Improving Access and Treatment for Co-occurring Opioid Use Disorders and Mental Illness
Phase: NA
Conditions: Opioid-use Disorder, Addiction, Depression, Post-traumatic Stress Disorder
Sponsor: RAND

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Protocol for Randomized Controlled Trial Comparing 
Collaborative Care and Enhanced Usual Care for 
Patients with Co-occurring Opioid Use Disorders and 
Depression and/or Posttraumatic Stress Disorder 
 
National Clinical Trial (NCT) Identified Number:  NCT04559893 
Principal Investigators: Katherine E. Watkins and Miriam Komaromy (Multiple 
Principal Investigators) 
RAND Corporation and Boston Medical Center 
 
Grant Title: Improving Access and Treatment for Co-occurring Opioid Use 
Disorders and Mental Illness 
Grant Number: U01 MH 121954 
Funded by: NIMH 
Version Number: 13.1 
November 15, 2024 

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Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Throughout 
Protocol 
Revised analysis and outcomes to correspond 
with Statistical Analysis Plan updates from 
November 2024, which was submitted and 
approved by our IRB. This included changing 
the operationalization of the primary 
outcomes, and combining the parent study 
and CR populations for all analyses. 
Ensure all design and analysis descriptions 
reflect latest knowledge and assumptions 
(e.g., actual sample size, best practices, data 
limitations, resource constraints, etc.) prior 
to unblinding  
 
 
 

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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recipient that no unpublished information contained herein will be published or disclosed without prior 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 Investigator or other participating study leadership and as consistent with the 
NIH terms of award.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 4 
1.1 
Synopsis ................................................................................................................................................ 4 
1.2 
Schema ............................................................................................................................................... 10 
1.3 
Schedule of Activities ........................................................................................................................ 12 
2 
INTRODUCTION .......................................................................................................................................... 14 
2.1 
Study Rationale .................................................................................................................................. 14 
2.2 
Background......................................................................................................................................... 15 
2.3 
Risk/Benefit Assessment .................................................................................................................. 21 
2.3.1 
Known Potential Risks ................................................................................................... 21 
2.3.2 
Known Potential Benefits .............................................................................................. 22 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 22 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 22 
4 
STUDY DESIGN ........................................................................................................................................... 27 
4.1 
Overall Design .................................................................................................................................... 27 
4.2 
Scientific Rationale for Study Design.............................................................................................. 29 
4.3 
Justification for Intervention ............................................................................................................. 31 
4.4 
End-of-Study Definition ..................................................................................................................... 32 
5 
STUDY POPULATION ................................................................................................................................ 32 
5.1 
Inclusion Criteria .................................................................................................................................. 5 
5.2 
EXclusion Criteria ................................................................................................................................ 5 
5.3 
Screen Failures .................................................................................................................................... 5 
5.4 
Strategies for Recruitment and Retention ........................................................................................ 5 
6 
STUDY INTERVENTION ............................................................................................................................ 16 
6.1 
Study InterventionAdministration ..................................................................................................... 16 
6.1.1 
Study Intervention Description ..................................................................................... 16 
6.1.2 
Administration ................................................................................................................. 19 
6.2 
Fidelity ................................................................................................................................................. 20 
6.2.1 
Interventionist Training and Tracking .......................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 21 
6.4 
Study Intervention Adherence ......................................................................................................... 22 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 23 
7.1 
Discontinuation of Study Intervention ............................................................................................. 23 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 24 
7.3 
Lost to Follow-Up ............................................................................................................................... 24 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 25 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 25 
8.2 
Safety Assessments .......................................................................................................................... 29 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 30 
8.3.1 
Definition of Adverse Events ........................................................................................ 30 
8.3.2 
Definition of Serious Adverse Events .......................................................................... 30 
8.3.3 
Classification of an Adverse Event .............................................................................. 31 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 32 

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8.3.5 
Adverse Event Reporting .............................................................................................. 33 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 33 
8.3.7 
Reporting of Pregnancy ................................................................................................ 35 
8.4 
Unanticipated Problems .................................................................................................................... 36 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 36 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 36 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 37 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 37 
9.1 
Statistical Hypotheses ....................................................................................................................... 37 
9.2 
Sample Size Determination .............................................................................................................. 38 
9.3 
Populations for Analyses .................................................................................................................. 40 
9.4 
Statistical Analyses............................................................................................................................ 40 
9.4.1 
General Approach .......................................................................................................... 40 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 41 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 41 
9.4.4 
Baseline Descriptive Statistics ..................................................................................... 42 
9.4.5 
Sub-Group Analyses ..................................................................................................... 42 
9.4.6 
Exploratory Analyses ..................................................................................................... 43 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 43 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 43 
10.1.1 
Informed Consent Process ........................................................................................... 43 
10.1.2 
Study Discontinuation and Closure ............................................................................. 44 
10.1.3 
Confidentiality and Privacy ........................................................................................... 44 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 48 
10.1.5 
Key Roles and Study Governance .............................................................................. 48 
10.1.6 
Safety Oversight ............................................................................................................. 50 
10.1.7 
Clinical Monitoring .......................................................................................................... 50 
10.1.8 
Clinical monitoring will be performed by the independent NIMH Data Safety and 
Monitoring Board (DSMB) and the RAND site. Quality Assurance and Quality Control ........................ 51 
10.1.9 
Data Handling and Record Keeping ............................................................................ 51 
10.1.10 
Protocol Deviations ........................................................................................................ 52 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 53 
10.1.12 
Conflict of Interest Policy .............................................................................................. 53 
10.2 
Abbreviations and Special Terms ................................................................................................... 53 
10.3 
Protocol Amendment History ........................................................................................................... 56 
11 
REFERENCES ............................................................................................................................................. 61 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials 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) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the RAND IRB – the Human Subjects Protection Committee 
(HPSC) -- 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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INVESTIGATOR’S SIGNATURE 
The signature below constitutes 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. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name:  Katherine E. Watkins (MPI) 
 
Title:  Senior Physician Policy Researcher 
 
Investigator Contact Information 
Affiliation: RAND Corporation 
Address: 1776 Main Street, Santa Monica, CA 90407-2138 
Telephone: 310.393.0411, x6509 
Email: kwatkins@rand.org 
 
[For multi-site studies, the protocol should be signed by the clinical site investigator who is responsible 
for the day to day study implementation at his/her specific clinical site.] 
Signed: 
 
Date: 
 
 
Name: Miriam Komaromy, MPI 
 
Title:  Medical Director, Grayken Center for Addiction 
 
Affiliation: Boston Medical Center 
 
Signed: 
 
Date: 
 
 
Name: Valerie Carrejo MD 

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Title:  Co-Investigator 
 
Affiliation: University of New Mexico Health Sciences Center 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Improving Access and Treatment for Co-occurring Opioid Use 
Disorders and Mental Illness 
Grant Number: 
U01 MH 121594 

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Study Description: 
This is a multi-site, randomized pragmatic trial in rural and urban 
primary care clinics located in New Mexico and California to adapt, 
harmonize and then test whether CC-COD improves access, quality and 
outcomes for primary care patients with co-morbid OUD and depression 
and/or PTSD. We will randomize patients with co-occurring OUD and 
depression and/or PTSD to receive either CC-COD or enhanced usual 
care (EUC). 
Summary of Competitive Revision (CR): The CR develops and then 
tests an enhanced version of the parent study’s collaborative care 
intervention for co-occurring disorders (CC-COD) to reduce the risk of 
suicide and opioid-related overdose among individuals with opioid use 
disorder (OUD) in combination with PTSD/depression. Within each 
clinic, once enrollment into the parent study has been completed 
(N=900), clinics will transition to delivering CC-COD+ and patients 
(N=300) will be randomized to either CC-COD+ or EUC. All study 
procedures and measures are identical for both the parent study and the 
CR. Because the CR did not enroll sufficient individuals to allow for 
separate analyses, it was decided to combine patients enrolled into the 
parent study intervention arm, with patients enrolled into the CLARO+ 
study intervention arm for all analyses.  This was discussed and 
approved by our Research Advisory Board. 
Hypothesis 1: Patients randomly assigned to CC-COD/CC-COD+ will 
have significantly increased buprenorphine access and quality of care, 
and depression and PTSD outcomes compared to patients assigned to 
EUC. 
Hypothesis 2: Patient experiences will mediate the effect of CC-COD on 
quality and outcomes compared to patients assigned to EUC. 
 
 

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Objectives: 
 
Primary Objective: To evaluate the effectiveness of CC-COD/CC-
COD+ on patient initiation of MOUD, quality of care for OUD; and 
depression and PTSD patient outcomes relative to EUC. 
 
Secondary Objectives: To test mediators (patient experiences with care 
and working alliance with the Care Coordinator) of treatment quality 
and patient-reported outcomes and, in exploratory analyses, test 
moderators of access, quality, and outcomes compared with patients 
assigned to EUC. 
 
Endpoints: 
Primary Endpoints: Our primary outcomes are buprenorphine continuity 
of care, buprenorphine access, MDD symptom severity, and PTSD 
symptom severity.  
Secondary Endpoints: Secondary outcomes include opioid use 
frequency, opioid overdose events, suicidality, access to MDD and/or 
PTSD treatment, quality of care for MDD, quality of care for PTSD, 
MDD remission, MDD response, PTSD remission, PTSD response, 
physical health functioning, and mental health functioning. 
 
 
 

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Study Population: 
The parent study will recruit 900 women and men adult patients with 
OUD and either depression or PTSD from 14 clinics in three large 
healthcare organizations that provide care throughout the state of New 
Mexico, and 7 clinics in two large healthcare organizations that provide 
care throughout Los Angeles County in California. The 7 clinics in 
California were collapsed into four sites because of geographical 
proximity and shared providers.  
 
Patients in these settings are mostly low-income, predominantly 
Hispanics in HPSAs for primary care, mental healthcare, or both. 
 
The CR will recruit 300 women and men adult patients with OUD and 
either depression or PTSD from 10 clinics in three large healthcare 
organizations that provide care throughout the state of New Mexico and 
7 clinics in two large healthcare systems that provide care throughout 
Los Angeles County in California. 
Because the CR did not enroll sufficient individuals to allow for 
separate analyses, in consultation with our Research Advisory Board, 
the NIMH scientific officer and the NIMH project officer, it was 
decided to combine patients enrolled into the parent study intervention 
arm, with patients enrolled into the CLARO+ study intervention arm for 
all analyses. 
Phase: 
N/A; This trial and the CR tests the effectiveness of a service delivery 
intervention. The service delivery intervention includes the organized 
delivery of multiple evidence-supported medications, psychosocial 
treatments, and care management approaches that are or could be 
furnished as part of routine care for the target population. 

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Description of 
Sites/Facilities Enrolling 
Participants: 
For both the parent trial and the CR, RAND will collaborate with the 
University of New Mexico Health Sciences Center (UNM HSC), and 
leverage relationships with sites from First Choice Health Care (FCCH) 
system in New Mexico; UNM’s Southeast (SE) Heights Health Center, 
Southwest Mesa and North Valley and Sandoval Regional Medical 
Center (SRMC); Hidalgo Medical Services (HMS) in New Mexico; 
Providence Health & Services – Southern California; and the Los 
Angeles County Department of Health Services under the auspices of 
the Olive View Education and Research Institute, also in Los Angeles, 
California.  There are multiple sites that are covered under our 
agreements with the Olive View Education and Research Institute, 
including the Hubert Humphrey Comprehensive Health Center, Mid 
Valley Comprehensive Health Center, and San Fernando Health Center 
(which is comprised of Glendale Health Center, West Valley Health 
Center, and San Fernando Health Center). 
 

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Description of Study 
Intervention/Experimental 
Manipulation: 
The intervention is an adaptation of Collaborative Care (CC) for use in 
resource-poor communities and for patients that have co-occurring 
disorders (CC-COD). It is a service delivery approach that uses multi-
faceted interventions to improve access and quality of care. Essential 
members of the CC-COD team include the Care Coordinator, primary 
care provider (PCP), Behavioral Health Provider (BHP) and Behavioral 
Health Consultant (BHC). Essential activities of the CC-COD model 
include population-based care supported by a clinical registry, the use of 
measurement-based care and treat-to-target practices, shared decision-
making and expert consultation by a team of BHCs with complementary 
expertise. All of these activities are facilitated by the Care Coordinator.  
 
CC-COD will also include access to supported treatments: MOUD, 
medication treatment for depressive disorders and/or PTSD, 
motivational interviewing, problem-solving therapy (PST) for 
depression, and Written Exposure Therapy (WET) for PTSD. The 
intervention will run for 36 months across patients but for six months 
per individual patient. The initial 45-minute patient contact with the 
intervention is intended to be face-to-face in the clinic (but could be 
virtual depending on the level of restrictions related to COVID-19); 
subsequent intervention contacts will be 15-minute telephone calls or in-
person contacts, and, as needed, through community outreach visits. 
 
CC-COD+ will add three additional components to CC-COD. Care 
coordinators will (1) educate family members about MOUD with the 
goal of increasing patient retention in treatment; (2) train a support 
persons (e.g., a family member, friend, or partner) and the patient to 
administer naloxone and on how to reduce opioid-overdose risk 
behaviors; and (3) implement Caring Contacts, a suicide prevention 
intervention that sends compassionate mailed or text messages to 
individuals to decrease social isolation and reduce suicide risk.  

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Study Duration: 
The study intends to enroll its first patient approximately 13 months 
from the study open (month 14, in November 2020). Recruitment is 
planned for 24 months with an additional six months to account for any 
recruitment problems, with baseline data collection completed by the 
middle of year 4 (May 2023) and both 3- and 6-month data collection 
completed by early year 5 (December 2023). The study will begin with 
recruitment at the New Mexico clinics in early year 2 (late 2020), as 
described above. The study intends to begin recruitment at the 
California clinics at the end of year 3 (summer of 2022). Mid-Valley 
Comprehensive Health Center and San Fernando Health Center clinics 
will be added in the fall/winter of 2022. We anticipate concluding 
recruitment in December 2023 with both 3- and 6-month data collection 
completed by June 2024.  
 
The CR intends to enroll its first patients in month 26 (September 2022) 
and is expected to continue data collection activities until June 2024. 
Participant Duration: 
Clinic staff will participate in data collection prior to the intervention 
(during months 10-15) and after the intervention is complete (months 
29-31). Patient participants for both the parent and the CR will be 
involved in the study for six months. 
1.2 
SCHEMA  
 
 
 

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Estimated Flow Diagram for Randomized Controlled Trial: Collaborative Care for Co-occurring Opioid 
Use Disorders and Depression and/or PTSD 
 
 
 
 
Note. OUD = opioid use disorder. COD = co-occurring disorder (Major Depressive Disorder and/or Post-
Traumatic Stress Disorder). CC-COD = Collaborative Care for COD. EUC = Enhanced usual care. Baseline, 
3-month, and 6-month measures, data analyses, and CC-COD intervention activities are detailed in 1.3. 
Schedule of Activities. 
 
 

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1.3 
SCHEDULE OF ACTIVITIES  
 
 
Eligibility 
screening 
(Pre-consent) 
 
Baseline  
Day 1 
3-Mo Follow-up  
Day 90 -14/+30 
6-Mo Follow-up  
Day 180 -14/ 
+30 
Probable OUD diagnosis (NIDA myTAPS1 or past 90 day receipt of MOUD) 
X 
 
 
 
Patient health questionnaire (PHQ-9) for depression2 
X 
 
 
 
Probable PTSD (PC-PTSD-5)3 
X 
 
 
 
Age 18 or older 
X 
 
 
 
Patient at participating clinic 
X 
 
 
 
Current receipt of both MOUD and psychotropic medication from provider(s) outside of the 
participating primary care health system (exclusion criterion) 
X 
 
 
 
Speak English or Spanish 
X 
 
 
 
Informed consent 
X 
 
 
 
Randomization 
 
X 
 
 
Adverse event reporting 
 
X 
X 
X 
Outcome Evaluation 
 
 
 
 
MOUD continuity of care4 (max number of continuous (i.e., no breaks of more than 7 days) days 
on MOUD; EHR review) 
 
 
X 
X 
MOUD access (receipt of MOUD prescription within 30 days of diagnosis; EHR review)5 
 
X 
X 
X 
MDD symptoms (PHQ-92 raw score change) 
 
X 
X 
X 
PTSD symptoms (PCL-5 raw score change) 
 
X 
X 
X 
Drug use frequency (NSDUH6 items) 
 
X 
X 
X 
Opioid use severity (PROMIS Substance Use Short Form7) 
 
X 
X 
X 
Alcohol use (AUDIT-C8)* 
 
 
X 
X 
Opioid overdose risk behaviors (Opioid Overdose Risk Assessment9) 
 
X 
X 
X 
Opioid overdose events (Naloxone Overdose Baseline Questionnaire10) 
 
X 
X 
X 
MDD remission (PHQ-92 score < 10) 
 
X 
X 
X 
MDD response (PHQ-92 score < 50% of baseline) 
 
X 
X 
X 
PTSD remission (PCL-5 score < 34) 
 
X 
X 
X 
PTSD response (PCL-5 score < 50% of baseline) 
 
X 
X 
X 
Suicidality (Columbia Suicide Severity Rating Scales11) 
 
X 
X 
X 
All-cause mortality (death records) 
 
 
X 
X 
MOUD initiation12 (receipt of MOUD prescription within 14 days of diagnosis; EHR review) 
 
 
X 
X 
MOUD engagement12 (receipt of two or more MOUD prescriptions within 34 days of diagnosis; 
EHR review) 
 
 
X 
X 
Access to MDD and/or PTSD treatment (receipt of medication and/or behavioral treatment 
associated with diagnosis; EHR review) 
 
 
X 
X 
Quality of care for MDD13 (4 psychotherapy visits in the first 8 weeks or an adequate (12-week) 
medication trial) 
 
 
X 
X 
Quality of care for PTSD13 (4 psychotherapy visits in the first 8 weeks or an adequate (60-day) 
medication trial) 
 
 
X 
X 

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*The full AUDIT will be administered at baseline. 
**Government Performance Results and Modernization Act of 2010.  
 
 
Eligibility 
screening 
(Pre-consent) 
 
Baseline  
Day 1 
3-Mo Follow-up  
Day 90 -14/+30 
6-Mo Follow-up  
Day 180 -14/ 
+30 
Veterans RAND 12-item General health functioning (VR-1214) 
 
X 
X 
X 
Demographics (sex, race, ethnicity, education level, marital status) 
 
X 
 
 
Alcohol use severity (AUDIT8) 
 
X 
 
 
Pain levels (PEG Pain Monitor15) 
 
X 
X 
X 
History of MOUD treatment (items developed by research team) 
 
X 
 
 
Current MDD/PTSD treatment (NSDUH6 items) 
 
X 
 
 
Prior experiences with Care Coordinator (items developed by research team) 
 
X 
 
 
Interpersonal support (presence of a support person who does not have problematic opioid use) 
 
X 
 
 
Homelessness (Homelessness Screening Clinical Reminder Tool;16 GPRA17** item) 
 
X 
X 
X 
Legal involvement (NSDUH items; Addiction Severity Index18 items) 
 
X 
X 
X 
Disability and impairment (Sheehan Disability Scale19) 
 
X 
 
 
Rurality (Rural-Urban Commuting Area code20 associated with 5-digit ZIP code) 
 
X 
 
 
Care Coordinator communication (AHRQ Consumer Assessment of Healthcare Providers and 
Systems21) 
 
 
X 
 
Ability to access treatment quickly (AHRQ CAHPS21) 
 
 
X 
 
Satisfaction with treatment (AHRQ CAHPS21) 
 
 
X 
 
Patient-Care Coordinator working alliance ( Modified form of Working Alliance Inventory – 
General Practice22) 
 
 
X 
 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
Problem/question. Untreated mental illness and substance use disorders are common and can have 
devastating consequences for the individual, their families and the community. Co-occurring opioid use 
disorders (OUD) with either depressive disorders and/or posttraumatic stress disorder (PTSD) are 
particularly concerning because of their prevalence in people with OUD. Co-occurring mental illness is 
also linked to an increased risk for opioid misuse and overdose, and because of the high prevalence of 
the chronic use of prescription opioids in individuals with mental illness, a risk factor for heroin use and 
the development of an OUD. Primary care is an important and underutilized setting in which to provide 
treatment for all three disorders, because OUD, depression and PTSD are frequently co-morbid with 
medical conditions. However, despite the effectiveness of treatments for all three disorders, many 
individuals never receive treatment; and, when treatment is provided, quality is low. With the rising 
number of opioid-related fatalities, this is a critical treatment and quality gap in a vulnerable and 
stigmatized population. 
Rationale for clinical trial and intervention choice. Collaborative care (CC) has potential to address 
these problems by improving access, quality and outcomes in primary care patients with common 
mental health (MH) conditions. However, CC has never been tested with co-occurring disorders (COD), 
despite research by our team suggesting it may be effective. This study will compare CC for COD (CC-
COD) with enhanced usual care (EUC) on study outcomes (described elsewhere). In addition to 
examining the effectiveness of the CC-COD intervention, this study will test whether intervention targets 
(patient experiences with care and working alliance with the Care Coordinator) mediate the effect of CC-
COD on quality and outcomes compared to participants randomized to EUC.  
Problem/question for CR. Deaths from suicide and overdose related to opioid use are a rapidly growing 
and major public health crisis.23 In 2017, more than 40% of suicide and overdose deaths were linked to 
opioid use, and opioid use disorders (OUD) have a strong relationship to both suicide and overdose.24-30 
Similarly, mental health conditions are also linked to suicide and unintentional overdose.31,32 It is no 
surprise that individuals with these co-occurring disorders (COD) are at higher risk of attempting suicide 
and dying from suicide or overdose31-34 than individuals with OUD or mental illness alone. In one study, 
67% of those with co-morbid OUD and major depression had attempted suicide in the past year, along 
with 47% of those with comorbid OUD and PTSD.35 OUD, depression, and PTSD commonly occur 
together with devastating consequences.36-42 
Medication for OUD (MOUD) reduces the risk of suicide attempts and unintentional overdose, and 
buprenorphine specifically is associated with a decrease in severe suicidal ideation among individuals 
with comorbid OUD and major depression.43,44 Yet despite the importance of MOUD, many people with 
OUD and COD never receive treatment, and 50–80% of those who do initiate MOUD discontinue 
treatment, often within weeks or months of initiation,45-48 putting them at increased risk of relapse and 

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overdose. Individuals are particularly vulnerable to suicide and overdose immediately after 
discontinuing MOUD, with comorbidity adding further risk.48 Rates of overdose are approximately 2-3 
times higher after MOUD is discontinued than rates among individuals who never received treatment 
for OUD at all. Treatment for depression and PTSD is also associated with less suicidality and mortality, 
but access is low, particularly for the COD population.49-51  
Rationale for CR. The parent study is among the first to adapt CC for co-occurring OUD, depression, 
and/or PTSD (CC-COD) and then test it in a randomized controlled trial with the goal of improving 
access, quality and patient outcomes. However, while the parent study includes measures of suicide and 
overdose as outcomes, the evidence-based interventions that our CC-COD model supports do not 
specifically address suicide risk, overdose prevention or naloxone training. In addition, CC-COD does not 
include outreach to support persons (e.g., family, friends, or partners), even though increasing evidence 
from our team and others suggests that support persons (SPs) can influence access to and retention in 
substance use treatment.52-61 In our proposed revision, we expand the scope of the parent grant to 
address these limitations and the public health crisis. The CR will develop and then test an enhanced 
version of the parent study’s collaborative care intervention for co-occurring disorders (CC-COD+) to 
reduce the risk of suicide and opioid-related overdose among individuals with opioid use disorder (OUD) 
in combination with PTSD/depression. 
 
2.2 
BACKGROUND  
Opioid use disorders, co-occurring with either depression or PTSD, are prevalent, burdensome, and 
too often left untreated. In 2015-16, there were over two million adults with a current OUD; 62% had a 
co-occurring mental illness and 24% had a co-occurring serious mental illness.34 While individuals with 
COD are more likely to receive MH treatment than OUD treatment, only 16-25% report receiving 
treatment for both conditions.34,62 Depression and PTSD are two of the most common MH co-
morbidities in people with OUD, and when present, are associated with poorer outcomes.38,39,41,63-68 
Both depression and PTSD are leading causes of disability, and mortality from OUD continues to rise.69,70 
Primary care is an important and underutilized setting in which to identify and provide treatment, but 
utilization and quality of OUD and behavioral health care is low.71-73 Although specialty OUD care plays 
a critical role for individuals with severe dependence, limited availability, the stigma associated with 
using specialty care, and a host of other barriers means that specialty care alone is unlikely to be able to 
address the unmet need for treatment.74,75 Recent federal legislation76,77 increased coverage for OUD 
treatment in primary care, and the prevalence of OUD is high among primary care patients.78,79 Primary 
care is also an important source of behavioral health care.80 Community health centers are of particular 
importance because they are the largest source of primary health care for underserved individuals and 1 
in 12 people in the U.S. receives primary care in a community health center.81 

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New Mexico is projected to have the highest death rate from drugs, alcohol and suicide by 2025 and is 
in the top quintile for age-adjusted opioid overdose death rates.82 New Mexico ranks 47/50 in rates of 
suicide death, 50/50 in rates of alcohol-induced death, 45/50 in homicide death and 43/50 in drug 
overdose death.82,83 A primarily rural state, it is majority Hispanic.84 Twenty percent of New Mexico’s 
population live below the poverty level, 9.2% are unemployed and nearly 16% do not have a high school 
diploma,84 contributing to high levels of need. Almost every county in New Mexico is designated as a 
HPSA, and the current workforce is estimated to meet only 23% of the healthcare need, making 
interventions to improve access and increase provider effectiveness crucial.85,86 The overdose death rate 
increased 80% between 1999 and 2014, with heroin accounting for 34% of the unintentional overdose 
deaths and prescription opioids for 48%.87,88 Statewide, the rate of OUD among Medicaid recipients is 
nearly three times the national rate.89 In 2018, eight of New Mexico’s counties had no buprenorphine 
prescribers, and fewer than 20% of specialty treatment providers offered buprenorphine maintenance.90 
New Mexico’s high rates of OUD, overdose death rates and shortage of health care professionals make it 
a high-need state where a CC model could have particular relevance, and its mixed rural and urban 
setting and diverse population give it the potential to demonstrate the impact of effective interventions 
across a wide range of populations and settings. 
We are adding additional sites in Los Angeles because of recruitment challenges.  In addition, adding 
these additional Los Angeles sites expands our sample beyond a single state which will strengthen 
generalizeability.  The new sites will also provide a broader context for understanding variation in 
implementation. 
Increasing access and quality in primary care could improve outcomes. OUD, depressive disorders and 
PTSD can be treated effectively with FDA-approved medications and/or brief psychotherapies, making 
them ideal for treatment within primary care.91-93 However, despite the potentially promising role of 
primary care in increasing access, only a small percentage of people who need treatment receive 
it.73,94,95 And, even when patients receive care, the quality of behavioral health care provided is low, 
contributing to poor outcomes.34,46,47,62,96,97  
There is a strong scientific premise for testing the effectiveness of CC in COD patients. Substantial 
evidence supports the use of CC for behavioral health disorders,98 and for behavioral health conditions 
co-morbid with medical illnesses.99-102 Significantly, CC programs are highly effective for safety net 
patients and can reduce health disparities in treatment utilization (which we define as access).103-108 
Work by our team demonstrated the effectiveness of CC for patients with opioid and alcohol use 
disorders,109-113 depressive disorders,114-117 depressive disorders co-morbid with substance misuse,118,119 
and PTSD,120 but CC has never been tested for COD. 
In our prior work, we identified patient engagement with individual treatment components as a key 
challenge.109,110,120-122 Our prior work indicated two problems with access and quality: many patients 
were not ready or motivated for treatment, and, when they were, getting timely access to a PCP or BHP 
appointment was challenging. In our current conceptualization of CC-COD we address patient treatment 

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readiness by having the Care Coordinator use MI to elicit change talk and motivation and make 
home/community visits. We address problems with timeliness by programming the registry to facilitate 
coordination between the Care Coordinator and the PCP and BHP. We will advance the science of CC 
effectiveness by testing whether patient engagement mediates CC outcomes in Aim 3, and by examining 
effectiveness across diverse settings. 
It is unknown what mediates the effect of CC on treatment quality and outcomes.22,98,120,123-127 Based 
on our prior work,109,110,120-122 we propose to test mediators that are strong proxies for engagement: 
working alliance22,123 and patient experiences21 of care. A central element of CC is the relationship or 
alliance between the patient and the Care Coordinator, and there is evidence that this relationship is 
critical to successful outcomes.22,98,120,123-127 Studies show that the patient-provider working alliance is 
positively related to improved patient satisfaction, increased compliance with medications, and greater 
service efficiency.125 We also hypothesize that positive patient-centered experiences (e.g., good 
communication with providers, getting treatment quickly, favorable ratings of treatment) will mediate 
the relationship between the CC-OUD intervention and outcomes, because better patient care 
experiences are associated with higher levels of adherence to treatment.128 We will also explore 
whether the treatment of MH conditions improves OUD outcomes, such as abstinence. 
This project has potential for high impact because it both improves public health and advances 
science. Our study simultaneously addresses critical public health problems—the opioid crisis and the 
undertreatment of OUD and co-morbid behavioral health problems—and advances science. The 
undertreatment of OUD is arguably the most important public health problem related to the opioid 
crisis. In 2015, 11.5 million individuals reported misusing opioids and 1.9 million reported being addicted 
to opioids,129 yet fewer than 20% receive any treatment.130,131 Individuals with COD face similar 
problems, with fewer than 25% reporting receiving treatment for both conditions. By experimentally 
testing a new approach—the CC-COD—and assessing implementation factors such as provider 
acceptability and feasibility, this study could improve public health by identifying an efficient and 
generalizable model to increase COD treatment delivery and decrease the downstream effects of 
untreated addiction and mental illness. Our research will advance science by examining whether patient 
engagement mediates improved outcomes, and whether approaches to improve patient engagement 
work—important advances in the science of CC. 
Background for CR: 
Suicide and overdose are prevalent among those with OUD and of heightened concern among those 
with co-occurring mental illness (COD). Suicidal ideation/behavior27,132 and overdoses27,132 are common 
in individuals with OUD, leading to high rates of morbidity and mortality.24 About 20-45% of those with 
OUD also experience either co-occurring depressive disorders39 and/or post-traumatic stress disorder 
(PTSD),38,41,42 and COD contributes to increased risk of death due to suicide (OR = 2.13-4.83)27 and 
overdose (OR = 4.34-7.06)133 compared to OUD alone.24 MOUD and treatment for mental illness are 
both associated with reduced mortality, yet access to and retention in treatment is low.45-48,134,135 

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Individuals are particularly vulnerable to suicide and overdose immediately after MOUD discontinuation, 
with comorbidity adding further risk.48,136-139 Rates of overdose are 2-3 times higher after MOUD 
discontinuation than among individuals with untreated OUD.48  
Reducing mortality in patients with COD is arguably 
the most important public health problem related to 
the opioid crisis, and New Mexico is particularly hard 
hit. New Mexico is in the top quintile for age-adjusted 
opioid overdose death rates and is projected to have 
the highest death rate from drugs, alcohol and suicide 
by 2025.82 New Mexico’s population is also distinct 
from other hard-hit states because it is majority 
Hispanic. The overdose death rate increased 80% 
between 1999 and 2014, with heroin accounting for 
34% of the unintentional overdose deaths and 
prescription opioids for 48%.87,88 Statewide, the rate of 
OUD among Medicaid recipients is nearly three times 
the national rate.89 Despite the need for MOUD 
treatment, eight of New Mexico’s counties had no 
buprenorphine prescribers in 2018, and fewer than 
20% of OUD providers offered buprenorphine 
maintenance.90 Our parent study takes place in 11 rural 
and urban primary care clinics located in Health 
Professional Shortage Areas (HPSAs). Understanding 
whether an enhanced version of CC can reduce suicide 
and overdose risk in a majority Hispanic population 
may have implications for the treatment of Hispanics in 
other states.  
Traditional CC models do not do enough to reduce 
suicide and overdose risk. In traditional models of CC, 
care coordinators typically measure symptoms and 
intervene if an individual endorses suicidal ideation. One study, Prevention of Suicide in Primary Care 
Elderly: Collaborative Trial (PROSPECT), focused on CC to prevent suicide, but prevention was defined as 
having Care Coordinators follow depression treatment guidelines and informing physicians by letter if a 
patient was identified as having suicidal ideation, with no proactive component or direct intervention 
with the patient. PROSPECT showed decreases in suicidal ideation in the CC condition,140,141 but the 
effect on suicide attempts and related mortality remains unclear.140 Mortality was highest among 
patients with medical comorbidities,142 which suggests complex patients may need more proactive 
supports. Our team conducted the first successful trial of CC for OUD in primary care,91,92,109-112,121,122,143-
149 and, like the traditional CC model, suicide risk was only addressed when participants stated they were 
Acronym list 
CC 
collaborative care 
CC-COD 
collaborative care for COD 
CC-COD+ Additions to CC-COD to reduce 
suicide and overdose risk 
CLARO 
Collaboration Leading to 
Addiction Treatment and 
Recovery from Other Stresses 
COD 
co-occurring disorder 
EUC 
enhanced usual care 
HH 
Hubert Humphrey 
INSPIRE 
Integrating Support Persons Into 
Recovery 
LACDHS 
Los Angeles County Department 
of Health Services  
MAP 
Map of the Adaptation Process 

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planning on self-harm. There was no proactive role for Care Coordinators to address suicide or overdose 
risk. Further, at the time of the study, evidence for naloxone was not widely established. Currently, 
naloxone is the primary antidote among first responders and in the community to reverse opioid 
overdose.150,151 Although New Mexico law mandates that patients being treated with MOUD be given 
naloxone, our provider advisory board tells us that overdose risk education is not consistently provided 
to patients and only rarely to family members.  
Reducing suicide and overdose risk in the COD population may require more than what CC-COD offers. 
In the parent study, we hypothesize that CC-COD will result in increased access to MOUD, depression, 
and PTSD treatment, and we expect that better treatment will result in better patient outcomes. We 
understand that treatment retention is likely to be a significant issue, and that poor MOUD retention 
increases the risk of relapse, overdose and death.45-48,134,135 The parent study addresses retention by 
having the CM monitor patient progress via a clinical registry, connect with the patient through routine 
calls, and refer when additional care is needed. However, the parent study does not include outreach to 
SPs, despite evidence that SPs can influence whether a patient remains in treatment. CC-COD also does 
not include proactive content specifically targeting suicide and overdose prevention. Given the high 
rates of both in this population, more interventions are warranted. In this CR we propose to strengthen 
CC-COD in three ways to reduce suicide and opioid-overdose risk: (1) intervening with SPs to increase 
patient treatment retention—particularly MOUD treatment, (2) adding naloxone training and overdose 
prevention education for both SPs and the patient, and (3) adding the Caring Contacts intervention for 
patients to decrease social isolation, a risk factor for suicide. 
There is a strong scientific premise that involvement of SPs may help strengthen MOUD retention and 
decrease mortality. The effectiveness of MOUD on overdose and suicide prevention hinges on finding 
innovative ways to increase retention.52-61 Family members and other SPs can be an important catalyst 
for engaging patients in substance use treatment because family members are more likely to recognize 
warning signs of substance misuse than the affected individual, who may not recognize or admit to 
symptoms.56,152-154 Family members tend to be highly motivated and typically want to help their loved 
one reduce their substance use, improve their relationship, and also alleviate their own difficulties 
associated with the person’s substance use.155-157 On the other hand, family members can perpetuate 
the patient’s use when they fail to recognize or reinforce the patient’s steps toward recovery, act as a 
barrier to the patient accessing effective treatments, or otherwise unknowingly facilitate the patient’s 
substance use. Family members often have concerns about using pharmacotherapies long term and the 
safety of opioid agonist therapies. In fact, a common barrier to MOUD retention is the assumption by 
both patients and families that MOUD is an addictive drug substitute.158 
Studies of SPs’ perspectives are uncommon. There are few studies of SPs’ perspectives on MOUD 
treatment and naloxone use. When asked, family members report lack of knowledge about 
administering naloxone and fears of legal consequences that might result from being associated with 
illegal drug use.159-161 Conflict between buprenorphine treatment and obligations to family members is a 
common reason for treatment drop out.159-162 Our stakeholders tell us that it would be helpful if SPs 

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knew more about MOUD because they often think buprenorphine is “another form of dope”, frequently 
ask patients when they can stop taking it, and judge them to the point that patients stop telling family 
members about their buprenorphine use (K. Saffier, personal communication, September 5, 2018). This 
feedback is consistent with our qualitative work with SPs who are eager for information but feel “there 
are no classes out there that help loved ones of people on heroin.”163 Thus, engaging family members or 
other support persons in qualitative research to adapt family interventions is essential and can ensure 
messaging is impactful, useful, and acceptable. This may be particularly important in Hispanic 
communities where family “familismo” and collectivism play a central role in influencing behavior.164 
The scientific premise for adding naloxone training for patients and SPs as an overdose prevention 
intervention is strong.165-168 An increasingly common prevention strategy is to provide laypersons with 
naloxone and related training,165,166,169 with most efforts (>80%) targeting persons with OUD.167,169 
Studies show that when family members are trained to use naloxone, their knowledge of overdose risks 
and the likelihood they will administer naloxone increases,159,168 and naloxone training of laypersons, 
including SPs, significantly decreases mortality.151,170,171 Training increases the odds of administration by 
1.35 times, and the likelihood of recovery from overdose is 8.58 times higher when naloxone is 
administered.169 The exact impact of SP training on mortality remains unclear, because studies have not 
isolated the effect of training SPs from other laypersons. 
By adding a suicide prevention intervention, CMs may be able to decrease suicide risk. Caring Contacts 
is a straightforward intervention that seeks to increase social connection (reducing social isolation, a risk 
factor for suicide) to providers without placing additional demands on distressed patients. The scientific 
premise is strong, and it is one of the only suicide prevention interventions to show decreased suicide 
deaths and attempts in randomized trials (up to 2 years post-intervention).172-175 It is effective in high-
acuity populations such as active military and veterans,176,177 and as an adjunct to ongoing mental health 
treatment.178 It has not been tested in primary care, or with individuals with substance use disorders or 
COD. 
The proposed study will have high public health impact. The United States is in the middle of two 
intertwined epidemics. Suicide and overdose deaths are at record levels. OUD and mental illness are 
major contributors to both, and individuals with COD are a complex population at high risk. In this 
population, universal prevention makes good public health sense. Medical and behavioral health 
providers are overburdened with OUD care and lack the time to proactively address suicide and 
overdose risk with all patients. In this study, we equip the CM to deliver opioid-overdose and suicide 
prevention to all COD patients and provide much-needed resources to SPs who are underserved. In 
doing so, this study could improve public health by increasing MOUD retention and decreasing suicide 
and overdose risk. Our research will advance science by examining whether educating patients and SPs 
and using Caring Contacts supported by CC accomplishes these goals. Given that more than 40% of 
suicide and overdose deaths in 2017 were linked to opioid use, the time is right for tackling these twin 
epidemics. 

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2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
 
Participation poses the following direct risks to patients: 
(1) Disclosure of Sensitive Information: Patients who are referred to the study coordinators, undergo 
eligibility screening, or participate in the study may be at risk of disclosure of sensitive information on 
their health including the presence of an addiction or mental health disorder, both stigmatizing 
conditions. 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 Health Insurance Portability and Accountability Act (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. 
(2) Psychological Distress: Patients who undergo screening and assessment for OUD, PTSD, or MDD may 
experience psychological distress. In addition, the questions about suicidality on the Columbia Suicide 
Severity Rating Scale may identify patients who need immediate attention. We will minimize any 
potential risk of distress by using a private space to interact with the patients. In completing survey 
items, we will also use a private space and clearly communicate to all prospective participants that 
participation is voluntary and explain to participants that they have the option of refusing to answer any 
of the survey questions, and that they are free to leave the study or end the survey at any time. We will 
train interviewers to be clinically sensitive to signs of distress and how to respond. At the conclusion of 
each interview, the interviewer will spend some time debriefing the participant by making ‘small talk’ 
and allowing the participant the opportunity to ask questions. If a participant remains distressed at the 
end of the interview, then the interviewer will be instructed to inform the appropriate member of the 
study staff and will seek permission to contact their PCP. We will have a protocol in place to address 
distress and suicidality which will aim to connect patients with a mental health provider either at the 
clinic or facilitated by the PCP on the research team (Dr. Komaromy) or psychiatrist on the research 
team (Dr. Watkins) if no mental health support is available at the site immediately upon discovery and 
within 24 hours. 

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(3) Adverse Effects of Treatments: Adverse effects of receiving standard-of-care treatment may include 
adverse drug reactions, side effects, interactions with other medications, medication errors, and other 
issues. These risks are similar to those of untreated OUD and/or co-occurring PTSD/depression, but the 
risks of treatment are lower. Decisions about treatment for our study participants will be made as in 
usual clinical practice: CC-COD consultants will make recommendations to primary treating physicians 
and patients, who may decline any suggestions to initiate MOUD, or treatment for PTSD or depression.  
(4) Financial Costs to Patients: Because patients will be receiving care at a FQHC, all treatments will be 
available to patients as covered through their insurance (e.g., either covered by Medicaid or on a sliding 
fee schedule). They will incur no additional financial costs as a result of this intervention. 
Participation in the CR will add no additional potential risks to participants. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Patients in both trial arms may benefit from the receipt of evidence-based treatment for their substance 
use and mental health conditions.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Although there are some risks of temporary psychological distress and untreated disorder, the benefits 
of having greater access to evidence-based treatments are likely to outweigh the risks.   
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
Primary 
 
 
 
To evaluate 
the 
effectiveness 
of CC-COD 
compared to 
EUC. 
Original primary endpoints: 
MOUD access:5 Patients with a new episode of 
OUD care (i.e., no care for at least 60 days prior) 
Patients 
randomly 
assigned to CC-
COD will have 
significantly 
increased 
We will test mediators 
that are strong proxies for 
engagement: working 
alliance and patient 
experiences of care. The 
relationship or alliance 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
receiving an MOUD prescription within the first 
30 days of that care episode  
MOUD continuity of care:4 Number of 
continuous treatment days (i.e., no breaks of 
more than 7 days) the patient receives MOUD 
within 180 days of study enrollment  
 
 MDD symptoms: PHQ-92 raw score change  
 
PTSD symptoms: PCL-5179 raw score change  
Revised primary endpoints**: 
Buprenorphine access:5 Number of days until 
first buprenorphine prescription after study 
enrollment for patients with a new episode of 
OUD care (i.e., no care for at least 30 days prior). 
Buprenorphine continuity of care:4 Number of 
cumulative treatment days the patient receives 
buprenorphine within 180 days of study 
enrollment 
MDD symptom severity: PHQ-92 at 6 months 
PTSD symptom severity: PCL-5179 at 6 months 
 
access and 
quality 
outcomes 
compared with 
EUC. 
between the patient and 
the Care Coordinator is a 
central element of CC, and 
there is evidence that this 
relationship is critical to 
successful outcomes. We 
also hypothesize that 
positive patient-centered 
experiences (e.g., good 
communication with 
providers, getting 
treatment quickly, 
favorable ratings of 
treatment) will mediate 
the relationship between 
the CC-OUD intervention 
and outcomes, because 
better patient care 
experiences are 
associated with higher 
levels of adherence to 
treatment.  
Secondary 
 
 
 
To evaluate 
the 
effectiveness 
of CC-COD 
compared to 
EUC. 
Mental Health 
 
Access to MDD and/or PTSD treatment: Receipt 
of medication and/or behavioral treatment 
associated with diagnosis for participants who 
did not have any visits (behavioral health 
treatment or medication) for MDD and/or PTSD 
in 30 days prior to study enrollment. 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
 
Quality of care for MDD:13 4 psychotherapy visits 
in the first 6 months or an adequate (60 day) 
medication trial for a new episode of MDD care 
(no MDD care for at least 30 days prior to 
enrollment) 
 
Quality of care for PTSD:13 4 psychotherapy visits 
in the first six months or an adequate (60-day) 
medication trial for a new episode of PTSD care 
(no PTSD care for at least 30 days prior to 
enrollment) 
MDD remission: PHQ-9 < 5 at 6 months, among 
study participants with probable MDD at 
baseline (PHQ-8 ≥ 10) 
MDD response: PHQ-9 score at 6 months less 
than 50% of baseline score, among study 
participants with probable MDD at baseline 
(PHQ-8 ≥ 10) 
PTSD remission: PCL-5 < 34 at 6 months, among 
study participants with probable PTSD at baseline 
(PC-PTSD-5 ≥ 3) 
PTSD response: PCL-5 score at 6 months less 
than 50% of baseline score, among study 
participants with probable PTSD at baseline (PC-
PTSD-5 ≥ 3) 
Active suicidal ideation: Dichotomized Columbia 
Suicide Severity Rating Scale11 at 6 months: 
answer YES to Question 3, 4, and/or 5 and/or 
YES to Question 7. 
 
 
Substance Use 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
Opioid use frequency: Days of opioid use in the 
past 30 days, measured using SAMHSA National 
Survey on Drug Use and Health (NSDUH6) items 
 
Opioid overdose events: Opioid overdose events 
in the previous three months, from Naloxone 
Overdose Baseline Questionnaire10 
 
 
Overall Health 
Physical health functioning: Veterans RAND 12-
item Health Survey (VR-12)14 – physical health 
subscale 
Mental health functioning: Veterans RAND 12-
item Health Survey (VR-12)14 – mental health 
subscale 
 
Tertiary/Explo
ratory  
 
 
 
To evaluate 
the 
effectiveness 
of CC-COD 
compared to 
EUC. 
Drug use frequency: Days of use in the past 30 
days for five drug categories (prescription 
opioids, heroin, cocaine/crack, 
methamphetamine/ other stimulants, and 
tranquilizers/sedatives), measured using 
SAMHSA National Survey on Drug Use and 
Health (NSDUH)6 items 
Stimulant use frequency: Days of stimulant use 
in the past 30 days from NSDUH)6 
Alcohol use: Alcohol Use Disorder Identification 
Test – Consumption (AUDIT-C)8 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
Opioid overdose risk behaviors: Opioid Overdose 
Risk Assessment9 
Opioid use severity: Patient- Reported 
Outcomes Measurement Information System 
(PROMIS) Substance Use Short Form7 
To test 
moderators of 
access, quality 
and 
outcomes.  
Buprenorphine access:5 Number of days until 
first buprenorphine prescription after study 
enrollment for patients with a new episode of 
OUD care (i.e., no care for at least 30 days prior). 
Buprenorphine continuity of care:4 Number of 
cumulative treatment days the patient receives 
buprenorphine within 180 days of study 
enrollment 
MDD symptoms: PHQ-92 at 6 months 
PTSD symptoms: PCL-5179 at 6 months 
 
 
 
 
Explore what 
factors 
moderate the 
effect of CC-
COD 
 - Demographics (sex and 
ethnicity) 
- Pain levels (PEG Pain 
Monitor15) 
- Housing status 
(Homelessness 
Screening Clinical 
Reminder Tool16) 
- Disability and 
impairment (Sheehan 
Disability Scale19) 
- Trauma/Interpersonal 
Violence (PTSD 
checklist for DSM-5, 
description of worst 
event179) 
- Stimulant use 
frequency (Days of 
stimulant use in the 
past 30 days from 
NSDUH6) 
- Number of care 
coordinator visits 
 
To test 
mediators of 
outcomes.  
 
 
 
Revised primary endpoints: 
Buprenorphine access:5 Number of days until 
first buprenorphine prescription after study 
Patient 
experiences 
will mediate 
the effect of 
CC-COD on 
Clinician communication 
(AHRQ Consumer 
Assessment of Healthcare 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
 
 
 
 
 
 
 
 
 
enrollment for patients with a new episode of 
OUD care (i.e., no care for at least 30 days prior). 
Buprenorphine continuity of care:4 Number of 
cumulative treatment days the patient receives 
buprenorphine within 180 days of study 
enrollment 
MDD symptoms: PHQ-92 at 6 months 
PTSD symptoms: PCL-5179 at 6 months 
 
quality and 
outcomes 
compared to 
participants 
randomized to 
EUC. 
Providers (CAHPS) and 
Systems21) 
 
Ability to access treatment 
quickly (AHRQ CAHPS21) 
 
Satisfaction with 
treatment (AHRQ 
CAHPS21) 
 
Patient and Care 
Coordinator working 
alliance (modified 
Working Alliance 
Inventory-General 
Practitioner22) 
**primary outcomes were revised prior to breaking the study blind. These changes and their justifications are further detailed in section 8.1. 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Hypotheses. For the intervention effectiveness analysis, we hypothesize that patients randomly 
assigned to CC-COD/CC-COD+ will have significantly increased MOUD access and quality of care, and 
depression and PTSD outcomes compared to patients assigned to EUC. To test mediators (patient 
experiences with care and working alliance with the Care Coordinator) of treatment quality and patient-
reported outcomes in exploratory analyses, we hypothesize that patient experiences will mediate the 
effect of CC-COD/CC-COD+ on quality and outcomes compared to participants randomized to EUC.  
Phase. This is a Phase 4 clinical trial to test the effectiveness of collaborative care for a population of 
patients with OUD and depression and/or PTSD in real world primary care settings. 

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Design. This study uses a pragmatic, randomized controlled trial (RCT) design implemented in 18 
primary care clinics to evaluate whether patients with COD who are randomized to CC-COD/CC-COD+ 
have improved access, quality and outcomes, as compared with those randomized to EUC. We will adapt 
our CC model to the New Mexico and California settings and a COD patient population, and use findings 
on organizational readiness180 to inform implementation (Aim 1). We will then recruit and randomize 
900 individuals with COD to receive either CC-COD/CC-COD+ or EUC, and test its impact on access, 
quality and patient outcomes (Aim 2). Primary outcomes include initiation of MOUD; quality of care for 
OUD (MOUD continuity), PTSD and/or depression; mental and physical health and wellbeing; and 
abstinence. We will also assess whether patient experiences of care and working alliance mediate the 
impact of CC-COD/CC-COD+ on quality and outcomes, and explore whether mental health treatment at 
3 months improves OUD outcomes (Aim 3); exploratory analyses will look at what factors moderate the 
effect of CC-COD/CC-COD+. Aim 4 assesses contextual factors and implementation outcomes to inform 
future dissemination, should the model be effective. 
Under a classification proposed by Curran et al.,181 our study is a Type 1 effectiveness-implementation 
hybrid design because we will simultaneously conduct a multi-site trial to determine the effectiveness of 
CC-COD/CC-COD+  while also assessing context and implementation. Our trial design is pragmatic,182 and 
is designed to improve usual practice and inform clinical and policy decisions. These design 
characteristics include: collaborations with the health care system to adapt the intervention to local 
conditions, multiple heterogeneous settings, broad patient eligibility criteria that reflect how the 
intervention will be used in clinical practice, usual care practitioners, multiple outcomes important to 
decision-makers, intent-to-treat data analysis, and prospective controls.182-185 We will randomize at the 
level of the individual patient. We recognize that with individual-level randomization, contamination 
may occur and lead to Type II error. We mitigate this concern by powering to detect an effect size 
smaller than found in prior studies.186 We note a recent Cochrane review of CC found significant effects, 
despite the use of individual level randomization in 69/90 (79%) of the studies,98 and in our previous CC 
study for addiction treatment with individual level randomization, we found positive effects.110  
Method. After enrollment and baseline assessment, individual subjects will be randomized 1:1 into CC-
COD or EUC. A stratified randomized block design will be used, with the strata determined by site and 
prior MOUD exposure. A randomization list will be generated for each stratum and include randomly 
permuted block sizes of 2 and 4. Staff will access the randomization module in the Research Electronic 
Data Capture system (Redcap). Staff will enter which stratum the patient is in and the intervention arm 
assignment will be generated. Enrollment will be continuous with the goal of reaching the desired 
sample size. 
Design considerations for CR: 
The parent study is a randomized controlled trial of CC-COD versus EUC with randomization at the level 
of the individual patient. The CR maintains enrollment of 900 patients into the parent study but adds 4 
clinics to the parent trial, allowing us to maintain the same timeline while recruiting 300 additional 

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patients. Within a clinic, recruitment for the parent study (phase 1; N=900) will be completed prior to 
the implementation of CC-COD+ (phase 2; N=300), at which point individuals will be randomized to CC-
COD+ versus EUC.  Thus, the timing of transition from CC-COD to CC-COD+ will vary for each site with 
each site following the permutated randomized blocks first generated for assigning individuals within 
their site to CC-COD versus EUC. All data collection procedures for the CR will follow the parent study’s 
protocols. While SPs will be invited to participate in the CC-COD+ clinical intervention, we will not enroll 
SPs into Aim 2 of the CR because we will not collect any trial data from SPs. We will collect the same 
baseline and follow-up data on the 300 additional patients who are being enrolled into phase 2.  
Study Design and Randomization. We will extend the randomized trial from the parent study to allow 
for a comparison of CC-COD+ to CC-COD. All participating clinics will start the study with enrolled 
patients being randomized between CC-COD and EUC (Phase 1). At specific milestones, each clinic will 
move to randomizing between CC-COD+ and EUC (Phase 2).   Milestones will be determined once we 
start enrollment at the California health care systems and can more accurately assess flow rates.  We 
have begun recruitment into phase 2 of the study for one health care system (FCCH) because they plan 
to end enrolling patients into the study at the end of 2022.  We plan to enroll 900 patients to the parent 
study using a stratified individual-level randomization, with strata defined by the participating clinics and 
prior MOUD use. Recruitment will continue until 300 patients are enrolled in the CR using the same 
stratified individual-level randomization design as the parent study. This plan allows us to complete 
recruitment of both projects within the parent timeline and minimizes the risk to the parent study since 
each clinic enrollment and randomization for phase 1 is completed prior to the clinic implementing CC-
COD+. Details on dates for clinic transitions to CC-COD+ can be found in the study SAP. 
 
 
 
 
 
 
 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 

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We carefully considered the comparison condition in conversations with our clinical partners and 
determined that all patients and providers must have access to the basic elements necessary to provide 
the continuum of care for COD, including training in the supported treatments. A cluster RCT was not 
feasible because of the large sample size, and with patient-level randomization it is not ethical to 
withhold these basic features of care. Additionally, our clinic partners told us that all treatments must be 
available to all patients at a given clinic. We are aware that in some clinics, Care Coordinator services are 
already available for some patients creating heterogeneity in the EUC condition. We will document this 
carefully and consider it if we find differences in outcomes across sites. Care Coordinators assigned to 
CC-COD will have resources not available to regular Care Coordinators: a patient registry to provide 
population-based care; training and materials to do measurement-based care; expert consultation with 
BHCs, case-based learning with other Care Coordinators, and training and supervision in MI and shared 
decision making. 
Rationale for CR study design: 
Original Design Choice: We carefully considered our Phase 1-Phase 2 design choice. While it is efficient 
and maximizes external validity by collecting data from patients at all 16 clinics, we recognize it poses a 
potential threat to internal validity. During the first 6 months that the CM provides the CC-COD+ 
intervention, they will continue to have CC-COD patients on their caseload (patients receive CM services 
for 6 months after enrollment) and it is possible for the CM to deliver the enhanced CC-COD+ 
intervention to these patients. This “contamination” could impact our ability to determine whether 
standard CC-COD is effective on its own and could affect the internal validity of the CR since CC-COD+ is 
being compared to CC-COD (See Figure 4.2 below). However, we believe contamination is unlikely and 
take steps to minimize the risk. The 3 components supported by CC-COD+ are discrete and independent 
of CC-COD (Overdose/suicide risk education, Naloxone training and Caring Contacts). The clinical registry 
will contain a field to help the CM keep the two populations separate, and fields related to SP contact 
and the suicide prevention intervention would be programmed to exclude CC-COD patients. Similarly, 
the system used to generate Caring Contacts postcards would be programmed to not include CC-COD 
patients. We would reinforce the scientific importance of not exposing CC-COD patients to the CC-COD+ 
intervention during CM training and clinical supervision, doing regular audits, eliciting any potential 
difficulties and problem solving.  
Revised CR design: Because the CR did not enroll sufficient individuals to allow for separate analyses, in 
consultation with our Research Advisory Board, the NIMH scientific officer and the NIMH project officer, 
it was decided to combine patients enrolled into the parent study intervention arm, with patients 
enrolled into the CLARO+ study intervention arm for all analyses.  The justification for this was that the 
objective of the trial was to test the Collaborative Care Model for individuals with co-occurring 
disorders, and the core model was identical across both the CLARO and CLARO+ trials.   
 

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4.3 
JUSTIFICATION FOR INTERVENTION 
We chose CC because it is a multi-faceted service delivery model proven to improve access and quality 
of care. We also chose to modify traditional CC to maximize its uptake in primary care settings in 
resource-poor communities and use with patients with multiple co-morbidities (called CC-COD). Our 
adaptation process is using a collaborative planning and development process to optimize CC-COD to 
the local setting and for this population, building upon tools and resources we developed for the 
Substance Use Motivation and Medication Integrated Treatment (SUMMIT) and Violence and Stress 
Assessment (ViStA) trials. The supported treatments include MOUD, medication treatment for 
depressive disorders and/or PTSD, motivational interviewing (MI), problem-solving therapy (PST) and 
written exposure therapy (WET). We chose these psychosocial treatments because they are flexible, 
easy to implement, applicable to a broad range of clients (including those with subthreshold disorders), 
and extremely safe. Essential members of the CC-COD team include the Care Coordinator, PCP, BHP 
(psychotherapist) and BHC. Essential activities of the CC-COD model include population-based care 
supported by a clinical registry, the use of measurement-based care and treat-to-target practices, 
shared decision-making and expert consultation by a team of BHCs with complementary expertise. 
There are several key differences between CC and CC-COD. We modified CC because of the unique 
characteristics of the setting (resource-poor, Health Professional Shortage Area, long distances); 
patients (highly stigmatized, multiple complex conditions, ambivalent about treatment) and organization 
(community health workers used as care extenders, not nurses). 
We have adapted the traditional CC model in several key ways. First, rather than having only a single 
disorder, patients in this study will have co-occurring disorders making it difficult for a single Care 
Coordinator to provide behavioral health treatment for all three conditions. To address this difficulty, 
we will add a psychotherapist to the CC-COD team to address patient complexity and deliver evidence-
based therapies. A second challenge is that in these types of settings, having a nurse in the Care 
Coordinator role is expensive and nurses are scarce. For this study, we will train community health 
workers to address these challenges. This better leverages scarce professional resources and may also 
address the prevalent perceptions of stigma in this population. The third challenge is the scarcity of 
psychiatric expertise and geographic remoteness of several settings which limits the opportunity for 
psychiatrists to work with the Care Coordinator in person. We will address this challenge by using the 
ECHO model (Extension for Community Healthcare Outcomes) and multi-disciplinary case conferences 
that include both pharmacotherapy and psychotherapy experts in addiction and mental illness. (ECHO is 
remote video-conferencing, for case-based learning, group supervision and mentoring). We will train 
community health workers to play this role and to address these challenges. 
Justification for CC-COD+ 
Individuals with COD are at higher risk of dying from suicide or overdose than individuals with mental 
illness or OUD alone.31-34 The parent study will provide a definitive answer as to whether collaborative 

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care (CC) improves access, quality, and outcomes of care for individuals with COD. While a primary goal 
is to improve access to and retention in medication treatment for OUD (MOUD) (which is linked to 
decreased mortality and overdose risk), the interventions CC-COD supports do not proactively address 
suicide or overdose risk, an important limitation. In addition, CC-COD does not include SPs in the 
patient’s care. We address these limitations and tackle the public health crisis of increasing deaths from 
suicide and overdose with the proposed CR. Because SPs can play an important role in a patient’s 
decision to engage with treatment and in overdose and suicide prevention, we investigate SPs’ views 
and use this information to strengthen CC-COD. This revision will develop and then test the incremental 
effectiveness of three additional CC-COD components. Care coordinators will (1) educate SPs about 
MOUD with the goal of increasing patient retention in treatment; (2) train SPs and the patient to 
administer naloxone and on how to reduce opioid-overdose risk behaviors; and (3) implement Caring 
Contacts, a suicide prevention intervention that sends compassionate mailed or text messages to 
individuals to decrease social isolation and reduce suicide risk.  
4.4 
END-OF-STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed the screening and 
baseline assessment, a 6-month course of the intervention (for up to 13 contacts with the Care 
Coordinator), and the 3-month and 6-month follow-up assessments. 
 
The end of the study is defined as completion of the 6-month follow-up assessment shown in the 
Schedule of Activities (SoA). 
 
5 
STUDY POPULATION 
New Mexico: We conduct our study in New Mexico because it is a state with extremely high need and 
has diverse populations and settings. New Mexico is projected to have the highest death rate from 
drugs, alcohol and suicide by 2025 and is in the top quintile for age-adjusted opioid overdose death 
rates.82 New Mexico ranks 47/50 in rates of suicide death, 50/50 in rates of alcohol-induced death, 
45/50 in homicide death and 43/50 in drug overdose death.82 Primarily a rural state, it also has urban 
and suburban counties; nearly every county is a HPSA for either behavioral health or medical care.86 
 
California: We identified the new systems in this state through colleagues to boost recruitment given 
our loss of one of the New Mexico systems. By focusing in Los Angeles County, the RAND team may have 
local access to the sites which will minimize costs and make the recruitment process more feasible. This 
is particularly important given the late stage of study entry. 
 
Clinical Settings: We leverage relationships developed by the UNM team, and partner with 18 clinics in 
five large healthcare organizations that provide care throughout the state of New Mexico and California. 
We include a map in the Facilities and Resources section. We selected the organizations in New Mexico 

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because we have relationships with them and they provide care in the regions of New Mexico with the 
highest rates of opioid overdose (northeast and central) or are primarily rural (Southwest),187 and have 
varying capacity to deliver treatment, ranging from clinics with 0 to 18 buprenorphine prescribers. We 
also leverage relationships developed by the RAND team, and will partner with two additional health 
systems in California for ease of recruitment. Most clinics provide primary care for mostly low-income, 
predominantly Hispanic patients, and are in HPSAs for primary care, mental healthcare, or both. 
Providence Health & Services – Southern California serves a different population of primarily insured 
and non-Hispanic patients, which adds diversity to the subject pool. Clinic and patient characteristics are 
shown in Table 5.1 below. 

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Table 5.1. Characteristics of Collaborating Organizations/Clinics 
 
 
Clinic 
Characteri
stics 
  
First Choice Community Health Care (FCCH) 
University of New Mexico 
(UNM) 
Hidalgo Medical 
Services (HMS) 
Provide
nce 
LA County DHS 
  
Alame
da** 
Alamo
sa 
Belen 
Edgew
ood 
Los 
Lunas 
N. 
Valley
** 
S. 
Broad
way 
S. 
Valley 
SE 
Height
s 
North 
Valley 
SW 
Mesa 
 
 
 
 
SRMC 
CHC 
Lordsb
urg 
Med 
Squa
re 
Santa 
Monica 
HHH 
Mid 
Valley 
San 
Fernan
do 
Health 
Center 
Health 
region of 
NM/CA 
centr
al 
centr
al 
centr
al 
NE 
centr
al 
centr
al 
centr
al 
centr
al 
centr
al 
centr
al 
centr
al 
 
 
X 
SW 
SW 
SW 
West 
Sout
h 
Centr
al 
 San 
Ferna
ndo 
Valley 
  San 
Ferna
ndo 
Valley 
Rural per 
HRSA/HPS
A 
no 
no 
part 
part 
part 
no 
no 
no 
no 
no 
no 
 
X 
yes 
yes 
yes 
no 
no 
 no 
no  
County 
Bernal
illo 
Bernal
illo 
Valen
cia 
Santa 
Fe 
Valen
cia 
Bernal
illo 
Bernali
llo 
Bernal
illo 
Bernal
illo 
Bernal
illo 
Bernal
illo 
Sandova
l 
Hidal
go 
Grant 
Gran
t 
LA 
LA 
LA 
LA  
HPSA 
primary 
care 
no 
no 
yes 
yes 
yes 
no 
no 
no 
no 
no 
no 
X 
yes 
yes 
yes 
no 
yes  
(sco
re 
13) 
no 
yes  
HPSA 
mental 
health 
yes 
yes 
yes 
no 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
X 
yes 
yes 
yes 
no 
yes  
(sco
re 
18) 
no  
no  
FQHC 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
no 
no 
no 
X 
yes 
yes 
yes 
no 
no 
 no 
no  
# of PCPs 
(FTEs) 
TBD 
5 
3 
5 
5 
5 
6 
11 
6 
3.5 
3.25 
X 
2 
4 
7 
43 
17 
16 
 6 
# of onsite 
BHPs* 
TBD 
2 
1 
2 
1 
1 
3 
4 
2 
0.7 
2 
X 
3* 
1 
4* 
7 
2 
 3 
2  
Access to 
staff 
psychiatrist 
TBD 
limite
d 
limite
d 
limite
d 
limite
d 
limite
d 
limite
d 
yes 
yes 
yes 
limite
d 
X 
limit
ed 
limite
d 
limit
ed 
no 
no 
 no 
no  
# waivered 
providers* 
TBD 
5 
2 
3 
0 
3 
3 
7 
18 
6 
5 
X 
1 
2 
2 
2 
12 
6 
 0 
# of Care 
Coordinato
rs* 
TBD 
2 
2 
2 
2 
2 
1 
4 
3 
1 
2 
X 
0 
0 
0 
1 
1 
1  
TBD  

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Screen for 
OUD 
Yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
X 
 
yes 
yes 
yes 
no 
no 
no  
no  
Screen for 
depression 
Yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
yes 
X 
yes 
yes 
yes 
yes 
yes 
yes  
yes  
Patient 
Demograp
hics 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
% Hispanic 
TBD 
87 
68 
32 
75 
67 
75 
89 
43 
52 
67 
X 
53 
53 
53 
11 
16 
 12 
12  
% African 
American  
TBD 
3 
2 
<1 
<1 
3 
4 
2 
5 
<1 
<1 
X 
1 
1 
1 
5 
25 
 7 
7  
% Asian 
TBD 
<1 
<1 
<1 
<1 
2 
1 
<1 
23 
<1 
<1 
X 
<1 
<1 
.<1 
8 
5 
 5 
 5 
% Native 
American/
AK native 
TBD 
1 
2 
<1 
1 
1 
1 
1 
2 
<1 
<1 
X 
<1 
<1 
<1 
<1 
<1 
 <1 
 <1 
% Women 
TBD 
57 
57 
57 
63 
55 
59 
58 
63 
63 
63 
X 
55 
55 
55 
60 
45 
 50 
50  
% 
Uninsured 
TBD 
15 
13 
6 
13 
11 
15.5 
18 
3 
5 
6 
X 
8 
8 
8 
1 
16 
15 
15  
% 
Medicaid 
TBD 
69 
>50 
40 
66 
66 
63 
65 
72 
29 
46 
X 
28 
28 
28 
1 
81 
80  
80  
% 
Monolingu
al Spanish 
TBD 
40 
19 
4 
26 
16 
33 
39 
19 
8 
24 
X 
3 
7 
3 
2 
30 
25  
25  
 
HRSA=Health Resources and Services; HPSA=Health Professional Shortage Area; NE=north east; SW=south west; AK=Alaskan. *May not be full-time as providers work across sites. 
limited=available by phone for consultation.**Alameda was added to replace North Valley due to low recruitment. For analytic purposes they are grouped together as one clinic. 
 
 
 
 
 

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5.1 
INCLUSION CRITERIA 
Patient participants will be eligible to participate in the study if they meet the following inclusion 
criteria:  
• 
Consider this clinic to be their usual source of care 
• 
Age 18 or older 
• 
Probable OUD diagnosis 
• 
Probable PTSD or major depression 
• 
Speak and understand English or Spanish 
• 
Have capacity to give informed consent 
• 
Provide a signed and dated informed consent form. 
Pregnant women will not be excluded. 
The CR uses the same inclusion criteria 
 
5.2 
EXCLUSION CRITERIA 
Patient participants will not be eligible to participate in the study if they meet the following exclusion 
criterion:  
• 
The patient requires immediate medical (emergency procedure needed) or psychiatric 
intervention (i.e., self-injured, active psychosis). 
• 
The patient is receiving both MOUD and psychotropic medication from a provider/s outside of 
the primary care health system at which the patient is enrolled. 
• 
The CR uses the same exclusion criteria 
 
5.3 
SCREEN FAILURES 
Screen failures are defined as participants who: 
1. Do not meet inclusion/exclusion criteria  
Screen failures will be given a screening ID. They may be eligible to be rescreened but will be assigned a 
new screening ID.  
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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Recruitment. Across both the parent study and the CR, we will recruit and enroll 1200 adults who are 
patients in one of 18 clinics from five organizations that provide primary care throughout the states of 
New Mexico and California. Some patients may be recruited through referral from primary care 
providers at UNM who are not part of the three clinics participating in the trial.  Seven Federally 
Qualified Health Centers (FQHCs) from First Choice Community Health Care, three large UNM primary 
care clinics (Southeast Heights, UNM North Valley, and UNM Southwest Mesa) and SRMC, three clinics 
from Hidalgo Medical Services (also an FQHC), three clinics/sites from the Los Angeles County 
Department of Health Services, (the Hubert Humphrey Comprehensive Health Center, Mid Valley 
Comprehensive Health Center, and San Fernando Health Center [which is comprised of Glendale Health 
Center, West Valley Health Center, and San Fernando Health Center]), and Providence Health & Services 
– Southern California (Providence Health & Services – Southern California have agreed to partner with 
the research team on the proposed study. We will recruit patients from these clinics and healthcare 
systems who screen positive for probable opioid use disorder (OUD) and for co-occurring major 
depression (MDD) and/or post-traumatic stress disorder (PTSD)). 
Because this is a disenfranchised population that may be difficult to recruit, we will use a number of 
strategies to boost recruitment and retention.  
To identify potential participants, we will use several recruitment strategies across sites. These include 
anonymous, population-based screening in clinic waiting rooms, referral from clinic staff, direct 
outreach to potential participants via mailings sent from the clinics to potential participants, plus 
posters in waiting rooms and exam rooms, and Electronic Health Record Review. We plan to take an 
adaptive approach in determining the optimal recruitment and retention strategies at each of these 
diverse clinic sites. We plan a one-month run-in phase at the start of our actual enrollment period in 
order to evaluate the most effective strategy/ies in each setting and to build these into our ongoing 
protocol. An additional reason for using a variety of methods is because some of the rural clinics are 
small, and it would not be cost efficient to station study personnel at them 5 days a week. It is important 
to note, due to the SARS-CoV-2 pandemic, there have been changes to service and patient flow at 
clinics, therefore we anticipate recruitment to vary by site. Adaptations will be made on an as needed 
basis, based on our observations, preliminary recruitment success, and the UNM Office of Research 
guidance and in consultation with our clinic partners. 
Eligibility Screening and Informed Consent. Screening of patients in the clinic waiting rooms will take 
place via a multi-step process. First, patients will be approached by a trained research assistant (RA) who 
is employed by the RAND/UNM research team. The RA will inform patients of the existence of the study 
and ask them if they would be willing to complete an initial anonymous screening to determine 
eligibility. We conduct eligibility screening anonymously because of research that suggest that patients 
are more likely to report risky drug use in the context of anonymous screening. Those who agree, will be 
provided with a tablet on which to complete the eligibility screen. Audio computer assisted self-
interview screening (ACASI) will be available to patients with low literacy.  

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Patients who are eligible (see eligibility criteria in Section C) will be offered enrollment in the study. If 
they wish to proceed, then they will participate in a detailed informed consent process. The RA 
(employed by the RAND/UNM research team) will complete a baseline interview in private with the 
enrolled participant to gather further information, such as overdose history, OUD severity and co-
morbid pain. After the baseline interview is completed they will be randomized to either the 
Collaborative Care (CC-COD) or the Enhanced Usual Care (EUC) arm of the study. Participants who are 
consented and engage in the interview will be remunerated with $100 for their time and effort. 
Participants will also be offered a $25 bonus incentive if they either: A) complete the baseline interview 
the same day as screening eligible, OR B) call the research team back later to complete the baseline 
interview. For those with only a single probable disorder (either OUD or depression/PTSD) or who are 
not eligible for the study, we will ask if they would like us to inform their PCP of their screening results, 
and will inform their PCP if they consent. All incentive payments may be paid in form of cash if allowed 
by the participant’s clinic. Otherwise, incentives will be paid in the form of a merchandise card. For 
Providence Health & Services – Southern California, all incentives will be paid with merchandise cards. 
Referral for clinic providers. Clinicians are uniquely positioned to aid in recruitment since they know 
their population and are already aware of potentially eligible patients. In order to increase recruitment, 
we will train clinic staff about study eligibility criteria and how to refer clients to the study. Clinical 
providers and staff may refer patients who have a diagnosis of PTSD, depression, or probable OUD 
(whether or not they are being treated with medications for this condition (buprenorphine or 
naltrexone)). We allow patients currently in treatment for PTSD or depressive disorders to enroll in the 
study as long as they continue to report symptoms, because of research that suggests that quality of 
care for behavioral health disorders is low in primary care settings, although we expect few people to be 
receiving treatment for either PTSD or depression, based on our conversations with the clinics. These 
patients will be approached by clinic or research staff, informed of the opportunity to participate in the 
study by completing an initial anonymous screening to help determine eligibility. They will then be 
assessed according to the above algorithm (Section 5.1.). 
Direct outreach to potential subjects. The study staff (employed by the RAND/UNM research team) will 
prepare letters of study invitation to participate in the study. These IRB approved materials (stamped, 
sealed letters) will be addressed and sent out by the clinics to all potential participants and will include 
contact phone number and email/social media contact information. We will develop posters and post 
them in the waiting room, along with study contact information. RAs will respond to queries from 
potential study subjects, and will screen and offer enrollment as described above. This procedure is 
designed to avoid giving the study staff access to the personal health information for these patients until 
they elect to participate in the study. 
Electronic Health Record (EHR) review. The UNM Clinical and Translational Science Center (CTSC) offers 
a UNM IRB-approved Patient Recruitment Service (PRS) to identify potential participants for research 
studies using the UNM EHR. Their procedures include a review of the EHR using ICD codes at 3 month 

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time intervals, then using an “honest broker” approach wherein, they contact these people and ask 
them if they are interested in being contacted about participation in a study. If the patient agrees, their 
contact information will be provided to the Collaboration Leading to Addiction Treatment and Recovery 
from Other Stresses (CLARO) study staff who will reach out to assess interest, screening and eligibility. 
We plan to review these procedures with other non-UNM clinics to assess a similar and suitable 
approach with these clinics. The script that is delivered to the patients regarding the study will be 
developed by the research staff and approved by the UNM HSC IRB. Please note that the study will not 
conduct an EHR review for recruitment at Providence. 
Recruitment rate and feasibility. We collected preliminary data from each of the original 13 sites (not 
including the California sites) site to determine potential flow rates. The 2-week pilot identified 1,145 
out of 1478 people (77%) who were eligible (over 18 and a patient at the participating clinic) and 
consented to participate in the pilot. The overall mean age of all participants was 48 years (standard 
deviation 17.3); 65.2% of participants identified as female, the survey was taken in Spanish by 10.7%, 
and 3.1% and 1.8% of respondents reported use of prescription pain pills or heroin, respectively in the 
past 3 months. In total, 51 (4.5%) patients surveyed had probable opioid use disorder (OUD), 214 
(18.7%) had probable depression; and 218 (19%) had probable PTSD. Based on responses to screening 
questions about probable OUD with co-occurring depression and/or PTSD, a total of 27 (2.4%) of 
participants would be eligible for participation in the CLARO study. Among these 27, 70.4% were female 
and 11.1% took the survey in Spanish. Prescription pain pill use in the past three months was reported 
by 66.7% of those eligible, and heroin use (past 3 months) was reported by 44.4%. Of these 27 eligible 
patients: 46.2% reported not getting any treatment for their substance use or mental health in the past 
30 days; 23.1% reported counseling only, 11.5% reported medication only, and 19.2% reported receiving 
both medication and counseling. Among those receiving counseling or therapy, 54.6% were receiving it 
at the same clinic or health system we interviewed them at. The majority (85.7%) of those who reported 
receiving medication for OUD or mental health were receiving that at the same clinic. While clinics 
reported that about 18.5% of patients were monolingual Spanish speakers, the pilot study only 
interviewed 142 patients (12.4%) in Spanish. Compared with the number of patients that clinic staff 
estimated they would identify over a two week period with OUD, depression and PTSD (based on 2018-
2019 clinic flow estimates), the pilot study identified a slightly higher number of patients than expected 
(See Table 5.2). These numbers support the feasibility of meeting recruitment goals for the study. The 
pilot also suggests that a significant proportion (46.2%) who are eligible are not getting treatment.  
These assumptions yield a total of 675 patients enrolled per year and 56 patients enrolled per month. 
Over 16 months, this will yield 1200 enrolled patients. We recognize that these are estimates, and have 
allowed for an additional four months of study recruitment in case these estimates are incorrect. Once 
again, we would like to note, that we could experience a delay in achieving our recruitment goals due to 
public health directives associated with the effects of SARS-CoV-2. We will make adjustments and 
modifications to our research and recruitment goals on an as needed basis. 

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Table 5.2. Summary of pilot results compared to data estimated from EMR in 2018-2019 for two week period.  
 
All Sites 
 
Clinic Flow Estimates 
(2018-2019) 
Pilot, Consented 
 
n 
% 
n 
% 
Total patients 
740 
--- 
1,145 
--- 
Total patients with OUD 
25 
3.4% 
51 
4.5% 
Total patients with Depression 
94 
12.7% 
214 
18.7% 
Total patients with PTSD 
27 
3.6% 
218 
19.0% 
Total patients with OUD + Depression and/or PTSD 
6 
0.8% 
27 
2.4% 
Total Number Monolingual Spanish/Took Survey in Spanish 
137 
18.5% 
142 
12.4% 
 
Study staff will keep logs of all patient enrollments as well as of problems and solutions that arise in 
recruitment. Staff will also track the number of screening and enrollment refusals, characteristics from 
the eligibility survey of people who refuse, and reasons for refusal. We will also identify those who drop 
out of the sample before the last follow-up assessment. These tracking data will be shared with our 
patient engagement and recruitment board and help us refine recruitment/retention procedures and 
inform our understanding of potential biases. In addition, we will conduct weekly meetings with the 
field staff to monitor recruitment and retention progress, troubleshoot and address implementation 
barriers. 
Table 5.3 shows the patient flow rates and based on those data, shows estimated recruitment rates and 
sample sizes. 

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Table 5.3 (Part 1)– 10/31/2022 through 2/20/2023  
 
 
 
 
 
 
 

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Table 5.3 (Part 2) – 2/27/2023 through 5/22/2023  
 
 
 

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In the SUMMIT trial we successfully recruited and enrolled 396 primary care patients with either alcohol 
or opioid use disorder; in the ViStA trial, we successfully recruited 400 patients from six FQHCs over the 
course of 18 months. We did not have referrals in either study. In a recent study of which UNM is one of 
8 sites (led by Dr. Page; HPC-1503-28122) providing hepatitis C virus (HCV) treatment in patients with 
active ongoing injection drug use and attending either outpatient community clinics or the UNM Alcohol 
and Substance Abuse (ASAP) clinic for methadone maintenance therapy, we screened 420 patients and 
enrolled 82 to be randomized to Patient Navigation or modified Directly Observed Treatment (for HCV 
treatment). We successfully followed 82% of those randomized. This population (currently injecting) is 
at significant risk for loss to follow up. With the 11 clinics, three of which are very large, and by including 
a referral strategy, we are confident we can meet our recruitment targets. Nevertheless, we include a 4 
month recruitment cushion if recruitment rates are lower than expected, or which could arise in 
association with the SARS-CoV-2 pandemic.  
Retention. Study subjects will be re-interviewed by telephone 3 and 6 months following enrollment. 
They will be offered $40 to complete the 3 month interview and $40 to complete the final interview at 6 
months, and they will be informed of these incentives at the time of initial enrollment. Incentive 
payments will be given in the form of a merchandise card. We will contact patients via phone, text or 
email (as they prefer) to schedule follow up interviews. We will make up to 20 attempts over the course 
of two weeks to contact the participant for each of the two follow-up interviews, and will follow up with 
hard copy letters to their address, asking them to contact us. We estimate we may lose up to 20% of 
enrolled subjects from our outcome assessment, due to lost to follow up, incarceration, and mortality, 
leaving an analytic N=720. A study being conducted by Dr. Page at UNM treating patients who are 
actively injecting substances has a cumulative 23% loss at 24 weeks (unpublished data). We discuss how 
we will minimize loss to follow up below. If all of these methods are unsuccessful, we will ask for help 
from the clinic staff to contact the patient, and if necessary will contact the patient at the time of one of 
their scheduled clinic visits to offer them a chance to complete the 3 or 6 month assessment. 
We recognize that the hardest subjects to reach in a target population might provide fundamentally 
different responses than members of the group who are relatively easier to find, introducing non-
response bias and threatening the quality of survey statistics and the validity and generalizability of 
research findings. We will use two categories of methods: strategies to stay in touch over the course of 
the study, and strategies for locating “lost” respondents. Research suggests that in addition to collecting 
extensive subject contact information, for substance users, online searching of public records, including 
jails/prisons and death records, and contacts with friends and family are important strategies when field 
tracking is not an option.  
Strategies to stay in touch with respondents. We will use the following strategies to stay in touch with 
respondents. (1) Collecting extensive contact and re-contact information at study enrollment, including 
contact information for two or more family members or friends who may know where the subject is. 
Contact information includes full name, date of birth, phone, cell, email, work address and phone; and 

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use of social networking sites. (2) Incentives. We will provide a $40 merchandise card incentive for 
completing the 3-month follow up survey, and $40 merchandise card for the 6-month survey. (3) 
Reminder gift item such as a cup or water bottle that contains study contact information with study 
branding to help respondents remember the study; (4) Social Media. We will document all tracking 
efforts in a tracking system. DataStat will also maintain a dedicated project telephone line. 
Strategies for locating respondents. For subjects who cannot be reached by telephone, email or 
through third party contacts, we will employ the following methods divided among the groups involved. 
(1) Look for change of addressing using online free record searches, querying the national address server 
and the United States Postal Service National Change of Address database (NCOA) (DataStat); (2) Paid 
online searches using Lexis Nexis and INtelius; directory assistance (SRG); (3) Jail and prison searches 
using the Federal Bureau of Prisons, Vinelink.com; County Sheriff’s websites, State Department of 
Corrections websites and inmate locators (SRG); (4) Death records and obituaries using the social 
security death index, and other vital records using state department of vital statistics websites (UNM); 
(5) Administrative records such as the Department of Motor Vehicles or court records (DataStat).  
Strategies that will be used to ensure a diverse, representative sample. First Choice Community Health 
Center (FCCH) clinics, Southeast Heights Clinic at the University of New Mexico, Hidalgo Medical Services 
in New Mexico; and Los Angeles County Department of Health Services in California all serve primarily 
low income, underserved, Hispanic patients. As such, patients enrolled for this study will reflect the 
ethnic and racial background of patients served in the participating sites. This population as a whole is 
very diverse. A total of 33% of patients receiving care across sites is non-Hispanic white, with 63% 
Hispanic, 2% Black, 1-2% Native American and 2% Asian. We recognize that the number of Native 
American subjects is lower than expected, as 11% of New Mexico’s population is Native American. We 
know that many Native Americans get care through the Indian Health Service, however it is also possible 
that the clinics are under-identifying Native Americans. We anticipate identifying and enrolling a similar 
sample for this study. The population will also be diverse in representing both genders with the percent 
female ranging from 51-63% across sites. 
Potential recruitment/enrollment challenges and strategies that can be implemented in the event of 
enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources).  
Due to the SARS-CoV-2/COVID-19 pandemic, there is a possibility that we may encounter potential 
recruitment and enrollment challenges. As the recommendations evolve, we will also adapt our research 
guidelines to be in compliance with directives and guidance shared by our clinic partners. We anticipate 
that patients may no longer feel as comfortable visiting a clinic for an unnecessary appointment or a 
study visit. We will remedy this by providing as many IRB approved remote opportunities as possible to 
continue study participation. If we cannot recruit participants from clinic lobbies or MAT sessions we will 
broaden our recruitment strategies and heavily target online platforms and advertisements, as well as 
referral opportunities from the clinics and community partners. We will monitor recruitment and target 
enrollment numbers closely in order to make timely modifications to our strategies. Additionally, the 

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CLARO research team will work closely with clinic staff and the care management team to monitor 
barriers to participation in the intervention due to the pandemic (or other reasons) and mediate these 
challenges for participants. Examples include, but are not limited to provision of transportation 
assistance, virtual appointments, or flexible scheduling. 
Another potential recruitment/enrollment challenge is the stigma associated with substance use 
disorder and behavioral health diagnoses. We have attempted to address this by providing patients in 
the waiting room with tablet computers to use for completing screening so that they do not have to 
have a conversation that is potentially audible to others, and by conducting anonymous eligibility 
screening. If patients still seem hesitant to complete the screener in the waiting room, we will also 
arrange a private area for people to complete the computerized screening questionnaires. 
Lastly, a possible challenge is identifying an adequate number of potential participants in the target 
clinics. If recruitment is slower than anticipated, one option would be to expand to other primary care 
clinic sites at the University of New Mexico. Another would be to work with additional organizations that 
offer primary care in NM, some of whom have signaled an interest in participating (e.g., Southwest Care 
organization, and Casa de Salud.) Lastly, we may implement an additional recruitment strategy such as: 
patient chain referral, also known as snowball sampling or respondent driven sampling. In this 
recruitment strategy, a participant recruits and refers people he or she knows who may be eligible, and 
then those new participants recruit people they know, and so on. As the participants share contacts, 
more participants are added to the study and there is an accumulation of participants over time. This 
type of recruitment and sampling is a nonrandom sampling technique, similar to convenience sampling, 
wherein there is not an equal chance for all participants to be chosen. Because snowball sampling allows 
participants to reach out and find more research subjects, researchers have access to potentially unique, 
hard-to-reach or marginalized populations. Snowball subject recruitment can be used in both 
quantitative and qualitative research and relies on the social networks of the participants to gather 
people for the study. A downside to this technique is the nonrandom nature of participant selection, 
meaning the results of a snowball sampling study may have limited generalizability to the population at 
large. 
Strategies that will allow for the study team to take advantage of new opportunities (e.g., policy 
changes or new financing mechanisms that have immediate practice implications). We are aware that 
UNM or FCCH could potentially begin a contract to provide healthcare in the state prisons and for 
individuals exiting incarceration. If we anticipated a large influx of recently-incarcerated individuals we 
could attempt to stratify randomization by recent-incarceration status, and could evaluate for a possible 
differential impact of the CC intervention on these two strata. The New Mexico Medicaid formulary 
includes sublingual buprenorphine but not injectable long-acting buprenorphine, and so few patients 
are receiving this treatment currently. If the injectable form were added to the formulary and the 
requirement for a prior authorization removed then we could examine whether patients respond 

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differently to the CC intervention if they are treated with the injectable long-acting formulation 
compared with the sublingual formulation. 
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
This is a non-investigational approach utilized with this patient population. The control group of the 
study will have usual care, the CC-COD group will use collaborative care which is a non-investigational 
approach already used in this population with a strong evidence basis.  
CC-COD intervention. The CC-COD intervention emphasizes the core principles of collaborative care 
including: patient-centered care (shared decision-making with the patient), population-based care 
managed through a clinical registry, measurement-based treatment to target (e.g., symptom 
management questions to assess program and adjust treatment plan as needed), and evidence-based 
psychotherapy and pharmacotherapy treatments188 (see Table 6.1 below). The intervention is based on 
a service delivery approach that uses multi-faceted interventions to improve access and quality of care. 
It is based on Wagner’s Chronic Care Model189,190 and subsequent modifications.98,191 We hypothesize 
that the intervention will improve access to the supported evidence-based treatments including 
supported treatments include MOUD,192,193 medication treatment for depressive disorders and/or PTSD, 
motivational interviewing (MI), problem solving therapy (PST) for MDD, and written exposure therapy 
(WET) for PTSD.  
Table 6.1. Description of how core-principles are integrated in the CC-COD Intervention 
Core-principles 
CC-COD intervention 
Patient-centered care194 
• 
Shared decision-making between the care management team 
and patients where problems to address are clearly defined, 
treatment plans are mutually agreed upon (e.g., initiation visit 
uses a menu of options to do this), and barriers are identified 
and addressed (e.g., social needs)  
• 
Designation of a community health worker as Care 
Coordinator to engage the patient, actively monitor their 
progress, make necessary modifications to the treatment plan, 
and link them to care  
Population-based care 
• 
Use of registry to track a caseload of patients 

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• 
Use of registry flags that inform care 
coordinators/supervisors/consultants of patients in need of 
higher-level care (e.g., patients with missed visits, suicidality) 
• 
Use of registry to track patient progress by symptoms (e.g., 
MBCs) and service receipt (e.g., MOUD, WET, PST) 
Measurement-based 
treatment to target 
• 
Routine symptom monitoring through measurement-based 
care and goal attainment questions to assess progress 
• 
Adjusting treatment plans by progress with the goal of 
symptom remission for all conditions  
Evidence-based care 
• 
Offering MOUD, WET, and PST to treat OUD and PTSD/MDD 
• 
Using MI to deliver care initiation and monitoring visits 
• 
Monitoring initiation, engagement, and retention of MOUD, 
WET, and PST 
Care Coordinators will utilize Motivational Interviewing and meet with patients individually for at least 
13 visits over six months. In the first two months, the Care Coordinator will meet weekly with the 
patient. In month three, they will meet biweekly. In months four through six, they will meet with 
patients once a month. Visits can be in-person or by phone, and ideally in-person prior to the PCP visit 
so that the Care Coordinator can relay information to the PCP before their visit (e.g., symptoms, insights 
regarding barriers to care). Visits can also be conducted more frequently or for longer than six months 
should the care team decide it is best for the patient. The Care Coordinator first meets the patient in a 
care initiation visit, where the Care Coordinator builds engagement, assesses various patient domains 
(e.g., OUD, MDD, PTSD, social needs), discusses the conditions to target, links the patient to care, and 
coordinates linkages with the PCP and BHP. Assessment includes asking the measurement-based care 
questions described earlier along with the WellRX to assess social needs, PEG Pain Monitor, and social 
support measures. The Care Coordinator then collaborates with the patient using MI to assess 
treatment experiences and barriers to care, provides information about treatment options, and then 
coordinates next steps with the patient. All but four of the opioid use questions used in measurement-
based care, PCL-5, and PHQ-9 are administered monthly. After the care initiation visit, Care Coordinators 
will then meet with the patient in monitoring visits for the remainder of the six-month intervention 
period. Care monitoring visits are similar to initiation visits, but abbreviated and also focus on 
engagement, assessment, and linkages.  
The Care Coordinator is supported by a behavioral health consultant (BHC) and a Care Coordinator 
supervisor with expertise in supervising community health workers. The Care Coordinator meet with 
BHC and Care Coordinator supervisor, respectively, on a weekly basis to discuss the Care Coordinator’s 
patient caseload. Finally, Care Coordinators enter patient information into a clinical registry on an 
ongoing basis, which tracks a Care Coordinator’s patient caseload and has four main purposes:195 (1) 
tracks population-level outcomes and engagement, (2) prompts the Care Coordinator with reminders 
and alerts to ensure accountable outreach when patients have upcoming appointments or need a 
higher-level of care, (3) prompts treatment-to-target through ongoing symptom management scores 

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that show trends over time in real-time and flags the Care Coordinator when to consult with the BHC, 
and (4) facilitates caseload review between the Care Coordinator, BHC, and Care Coordinator supervisor 
through caseload-level reports that display patient-level ID numbers of those who should be discussed.  
Enhanced Usual Care intervention. We carefully considered the comparison condition in conversations 
with our clinical partners and determined that all patients and providers must have access to the basic 
elements necessary to provide the continuum of care for COD, including training in the supported 
treatments. A cluster RCT was not feasible because of the large sample size, and with patient-level 
randomization, it is not ethical to withhold these basic features of care. Additionally, our clinic partners 
told us that all treatments must be available to all patients at a given clinic. Thus, EUC includes both the 
evidenced-based psychotherapy (i.e., Problem Solving Therapy196,197 for depression and Written 
Exposure Therapy for PTSD198-200) and pharmacotherapy (i.e., MOUD and psychotropic medications for 
MDD/PTSD) provided in CC-COD, but the primary difference is the absence of a care management team 
and a clinical registry to coordinate care with the patients in EUC.  
CC-COD+ intervention. CC-COD+ adds three components to the existing CC-COD intervention (see Table 
6.2). Education. We draw from materials from our prior work with OUD SPs to provide psychoeducation 
to reduce suicide and overdose risk.163,176 In our qualitative work on other related projects, patients and 
SPs told us they had questions about the process of addiction and buprenorphine (e.g., Is it drug 
swapping? Is relapse common? How long will they be on buprenorphine?). Often, misinformation led 
patients to leave treatment because of unsupportive SPs who thought the patient was still using. Thus, 
our goals for providing education are to explore these common questions about OUD and MOUD and 
correct any misperceptions. Topics from our other intervention manual includes how addiction is 
chronic, that buprenorphine is safe and effective, and that MOUD decreases withdrawal symptoms and 
cravings. CCs will also assess patient’s overdose risk using the Overdose Risk Assessment scale and 
provide personalized feedback on behaviors that escalate risk (e.g., using sedatives within 2 hours 
before or after using an opioid) and discuss alternate options to lower risk.9 Finally, CCs will conduct 
lethal means counseling to decrease suicide risk (e.g., using gun locks or biometric gun safe/boxes, 
storing ammunition separate from guns; removing guns from the home).201-203 Naloxone training. CCs 
will educate patients and SPs about the importance of naloxone, how to recognize signs of overdose,204 
and will provide patients and SPs with naloxone training.165,205 Caring Contacts. We adapt the Caring 
Contacts intervention to best suit the needs of the target population and setting. Several key aspects of 
the intervention can be tailored, including the (a) sender, (b) modality of the message, (c) message 
content, (d) patient population included, and (e) schedule of messages.206 We anticipate that CCs will 
mail postcards/send text messages to all CC-COD+ patients with a brief message that does not require a 
response (see Figure 6.1). Cards will be mailed routinely before the patient’s birthday, one week after 
the first CC visit, and each month thereafter for the six-month intervention period. Each card will be 
tailored to the purpose (e.g., birthday, after a visit, or “thinking of you”). The patient registry will 
support the schedule on which CCs should be mailing cards. We will adapt existing protocols used by Dr. 
Landes for responding to patient replies to Caring Contacts (e.g., messages of thanks, questions, 

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crisis).176,178 Patients without SPs (~20% based on preliminary data) assigned to CC-COD+ will receive all 
three components minus the SP education.  
 
 
Table 6.2. Description of the new components to the 
CC-COD+ Intervention 
6.1.2 ADMINISTRATION  
As stated above, the care coordinators will meet with 
patients individually for at least 13 visits over six 
months. In the first two months, the Care Coordinator 
will meet weekly with the patient. In month three, they will meet biweekly. In months four through six, 
they will meet with patients once a month. Visits can be in-person or by phone. Care coordinators will 
be community health workers compared to nurses or behavioral health providers in more traditional 
 
 
CC-COD+ 
component 
CC-COD+ Activities 
Length of time 
(1) Overdose/suicide 
risk education 
Educate and explore questions about MOUD 
with SPs 
Educate SPs about addiction 
Assess overdose risk and discuss with patient  
Conduct lethal means counseling with patient 
One individual 30-minute session with 
an SP 18+ nominated by the patient. If 
the patient wants to nominate more 
than one adult SP, two can attend this 
session. 
 
Overdose risk and lethal means 
counseling with the patient will be 
integrated into the patient’s care 
initiation visit with the care coordinator. 
(2) Naloxone training 
Educate patients and SPs on signs of 
overdose and the importance of naloxone 
Train patients and SPs on use of naloxone 
15 minutes (SPs will receive in their 
session; patients will receive in their 
care initiation session) 
(3) Caring Contacts 
Convey concern/compassion via mailed cards 
Sent to patient weekly/monthly (titrated over 
six months) and on patient’s birthday 
Ongoing mailed contacts to patients 
Figure 6.1. Example of Caring Contacts 
message
 

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collaborative care studies to address the provider shortage in New Mexico and to increase patient buy-
in with a peer delivering the intervention. Each patient participant will be assigned one Care Coordinator 
to interact with during the six-month intervention period. Participants are not expected to interact with 
other participants in the intervention. Intervention dose will be measured by the number of visits each 
patient has with the Care Coordinator and these data will be gathered in the clinical registry. 
 
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
Care coordinator training: Care Coordinators will receive at least 40 hours of training that correspond to 
the five core principles of collaborative care. Specifically, Care Coordinators will receive didactics on the 
symptoms underlying OUD, depression, and PTSD, and what evidence-based approaches will be offered 
in CC-COD to treat these illnesses. Care Coordinators will also receive MI training and will participate in 
several interactive exercises and role-plays to practice MI in the context of their rehearsal of CC-COD 
initiation and monitoring visits. Finally, Care Coordinators will receive training where they will learn to 
administer the measurement-based care questions, interpret findings to aid treatment planning, track 
patients in the registry (population-based care), and facilitate communication with the patient and 
members of the care team. Competency will be assessed while observing practice role-play sessions and 
through audio recordings of patient interactions upon starting the clinical trial. Care coordinators will 
obtain verbal consent to audio record intervention sessions. 
Prior to the implementation of the RCT, success of Care Coordinator training will be determined three-
fold using role-plays to determine (1) proficiency of motivational interviewing skills, (2) competency in 
working with the clinical registry, and (3) comprehensiveness of delivering initiation and monitoring 
visits. As training materials are developed, benchmarks to determine competence in these three 
domains will be determined. For example, to measure MI proficiency, we may utilize the Motivational 
Interviewing Treatment Integrity Scale (MITI 4.2.1) and consider a score of 3.5 on the relationship 
subscale and/or a 3 on the technical subscale as passing criterion.207 For the registry, we may have 
several scenarios that Care Coordinators need to accomplish in order to pass (e.g., entering a new 
patient, resolving a flag, escalating a patient to the BHC, generating a report for the PCP). Finally, for the 
role-playing a visit, we have a checklist of items to be discussed in each visit and could use a 90% score 
as a passing metric. 
Care coordinator supervision: Care Coordinators receive three hours of weekly supervision. They 
receive one hour of individual supervision with a behavioral health consultant with an addiction 
psychiatry background to discuss patients in their caseload. In addition, they will receive group 
supervision to discuss fidelity to the intervention and other research study concerns. Finally, they will 
participate in a group Extension for Community Healthcare (ECHO) each week. On alternating weeks, 

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the ECHO will focus on either reflective supervision or case presentation (i.e., a care coordinator 
presents a case for group discussion). Reflective supervision focuses on reflection between the Care 
Coordinator and the supervisor to builds on the Care Coordinator’s use of their thoughts, feelings, and 
values within a service encounter. 
CC-COD fidelity: During the RCT, intervention delivery fidelity will be measured through weekly 
supervision with the BHC and Care Coordinator supervisor who will monitor the Care Coordinator visit 
attendance including patient visits that were completed or missed in the past week. These meetings will 
focus on ways to increase delivery fidelity including brainstorming barriers for missed visits and ideas for 
completing them.  
Care coordinator training and supervision for CC-COD+. The training will involve a mix of didactic 
presentation, demonstration, and role-playing. The training will focus on ways the Care Coordinators 
can respond to questions about suicide and overdose risk, work with patients who are suicidal or at risk 
of overdose, coordinate with healthcare providers, and facilitate MOUD retention. In addition, they will 
learn about harm reduction strategies to reduce overdose risk. Mr. Bernie Lieving, the Statewide 
Overdose Prevention Education Coordinator for New Mexico’s Office of Substance Abuse Prevention, 
will provide naloxone training to Care Coordinators. Then the focus will shift to Caring Contacts, 
including logistics (who, when, how to send messages), ways to respond to patients who reach out, and 
what resources to use when patients present with risk. Dr. Osilla will provide feedback to each Care 
Coordinator and practice role-plays with them as needed until the Care Coordinator can cover all 
intervention content in a MI-consistent manner. As in the parent study, Care Coordinators will meet 
with a supervisor weekly to discuss patient cases and review intervention content.  
CC-COD+ Fidelity: As part of the parent study, we will measure fidelity to the CC-COD intervention 
during the 3 and 6 month follow-up, with questions asking participants in both the EUC and CC-COD to 
what extent they interacted with a community health worker that exhibited elements of MI (e.g., 
collaborative, nonjudgmental), connected them with MOUD and/or behavioral health services and 
asked them questions about their OUD/PTSD/MDD symptoms. We will add to this measure questions 
related to whether the participants were exposed to the components of CC-COD+. Specifically, the CC 
will monitor if the following CC-COD+ activities occurred during a one-month period: (1) SP education 
session, (2) patient suicide risk session, (3) naloxone session (SP vs. patient vs. both present), and (4) the 
number of caring contacts cards sent.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants will be randomly assigned to a study condition (CC-COD vs. EUC; and then CC-COD+ to EUC) 
following their baseline assessment, conducted by the research assistant (employed by the RAND/UNM 
research team). More specifically, this study will use a stratified randomization to assign individuals to 

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CC-COD (or CC-COD+) versus EUC, with strata defined by prior MOUD exposure and site.  A 
randomization list will be generated for each stratum and include randomly permuted block sizes of 2 
and 4. We will stratify on prior MOUD to mitigate confounding, as patients who have used MOUD 
previously are more likely to initiate MOUD subsequently. Research staff will access the randomization 
module in REDCap. Staff will enter which prior MOUD exposure stratum and site the patient is in, and 
the intervention arm assignment will be generated. The timing of transition from CC-COD to CC-COD+ 
will vary for each site with each site following the permutated randomized blocks first generated for 
assigning individuals with their site to CC-COD versus EUC. Following baseline data collection and 
randomization, the research assistant (employed by the RAND/UNM research team) will inform the 
assigned Care Coordinator any time a participant is assigned to the CC-COD or CC-COD+ condition. 
 
 
Data collection for 3- and 6-month follow-up assessments will be conducted by an independent research 
firm, DataStat, and the individuals collecting follow-up assessments will also be blind to study condition. 
DataStat has not and will not be informed of the content of the intervention or the enhanced usual care. 
Study participants will not be blind to study condition once they have been randomized. To minimize 
bias, participants will not be told the study hypotheses and be encouraged to provide information that is 
based on their experiences (e.g., there are no right or wrong answers to the questions). There is minimal 
risk for potential bias due to the participant telling the DataStat surveyor which treatment group they 
are in. 
In addition to blinding for research procedures, it is worth noting that providers at the primary care 
clinics will not be blind to participants’ assignment to the CC-COD or CC-COD+ study condition because 
those participants will be assigned a Care Coordinator.  
 
6.4 
STUDY INTERVENTION ADHERENCE 
Intervention participants’ adherence with the study procedures will be tracked through the patient 
registry maintained by the Care Coordinator.  
To measure patient fidelity to the CLARO intervention, we will measure whether the following activities 
occurred in the same month period208 (see Table 6.2): (1) documentation of a care initiation and 
monitoring visit in the registry, (2) symptom monitoring defined as documenting scores from the 
measurement-based care questions in the registry, and (3) documentation of patient progress by 
printing registry reports for meetings with the behavioral health consultant . Fidelity will be coded in 
one of three ways: (1) dichotomously (yes/no) if all three activities happened in a one month period 
(i.e., in prior studies,208 a “yes” across a two-month period was considered high fidelity; the two-month 

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period could be examined as ever happening during the intervention period or at the early/later stages 
of the intervention), (2) a count of whether each activity happened each month (e.g., one monthly visit 
across the six-month intervention period would warrant a score of six, measurement-based care scores 
entered for only three months in the six-month period would warrant a score of three), and (3) the 
extent to which each activity happened in the past month (e.g., 0=absent, 1=partially, 2=fully). 
Table 6.2. CC-COD Fidelity Definitions 
 
Within the same month 
Care management visits 
At least one visit documented in the registry 
 
Symptom monitoring 
 
Scores for OUD and MDD/PTSD symptoms 
entered once in the registry 
 
Consultation/supervision 
 
One meeting with BHC and one meeting with 
Care Coordinator supervisor* 
*NOTE: BHCs and Care Coordinator supervisors will track attendance. It will be challenging to track whether specific 
patients were discussed within the month period so we may measure occurrence of consultation/supervision at the 
case manager-level instead. 
Adherence to CC-COD+ will be monitored by the CC supervisor. Specifically, the CC supervisor will 
monitor if the following activities occurred during a one-month period: (1) SP education session, (2) 
patient suicide risk session, (3) naloxone session (SP vs. patient vs. both present), and (4) the number of 
caring contacts cards sent.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
A participant will be discontinued from the study intervention when there is clear evidence of harm to 
patient or staff. The data to be collected at the time of study intervention discontinuation will include 
the following: 

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• 
The reason(s) for discontinuing the participant from the intervention  
When a participant discontinues from the study intervention but not from the study, remaining study 
procedures will be completed as indicated by the study protocol (e.g., the follow-up interviews). 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Patient Requests Study Withdrawal – If a study participant writes to the PI stating that they would like 
to withdraw from the CLARO study, we will stop collecting survey data and we will not use electronic 
health record or registry data for evaluation purposes after that date. Patients withdrawing from the 
CLARO study may continue to receive clinical care and care management for OUD and/or 
depression/PTSD. 
PI Withdraws Patient from Study – A PI may terminate a enrollees participation in the randomized 
control trial for the following reasons:   
• 
The PI learned that the study participant did not meet inclusion criteria or did meet exclusion 
criteria at the time of enrollment.   
• 
Other unanticipated reasons 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Study 
Status data collection form. Patients withdrawn from the study by the PI may continue to receive clinical 
care and care management for OUD and/or depression/PTSD. 
 
7.3 
LOST TO FOLLOW-UP 
Definition of Lost to Follow-Up – Subjects who sign the informed consent form, complete the baseline 
assessment, and are randomized, but subsequently withdraw, or are discontinued from the study for 
any reason, will not be replaced. A study participant will be considered to have been lost to follow-for 
the follow-up wave if it has been more than one month after the target follow-up date. If both the 3-
month or 6-month follow-up survey cannot be completed, and follow-up EHR data are unavailable, the 
patient will receive a lost to follow-up study status. 
Retention – Consenting patients will be asked to provide at least two alternative contacts, in addition to 
their own telephone number, address, and email address, and to agree for us to contact these 
secondary contacts. In addition, to mailing reminders about completing the follow-up surveys, we will 
also request permission from patients to text and/or email them reminders to call a toll free number to 
complete the follow-up phone interview. We will identify ourselves as members of a research project 

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but will not disclose any other details about the purpose for trying to reach the participant. CLARO team 
members will reach out to clinic staff if contact with the study participant cannot be made at follow-up 
in order to retrieve updated contact information. Patients will receive a $40 incentives (in the form a 
merchandise cards) to complete each telephone follow-up survey. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
Assessment Procedures. Once a potential participant has indicated interest in the study, trained 
research staff will screen the individual for eligibility. In the screening assessment, a research assistant 
(employed by the RAND/UNM research team) will ask the individual’s age and whether they are 
receiving primary care at one of the eleven participating clinics. The research assistant (employed by the 
RAND/UNM research team) will then administer the NIDA Tobacco, Alcohol, Prescription medication 
and other Substance use (myTAPS) screener to assess for probable OUD, the 9-item Patient Health 
Questionnaire (PHQ-9) to assess for probable depression, and the Primary Care PTSD Screen for DSM-5 
(PC-PTSD-5) to assess for probable PTSD. 
Patients will be eligible to participate in the study if they meet the following criteria: age 18 or older; are 
receiving primary care at a participating clinic; probable OUD diagnosis, defined by myTAPS1 scores ≥1 or 
past 90 day receipt of MOUD; have probable depression (a score ≥10 on the PHQ-92) or probable co-
occurring PTSD (having a score ≥3 on the PC-PTSD-53); speak and understand English or Spanish; have 
capacity to give informed consent; and provide a signed and dated informed consent form. The 
screening process will be terminated if the patient indicates they do not meet any of the previous 
criteria. The only other reasons for exclusion from the study are if the patient requires immediate 
medical (emergency procedure needed) or psychiatric intervention (i.e., self-injured, active psychosis) or 
if the patient is receiving both MOUD and psychotropic medication from a provider outside of the 
primary care system at which the patient is enrolled. 
Note that we will not administer item 9 from the PHQ-9 (“thoughts that you would be better off dead, 
or of hurting yourself”) during eligibility screening. This avoids asking for information that could require 
us to break confidentiality before a participant has completed the informed consent process. It does not 
affect our eligibility criteria because the 8-item and 9-item versions of the PHQ are scored identically.209 
We will obtain a complete initial PHQ-9 score during the baseline interview in one of two ways: (1) if 3 
or fewer days pass since the eligibility screener, administer PHQ item 9 during the baseline interview, 
then combine it with items 1-8 from the eligibility screener for scoring; or (b) if more than 3 days have 
passed since the eligibility screener, re-administer the full PHQ-9 during the baseline interview and use 
that full score for all subsequent analyses (this latter option does not affect the eligibility 
determination). 

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Patients who screen eligible will be contacted within 4 weeks to participate in the study. The research 
assistant (RA), who is employed by the RAND/UNM research team, will contact the participant to 
schedule a study visit that will consist of a screening questionnaire, the informed consent process and a 
baseline interview assessment. Due to COVID-19, the consent may or may not be conducted in 
person. We have created a contingency plan based on recommendations from institutional revisions to 
research procedures. If the consent process will not be conducted in person, the RA will consent the 
participant via an IRB approved, virtual method: verbal consent with electronic documentation of the 
consent process. Regardless of whether or not the consent is obtained via telephone or a video 
conferencing platform, this should not impact the RA's ability to move directly into the baseline 
assessment immediately following the consent. The participant will be notified ahead of time that they 
should plan on spending approximately 1 hour to complete this study visit. 
After the subject has consented to participate in the study, they will be given a baseline interview and 
then randomized to the intervention or control group. Research assistants (employed by the 
RAND/UNM research team) will administer the baseline assessment in-person, over the phone, or over a 
video conferencing platform following consent. If the participant is unable to take the baseline 
assessment immediately following the consent process, the RA will obtain the assessment within two 
weeks of consenting. If the participant has a time constraint, the RA will stop the assessment after the 
screening questionnaire and reserve the consent and baseline assessment for another day. After 
completing the baseline assessment, the participant will be randomized to one of two study conditions: 
CC-COD (intervention) or EUC (control) (the randomization is described in section 6.3). 
DataStat will conduct follow-up interviews by phone 3 and 6 months after study enrollment, with a 
window of -2 weeks/+4 weeks to conduct each assessment. Follow-up interviewers will be blind to study 
condition. We will make up to 12 attempts during this window to contact the participant for each of the 
two follow-up interviews, and will follow up with hard copy letters to their address, asking them to 
contact us. If all of these methods are unsuccessful, we will ask for help from the clinic staff to contact 
the patient, and if necessary will contact the patient at the time of one of their scheduled clinic visits to 
offer them a chance to complete the 3 or 6 month assessment. Research staff will conduct additional 
follow-up assessments with a review of the electronic health record (EHR). 
These procedures are identical for both the parent study and the CR. 
Endpoints. Our primary outcomes focus on use of buprenorphine and PTSD and MDD symptom severity. 
We will also examine a variety of secondary/exploratory outcomes and mediators/moderators of 
treatment quality and outcomes.  
Our original four primary patient outcomes were described as follows: (1) MOUD continuity of care,4 
which refers to the maximum numbers of continuous (i.e., no breaks of more than 7 days) days the 
patient receives MOUD the 180 days after study enrollment; (2) MOUD access,5 defined as patients with 
a new episode of OUD care (i.e., no care for at least 60 days prior) receiving an MOUD prescription 

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within 30 days; (3) MDD symptoms, as measured by the PHQ-92); and (4) PTSD symptoms, as measured 
by the PCL-5.179 MOUD continuity and access will be based on prescription (data and frequency) data 
from the EHR, supplemented by New Mexico Prescription Drug Monitoring Program data if feasible. 
During data collection and prior to breaking the study blind, we changed the operationalization of the 
first two primary outcomes due to data quality issues. Both outcomes were revised to focus on 
buprenorphine rather than MOUD, due to missing methadone data. Under federal regulations, primary 
care providers are not permitted to initiate or prescribe methadone for OUD and there is no objective 
data on methadone initiation from methadone treatment programs equivalent to the data in the PMP. 
We also do not include injectable naltrexone because in our data fewer than 1% reported receiving it.  
 
We also changed the specification of MOUD continuity of care to be operationalized as cumulative days 
of care, removing the requirement for no breaks in care of more than seven days. It is important to note 
that there is no “gold standard” for measuring OUD quality of care.210-212 While the National Quality 
Forum measure on which our measure is based has a requirement for no breaks in care, we believe that 
this requirement introduces measurement bias. We know from clinical experience and the scientific 
literature, medication nonadherence is common, and that patients will reduce their dose due to cost 
barriers or in an attempt to wean themselves off, introducing measurement bias.213,214 Measures of 
buprenorphine adherence do not include the requirement for no breaks in care215,216 and patients with 
percent days covered of >0.80 are classified as adherent. While it is widely agreed upon that longer 
MOUD care is better, there is no empirical evidence of an ideal length of time, or for how breaks in care 
are related to long-term outcomes such as mortality.48,217,218 Recent studies have cautioned against 
rigidly defining MOUD success and continuity due to patients’ nonlinear treatment trajectories and the 
crucial impact of MOUD even after gaps in care.211,219,220 Therefore, we believe it is both more 
meaningful and more valid to assess OUD quality of care as a count of total days of MOUD treatment 
rather than rely on a contested definition of care discontinuity.   
 
For MOUD access, we changed the specification of the outcome from a binary measure to a time-to-
event measure. We specify a time to event measure because ‘the number of days until first 
buprenorphine prescription’ is available in the Prescription Monitoring Program (PMP) and allows for 
more information around the distribution of times until beginning buprenorphine.  
  
We originally proposed to use the EMR to obtain information on patient outcomes but changed the 
source of data to the participant surveys and PMP. We believe this increases the validity of both primary 
OUD endpoints the study is measuring. Previous research indicates that the EMR contains missing data 
at both the variable and observation levels, and that this negatively impacts the validity of quality 
measures.221-223 In contrast, all study participants have completed the study screener that contains 
questions from myTAPS,1 a clinically validated composite measure to establish probable OUD. In 
addition, the change in data source for prescription information will result in a more accurate measure 
for receipt of buprenorphine. In the EMR, providers record prescriptions that have been written, and the 

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software does not contain information on whether a patient has ever filled the prescription. In contrast, 
as required by law, the PMP includes information on both the number and duration of prescriptions for 
controlled substances, including buprenorphine, that have been filled. It also includes prescriptions that 
may have been written by providers outside of the health care system that the patient is assigned to as 
part of the study. While neither a written prescription nor a filled prescription can be considered a 
perfect proxy for medication that has been taken, a prescription fill provides stronger evidence for 
taking a medication. Where available, we include self-reported data on MOUD use from the participant 
follow-up surveys.  
Our revised outcomes are as follows: (1) Buprenorphine continuity of care,4 which refers to the  
numbers of cumulative days the patient receives buprenorphine during the 180 days after study 
enrollment; (2) Buprenorphine access,5 defined as number of days until first buprenorphine prescription 
after study enrollment, among patients with a new episode of OUD care (i.e., no care for at least 30 days 
prior); (3) MDD symptom severity, as measured by the PHQ-92; and (4) PTSD symptom severity, as 
measured by the PCL-5.179 Buprenorphine continuity and access will be based on prescription (data and 
frequency) data from the follow-up assessments and New Mexico and California Prescription Drug 
Monitoring Program data. MDD and PTSD symptom severity will be collected in baseline and follow-up 
assessments, with primary outcome analyses based on final scores across the six-month period.  
Given the extensive scope and complexity of the CC-COD/CC-COD+ intervention, we will examine 
numerous secondary outcomes of interest related to substance use and mental health symptoms, 
health service utilization and quality, and general patient functioning. Substance use measures include: 
opioid use frequency, measured as days of opioid use in the past 30 using SAMHSA National Survey on 
Drug Use and Health (NSDUH6) items, and  opioid overdose events10 in the previous three months. 
Mental health measures include additional analyses of MDD symptom severity at follow-up, based on 
rates of remission (PHQ-9 < 5) and response (PHQ-9 score less than 50% of baseline score); PTSD 
symptom severity at follow-up, again including remission (PCL-5 < 34) and response (PCL-5 score less 
than 50% of baseline score); and active suicidal ideation, measured with the widely used Columbia 
Suicide Severity Rating Scales11 and analyzed as a binary measure based on affirmative responses to 
questions 3, 4, and/or 5 and/or an affirmative response to Question 7.224  Service utilization and quality 
measures are all derived from EHR and survey data and include access to MDD and/or PTSD treatment, 
meaning receipt of medication and/or behavioral treatment associated with a given diagnosis; and for 
new episodes of MDD or PTSD care (no visits associated with that diagnosis in the previous 30 days), 
(14) quality of care for MDD,13 which includes 4 psychotherapy visits in the first six months or an 
adequate (60 days) medication trial; and (15) quality of care for PTSD,13 which includes 4 psychotherapy 
visits in the first six months or an adequate (60 days) medication trial. Finally, we will assess physical and 
mental health functioning outcomes using the Veterans RAND 12-item Health Survey (VR-1214). 
A number of patient characteristics could moderate CC-COD/CC-COD+ outcomes. Some characteristics 
will be measured at baseline only; others will be measured in follow-ups as well, either because they 

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could have a time-varying interaction with the intervention or because the most current information is 
needed for records retrieval (e.g. National Death Index). Exploratory moderator variables include 
demographic characteristics (i.e., sex and ethnicity); trauma/interpersonal violence, measured using the 
PTSD checklist for DSM-5, description of worst event; pain levels, measured for the past week using the 
PEG Pain Monitor;15 housing status, measured using the Homelessness Screening Clinical Reminder 
Tool;16 disability and impairment, measured using the three-item Sheehan Disability Scale;19 stimulant 
use frequency, measured using days of stimulant use in the past 30 days from NSDUH6 items; and 
number of care coordinator visits, based on registry entries made by care coordinators. 
During follow-up assessments, we will measure key care processes thought to mediate the effects of CC-
COD/CC-COD+ on patient outcomes. Specifically, we will examine potential changes in (1) clinician  
communication, (2) ability to quickly access treatment, and (3) satisfaction with treatment, all using 
AHRQ Consumer Assessment of Healthcare Providers and Systems survey items,21 as well as (4) patient 
and Care Coordinator working alliance using a modified Working Alliance Inventory.22 Potential 
mediation will be included in exploratory analyses. 
Finally, we have several potential exploratory outcomes: drug use frequency, measured as days of use in 
the past 30 days for five drug categories (prescription opioids, heroin, cocaine/crack, 
methamphetamine/ other stimulants, and tranquilizers/sedatives) using SAMHSA National Survey on 
Drug Use and Health (NSDUH)6 items; stimulant use frequency, measured as days of stimulant use 
(cocaine/crack, methamphetamine/ other stimulants) in the past 30 days from NSDUH;6 alcohol use, 
measured using the 3-item Alcohol Use Disorder Identification Test – Consumption (AUDIT-C)8 for the 
previous 3 months; opioid overdose risk behaviors, measured with the Opioid Overdose Risk 
Assessment;9 and opioid use severity, measured using the 7-item Patient-Reported Outcomes 
Measurement Information System (PROMIS) Substance Use Short Form7 for the previous 30 days. 
 
 
8.2 
SAFETY ASSESSMENTS 
Safety data will be gathered from both solicited (baseline and follow-up interviews) and unsolicited 
reports (e.g. Self-reported by participant or provider) and reported at those specific time intervals as 
described below in Section 8.3.3.1. We will not report on safety during the screening assessment. All 
screened participants will be provided a referral as requested and if the information is reportable, the 
appropriate agencies will be notified.   
The safety assessments are identical for the parent study and the CR. 
 

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
An AE is any untoward medical or social occurrence in a clinical investigation subject who has received a 
study intervention and that does not necessarily have to have a causal relationship with the study 
intervention. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with study activities, whether 
or not considered related to the study intervention.  
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is an adverse event or suspected adverse reaction that is considered 
“serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event (i.e., suicide attempt that resulted in admission to hospital )*, 
• 
Inpatient hospitalization or prolongation of existing hospitalization, 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse. 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the subject or subject at immediate risk of 
death. It does not include an adverse event, had it occurred in a more severe form, might have 
caused death. 
The research team will monitor for SAEs from data collected at research visits, from data collected by 
DataStat, and other potential sources. Any SAEs will be reported according to the IRB requirements of 
the RAND Human Subjects Protections Committee (HSPC), the University of New Mexico IRB, and the 
requirements of the NIMH DSMB, as well as each of the partnering clinics that the participant is enrolled 
through. The initial SAE report will be followed by a submission of a completed SAE report to RAND’s 
HSPC and the NIMH DSMB. In the event that a research subject either withdraws from the study or the 
investigator decides to discontinue a patient due to an SAE, the patient will be monitored by the 

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investigator via ongoing status assessment until: (1) a resolution is reached, (2) the SAE is determined to 
be clearly unrelated to the study intervention, or (3) the SAE results in death. Outcomes of SAEs will be 
periodically reported to RAND HSPC and the NIMH DSMB. A summary of the SAEs that occurred during 
the previous year will be included in the annual progress report to NIMH. For each SAE, Dr. Miriam 
Komaromy will serve as the clinical monitor, to determine if the SAE was related to the study. A second 
opinion will be obtained from an independent monitor if needed.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
Event severity will be graded according to parameters shown below. This process will be started by a  
research assistant (employed by the RAND/UNM research team), care coordinator or other research 
staff member and subsequently confirmed or amended by one of the study investigators with clinical 
experience. The Project Director and Clinical Investigators (including the study PIs and clinical 
champions) will be notified immediately if any symptoms are graded severe or higher: 
1 = Mild (awareness of a symptom but the symptom is easily tolerated; the symptom requires minimal 
or no treatment) 
2 = Moderate (discomfort enough to cause interference with usual activity) 
3 = Severe (incapacitating; unable to perform usual activities; requires absenteeism/bed rest) 
4 = Life-threatening  
5 = Death 
Event Reporting 
We will report the following AEs: 
01. Self-injury that results in ED Visit 
02. Other____________________ 
We will report the following SAEs: 
01 Suicide attempt resulting in hospitalization  
02. Suicide resulting in death 
03. Death (not suicide or unsure if suicide) 
04. Non-suicidal self-injury that resulted in Hospitalization 
05. Hospitalization (not due to suicide attempt or non-suicidal self -injury) 

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06. Non-lethal Overdose (resulting in ED visit) 
07. Other: _____________ 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) will have their relationship to the study procedures, including the intervention, 
assessed by a designated clinical monitor. Dr. Miriam Komaromy will serve as the clinical monitor, to 
determine if the AE or SAE was related to the study. A second opinion will be obtained from an 
independent monitor if needed.  
The determination of seriousness, severity, and causality will be made by one of the study investigators 
who is qualified and licensed to diagnose adverse event information, provide a medical evaluation of 
adverse events, and classify adverse events based upon medical judgement.  
Relationship to Study: The clinician’s assessment of an AE's relationship to the study is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. All 
AEs must have their relationship to the study assessed using the terms: related or not related. In a 
clinical trial, the study intervention must always be suspect. The degree of certainty about the causality 
will be graded using the following categories below: 
Related – There is a reasonable possibility that the study intervention and/or study caused the 
adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study intervention and/or study and the adverse event. 
Not Related – There is not a reasonable possibility that the study intervention and/or study caused 
the event. 
 
8.3.3.3 EXPECTEDNESS  
We will use a binary classification of the extent to which an adverse event is expected or unexpected. 
Because the study population includes patients with co-occurring disorders that place them at increased 
risk for suicidal ideation, asking repeatedly about depressive symptoms, including suicidal ideation, is 
expected to trigger risk in some cases. Our emergency procedures explain how we will document these 
events as described in the sections below. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 

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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
As listed in our Incident Report form, all AEs, not otherwise precluded per the protocol, will be captured 
on that form. Information to be collected includes event description, time of onset, which providers 
were notified, type of event, and corrective action taken. Assessment of severity and assessment of 
association will also be included and documented on the Incident Report Form. All AEs occurring while 
on study will be documented appropriately regardless of relationship. All AEs 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. 
Data collection staff will record events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
For each AE, the interviewer will fill out an Incident Report within 24 hours and email it to their 
supervisor and the Project Director. If any pertinent information is missing from the email or Incident 
Report Form, or, it is not clear how a situation was resolved, the supervisor will follow up with the 
interviewer as appropriate. AEs will be reviewed by the study PIs within 72 hours of being reported. A 
monthly summary report will be provided to the Principal Investigators, Dr. Katherine Watkins and Dr. 
Miriam Komaromy, to review all events and ensure reporting and documentation have been conducted 
in a timely manner. In addition, they will review the log to ensure that each event would NOT have been 
considered a serious adverse event. They will provide an annual report summarizing the adverse events 
to UNM’s IRB, RAND’s Human Subjects Protection Committee (HSPC) and the NIMH Data Safety 
Monitoring Board (DSMB). 
All adverse events and serious adverse events will be tracked in an “Adverse Events” table or form in the 
study database. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  

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For SAEs, the Incident Report form will be forwarded to the MPIs within 72 hours. If the patient has 
reported child or elder abuse to clinic staff, the clinic must report the event to the Division of Health 
Improvement (DHI), Incident Management Bureau (IMB) using the DHI incident report form, available 
here: http://dhi.health.state.nm.us/imb/imb_irform.php. The next step(s) depend(s) on the type of 
event: 
• 
A PI will report all SAEs to their respective IRBs following IRB protocols for reportable events. For 
SAEs that are deemed expected and/or unrelated to the study, a PI will include them in the 
triannual report to the NIMH DSMB. For unexpected SAEs related to the study, a PI will report it 
to the NIMH Program Officer and DSMB liaison within 10 business days. 
• 
If a patient has died (from any cause), while enrolled in the study, a PI will report it to NIMH PO 
and DSMB liaison within 5 business days. 
• 
If the patient makes a credible threat to harm another person, Dr. Katherine Watkins and Dr. 
Valerie Carrejo will consult legal counsel at their respective institutions to determine whether 
the incident should be reported to authorities within 24 hours.  
• 
If the patient has reported child abuse to the interviewer: 
o For NM sites, the UNM PI will report it, since New Mexico law requires reporting child 
abuse to local law enforcement or the state’s Children, Youth and Families Department 
(855-333-7233) within 48 hours. If the incident involves “any Indian child residing in 
Indian country,” tribal law enforcement or a social services agency must be notified. 
o For CA sites, the local PI will report it, since California law requires reporting child abuse 
to local law enforcement or the state’s Child Protection Hotline and file mandatory 
online report (800-540-4000; https://mandreptla.org/) within 36 hours.  
• 
If the patient has reported elder abuse to the interviewer: 
o For NM sites, the UNM PI will report it within 24 hours, since New Mexico law requires 
reporting elder abuse to Adult Protective Services, 866-654-3219 or 505-476-4912. 
o For CA sites, the local PI will report it as soon as possible or within 2 business days, since 
California law requires reporting elder abuse to Adult Protective Services, 877-477-3646 
or 888-202-4248. 
• 
If the interviewer is injured: 
o For NM sites, the UNM PI will notify UNM Employee Health or other appropriate body, 
and the interviewer’s supervisor will complete any forms required by the organization. If 
the is harm by a participant, the police will be notified, and that participant will be 
discontinued from the study.  
o For CA sites, follow local clinic guidelines.  
Study staff will complete an incident report form for all Serious Adverse Events. Like AEs, SAEs will be 
tracked in an “Adverse Events” table or form in the study database. When a SAE is entered into the 
system, an email will be sent to the PI and relevant research team members for their review. 
Additionally, a weekly summary report listing the SAEs and their details will be provided to the PI and 

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research study team.  If a clinical staff member becomes aware of a SAE they will report it to the care 
coordinator.  Care coordinators are trained on how to document SAEs and report them to the study 
team. 
The following table outlines the NIMH’s reportable events policy for AEs, SAEs, death, unanticipated 
problems, protocol deviations, non-compliance, suspensions and terminations. 
 
Reportable Event 
When is Event Reported to the NIMH 
Reported By 
IRB/ISM/DSMB/OHRP/FDA 
Suspensions or Terminations 
Any suspension or termination of approval must 
include a statement of the reason(s) for the action and 
must be reported promptly to the NIMH PO within 
3 business days of receipt. 
Regulatory or 
Monitoring Entity and 
Investigator 
Deaths related to study 
participation 
Deaths must be reported immediately (no later than 
within 5 business days) of the principal investigator 
first learning of the death. 
Investigator 
Unexpected Serious Adverse 
Events related to study 
participation 
Reported to the NIMH PO within 10 business days of 
the study team becoming aware of the SAE. 
Investigator 
Unanticipated Problems 
Involving Risks to Subjects or 
Others 
Reported to the NIMH PO within 10 business days of 
the investigator learning of the event. 
Investigator 
Serious or Continuing 
Noncompliance  
Reported to the NIMH PO within 10 business days of 
IRB determination. 
Institution 
Adverse Event 
For all AEs and SAEs that are deemed expected and/or 
unrelated to the study, a summary should be 
submitted to the NIMH PO with the annual progress 
report. 
Investigator 
Protocol Deviations 
With the annual progress report. 
Investigator 
8.3.7 REPORTING OF PREGNANCY  

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Although not an AE, pregnancies are reportable events. The study team will attempt to obtain data and 
report on pregnancy and birth outcomes for any pregnancies that occur during the study period in 
women who have received any study intervention will be reported.  
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems 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 the 
procedures involved in the research); 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. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the UNM principal investigator (PI, Valerie Carrejo). The UP report will include the following 
information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
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 UP 

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• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
• 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the NIMH Program 
Officer and DSMB Liaison within 10 business days of the investigator becoming aware of the 
event.  
• 
Any other UP will be reported to the IRB and to the NIMH Program Officer and DSMB Liaison 
within 10 business days of the investigator becoming aware of the problem.  
• 
All UPs will be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 business days of the IRB’s receipt of the report of 
the problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
We do not anticipate the need to report unanticipated problems to participants since this study only 
involves the use of FDA-approved medications and standard clinical treatments. However, in the rare 
event that there are unanticipated problems (e.g., breaches in privacy or confidentiality), we will report 
them to participants. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
The Statistical Analysis Plan (SAP) includes all statistical considerations for this study. This protocol 
provides a summary of these. See the SAP for details.  
There are four primary endpoints that will be evaluated. The testable null and alternative hypotheses for 
the primary outcomes are as follows: 
1. We hypothesize that patients with a new episode of OUD care (i.e., no care for at least 30 days 
prior) who are randomized to CC-COD/CC-COD+ will receive buprenorphine within fewer days 
after that care episode begins than new OUD patients who are randomized to enhanced usual 

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care. Alternatively, the null hypothesis is that there will be no difference in the number of days 
until receipt of buprenorphine with a new OUD episode of care.  
2. We hypothesize that patients who are randomized to CC-COD/CC-COD+ will have more days of 
buprenorphine treatment within 180 days of study enrollment than patients who are 
randomized to enhanced usual care. Alternatively, the null hypothesis is that there will be no 
difference in the number of days of cumulative buprenorphine treatment within 180 days of 
study enrollment. 
3. We hypothesize that, among patients with probable depression at study enrollment, those who 
are randomized to CC-COD/CC-COD+ will have a greater reduction in depression symptom 
severity 6 months after study enrollment compared to those who are randomized to enhanced 
usual care. Alternatively, the null hypothesis is that there will be no difference in depression 
symptom severity 6 months after study enrollment among those with probable depression at 
enrollment. 
4. We hypothesize that, among patients with probable PTSD at study enrollment, those who are 
randomized to CC-COD/CC-COD+ will have a greater reduction in PTSD symptom severity 6 
months after study enrollment compared to those who are randomized to enhanced usual care. 
Alternatively, the null hypothesis is that there will be no difference in PTSD symptom severity 6 
months after study enrollment among those with probable PTSD at enrollment. 
 
• 
Secondary Endpoint(s): See 9.4.3. 
 
9.2 
SAMPLE SIZE DETERMINATION 
The four primary hypotheses described in the Section 9.1 were used for the power calculations. All 
calculations are for 80% power at a Type I error rate of 1.25%, which accounts for the multiple primary 
outcomes using a Bonferroni correction to control the family-wise error rate at 5% (0.05/4 = 0.0125). All 
calculations assume 900 total study participants and, if relevant, 20% loss to follow up. Initial 
assumptions for the power calculations were: 
1. At enrollment, 50% of study participants will have a new OUD episode of care, defined as no 
visits with an OUD diagnosis in the past 60 days.  
2. At enrollment, one third of study participants will have probable depression, one third will have 
probable PTSD, and one third will have both probable depression and PTSD.  
3. At enrollment, 25% of patients110 with a new OUD episode of care who receive enhanced usual 
care will initiate medication for OUD within the first 30 days of that care episode.  

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4. Among those who initiate medication for OUD who receive enhanced usual care, the mean 
number of days of continuous treatment for OUD is 80 with a standard deviation is 65 (personal 
communication, Asa Wilks).  
5. Among those with probable depression at enrollment (PHQ-9 ³ 10), assume a mean depression 
symptoms score (PHQ-9) at 6 months of 12 and standard deviation of 6. 
6. Among those with probable PTSD at enrollment (PC-PTSD-5 ³ 3), assume a mean PTSD 
symptoms score (PCL-5) at 6 months of 50 and standard deviation of 11. 
Simulation-based power calculations were performed by randomly generating outcomes based on the 
assumptions described here. A total of 1000 random datasets were generated, and each analyzed using 
the statistical model described in the SAP. We varied the effect size of CC-COD/CC-COD+ across a range 
of plausible values to determine the power. We have 80% power to detect: 
1. A 15 percentage point increase in initiation of medication for OUD within the first 30 days of 
that care episode. A previous study of collaborative care for opioid and alcohol use disorders 
found a 22 percentage point increase over enhanced usual care. 110 
2. 14 additional days of continuous OUD treatment within the first 180 days. A growing body of 
evidence suggests the mortality is lower during OUD treatment, and that mortality is increased 
in the first four weeks after treatment cessation.135 
3. A 2 point reduction in depression symptoms (PHQ-9). This provides power to detect effects 
below the clinically important difference for individual change of 5 points.225 
4. A 3.5 point reduction in PTSD symptoms (PCL-5). A previous study of delivering PTSD treatment 
in primary care setting to active duty military found a reduction in PTSD symptoms of 7 
points.226 
Prior to breaking the study blind but after completion of data collection, the above distributions and 
power calculations were updated in the SAP to reflect observed data.  
Dropout is of minimal concern in this study, as all analyses are intention-to-treat. For the outcomes 
based on self-reported symptoms, i.e. depression symptoms and PTSD symptoms, we expect a 20% loss 
to follow up. This loss to follow up has been accounted for in the power calculations.  
The sample size provides sufficient power for secondary outcomes. Details are included in the SAP. 
Original Sample size considerations for CR: 
Figure 4.2 (above in Section 4.2) illustrates the sample sizes in each arm and in each phase of the study, 
along with a conceptual representation of the revision analyses. A total of 900 individuals will be 
randomized between CC-COD and EUC (Phase I) and a total of 300 individuals will be randomized 

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between CC-COD+ and EUC (Phase II). Based on data from the INSPIRE study, we assume 80% of patients 
have SPs who are willing to participate in treatment and that the effect of CC-COD+ for the 20% of 
patients without SPs willing to participate will be the same as CC-COD. Using the same assumptions for 
the power calculations as above, we have 80% power to detect an incremental effect of CC-COD+ over 
CC-COD on the number of days of continuous MOUD care of 14 days. A growing body of evidence 
suggests the mortality is lower during OUD treatment, and that mortality is increased in the first four 
weeks after treatment cessation.135 Two weeks of additional OUD treatment reflects a clinically 
significant increase in the duration of treatment given these known mortality patterns after treatment 
cessation. The sample size for the CR was determined based on this clinically meaningful effect size. 
As noted elsewhere, it was later decided to combine the CR and parent study populations for all 
analyses. This decision was made in consultation with our Research Advisory Board, the NIMH scientific 
officer and the NIMH project officer due to lower than expected recruitment. 
9.3 
POPULATIONS FOR ANALYSES 
All analyses are intention-to-treat based on randomization. The primary study outcomes have the 
following analysis populations: 
1. Buprenorphine access is limited to randomized participants with a new OUD episode of care 
at enrollment, defined as no visits with an OUD diagnosis in the past 30 days.  
2. Cumulative days of buprenorphine for OUD includes all randomized participants. 
3. Depression symptom severity includes all randomized participants with likely depression at 
enrollment, defined as PHQ-8 ³ ≥ 10. 
4. PTSD symptom severity includes all randomized participants with likely PTSD at enrollment, 
defined as PC-PTSD-5 ³ ≥ 3. 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
This protocol provides a summary of the statistical analyses, and the SAP provides additional details. 
• 
Descriptive statistics will be reported by study arm. Categorical data will be presented as 
percentages, and continuous data will be summarized as means and standard deviations.  
• 
Buprenorphine access will be compared between arms by fitting a logistic regression model. 
Specification of the model is available in the SAP. 

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• 
Cumulative days of buprenorphine will be compared between arms by fitting a linear regression 
model. Specification of the model is available in the SAP. 
• 
Depression symptom severity and PTSD symptom severity will be analyzed using non-response 
weighted linear regression models. Additional model details and specification of covariates are 
provided in the SAP. 
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
This protocol provides a summary of the statistical analyses, and the SAP provides additional details. 
• 
Buprenorphine access is a time-to-event outcome and will be compared between arms by fitting 
a Cox proportional hazard regression model. Specification of the model is available in the SAP. 
• 
Days of cumulative buprenorphine treatment will be compared between arms by fitting a linear 
regression model. Specification of the model is available in the SAP. 
• 
Depression symptom severity and PTSD symptom severity are ordinal scales and will be 
analyzed using non-response weighted linear regression models. Additional model details and 
specification of covariates are provided in the SAP. 
The primary analyses will be performed for the intention-to-treat population, which consists of all 
randomized subjects. Procedures for handling missing data are provided in the SAP. 
A union-intersection test will be used to test the overall success of the study that combines the four 
primary outcomes into a single composite hypothesis. In particular, the null hypothesis is the 
intersection of the four primary outcome null hypotheses (i.e., all null hypotheses are true), and the 
alternative is the union of the alternative hypotheses (i.e., at least one alternative hypothesis is true). A 
Bonferroni or Benjamini-Hochberg correction on the individual hypotheses will be used to control the 
error rate of this composite test. The four primary hypotheses will be analyzed with a Type I error of 
1.25%, which accounts for the multiple primary outcomes using a Bonferroni correction to control the 
family-wise error rate at 5% (0.05/4 = 0.0125). 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary endpoints will be grouped into domains of conceptually related endpoints, and each will be 
analyzed adjusting for multiple comparison within domain. Preliminary domains are as follows:  
 
Mental Health  
• 
Access to MDD and/or PTSD treatment 
• 
Quality of care for MDD 

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• 
Quality of care for PTSD 
• 
MDD remission 
• 
MDD response 
• 
PTSD remission 
• 
PTSD response 
• 
Active suicidal ideation 
 
Substance Use 
• 
Opioid use frequency  
• 
Opioid overdose events 
 
Overall Health 
• 
Physical health functioning 
• 
Mental health functioning 
Secondary endpoints will be analyzed using similar approaches as described for the primary endpoints. 
Additional model details are provided in the SAP. Other statistical issues, e.g. loss to follow up and 
missing data, will be accounted for using the same techniques as with the primary outcomes.  
 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
Baseline descriptive statistics will be reported by study arm. Categorical data will be presented as 
percentages, and continuous data will be summarized as means and standard deviations. Two-sample 
comparisons of study arms will be reported using appropriate statistical tests (e.g. two sample t-tests 
and chi-squared tests). The SAP provides additional details and a list of baseline characteristics to be 
summarized.  
Baseline Descriptive Statistics for CR: 
The CR will use the same baseline descriptive statistics as the primary study.  
 
9.4.5 SUB-GROUP ANALYSES 
Analyses of moderators of the effectiveness of CC-COD on study outcomes will be conducted. The sub-
groups of interest for these analyses are documented in Section 3. Similar models to those for the 
primary and secondary analyses will be used, but the models will include the necessary interaction 
between the randomization assignment and the sub-group. The SAP provides additional details. 
Sub-Group Analyses for CR:  

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N/A 
 
9.4.6 EXPLORATORY ANALYSES 
All planned exploratory analyses will be described in the SAP. 
 
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 
The consent form used in this study complies with all required regulatory elements. The consent form 
describes in detail the study intervention, study procedures and the risks involved. The participant will 
need to give explicit permission prior to participating in the study. This permission will be documented 
in the data collection form and a copy of the informed consent form will be given to every participant 
for their records. The informed consent will be available in English and Spanish. The correct form will be 
selected based on the participant’s preference and status of language proficiency. A copy of both 
consent forms is included with this protocol. 
Because SPs will not be participating in any research activities, they will not be enrolled and consented 
in the CR trial. As part of the consent process for participation in the CR, participants will be told that if 
they are randomized to CC-COD+, the care coordinator will ask if they have an SP who might be willing 
to meet with the care coordinator to learn about ways to support the participants recovery. However 
having an SP is not an inclusion criterion. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent will be administered by a research assistant (employed by the RAND/UNM research 
team) after screening. If administering the informed consent in person poses a risk of viral infection for 
the participant or members of the research team, we will administer the informed consent via an IRB 
approved electronic or virtual method. There will not be any waivers for obtaining an informed consent. 
If the patient refuses to complete the informed consent form they will not be enrolled in the study. The 

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informed consent form will be available in English and Spanish. Our research team will be inclusive of 
both English and Spanish speakers in order to be able to administer the informed consent in both 
languages. If the client speaks only a language other than English or Spanish they will not qualify to 
participate in the study. Competency and comprehension of the above mentioned procedures will be 
determined by the research team. The research team will participate in various trainings during their 
orientation to learn how to make these assessments. If the participant is deemed to lack competency or 
an appropriate level of comprehension to conduct the study activities, they will not be enrolled into the 
study. Prospective participants who need surrogate consent will not be asked to participate in the study 
due to diminished autonomy. Children and individuals younger than 18 years of age will also be 
excluded from this study. If consented in person, a copy of the signed and dated consent form will be 
provided to the patient. If consented remotely, a copy of the signed and dated consent will be either 
sent by mail, email, or may be picked up in-person. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
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, investigator, NIMH, and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigators 
(PIs) will promptly inform study participants, the Institutional Review Board (IRB), and NIMH Program 
Officer and DSMB Liaison and will provide the reason(s) for the termination or suspension within three 
business days upon receipt. 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 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
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 NIMH DSMB and the RAND, and UNM IRBs. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
The Patient Informed Consent Form will assure potential participants that we will keep all of their 
responses and information completely confidential, that we will not share or tell their name or anything 

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that may identify them to anyone outside of the research staff, except for the information we told you 
we would share with the Care Coordinator. Their name will never appear in any project reports or 
presentations. Information in these reports or presentations will be grouped together with all of the 
people in the project so no person can be identified.  
 
Information about their participation in the project and any treatment they receive will be documented 
in their medical record as part of routine clinical care. This information is covered by confidentiality 
regulations and state and federal laws.  
 
We will also tell them that their information is also protected by a Certificate of Confidentiality (CoC) 
from the National Institute of Mental Health, which protects researchers from being forced, even by 
court order or subpoena, to identify them. We explain that a CoC does not prevent them or a member 
of their support system from voluntarily releasing information about them or their involvement in this 
research. Additionally, if at any time during the project, they share that they plan to harm themselves or 
others or we hear about or suspect child abuse, or we hear about or suspect elder/dependent adult 
abuse, the Certificate does not protect that information from being released to the proper authorities.  
 
General Data Safeguarding Principals 
The study PIs will have overall responsibility for ensuring data confidentiality, privacy, and safeguarding 
and will be responsible for serving as local data safeguarding officers, assuring adherence to the study 
data safeguarding and transfer plan (DSTP) and training in human subjects protections. A DSTP will be 
shared with all members of the study team who will need to handle data. NIMH has provided a 
Certificate of Confidentiality to further protect study patients. All key study staff have completed 
Confidentiality Agreements and CITI certificates have been assembled by the PIs, who are tasked with 
overseeing compliance with procedures for human subjects' protections as well as data and safety 
monitoring.  
The study team will monitor the safety of participants and the validity and integrity of the data in 
accordance with the Data Safety and Monitoring Plan (DSMP). The level and frequency of monitoring 
will be commensurate with the risks, nature, and complexity of the clinical trial. Data safeguarding 
procedures will adhere to standards established by applicable regulations including those by the NIH, 
the Department of Health and Human Services, recent HIPAA regulations, and standards set by the 
RAND Corporation Institutional Review Board. The UNM SDCC/RAND SRG is responsible for data 
collection and monitoring of data quality and completeness and ensuring the integrity of data provided 
to RAND for analyses. All of these investigators have extensive experience in handling sensitive 
information.  
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 

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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. Appropriate data use agreements will be implemented before receipt of any 
data from the clinic sites, DataStat, the NIMH NDA, the University of Washington, and state vital records 
offices or before any data is sent to DataStat, RAND, NIMH NDA, or University of Washington. 
To monitor data and safety issues, this team will meet regularly throughout the study project, enabling 
any concerns to be addressed rapidly. Monthly quality control reports will be sent to the data entry staff 
that will identify missing, out-of-range, and discrepant data and require corrections or justifications.  
In addition to safety monitoring by HSPC, this cooperative agreement is also assigned to an NIMH-
constituted DSMB (NIMH DSMB) for monitoring of data integrity and participant safety. The NIMH 
DSMB will be responsible for ensuring that appropriate monitoring systems are in place, that the quality 
of the monitoring activity is adequate, and that the IRB, PDs/PIs, and NIMH staff are informed of 
recommendations emanating from monitoring activities overseen by the NIMH DSMB.  
Data Storage 
All study data collected before 8/15/22 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 
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 10 years following completion of the CLARO study, 
per UNM policies, and will be destroyed at that time or according to NIH guidelines. 
All study data collected after 8/15/22 will be stored in a HIPAA-compliant REDCap Cloud database. All 
participant contact information will also be stored in a Record Management System (RMS) on SRG’s 
secure network segment. Computers on the secure network segment are isolated from the rest of the 
RAND network (e.g. no Internet access, e-mail or file sharing between these computers and the 
unclassified network) minimizing the possibility of infection by malicious software and unintentional 
exposure of sensitive data.  The computers on the segment will also employ standard password 

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protection along with file and folder permissions limiting access to appropriate project staff.  All servers 
on the secure network segment are located in the RAND Data Center and all client computers are 
located in offices with limited OmniLock access.  Within the segment the RMS database containing the 
sample data uses a separate password to restrict access. All data entry, scanning, and RMS functions will 
be conducted using computers on SRG’s secure network segment. 
Data Sharing 
Section 10.1.11 describes the study’s data publication and sharing policy. Data from this study will 
comply with the NIH requirement to submit to the NIMH National Data Archive (NDA) using 
standardized formatting. Any requests for anonymized data from this study can be obtained via the 
NDA.  
Data Transmittal 
Contact information of participants will be entered into a study database in a separate form from the 
main study data and will include the participant study ID numbers but not their medical record number 
(MRN). Designated study staff will create a login and profile with DataStat for their Data Transfer Web 
Portal to which this contact data will be uploaded for the 3- and 6-month follow-up surveys they will 
conduct. Similarly, the study team will download data from DataStat via the same portal on a regular 
schedule (e.g., monthly). This data will be saved on CLARO’s secured servers, as described above. 
Electronic Health Record (EHR) data for study-related diagnoses, prescribed medications, and behavioral 
health treatment will be obtained during the patients’ enrollment in the study covering the period 6 
months before enrollment to their final study visit. Prior to 8/15/22, the clinic staff will send this data to 
the UNM Statistics and Data Coordinating Center (SDCC) as requested via UNM’s Secure File Transfer 
Protocol (SFTP) for storage on the UNM secured servers and merged with other study data. After 
8/15/22, the clinic staff will send this data to RAND SRG as requested via Kiteworks for storage on the 
HIPAA-compliant REDCap Cloud or the SRG secure segment. 
Participant identifiers will also be entered by the Care Coordinators into the patient registry, including 
name, date of birth, and MRN. This data will only be accessible by pre-authorized clinic and research 
personnel (Research Assistants, Care Coordinators, Care Coordinator Supervisors, and Clinic 
Administrators) and CLARO’s Behavioral Health Consultants. At study completion, the clinics will send 
this data to RAND SRG via Kiteworks for storage on the SRG secured segment and merged with other 
study data. 
Identifying information will be used to obtain data on participant mortality from state vital records 
offices and state prescription monitoring programs (the New Mexico Prescription Monitoring Program 
and the Controlled Substance Utilization Review and Evaluation System). PMP data will be sent in 
batches with identifiers to UNM for requests made prior to 8/15/22 and RAND SRG for requests made 
on or after 8/15/22. The study team will link the PMP data with the CLARO study data using identifiers 

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and then de-identify the PMP data before providing to the the analytic team. These procedures will be 
reviewed by the IRB and implemented once approved. 
Deidentified study data will be uploaded two times per year to the NIMH National Data Archive. A 
universal subject ID (Global Unique Identifier, “GUID”) will be generated for each participant and will be 
linked to the participants’ unique study ID assigned in REDCap. This key will be stored on CLARO secured 
servers and will not be accessible to anyone outside of the UNM SDCC/RAND SRG staff. All raw data will 
be uploaded every six months to the NIMH NDA per their policies and in accordance with UNM’s 
information security policies. Additionally, all analysis data sets used for manuscripts must be uploaded 
to the NIMH NDA, identified by GUID. 
The SDCC/RAND SRG will provide deidentified analysis data sets for the final analyses. Participant-level 
data will be enumerated with their study IDs and no MRNs or other personal identifying information will 
be shared with them. Data will be transmitted via RAND’s secured data transfer protocol, Kiteworks. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
UNM will store all data on their secured servers for up to seven years following completion of the CLARO 
study, per UNM and federal policies, and will be destroyed at that time or according to NIH guidelines. 
RAND will store all data on their secured servers for up to 7 years following completion of the CLARO 
study, per RAND and federal policies, and will be destroyed at that time or according to NIH guidelines. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Principal Investigator 
Medical Monitor 
Katherine E. Watkins, MD, MSHS, 
Senior Natural Scientist 
Miriam Komaromy, MD 
Miriam Komaromy, MD 
RAND Corporation  
Grayken Center for Addiction, 
Boston Medical Center 
Grayken Center for Addiction, 
Boston Medical Center 
1776 Main Street, Santa Monica, 
CA 90401 
801 Massachusetts Ave, 1st 
floor, #1039, Boston MA 02118 
801 Massachusetts Ave, 1st 
floor, #1039, Boston MA 02118 

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310-393-0411 x6509 
505-715-0394 
505-715-0394 
kwatkins@rand.org 
Miriam.Komaromy@bmc.org 
Miriam.Komaromy@bmc.org 
The study includes an independent Research Advisory Board (RAB) comprised of experts in addiction 
medicine and mental health. The committee meets on an ad hoc basis to advise on the research 
protocol, study progress and results. CLARO is running the meetings via teleconference by providing 
structured updates on the project and inviting discussion. The study team will also reach out to selected 
RAB members on an ad hoc basis to get advice on specific topics. Dr. Komaromy chairs the RAB. Board 
members will be blind to the randomization of patients to study conditions. This board complements 
(and does not conflict) with the NIMH DSMB because the focus is on the research content rather than 
on the monitoring of patient safety. 
Dr. Watkins is responsible for the oversight and coordination of the project management for the trial 
working closely with Drs. Komaromy, Meredith, Carrejo, and Osilla. She will also have responsibilities in 
guiding the analyses. 
Dr. Komaromy has oversight and coordination of the project for local intervention adaptation and 
implementation working closely with Drs. Watkins, Osilla, and Dopp. She will play a crucial role as liaison 
with the sites in New Mexico for maximizing the fit of the intervention to the local community. Dr. 
Komaromy will also work closely with the data collection team to ensure that recruitment goals are met 
on time and data are of high quality. 
Dr. Carrejo is the lead for the UNM team. 
Ms. Becker is the Director of the RAND Survey Research Group (SRG) who is working closely with the 
UNM SDCC team to collect the study data. Ms. Becker will lead all RAND SRG data collection. 
Dr. Beth Ann Griffin is the RAND statistician leading the RCT design, sampling plan, power calculations, 
and analysis of the RCT data. 
Dr. Dopp is leading the intervention implementation team and measurement development. 
Dr. Evans is leading the organizational readiness team working closely with Drs. Ober and Meredith as 
well as Mr. Bharadwaj. 
Dr. Meredith is contributing expertise about collaborative care and mental health throughout the 
project including planning and implementation of the RCT design, intervention adaptation, and 
organizational readiness teams. 

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Dr. Murray-Krezan, at the University of Pittsburgh (formerly at UNM), is the biostatistician responsible 
for oversight of all data management activities including reporting and analysis of recruitment, 
screening, enrollment, and safety data for data collected prior to 8/15/22. 
Dr. Ober is providing her expertise from SUMMIT on organizational readiness. 
Dr. Osilla is leading the intervention adaptation team working closely with Drs. Watkins, Komaromy, 
Dopp, and Meredith at RAND. 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) convened by 
NIMH. The DSMB includes experts in scientific disciplines needed to monitor the data and ensure 
patient safety during the conduct of this study, including addiction and mental health experts, clinical 
trial experts, biostatisticians, and bioethicists. DSMB members have no association with the project 
investigators, and no conflicts of interest with study outcomes. The DSMB will meet at least three times 
a year to assess safety and data of the study. The DMSB will operate under the rules of an approved 
charter. The DSMB will provide its input to NIMH staff.  
DSMB procedures conform with usual standards, including reviewing emerging trial data and 
maintaining confidentiality. The main responsibilities of the NIMH DSMB include, but are not limited 
to the following: (1) reviewing the research protocol, consent form(s) and plans for data and safety 
monitoring prior to the initiation of the study; (2) monitoring of the progress of the study, including 
data quality, timeliness, recruitment and retention of study participants, adverse events, serious 
adverse events (SAEs), reasons for participant withdrawal, adherence to the timeline of the study, 
protocol deviations, performance across study sites, and factors that may affect the risks and benefits 
of the study such as emerging literature; and (3) making directives about the continuation, 
modification, or termination of the study, based on the balance of adverse events and beneficial 
outcomes. Throughout the study, notification of SAEs as well as any proposed investigator-initiated 
changes in the protocol will be submitted to the NIMH DSMB. Based on its review of the protocol, the 
NIMH DSMB will identify the data parameters and format of the information to be regularly reported. 
The NIMH DSMB may at any time request additional information from the Principal Investigators. 
 All SAEs and adverse events (AEs will only be reported to the NIMH DSMB annually) will be tabulated 
and submitted to the NIMH DSMB in the triannual DSMB data reports. Based on review of safety data, 
the NIMH DSMB will issue directives concerning the conduct of the study. Recommendation/directives 
made by the DSMB may include amending safety monitoring procedures, modifying the protocol or 
consent, terminating the study, or continuing the study as designed.  
 
10.1.7 CLINICAL MONITORING 

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10.1.8 CLINICAL MONITORING WILL BE PERFORMED BY THE INDEPENDENT NIMH DATA 
SAFETY AND MONITORING BOARD (DSMB) AND THE RAND SITE. QUALITY ASSURANCE 
AND QUALITY CONTROL 
Data Collection Training. All research assistants (RAs) will receive comprehensive in-person or online 
training for accessing and using REDCap for data collection. The UNM Statistics and Data Coordinating 
Center (SDCC) will assist the RAs in obtaining individual and secured access to REDCap for data collected 
prior to 8/15/22. RAND SRG will assist the RAs in obtaining individual and secured access to REDCap for 
data collected on or after 8/15/22. SDCC and SRG will ensure RAs receive help troubleshooting any 
problems that may arise during the course of the study. Access to the CLARO REDCap database will be 
limited to data entry only; users will not be able to download any data. Should there be any staff 
turnover, the departed staff’s access to REDCap will be removed. The SDCC manages all access and 
permissions for UNM REDCap access; SRG manages all access and permissions for REDCap Cloud access. 
Quality control of data collected. All study data will be entered in real time to the REDCap data capture 
system. Range and required field checks will be automatically implemented upon data entry. The SDCC 
will create monthly standardized quality control (QC) reports with queries for the RAs to review and 
correct and/or confirm. SRG will continue to implement all QC procedures. 
Source documents and the electronic data. Data will be captured electronically in the REDCap database 
and only in the event of internet instability or power failure will data be captured on paper source 
documents and entered into REDCap as soon as possible. See Section 10.1.9, Data Handling and Record 
Keeping. If a paper data collection form (source document) is used, then to ensure accuracy research 
staff will compare the source data against the database. Paper documents will be stored in a locked file 
cabinet and will be destroyed seven years following study completion. 
Protocol Deviations. Protocol deviations will be entered into the “Protocol Deviations” data capture 
form. The study team will review a weekly protocol deviations report and will implement corrective 
actions when the quantity or nature of deviations are deemed to be at a level of concern. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be the responsibility of the clinical trial staff (RA) under the supervision of the Clinical 
Research Manager and SRG Survey Coordinators. The investigator will be responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported. 
Any source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data. 

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Hardcopies of the study visit instruments will be provided for use as source document for recording data 
for participants consented/enrolled in the study, only in the event of loss of internet or power such that 
REDCap cannot be used. Data recorded in the electronic case report form (eCRF) derived from source 
documents will checked for consistency with the data recorded on the source documents. 
All administered instruments and adverse events (AEs) prior to 8/15/22, will be entered into the UNM 
REDCap system, a 21 CFR Part 11-compliant data capture system provided by the University of New 
Mexico Data Coordinating Center. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. After 8/15/22 all administered instruments will be entered into the HIPAA-compliant RAND 
REDCap Cloud. See section 10.1.3 for additional information on data storage. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents including data stored electronically will be retained for a minimum of seven years 
following completion of the study. No records will be destroyed without the written consent of the 
NIMH, if applicable. It is the responsibility of the sponsor/funding agency to inform the investigator 
when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS 
The term “protocol deviation” is not defined by either DHHS human subjects regulations (45 CFR 46) or 
FDA human subjects regulations (21 CFR 50). A protocol deviation is a departure from the approved 
protocol’s procedures made with or without prior IRB approval. Such departures may be major or 
minor/administrative in nature and result from different sources.  
Examples of protocol deviations include: 
• 
Inadequate or delinquent informed consent. 
• 
Inclusion/exclusion criteria not met. 
• 
Unreported serious adverse events. 
It will be the responsibility of the Co-PIs (Drs. Watkins, Komaromy, & Carrejo) to use continuous 
vigilance to identify and report deviations within 10 working days of identification of the protocol 
deviation, or within 10 working days of the scheduled protocol-required activity. All deviations will be 
addressed in study source documents and reported to the PIs. Protocol deviations will be sent to the 
reviewing Institutional Review Board (IRB) and the NIMH per their policies. The site investigator will be 

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responsible for knowing and adhering to the reviewing IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. Protocol deviations will be entered into 
CLARO database in the “Protocol Deviations” form and a regularly scheduled report of all protocol 
deviations will be sent to the PIs. 
For California sites all protocol deviations will be reported to the PIs. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
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 will comply with the NIH requirement to submit to the NIMH 
National Data Archive (NDA) using standardized formatting. Any requests for anonymized data from this 
study can be obtained via the NDA.  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence 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 (MPIs Katherine Watkins and 
Miriam Komaromy) in conjunction with the National Institute of Mental Health has established 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 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
adverse event 

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AHRQ CAHPS 
Agency for Healthcare Research and Quality, Consumer Assessment of 
Healthcare Providers and Systems 
AUDIT-C 
3-item Alcohol Use Disorder Identification Test – Consumption 
BHC 
behavioral health consultant 
BHP 
behavioral health psychotherapist 
CC 
collaborative care 
CC-COD 
collaborative care for COD 
CFR 
Code of Federal Regulations 
CA 
California 
CMP 
clinical monitoring plan 
CLARO 
Collaboration Leading to Addiction Treatment and Recovery from Other 
Stresses 
COD 
co-occurring disorder 
CRF 
case report form 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
EHR 
electronic health record 
EUC 
enhanced usual care 
FCCH 
First Choice Community Healthcare 
FDA 
Food and Drug Administration 
FQHC 
Federally qualified health centers 
GCP 
good clinical practice 
HCA 
Hepatitis C virus 
HH 
Hubert Humphrey 
HIPAA 
Health Insurance Portability and Accountability Act 
HMS 
Hidalgo Medical Services 
HPSA 
health professional shortage area 
ICH 
International Council on Harmonization  
LACDHS 
Los Angeles County Department of Health Services  
IRB 
Institutional Review Board 
MDD 
major depressive disorder 
MH 
mental health 
MI 
Motivational interviewing 
MV 
Mid Valley Comprehensive Health Center 
MOP 
Manual of Procedures 
MOUD 
medications for opioid use disorder 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NM 
New Mexico 
NSDUH 
National Survey on Drug Use and Health 
OHRP 
Office for Human Research Protections 
OUD 
opioid use disorder 

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OV-ERI 
Olive View Education and Research Institute 
PC-PTSD-5 
Primary Care PTSD 5-item checklist 
PCL-5 
Posttraumatic stress disorder checklist for DSM-5 
PCP 
primary care provider 
PHQ-9 
Patient Health Questionnaire for Depression – 9 item 
PI 
Principal Investigator 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
Providence 
Providence Health & Services – Southern California 
PST 
problem solving therapy 
PTSD 
posttraumatic stress disorder 
RA 
Research Assistant 
RAB 
Research Advisory Board 
RCT 
randomized clinical trial 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDCC 
Statistics and Data Coordinating Center 
SFC 
San Fernando Health Center  
SRG 
Survey Research Group 
SRMC 
Sandoval Regional Medical Center 
SUMMIT 
Substance Use Motivation and Medication Integrated Treatment 
UNM 
University of New Mexico 
UP 
unanticipated problem 
ViStA 
Violence and Stress Assessment 
VR-12 
Veterans RAND 12-item Health Survey 
WET 
Written Exposure Therapy 
 
 
 
 

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10.3 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. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
10/12/20 
We amended the Protocol in major 
ways to include the activities which 
will occur as part of our newly 
funded Competitive Revision (CR). 
The amended protocol additionally 
includes some minor changes to the 
parent study. We include the 
 CR in the amended protocol under 
guidance from our project officer, 
Dr. Michael Freed and because the 
CR and the parent study are 
operationally tied together. Thus, for 
NIMH DSMB review, we have 
provided one unified protocol that 
includes all components. 
There are 3 main reasons for 
these changes: (1) to add 
information about the CR, (2) to 
insure compatibility with 
changes requested from 
RAND’s Institutional Review 
Board, and (3) because 
additional discussion among 
our team led to greater clarity 
 in describing procedures. 
3.0 
2/3/21 
We responded to queries about 
circumstances warranting 
termination (#4 in memo), stopping 
rules (#6 in memo), and protocol 
deviations/violations (#9 in memo). 
We also added a paragraph 
explaining how the PHQ works 
across the eligibility screener and 
the baseline interview. 
To be responsive to the board 
and to describe a change in 
screening that was approved by 
Dr. Freed. 
4.0 
3/15/21 
We made changes to the Statistical 
Considerations section (section 9) in 
accordance with DSMB queries 
Most changes in this 
amendment were made in 
response to DMSB queries or 

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about statistical power and other 
points of analysis. We clarified 
language around reporting of AEs, 
SAEs, protocol deviations, and 
unanticipated problems. We added 
additional detail about Care 
Coordinator training and 
supervision, updated the eligibility 
criteria to indicate that participants 
cannot be receiving both MOUD and 
psychotropic medication from an 
external provider prior to study 
enrollment, and updated the 
eligibility screener to include the 
PHQ-8 rather than PHQ-9. Finally, we 
made some minor wording changes 
to maintain internal consistency 
within the protocol.  
to increase internal consistency 
and clarity of procedures 
described in the protocol. 
Eligibility criteria were updated 
to ensure that participating 
patients are in a position to 
receive COD care coordination 
at their primary care clinic. We 
changed the PHQ-9 to the PHQ-
8 at eligibility screening to 
avoid asking for information 
that could require us to break 
confidentiality before a 
participant has completed the 
informed consent process. 
5.0 
6/24/21 
We added First Choice Alameda to 
tables 5.1 and 5.3 of clinic-level 
characteristics/data. Please note 
that at this time we are still waiting 
for our clinic partners to provide us 
with some of the specific site 
characteristics, so some fields for 
Alameda are blank. We changed the 
number of clinics from 13 to 14. 
The study added a new site, 
First Choice Alamedia to the 
trial. 
6.0 
12/9/21 
We updated throughout to indicate 
that we have two more clinics in a 
new health system, CSV: Baker 
Street Village and Kern River. We 
increased the number of clinics from 
14 to 16 throughout. We removed 
MDD and PTSD remission/response, 
opioid overdose risk behaviors, and 
general health functioning outcomes 
as secondary outcomes. 
To boost recruitment, we have 
added a new health system in 
central California – Clinica 
Sierra Vista. We may add more 
CSV sites after we onboard the 
first two. We revised the 
outcomes to boost power. 

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6.1 
1/26/22 
We changed the number of clinics 
from 14 to 16 and added a new 
health system, Clinica Sierra Vista. 
We did this to boost 
recruitment. 
6.2 
3/22/22 
We removed Clinica Sierra Vista and 
added two new health systems  in 
Los Angeles County, California 
(Providence & HH). 
 
We doubled the patient incentive 
amount for the baseline survey and 
added a $25 bonus incentive to 
encourage same day or call-back 
later completion. 
These new  health systems 
were recently engaged to 
replace the systems we lost. 
 
 
To boost patient enrollment. 
6.3 
5/27/22 
We updated the study timeline. 
 
 
 
We added information explaining 
the addition of the California clinics. 
 
We added information about the 
process for reportable events at 
participating California clinics, and 
we made other minor changes to 
clarify information for the new 
California sites. 
 
To account for recruitment 
challenges and addition of new 
clinical sites. 
 
To provide a rationale for our 
selected study sites. 
 
Changes made per the request 
of partnering California clinics. 
 
 
 
 
 

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We updated Dr. Cristina Murray-
Krezan’s institutional affiliation to be 
the University of Pittsburgh. 
Dr. Murray-Krezan moved from 
UNM to the University of 
Pittsburgh. 
7.0 
7/29/22 
We added information detailing 
RAND taking over data collection 
from UNM.  
 
The parent and supplement 
(CLARO+) consents (dated 
7/21/2022) were updated with new 
contact information to reflect the 
SRG transition and allow the SRG to 
receive patient contact information, 
as well as added language clarifying 
which study incentives may be in the 
form of cash and which may be in the 
form of a merchandise card. 
Additionally, a sentence specifying 
that the study may collect mortality 
data from the state vital records 
office was added, which will allow 
us to collect mortality data from 
California. The protocol contained all 
of these changes, as well as a few 
minor staffing changes and a 
sentence on the patient demographics 
at the Providence clinics.   
 
To provide details on the 
transition from UNM to RAND 
in anticipation of the change in 
data collection activities 
8.0 
10/5/22 
Added details on the transition from 
parent to supplement at various 
clinics  
To account for updates in 
recruitment status and provide 
a realistic explanation of 
transitioning from CLARO to 
CLARO+ 

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9.0 
10/11/22 
Added Mid Valley Comprehensive 
Health Center and San Fernando 
Health Center to the study, clarified 
the parent system for these new 
clinics, and rectified some 
mislabeling of clinic numbers from 
previous iterations of the protocol 
To boost recruitment  
10.0 
01/13/23 
Changed name of PSJ to Providence 
Health & Services– Southern 
California  
To include a wider net of PSJ 
clinics and hopefully boost 
recruitment. 
11.0 
05/26/23 
End of recruitment at PSJ was noted. 
We also noted that some patients 
who are receiving primary care at 
UNM may be referred to the study 
from UNM providers outside of the 
three UNM clinics. 
Changed duration of study 
recruitment period to reflect extended 
recruitment period. 
To transition study resources to 
a site that will likely be more 
productive for recruitment and 
enrollment, and to increase 
potential for study recruitment. 
To provide additional time to 
meet the target sample size. 
 
12.0 
06/14/23 
JWCH Institute Inc. was added as a 
participating healthcare system, and 
end of recruitment at PSJ was noted.  
 
 
To transition study resources to 
a site that will likely be more 
productive for recruitment and 
enrollment, and to increase 
potential for study recruitment. 
 
13.0 
6/27/23 
Added Sandoval Regional Medical 
Center (SRMC) as an additional 
recruitment site in New Mexico. SRMC 
is part of the UNM system. 
To increase potential for study 
recruitment.  
 
 

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