as a marker for income), race, and ethnicity. Additional 
covariates identified for the primary and secondary analyses may also be included. The proportional 
hazards assumption will be assessed. The relative risk and 95% CI for the two arms will reported and 
median times to linkage will be reported.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and documentation (e-signature) of informed consent will be completed prior to starting the 
study intervention. The consent form will be prepared in English and Spanish. 
English and Spanish consent forms are included in Appendix 11.1.   
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The consent process for eligible patients is as follows: 
 
1. Approved study staff will provide the full consent form and review the consent summary (see 
Appendix 11.1) with patient. 
2. Consent will be obtained in-person either on paper or electronically using an approved platform 
or remotely using an approved platform. 
3. When signing electronically, patients will be offered the option of receiving a copy of the signed 
and dated consent form by encypted email. Otherwise, they will be given a paper copy. 
4. Approved study staff will enroll consented, eligible patients by assigning a study ID in the 
REDCap project. 
 
The consent form will be translated into Spanish. For Spanish-speaking participants, Spanish-speaking 
research staff or English-speaking staff with a Spanish-speaking interpreter will obtain consent.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 

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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, and funding 
agencies.  
 
If the study is prematurely terminated or suspended, the lead Principal Investigator (PI) (Danovitch) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor/funding agencies 
and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance of study staff to the protocol (i.e., significant protocol violations) 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the funding agencies, sponsor, IRB, DSMB. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the DMSB and funding agencies. This confidentiality is extended to the data being collected as part of 
this study. Data that could be used to identify a specific study participant will be held in strict confidence 
within the research team. No personally identifiable information from the study will be released to any 
unauthorized third party without prior written approval of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made 
available to the public (see https://grants.nih.gov/policy/sharing.htm). The PIs will ensure all 
mechanisms used to share data will include proper plans and safeguards for the protection of privacy, 
confidentiality, and security for data dissemination and reuse (e.g., all data will be thoroughly de-
identified and will not be traceable to a specific study participant). Plans for archiving and long-term 
preservation of the data will be implemented, as appropriate.  
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), 
has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, 
clinical or other human subjects research funded wholly or in part by the federal government. Recipients 

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of NIH funding for human subjects research are required to protect identifiable research information 
from forced disclosure per the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). 
As set forth in 45 CFR Part 75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported 
research covered by this Policy are required to establish and maintain effective internal controls (e.g., 
policies and procedures) that provide reasonable assurance that the award is managed in compliance 
with Federal statutes, regulations, and the terms and conditions of award. It is the NIH policy that 
investigators and others who have access to research records will not disclose identifying information 
except when the participant consents or in certain instances when federal, state, or local law or 
regulation requires disclosure. NIH expects investigators to inform research participants of the 
protections and the limits to protections provided by a Certificate issued by this Policy. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at UNM SDCC.  After the study is completed, de-
identified, archived data will be transmitted to and stored at each site for future analyses. Data will not 
be stored in a central repository. UNM will store all identifiable study data on their secured servers for up 
to seven years following completion of the START study, per UNM and federal policies, and will be 
destroyed at that time or according to NIH guidelines. Each site may retain their site-specific, identified 
data on their own password-protected, secured servers behind their institution’s firewall for additional 
analyses. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigators  
Principal Investigator (Contact) 
Principal Investigator 
Itai Danovitch, MD, MBA (MPI) 
Allison Ober, PhD, MSW (MPI) 
Cedars-Sinai Medical Center  
RAND Corporation 
8730 Alden Drive, Suite E-135 
Los Angeles, CA 90048 
1776 Main Street, Santa Monica, 
CA 90407 
310.423.2600 
310-393-0411 ext. 6639 
Itai.danovitch@csmc.org 
ober@rand.org 
 
The study has a Steering Committee that consists of the MPIs and Co-Is, workgroup leads, and other 
relevant study staff. The Steering Committee meets monthly to discuss issues relevant to study design, 
administration, and implementation. Site responsibilities and leadership are further enumerated below. 
 
Key Roles 
 
Principal Investigator (MPI - 
Contact) 
Itai Danovitch, MD, MBA 
Cedars-Sinai Medical Center 
8730 Alden Drive, Suite E-135 
Los Angeles, CA 90048 
Research Activities:  Overall study oversight; lead clinical intervention    
Principal Investigator (MPI) 
Allison Ober, MSW, PhD (MPI) 

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RAND Corporation, 1776 Main Street, Santa Monica, CA 90407; 310-
393-0411 ext. 6639 
Research Activities:  Lead RCT implementation and evaluation; oversee 
organizational context analysis     
Sponsor/Funders 
Pablo Cure (Program Officer) NCATS National Center for Advancing 
Translational Sciences;  
NIDA (National Institute on Drug Abuse) 
Study Sites/Statistics and Data 
Coordinating Center (SDCC) 
Kimberly Page, PhD, MPH (Co-I);  
Cristina Murray-Krezan, PhD (Study Statistician) 
University of New Mexico Health Sciences Center, MSC10 5550, 1 
University of New Mexico, Albuquerque, NM 87131; (415) 350-0625 
Research Activities: Conduct RCT. Serve as multisite statistics and data 
coordinating center (SDCC) - obtain EMR, patient survey and follow-up 
medical records data variables, and analyze RCT outcomes  
 
Peter Friedmann, MD, MPH (Co-I) 
Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199; 
(413) 794-3391 
Research Activities: Conduct RCT 
CTSA  
 
Research Activities:  Support sites as needed inpatient identification and 
recruitment procedures 
Data Safety and Monitoring Board 
 
UCLA Data and Safety Monitoring Board for Addiction Medicine (DSMB-
AM, led by Dr. Steven Shoptaw of UCLA Department of Family 
Medicine).  
Research Activities:  Serve as DSMB for multisite trial 
 
10.1.6 SAFETY OVERSIGHT 
The NIH requires the establishment of DSMBs for multi-site clinical trials involving interventions that 
entail potential risks to the participants, even trials that pose little likelihood of harm. This study's DSMB 
will be established through the UCLA Data and Safety Monitoring Board for Addiction Medicine (DSMB-
AM, led by Steven Shoptaw).  
The UCLA DSMB-AM will monitor throughout the entire course of the study, specifically during the 
period that involves any human involvement (e.g., enrollment stage, during course of study treatment, 
throughout any follow-up assessments, etc.). The DSMB-AM will conduct an initial review at the 
beginning of study, when the team will be applying for Institutional Review Board approval. After that, 
they will hold annual interim reviews. Once all data collection for human subjects is complete, the 
DSMB-AM will conduct a final review. The DSMB-AM will reserve the right to request additional interim 
reviews, in the unlikely instance that there is an increased risk during the course of the study.  
The DSMB-AM includes experts in all scientific disciplines needed to interpret the data and ensure 
patient safety, including addition experts, clinical trial experts, biostatisticians, and bioethicists. DSMB 
members will have no association with the project investigators, and no conflicts of interest with study 
outcomes. DSMB procedures will conform with usual standards, including reviewing emerging trial data 
and maintaining confidentiality. DSMB members will serve the following functions: (1) reviewing the 

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research protocol and plans for data and safety monitoring; (2) monitoring data quality, timeliness, 
recruitment, retention, performance across study sites, and factors that may affect the risks and 
benefits of the study such as emerging literature; and (3) making recommendations regarding 
continuation of the trial. 
10.1.7 CLINICAL MONITORING 
N/A 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent — Study staff at each site will review both the documentation of the consenting 
process as well as a percentage of the completed consent documents.  This review will evaluate 
compliance with GCP, accuracy, and completeness.  Feedback will be provided to the larger study team 
to ensure proper consenting procedures are followed.  
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. Section 9.5.10 provides information on protocol deviations and reporting. 
Data – PI Page and the SDCC team at UNM will be responsible for data quality control, including 
evaluating data for adherence with the protocol and for accuracy. Site queries will occur every 2-4 
weeks.  Study status reports generated from the database will provide a basis for ongoing monitoring of 
subject accrual and retention, as well as completeness of data. These will be used to identify and resolve 
problems that may arise. Data extracted from each site’s electronic medical record will be uploaded to 
the UNM SDCC via secure file transfer protocol (SFTP) and checked monthly during the study. Follow-up 
survey data will be entered directly into REDCap. Under the direction of a statistician, a quantitative 
analyst will check the data for completeness and accuracy.  
Should independent monitoring become necessary, the PI will provide direct access to all trial-related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  

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Source Documents 
• 
Source documents are:   
o REDCap eligibility form 
o REDCap electronic consent 
o REDCap baseline and follow-up survey forms (RAND SRG will enter follow-up interview 
data directly into REDCap) 
o REDCap contact information form  
o Medical records from providers indicating service utilization, faxed to each site then 
uploaded into REDCap 
o Patient tracking spreadsheet 
o Patient registry (This is part of the intervention; these records will be linked to study 
records using the MRN, which will be in REDCap and in the Registry.) 
Data Management 
Data will be collected from multiple sources throughout the course of the study. All prospectively 
collected data will be directly entered into the UNM REDCap electronic data capture system which is 
administered by the UNM Clinical and Translational Science Center (CTSC). The UNM Statistics and Data 
Coordinating Center (SDCC) will develop electronic data collection forms of the patient interviews in 
REDCap and will maintain access rights to the database. All data will be stored on UNM HSC’s secured 
servers and behind their firewall. Other data sent to UNM will be transferred via SFTP following all 
institutional policies and executed data use agreements. Data to be curated by the UNM SDCC includes 
the following sources: 
• 
Potentially eligible participants will be identified from reports generated from the electronic 
medical record (EMR) 3-5 times per week by the sites’ informatics teams. These reports will be 
restricted to admitted patients who meet the eligibility criteria specified in Section 5. 
• 
Consent forms obtained electronically may be sent to participants by encrypted email.  
• 
Baseline and outcome interview data will be collected by Research Assistants at each site and 
follow-up interview data will be collected by RAND SRG by telephone. All data will be directly 
entered into the UNM SDCC’s REDCap system.  
• 
In the event that the UNM SDCC’s REDCap system cannot be accessed, the sites may enter data 
in a copy of the project on their local REDCap system or utilize paper forms. In these cases, the 
data will be merged into the the UNM SDCC’s REDCap system when it becomes available, either 
by site staff or by transmission to UNM SDCC via SFTP for entry into their system.  
• 
Additional outcome data will be obtained from the sites’ EMR and will be retrieved by their 
informatics teams. This data will be sent to the UNM SDCC via SFTP and will be merged with the 
other study data. 
Data Storage 
• 
All study data will be stored in a REDCap database behind UNM Health Science Center’s (HSC) 
firewall on a secured and encrypted password protected server following UNM HSC data 

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security policies. Any identifiable information (such as contact information and medical record 
number) will be stored in a REDCap database (“project”) in an encrypted format behind a 
firewall on UNM’s secured servers and is accessible only to designated personnel on a case-by-
case basis. The UNM data center is staffed with onsite security personnel 24x7x365 and 
provides multilevel physical and logical security protection including: monitoring, video 
surveillance, biometric and access card and man-trap access to datacenter floor, encrypted and 
password protected servers, and restricted logical access, with a dedicated and encrypted data 
drive behind a firewall. Access to the data is provided only to authorized users through an 
encrypted transmission channel with a password-protected application interface. UNM will 
store all data on their secured servers for up to 7 years following completion of the START study, 
per UNM policies, and will be destroyed at that time or according to NIH guidelines. Should 
medical record data need to be received by the SDCC via fax, it will be uploaded to REDCap and 
paper copies will be destroyed. Should paper collection of study data or forms need to be 
utilized, they will be destroyed once they are confirmed to be in the electronic system.   
Additionally, all deidentified analysis data sets will be transmitted via SFTP to the Principal 
Investigators at the participating sites for additional analyses where the data will be stored 
behind their institution’s firewalls on password-protected and encrypted servers. 
Responsibility for Data Safety and Monitoring 
The study team will monitor the safety of participants and the validity and integrity of the data. Data 
safeguarding procedures will adhere to standards established by applicable regulations including those 
by the NIH, the Department of Health and Human Services, local HIPAA regulations, and standards set 
by the Cedars-Sinai Institutional Review Board.  
As Co-PIs, Drs. Itai Danovitch and Allison Ober carry ultimate responsibility for ensuring compliance with 
the trial Protocol as well as the Data and Safety Monitoring Plan. Dr. Nuckols at Cedars-Sinai will be 
tasked with overseeing compliance with procedures for human subjects' protections as well as data and 
safety monitoring, under the guidance of Drs. Ober and Danovitch. Researchers at the University of New 
Mexico SDCC will be responsible for monitoring the data quality and completeness, and ensuring the 
integrity of descriptive and statistical analyses. All of these investigators have extensive experience in 
handling sensitive information.  
To monitor data and safety issues, this team will meet regularly throughout the study project, enabling 
any concerns to be addressed rapidly. We will monitor reasons that patients give for declining to 
participate in the study, as well as reasons for stopping their study participation after initially giving 
consent. Drs. Ober and Danovitch will report to the Cedars-Sinai Institutional Review Board, the single 
IRB for the project, through annual progress reports. Site investigators also will report to their local IRB, 
as required by each IRB. 
10.1.9.2 STUDY RECORDS RETENTION  

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All study records will be retained for a minimum of 7 years (as required for NIH-funded studies) after the 
formal discontinuation the study intervention. These documents will be retained for a longer period, 
however, if required by local regulations.  For research data and materials involving Protected Health 
Information (PHI), the PI must retain the signed consent forms that contain the permission to use the PHI 
for six (6) years beyond the expiration date of the authorization (i.e. the consent form or authorization). 
10.1.10 
PROTOCOL DEVIATIONS   
This protocol defines a protocol deviation (PD) as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP), Protocol) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions will be developed by the site and implemented promptly. Examples 
of protocol deviations may include enrollment of an ineligible subject, follow-up interview conducted out-
of-window, or a START member seeing a usual care patient. 
 
These practices are consistent with ICH GCP:  
 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
PDs will be recorded by each site’s study coordinator in the REDCap Reporting Form. Each site PI and/or 
clinical designee will review the form and investigate each event further to ascertain: (1) nature of the 
event (subject eligibility, consent process), (2) type and degree of potential or actual harm 
(social/psychological), (3) potential contributing factors, and (4) potential for recurrence. The research 
team will confer on how to handle the events, including discussing them with the IRB, if uncertainty exists. 
Further details about the handling of protocol deviations are included in the MOP. 
Completed PD Forms will be automatically sent through REDCap to Dr. Danovitch and the CSMC study 
coordinator, who will review and notify the Cedars-Sinai IRB, the DSMB, and the study Project Officer as 
required and outlined below.  
IRB reporting: The site PIs and Dr. Danovitch, will assist in determining whether the deviation must be 
reported to the Cedars-Sinai IRB. A minor logistical deviation (e.g., an out-of-window study visit or 
procedure, a missed weekly phone check-in) does not need to be reported to the IRB. A protocol 
deviation must be reported to the IRB if the study investigators determine it poses a threat to the 
integrity of the study or if the deviation impacts participant rights, safety, or welfare. For example, 
deviations related to subject eligibility or consent procedures (e.g., patient enrolled despite meeting an 
exclusion criterion, consent not obtained prior to study start, consent obtained by unauthorized 
individual, incorrect version of consent form used) must be reported. Reportable events must be 
reported by the sites to the CSMC study team as soon as possible but no later than 10 business days 
from the relying site’s awareness of the event. The CSMC study team must submit the event in CS-IRB as 

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soon as possible but no later than 10 business days from the CSMC study team’s awareness of the event, 
via a Reportable New Information (RNI) form in CS-IRB, selecting the most appropriate type of report, 
and including copies of any relevant documentation. 
In the event that the protocol exception needs to be requested to accommodate a single subject, the 
CSMC IRB must be notified in advance. Deviations made to avoid immediate hazard to a participant 
must be reported to the CSMC IRB within 5 business days. Unintentional protocol deviations must be 
reported within 10 business days. 
DSMB reporting: All PDs will be summarized and reported to the DSMB at three timepoints: At three 
time points during data collection, when the enrollment reaches one-third (N=137), two-thirds (N=272), 
and upon completion (N=414).  
NIH reporting: PDs that require IRB reporting (as described above) will be reported to the project officer 
by email within 10 business days. 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers after the completion 
of the primary endpoint by contacting the PIs. Reasonable request for sharing data will be considered by 
the PIs (see Publications and Dissemination Policies and Procedures). Considerations for ensuring 
confidentiality of these shared data are described in Section 10.1.3. 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership 
in conjunction with the National Center for Advancing Translational Sciences (NCATS) has established 

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policies and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest. 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
AMS 
Addiction Medicine Specialist 
ASSIST 
Alcohol, Smoking, and Substance Involvement Screening test 
BH 
Baystate Health 
BNI 
brief negotiated interview 
CCT 
collaborative care team 
CFIR 
Consolidated Framework for Implementation Research 
CIs 
confidence intervals 
CM 
Care Manager 
CSMC 
Cedars-Sinai Medical Center 
DRGs 
Diagnosis Related Group 
DSMB 
Data and Safety Monitoring Board 
EMR 
electronic medical record 
GAD 
Generalized anxiety disorder 
GAIN 
Global Appraisal of Individual Needs 
IPW-MI 
inverse probability weighting and multiple imputation 
MRN 
medical records number 
MOUD 
medication for opioid use disorder 
NSDUH 
National Survey of Drug Use and Health 
NIDA 
National Institute on Drug Abuse 
OUD 
opioid use disorders 
OR 
odds ratio 
PACIC 
Patient Assessment of Chronic Illness Care 
PEG 
pain intensity (P), interference with enjoyment of life (E), and interference with general activity (G) 
PHQ 
Patient Health Questionnaire 
RED 
re-engineered discharge 
REDCap 
Research Electronic Data Capture 
START 
Substance Use Treatment and Recovery Team 
SIP-AD 
Short Inventory of Problems Alcohol and Drugs 
SDCC 
Statistics and Data Coordinating Center 
SFTP 
Secure File Transfer Protocol 
SASS 
Substance Abuse Stigma Scale 
UC 
Usual Care 
UCLA 
University of California, Los Angeles 

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UNM 
University of New Mexico 
WHO 
World Health Organization 
10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale.  
Table 12. Protocol Amendment History  
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
06/23/2021 
Add RCT component 
Transition from Orgnaizational 
Context to RCT 
1.2 
10/21/2021 
Process for sending participants a 
copy of the electronic consent form 
by encrypted email 
Ensure accurate description of 
process 
1.3 
02/02/2021 
Follow-up period extended from 30 
to 60 days; for participants in the 
intervention arm who are discharged 
prior to intervention initiation, 
intervention will be delivered 
telephoincally  
Retention improvement; allow 
flexibility of intervention 
delivery 
1.4 
04/21/2022 
Use of paper forms in the event that 
electronic data capture is not 
accessible 
Allow flexibility in the event of 
Internet or database outage 
1.5 
06/15/2022 
Optional, rather than required, 
validation of self-reported outcome 
measures with providers; increase 
follow-up incentive 
Difficulty in validating outcome 
measures with providers; 
retention improvement 
1.6 
10/27/2022 
Update includion criteria to clarify 
that "inpatient" also refers to 
patients under observation 
Expand eligibility criteria to be 
more inclusive 
1.7 
08/08/2023 
Describe planned interim analysis  
Determine if current sample 
size is sufficient to analyze 
second primary outcome 
11 APPENDICES 
(May be found as separate documents as listed below.) 
11.1 RECRUITMENT AND ENROLLMENT 
• 
Consent 
• 
Consent Checklist 
• 
Eligibility Screener 
• 
Eligibility Checklist  

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• 
Study Physician Flyer 
• 
Physician Screening Card 
• 
Baystate and UNM: Physician to Patient Letter, Physician Recruitment Letter with FAQs 
about START 
• 
CSMC: Direct-to-Patient Recruitment Letter, Physician Recruitment Letter with FAQs about 
START 
• 
Patient & Family Education Materials 
11.2 EVALUATION 
• 
Baseline Survey 
• 
Follow-up Survey 
11.3 DATA SAFETY AND MONITORING 
• 
Adverse Event Form 
• 
Adverse Event Summary Form 
• 
List of “expected” AE 
• 
Protocol Deviation Form 
 
 
 

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12 REFERENCES  
 
1. 
Ronan MV, Herzig SJ. Hospitalizations Related To Opioid Abuse/Dependence And Associated 
Serious Infections Increased Sharply, 2002-12. Health Aff (Millwood). May 01 2016;35(5):832-
837. PMC5240777. 
2. 
Fanucchi L, Lofwall MR. Putting Parity into Practice - Integrating Opioid-Use Disorder Treatment 
into the Hospital Setting. N Engl J Med. Sep 1 2016;375(9):811-813. 
3. 
Rosenthal ES, Karchmer AW, Theisen-Toupal J, Castillo RA, Rowley CF. Suboptimal addiction 
interventions for patients hospitalized with injection drug use-associated infective endocarditis. 
Am. J. Med. May 2016;129(5):481-485. 
4. 
Reif S, Acevedo A, Garnick DW, Fullerton CA. Reducing Behavioral Health Inpatient Readmissions 
for People With Substance Use Disorders: Do Follow-Up Services Matter? Psychiatr Serv. Aug 1 
2017;68(8):810-818. 
5. 
Nordeck CD, Welsh C, Schwartz RP, et al. Rehospitalization and substance use disorder (SUD) 
treatment entry among patients seen by a hospital SUD consultation-liaison service. Drug 
Alcohol Depend. May 1 2018;186:23-28. 
6. 
Walley AY, Paasche-Orlow M, Lee EC, et al. Acute care hospital utilization among medical 
inpatients discharged with a substance use disorder diagnosis. J Addict Med. Mar 2012;6(1):50-
56. 
7. 
Hsu DJ, McCarthy EP, Stevens JP, Mukamal KJ. Hospitalizations, costs and outcomes associated 
with heroin and prescription opioid overdoses in the United States 2001-12. Addiction. Sep 
2017;112(9):1558-1564. 
8. 
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