Initiating Substance Use Disorder Treatment for Hospitalized Opioid Use Disorder Patients.
Phase: NA
Conditions: Opioid-use Disorder
Sponsor: Brigham and Women's Hospital

Cover Page for Clinical Trials Document Posting
Official Title:
Initiating Substance Use Disorder Treatment for Hospitalized Opioid Use
Disorder Patients (ISTOP)
NCT Number:
03212794
Version Date:
09/04/2020
Description:
ISTOP Study Protocol with Statistical Analysis Plan (SAP)

1 
 
Detailed Protocol 
 
Title: Initiating Substance use disorder treatment for hospitalized opioid use disorder patients: A 
randomized trial of recovery coaches. 
 
Version Date: 09/04/2020 
 
I. Background:  
Hospitalizations may be important opportunities to engage opioid use disorder (OUD) 
patients: Patients with OUD are susceptible to a variety of medical, psychiatric, and social 
complications, and utilize acute health services at a rate nearly 7 times as many as those 
without OUD.1,2 Hospitalizations related to OUD have increased dramatically in the context of 
the national opioid crisis.3,4 Due to the complex nature of the co-morbidities, their need for acute 
medical care is enormous. In a study of 58,243 Medicaid patients in New York State with a drug 
use disorder, 37.5% of HIV-negative individuals had at least one hospitalization in that year, 
with an average of 24.5 inpatient days.5 OUD patients’ admissions incur 2.5 times the financial 
charges as compared to patients without OUD.6 Once discharged, patients with substance use 
disorders (SUD) are readmitted at much higher rates than those without a SUD.7–9 Given the 
frequency in which OUD patients access hospital care, hospitalizations represent an important 
opportunity to engage these patients into SUD treatment and avoid readmissions once in the 
community.10 
Screening, brief intervention, and referral to treatment (SBIRT) is insufficient to engage 
out-of-treatment OUD patients: A large majority (90%) of individuals with active SUD are not 
engaged with any formal treatment.11 For OUD patients, the shortage of physicians willing to 
prescribe buprenorphine is a contributing factor.12,13 A promising approach so far in engaging 
out-of-treatment SUD patients has been Screening, Brief intervention, and Referral to Treatment 
(SBIRT).14–18 SBIRT uses universal and opportunistic screenings for substance use in medical 
settings using validated tools (i.e. AUDIT-C19), followed by a brief intervention and/or referral to 
treatment, making it one of the highest-ranking preventative services offered in general health 
care settings.20–22 However, in contrast to its efficacy in at-risk drinkers, studies of SBIRT for 
out-of-treatment drug users have been largely negative.23–28 Therefore, SBIRT alone is 
insufficient in reducing drug use in hospitalized patients, and clinicians and researchers need to 
look at interventions that focus on engagement with SUD treatment, initiation of medication-
assisted treatment, or lengthier interventions.7,28 
Initiation of buprenorphine for hospitalized OUD patients is feasible but not enough: 
Medication-assisted treatment with buprenorphine is almost always initiated in the outpatient 
setting.29–31 Indeed, only a small fraction (10.7-16.7%) of patients admitted for an opioid-related 
issue received any FDA-approved OUD medication within 30-days of discharge.32,33 Delaying 
the initiation of treatment places hospitalized patients at very high risk for relapse immediately 
after discharge. Studies have documented the feasibility of initiating buprenorphine during 
hospitalization.34–37 In our previous study of 47 hospitalized OUD patients initiated on 
buprenorphine, 46.8% successfully continued treatment following discharge.35 In another study 
of 145 hospitalized OUD patients randomized to either initiation of buprenorphine and linkage to 
treatment (intervention) or buprenorphine detoxification alone (control), those in the intervention 
arm were significantly more likely to continue outpatient treatment (72.2% vs 11.9%).34 
However, by 6 months after discharge, only a small proportion of those subjects in either arm 
remained in treatment (16.7% intervention vs 3.0% control). In a randomized trial of 329 OUD 
patients in the emergency room, subjects received 1) screening and referral [referral], 2) 
screening, brief intervention, and referral [brief intervention], or 3) screening, brief intervention, 
and initiation of buprenorphine [buprenorphine]. Those initiated on buprenorphine, compared to 
those who were not, were significantly more likely to be engaged with buprenorphine treatment 

2 
 
following discharge (78% [buprenorphine] vs 45% [brief intervention] vs 37% [referral], 
p<0.001).37 However, the rate of opioid negative urines at 30 days did not differ significantly 
across the 3 groups. These results suggest that initiation of buprenorphine in acute care 
settings facilitate linkage to outpatient treatment. However, because patients face numerous 
internal and external barriers to remaining engaged with treatment and reducing illicit opioid 
use, a more intensive intervention that continues into the community may be needed. 
Interventions that improve transitions of care tailored to OUD patients are needed to 
reduce readmissions: In the US, almost 20% of all hospitalized patients are readmitted within 30 
days after discharge, and close to half are readmitted within 6 months.38 High rates of avoidable 
30-day re-admission rates can result in financial penalties for the hospital.38,39 To improve the 
transitions of care between the hospital and outpatient treatment, interventions that address the 
following domains appear to be most effective in reducing readmissions: 1) monitoring and 
managing symptoms, 2) educating and promoting self-management skills, and 3) enlisting 
social and community supports.40–43 Even though SUD patients, compared to those without, are 
1.5 times more likely to be re-admitted due to their complex biopsychosocial needs, research to 
reduce readmissions has not focused on SUD patients.7–9,44 In a randomized trial of 749 
hospitalized patients, a nurse helped plan and coordinate the discharge, while a pharmacist 
provided a telephone follow-up to provide education and support.45 The intervention reduced 
readmissions (0.695, 95% CI, 0.515 to 0.937), but patients with drug use disorders still had 
twice the odds of readmission (1.97, 95% CI, 1.06 to 3.63).7 Given that drug using patients 
receiving regular SUD treatment can experience a 15% reduction in subsequent 
hospitalizations, more research is needed with interventions tailored specifically for OUD 
patients.5 
Care management may be needed during transitions of care to educate and support 
hospitalized OUD patients: Care management interventions are designed to meet the needs of 
individual patients by helping to manage their medical conditions more effectively, showing 
promise with a variety of illnesses including SUD. 46–54 In an 8-week study of dual diagnosis 
patients, 102 veterans being discharged from an inpatient psychiatrist facility were randomized 
to an intervention delivered by a care manager and a peer support specialist (recovery 
coaches), or to a matched attention control consisting of health education sessions.55 The care 
manager helped with treatment planning following discharge, encouraged adherence to 
treatment, and educated about addiction and relapse prevention skills. Those in the intervention 
arm were more likely to be engaged with outpatient treatment at 8 weeks than compared to 
control subjects (44 vs 22%, p<0.01). Given the complex medical and psychosocial needs of 
hospitalized OUD patients, more research on care management interventions that focus on the 
transitions of care for OUD patients is needed.  
Recovery coaches (i.e. peer-driven recovery supports) may be necessary to support 
OUD patients in the community: There is a growing body of evidence for the benefits of 
recovery coaches, who provide peer-delivered support services, to help SUD patients in the 
community.55–63 Tracing their origin to mutual support groups to supplement traditional clinical 
services, recovery coaches are individuals with lived experience of recovery, and are referred to 
by a variety of names in the literature (i.e. consumer providers, peer support specialists, peer 
workers/mentors). Recovery coaches typically provide services in four domains: 1) emotional 
(demonstrate empathy, bolster confidence, and foster hope), 2) informational (share knowledge 
and help skill-building), 3) instrumental (provide assistance with housing, employment, 
transportation, etc.), and 4) affiliational (create community and sense of belonging).57 Studies of 
recovery coaches have demonstrated greater treatment retention, reduced substance use, and 
reduced inpatient utilization.59,62,55,63,64 However, no prior studies have examined the impact of 
recovery coaches in improving buprenorphine treatment retention. 
The proposed project addresses these unmeet needs by testing a novel intervention to 
improve the treatment of OUD patients hospitalized for medical reasons. The intervention will 

3 
 
combine 1) medication-assisted treatment with buprenorphine initiated in the hospital, 2) care 
management to address domains known to improve transitions of care (monitoring and 
managing symptoms, encouraging self-management skills, and enlisting community and social 
supports40–43), and 3) recovery coaches to assist the patient in the community after discharge 
from the hospital. Previous studies lacked one or more of these components, or were not 
focused on OUD patients. While the use of buprenorphine has been studied with hospitalized 
patients, previous studies did not provide longitudinal support in the community following 
discharge.34,36 Previous studies on transitions of care have not specifically targeted hospitalized 
OUD patients, even though drug use is a well-known risk factor for readmissions.7 Care 
management has been frequently utilized to manage complex patients, but no prior studies 
have targeted hospitalized OUD patients being discharged into the community. Finally, recovery 
coaches have also not been studied to improve treatment retention of OUD patients treated with 
buprenorphine59. In this study, the trainings and responsibilities of the recovery coach and care 
management will be merged into one role. Further, this study brings these promising elements 
together into one novel model. If successful, this model could prove useful for engaging 
hospitalized out-of-treatment OUD patients.  
 
II. Aims: 
Our hypothesis is that the recovery coach intervention will be associated with greater 
success not only in remaining in treatment, but also in reducing the likelihood of hospital 
readmissions.  
 
Specific Aim #1: To assess whether subjects randomized to the recovery coach intervention 
will demonstrate greater retention in treatment and better opioid use outcomes at 24 weeks 
compared to control subjects in a randomized controlled trial. 
Hypothesis 1a: Subjects receiving the intervention will be more likely to remain in treatment 
at 24 weeks, as compared to control subjects.  
Hypothesis 1b: Subjects receiving the intervention will report fewer days of illicit opioid use 
in the prior 30 days at 24 weeks, as compared to control subjects. 
 
Specific Aim #2: To assess whether subjects receiving the intervention will demonstrate fewer 
hospital readmissions at 24 weeks compared to control subjects in a randomized controlled trial.  
Hypothesis 2: Subjects receiving the intervention will report fewer hospital readmissions at 
24 weeks compared to control subjects. 
 
III. Subject selection:  
Inclusion criteria: 
• English speaking, adults aged 18-75 
• DSM-5 opioid use disorder, severe, actively using illicit opioids until the time of hospitalization 
• Have a working telephone 
• Can identify at least 2 individuals who can act as points of contact following discharge from 
the hospital 
• Willing to engage in treatment (either a psychosocial treatment program AND/OR any 
medication treatment with methadone or buprenorphine) 
• In SUD treatment for less than 6 months and/or not currently in treatment 
 
 
Exclusion criteria: 
• Liver function test >3x upper normal limit 
• Pregnant 
• Psychotic disorder, active suicidality or homicidality  

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• Condition likely to be terminal in 24 weeks such as cancer 
• Unable to perform consent due to mental status 
 
 
IV. Subject enrollment:  
Recruitment will be conducted at BWH and BWFH. Study population will include 
hospitalized OUD patients currently not engaged in any outpatient SUD treatment, and who are 
willing to engage in treatment (either a psychosocial treatment program and/or any medication 
treatment with methadone or buprenorphine). The electronic medical record will be programmed 
to produce a daily report of any patient with OUD admitted to the inpatient medical units. This 
program will utilize a natural language processing algorithm, which will use medical records to 
find patients with OUD who are not currently on buprenorphine but may be candidates for it (and 
therefore also potentially eligible for the study). Because the algorithm will need to be trained to 
correctly identify potential patients based on inclusion/exclusion criteria, there will also be a non-
intervention/non-interaction group, specifically patients who do not have OUD (and thus would 
not be potential subjects for recruitment). The data from these patients would be obtained via 
RPDR, with the sole purpose of training the algorithm and confirming that it is indeed correctly 
excluding ineligible subjects based on our inclusion/exclusion criteria. Hospitalists will also be 
informed of the study to help identify additional patients to be approached. Finally, all patients 
with OUD who are referred for an addiction consultation, and willing to engage in treatment after 
discharge will be approached for possible inclusion.   
Either the primary medical team or the addiction psychiatry team will first inform the 
patient about the study. If the patient expresses interest and consents to be approached by the 
study staff, the research assistant will be notified. The research assistant will first ask the 
patient’s inpatient nurse about the appropriateness of approaching the patient. Once the nurse 
agrees that the patient can be approached, the research assistant will provide further 
information to the patient about the study.  The patient will also be provided with a flyer that 
provides a concise summary of the study to allow ample time for patients to consider the study.   
Due to the COVID-19 pandemic, and as this is a minimal risk study, we also propose an 
option for remote consenting for the duration of the public health emergency. As the research 
assistant will only be allowed on-site for a limited number of days each week, there is a 
possibility that part of the enrollment or consenting process will have to happen remotely before 
the subject is discharged. In this case, all preceding recruitment procedures will remain the 
same; either the primary medical team or the addiction psychiatry team will inform the patient 
about the study and ask whether the patient consents to be approached by the study team. If 
the patient consents, the research assistant will introduce the study, answer questions, 
determine preliminary study eligibility, and allow ample time for the patient to consider whether 
to enroll. The research assistant will also leave a physical copy of the Research Study Fact 
Sheet, the informed consent form, and the “Notification of Changes due to COVID-19” general 
information sheet. These will be for the patient to keep and review in case the research 
assistant is unable to return for an in-person follow-up to review and sign the consent form, after 
the patient has had time to consider the study. In the case that enrollment will continue 
remotely, the research assistant will call the participant to conduct the consent discussion, and 
then subsequently randomize the participant and conduct the baseline measures remotely via 
phone. Since this is a minimal risk research study, the remote process would use a verbal 
consent process which requires waiver of informed consent documentation (no signature will be 
obtained on the consent document).  
A study staff will approach potential participants to determine preliminary study eligibility. 
Based on prior studies of this population, we expect OUD patients to have the following 
characteristics: 50% male, 70% Caucasian, 40% with prior heroin use, admission diagnosis of 
acute pain (40%) and infection (20%), length of stay of 11 days, and 80% needing opioid 

5 
 
analgesia.  At the initial screen, all 
eligible English-speaking OUD 
patients will be offered a referral to 
methadone treatment and informed 
about the trial. Extended-release 
naltrexone, which requires that all 
opioids be stopped 7-10 days prior 
to initiation, will not be offered 
because the vast majority of 
patients screened will have 
received opioid analgesic during 
the hospitalization. As such, most 
potential patients would not be able 
to initiate naltrexone prior to 
discharge. Initiation of 
buprenorphine will be considered 
for patients who are medically 
stable enough to undergo induction, 
have an interest in initiating 
buprenorphine maintenance 
treatment, and have no medical or 
surgical contraindications. The full 
inclusion and exclusion criteria will 
then be applied. 
 
V. Study procedures:  
Randomization: After informed 
consent is given, participants will be 
randomized using a computerized 
random number generator with 
numbers in sealed envelopes in 
study binders. 
 
Interventions: 
Control group: Participants in the 
control arm will receive treatment-
as-usual at our hospital. All 
participants will receive a thorough 
psychosocial evaluation to help with 
discharge planning. Following 
initiation of buprenorphine or 
methadone, the addiction social 
worker will provide the participant 
with the intake number for the 
BWH-affiliated buprenorphine 
programs, or contact information for 
relevant methadone programs. 
Patient preference due to 
geographic considerations will be 
taken into account when choosing 
the clinic to which participants are 
Table 2: Components of the ISTOP intervention 
In-hospital component (adapted from MISSION manual) 
Session #1: (90 minutes with Recovery Coach) 
1) Introduce recovery coach, and review overall intervention 
2) Complete a psychosocial needs assessment 
3) Create a provisional treatment plan based on identified service needs 
and prioritizing of goals. 
4) Refer to BWH/BWFH-affiliated buprenorphine clinic 
5) Use motivational interviewing to increase motivation for treatment  
6) Review the following areas: 
A. Monitoring and managing symptoms:  
• Review importance of buprenorphine adherence in managing 
cravings and preventing relapse.  
• Help identify cravings and warning signs of relapse 
B. Patient education and self-management: 
• Educate about addiction and role of buprenorphine. 
• Review relapse prevention skills to cope with high-risk 
situations, cravings, and negative emotions 
C. Enlisting community and social supports: 
• Encourage self-help group attendance 
• Review importance of establishing a support system 
 
Session #2: (60 minutes with Recovery Coach) 
1) Review treatment plan 
2) Organize post-discharge appointments and problem-solve potential 
barriers in keeping appointments. 
3) Reconcile discharge medication regimen. 
4) Review the use of naloxone overdose rescue kit. 
5) Invite family members to attend session if applicable. 
6) Notify treatment plan to outpatient providers if applicable. 
 
Post-discharge component (adapted from MISSION manual) 
Recovery coach (2-3 hours per week of direct contact) 
1) Assist implementing Treatment Plan and help prioritize goals 
2) Weekly coach-led sessions utilizing the ISTOP treatment manual 
• Brief introduction to day’s topic 
• Offer personal insights or a story to further setup topic 
• Questions, if needed, to spark discussion 
• A facilitated discussion on the topic 
3) Provide support in the following areas: 
A. Monitoring and managing symptoms:  
• Encourage continuation of buprenorphine treatment  
• Accompany participants to appointments 
• Liaison between participants and clinicians 
B. Patient education and self-management: 
• Help determine and increase motivation for recovery goals 
• Share and suggest coping strategies 
• Reinforce relapse prevention skills 
• Recreational planning and modeling healthy living 
C. Enlisting community and social supports: 
• Role modeling and inspiring hope 
• Provide support during crises or job stresses 
• Identify and link to community recovery programs 
• Assist with essential life skills such as setting up bank 
accounts, getting a driver's license, using public transit, etc 

6 
 
referred. The participants will be encouraged to schedule an appointment prior to discharge. 
Instructions on safely tapering the buprenorphine will be reviewed prior to discharge, in the 
event the participant does not initiate treatment before the prescription runs out. Participants will 
be provided with community resources including outpatient addiction programs, 12-step 
meetings, and referral to outpatient mental health treatment if needed. We recognize that the 
control group does not balance non-specific effects of the intervention (e.g. increased attention). 
If our finding is promising, this study will help inform better control group design to account for 
non-specific effects of the intervention.  
 
ISTOP intervention group: The intervention arm will include in-hospital and post-discharge 
components (Table 2). Both components will be adapted from the MISSION-VET manual68 
under supervision from the mentors to be used for the ISTOP treatment manual. The candidate 
and recovery coaches will meet weekly to review all participants in the study. If the participant is 
re-hospitalized during the study period, the team will remain engaged with the patient, and the 
in-hospital component of the intervention repeated if the hospitalization occurs at BWH or 
BWFH.  
 
In hospital component: There will be 2 sessions during the hospitalization, unless the patient 
is being discharged imminently, in which case both sessions will be completed at the same 
time (Table 2). Due to the COVID-19 pandemic, all recovery coach visits (both “in-hospital” 
and post-discharge) will occur remotely (either via phone or Partners Enterprise Zoom) until 
further notice. During the first session, the recovery coach will review goals of the intervention, 
complete a psychosocial needs assessment, and create a provisional treatment plan based 
on identified service needs. Following initiation of buprenorphine or methadone, the addiction 
social worker will provide the participant with the intake numbers for the BWH-affiliated 
buprenorphine programs and contact information for any relevant methadone programs. 
Patient preference due to geographic considerations will be taken into account when choosing 
the clinic to which participants are referred. The participants will be encouraged to schedule 
an appointment prior to discharge. The importance of continuing treatment will be reinforced. 
The recovery coach will focus on monitoring and managing symptoms, educate about the 
nature of recovery and relapse prevention skills, and reinforce the importance of community 
and social supports. The MISSION-VET manual, which covers the above elements, will be 
used to manualize the recovery coach intervention while in the hospital.68 During the second 
session, the Recovery Coach will review the treatment plan, organize post-discharge 
appointments, reconcile medications, and provide naloxone rescue training. If applicable, 
family members will be encouraged to be present for all in-hospital sessions.  
 
Post-discharge component: Following discharge, the recovery coach will meet with the 
participant up to 3 hours per week (Table 2). Each recovery coach will carry a caseload of no 
more than 3 participants at a time. More frequent contact will be permissible if the care team 
needs to respond to emergencies or other clinical issues requiring additional contacts. For 
participants who may live outside of Boston or are otherwise unable to return to the Brigham 
Hospital area, the recovery coach will meet with participants via phone call or video 
conferencing. Each week, the coaches will conduct peer-led individual sessions using topics 
adapted from the MISSION-VET manual. The recovery coaches will encourage the 
continuation of treatment and accompany participants to appointments if necessary, and 
function as a liaison between the participant and the clinicians. The coaches will help 
determine recovery goals, share and suggest coping strategies, and model healthy living. The 
coaches will also instill hope through example, and provide support during crises. The 
coaches will assist with linkage to community programs, and assist with essential life skills 
such as setting up a bank account or using public transportation. The candidate will meet 

7 
 
weekly with the recovery coaches to review each case. If the participant successfully linked 
with the BWH-affiliated buprenorphine clinic, retention in treatment will be confirmed with the 
clinic.  
 
Fidelity: The MISSION Fidelity Index from the MISSION-VET manual68 will be adapted for this 
study to ensure intervention fidelity. The index is designed to document services delivered as 
indicated in the manual.  
Compensation: Participants will be reimbursed $50 for the baseline, 4- and 12-week follow-up 
visit, and $100 for the 24-week visit. 
 
Schedule of Assessments: Baseline measures will be obtained during the hospitalization. Follow 
up assessments will occur at 4, 12 and 24 weeks after discharge. A research assistant blinded 
to study assignment will collect all data. Patients who are unable to return to the hospital for the 
follow-up assessments will complete their measures via phone call or Partners Enterprise Zoom 
(if participant prefers) with the research assistant.   
Measures: As recommended by notice NOT-DA-12-008, measures from the Substance Abuse 
and Addiction Collection of the PhenX Toolkit were chosen where appropriate. The schedule of 
assessments is summarized in Table 3.  
• 
Demographic measures (Core Tier 1 measures): A questionnaire to collect 
demographic information on age, gender, ethnicity, marital status, employment, 
housing, education, and socioeconomic status. 
• 
Mini-International Neuropsychiatric Interview (MINI)72: A brief structured psychiatric 
diagnostic interview that was designed to permit the rapid diagnosis of the major 
psychiatric disorders. 
• 
Pregnancy test: Females will undergo pregnancy testing at the time of screening. 
• 
Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES)74: To 
assess readiness. 
• 
Urine toxicology: Routine urine immunoassay screen will be obtained to assessed, 
including opioids. These will be obtained during routine clinical visits, separate from 
study visits. 
• 
Addiction Severity Index 5th edition (ASI)75: The ASI will assess multiple dimensions of 
SUD.  
• 
Opioid craving76,77: A single-item questionnaire will be used to determine craving for 
opioids. 
• 
Patient Health Questionnaire 9-item (PHQ9)78: This questionnaire will assess 
depressive symptoms. 
• 
Brief Pain Inventory79: Pain severity and the degree to which pain interferes with life 
will be assessed.  
• 
Time-line follow back (TLFB)81: Assess past 30-day use of substances. 
• 
Verification of treatment retention: Treatment retention will be verified by the 
BWH/BWFH-affiliated clinic.  
• 
The Health-Care Climate Questionnaire - Recovery Coach version (HCCQ-RC): A 
brief 15-item measure added to assess patients' perceptions of the degree to which 
they experience their recovery coach to be autonomy supportive. 
• 
Adverse Childhood Experiences International Questionnaire (ACE-IQ): A survey 
designed to collect information from adults about events they experienced in the first 
18 years of their lives, including family dysfunction and exposure to violence.  
• 
Health-Care Climate Questionnaire – Hospital Care Team Version (HCCQ-HCT): A 
brief 15-item measure added to assess patients' perceptions of the degree to which 

8 
 
they experienced the hospital care team (e.g. nurses, doctors, social workers) to be 
autonomy supportive.  
• 
PTSD Checklist (PCL-5): A 20-item self-report measure that assesses the presence 
and severity of PTSD symptoms, corresponding with DSM-5 criteria for PTSD. 
• 
Brief Addiction Monitor (BAM): A 17-item, progress-monitoring instrument for patients 
in treatment for a substance use disorder, used to assess risk factors for substance 
use, protective factors that support sobriety, and drug and alcohol use.  
• 
Short Form 12 health survey (SF-12): A short 12-item survey that assesses mental 
and physical functioning as well as overall health-related quality of life.  
 
 
Screening 
Baseline 
4 weeks 
12 weeks 
24 
weeks 
Demographics 
X 
 
 
 
 
MINI 
X 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
Readiness to Change 
X 
 
 
 
 
Liver function tests 
X 
 
 
 
 
ASI 
 
X 
X 
X 
X 
Opioid cravings 
 
X 
X 
X 
X 
PHQ9 
 
X 
X 
X 
X 
BPI 
 
X 
X 
X 
X 
TLFB 
 
X 
X 
X 
X 
Verification of 
Treatment 
 
 
 
 
 
HCCQ-RC 
 
X 
X 
X 
X 
ACE-IQ 
 
X 
 
 
 
HCCQ-HCT 
 
X 
 
 
 
PCL-5 
 
X 
X 
X 
X 
BAM 
 
X 
X 
X 
X 
SF-12 
 
X 
X 
X 
X 
 
 
 
Project Timeline: The first 8 months of Year 1 will be devoted to hiring of the study staff, the 
intervention manual development, staff training, pilot-testing the protocol with 2 participants, and 
protocol refinement. During the intervention period, 6 patients will be screened for potential 
enrollment every month, enrolling 2 participants per month on average for 30 months, 
concluding by the beginning of Year 4. Manuscript submission will begin in Year 1. Year 4-5 will 
be devoted to data analysis, and submission of an R01 grant application (Table 4). 
Anticipated problems:  
Slow recruitment: If recruitment does not proceed as planned, we will increase outreach to 
hospitalists to help identify potential participants admitted to BWH and BWFH inpatient 
medical unit.  
Adjustments to the intervention: The first 2 participants will function as pilot cases to identify 
any problems with the study intervention. Appropriate adjustments to the standard operating 
procedures, recruitment, manual adaptation, and measures will be made according to these 
Table 3: Schedule of measures 

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2 pilot cases. Because the study procedures will be adapted from the MISSION manual, an 
established treatment manual, 2 participants should be sufficient to assess the need for 
modifications.  
 
 
VI. Biostatistical analysis: 
Sample size/power analysis:  In a study of a care management intervention for patients with 
substance use disorder in primary care, individuals receiving the intervention were more likely 
to remain in treatment at 24 weeks (40% vs 10%).52 While this study is entirely community 
based, no other comparable studies have been conducted with OUD patients on 
buprenorphine. Based on this effect size, we plan to screen 145 participants, assuming a 60% 
attrition due to screening failure, allowing for a sample size of 58 available for analysis, evenly 
divided between the control and intervention arm. This will yield a statistical power of 0.8 and 
95% confidence level to detect differences in proportions of participants who remain in 
treatment at 24 weeks, as confirmed by the BWH-affiliated clinic. The study will not be 
powered to detect smaller effect sizes, but will be helpful in providing important information 
about effect sizes to adequately power future studies.  
Specific Aim #1: The hypothesis that participants receiving the intervention will be more likely 
to remain in buprenorphine treatment at 24 weeks will be tested using logistic regression, 
treating the endpoint as a categorical variable. Treatment retention data will be obtained 
directly from the BWH/BWFH affiliated buprenorphine clinics. The hypothesis that 
participants receiving the intervention will report fewer days of illicit opioid use at 24 weeks 
will be tested using mixed effects ANOVA modeling, treating the endpoint as a continuous 
variable. ANCOVA will be used to adjust for relevant covariates, including age, sex, 
ethnicity/race, and baseline illicit opioid use. Illicit opioid use will be determined from the 
TLFB and urine toxicology results.  
Specific Aim #2: The hypothesis that participants receiving the intervention will be less likely 
to be readmitted at 24 weeks will be tested using logistic regression, treating the endpoint as 
a categorical variable. Readmission data will be obtained from the ASI and GAIN service 
utilization items.80 Results will be adjusted for relevant covariates, including demographic 
variables and baseline clinical variables. While 30-day readmission rate is an important 
metric for hospitals, the readmission rate at 24 weeks may better evaluate the impact of the 
proposed intervention.  
Missing data: Extensive efforts will be made to avoid missing data by vigorous outreach. 
Missing data on treatment continuation or retention will be imputed as treatment 
discontinuation (i.e. participant did not continue or remain in treatment). Missing urine 
toxicology samples will be treated as positive for illicit opioid use. Data on possible reasons 
for missing observations will be collected so that missing data mechanism may be 
appropriately modeled statistically. Using methods to manage missing data, results will be 
compared to the original dataset to identify any discrepancies and verify conclusions.  
 
 
 
VII. Risks and discomforts 
The well being of the study participants is of utmost importance. The in-depth screening 
procedure has been designed to ensure that individuals with any underlying medical or 
psychiatric illness are identified that may place them at greater risk for experiencing adverse 
effects during the study. The study procedures are designed to be minimally invasive and 
associated with minimal risk. Alternative procedures with lower risk are not available. 
Nevertheless, the protocol raises several areas of concerns: confidentiality, emotional distress, 
suicidal ideation, buprenorphine medication, intoxication, and overdose.  

10 
 
Confidentiality: Confidentiality is of utmost importance given the sensitive nature of the 
illness and data collected. During research there is always a possibility for a breach of 
confidentiality, which may potentially cause personal, social, occupational, legal, and other 
harm. Our research team is very aware of the importance of maintaining strict confidentiality and 
has prior experience dealing with sensitive information. The following precautions will be used to 
protect the privacy of participants and maintain confidentiality of research data: all staff will be 
trained in confidentiality and data security procedures; privacy will be maintained by conducting 
all study procedures in private hospital rooms or in close, sound-proof rooms; data will be de-
identified and coded with unique ID numbers; data will be securely stored in locked filing 
cabinets in locked rooms; electronic data will be stored in password protected documents 
located on password protected computers and secure servers; the key linking participants 
names and ID numbers will be stored in a separate password protected document in a 
password protected computer; access to data storage areas will be restricted to authorized 
study personnel; and all analysis will be conducted on de-identified data. While breach of 
confidentiality is possible, these safeguards will ensure that such a breach will be highly 
unlikely.  
Emotional distress: Some patients may experience discomfort or embarrassment 
related to providing urine samples or answering questions about substance use and other 
personal behaviors. They could also experience unexpected encounters with friends or 
associates while in the study. However, based on prior studies with this population, we expect 
the degree of distress to be very limited. All research personnel will be extensively trained on 
study procedures, including the conduct of the interviews that elicit personal information, and 
the importance of being sensitive to and respectful of all participants. In cases where emotional 
distress does occur, research personnel will be trained on how to identify and address it, and 
when to terminate an interview. Multiple levels of back-up support for research personnel will be 
developed. The candidate is a board certified psychiatrist, and will be able to ensure that 
appropriate services are received.  
Suicidal ideation: Patients with OUD frequently have psychiatric co-morbidities, namely 
depression. Participants who disclose any suicidal ideation during the study (either through self-
report during an assessment or self-reported on the PHQ-9) will be addressed appropriately and 
with sensitivity. Any disclosures will be handled within existing legal mandates, clinical practice, 
and social norms. Consistent with standard clinical practice, when possible, disclosures will be 
discussed with the participant to determine the best management options. This may include 
notifying the inpatient/outpatient providers or family members, referring to medical treatment, 
calling emergency services, or escorting the participant to the Emergency Room at Brigham and 
Women’s Hospital. When required by law, the police department will be notified. The candidate 
is a board certified psychiatrist and has extensive experience managing acutely distressed 
patients with mental or substance use disorders.  
Buprenorphine medication safety: All subjects in the trial will be started on 
buprenorphine prior to randomization, and will be deemed appropriate for the medication by 
consensus of the treating physicians and a buprenorphine-waived physician on the addiction 
consultation-liaison team. Buprenorphine has been tested extensively and is FDA-approved for 
the treatment of OUD. Indeed, medication-assisted treatment (with buprenorphine, methadone 
or naltrexone) is the standard of care for the treatment of OUD. Because buprenorphine is a 
partial mu-opioid agonist, the medication can in some individuals cause intoxication, especially if 
used intravenously. As such, only the combination tablet that contains naloxone will be used, 
unless the participant has a documented allergy to naloxone. The combination tablet will 
produce a clinically significant opioid withdrawal if injected. All participants will be told of this 
reaction, and will also be asked to refrain from injecting the medication. Buprenorphine can also 
cause a mild euphoria and respiratory depression, but much less than compared to full agonists. 
Subjects will be monitored during the hospitalization to ensure they can adequately tolerate the 

11 
 
medication. Commonly reported side effects include nausea, vomiting, constipation, muscle 
cramps, insomnia, irritability, sweating, and fevers. Subjects will be asked to report any side 
effects to the study staff, hospital staff, or their buprenorphine prescriber. If these side effects 
are reported to study staff, the candidate will be informed and will take appropriate action. The 
candidate has extensive experience managing OUD patients with buprenorphine, and is well 
versed in the appropriate clinical management of any emergent side effects from 
buprenorphine. Subjects will also be advised that ingesting buprenorphine with other sedative 
drugs, such as benzodiazepines, dramatically raises the possibility for a synergistic reaction that 
can cause an overdose or even death. Individuals with any underlying liver disease or have a 
history of hepatitis C will be informed that buprenorphine use has been rarely associated with 
liver failure, and that liver function test will be obtained. Subjects will be informed that 
buprenorphine medication should be stored in a secure location, ideally with a lock-box, to 
ensure no one else can access the medication including children. Finally, studies show that 
after stopping buprenorphine medication, individuals are at heightened risk of relapse to illicit 
opioid use, as well as greater likelihood of non-fatal and fatal overdoses. As such, subjects will 
be counseled about the risks of relapse and overdose throughout the study period. 
Intoxication: The study population targets OUD patients, who were actively using illicit 
opioids prior to the hospitalization. As such, it is possible for participants to be intoxicated from 
illicit opioids or other substances during the their work with recovery coaches or during study 
visits. Participants will be required to abstain from substances other than buprenorphine for at 
least 4 hours prior to each study visit. Intoxication will be determined through self-report and 
clinical observation. If a participant is intoxicated in any way, they will not be permitted to 
complete the visit, and the visit will be rescheduled at the earliest convenient time. Consistent 
with standard clinical practice, when possible, the recovery coaches will discuss with the 
candidate to determine the best management options. This may include notifying the 
inpatient/outpatient providers or family members, referring to medical treatment, calling 
emergency services, or escorting the participant to the Emergency Room at Brigham and 
Women’s Hospital.  
 
Overdose: Patients with OUD are at heightened risk from fatal and non-fatal overdoses 
during and after buprenorphine treatment, especially if using alcohol or sedative drugs such as 
benzodiazepines. As such, participants will be required to abstain from using these substances. 
However, given their underling illness, some participants may still ingest these other substances 
during the study period. All study staff, including recovery coaches, and all participating subjects 
will be trained in the recognition and initial management of an overdose using the naloxone-
rescue kits. Subjects will also be asked to identify family or supports that can carry the naloxone 
rescue kits. The candidate is a board certified addiction psychiatrist well versed in the 
recognition and management of overdoses, and appropriate clinical action will be taking in the 
event of an overdose. In addition, all recovery coaches will be receive training on overdose 
prevention and the use of naloxone rescue kits.  
 
 
VIII. Potential benefits:  
The risk/benefit ratio for this study is relatively low, primarily because the intervention 
and the data collection procedures are minimally invasive. An extensive screening procedure 
will ensure that individuals entering the trial will have no contraindications. Trained research 
personnel will perform all study procedures to minimize risks, discomforts, and adverse effects. 
Buprenorphine treatment is a FDA-approved treatment for the treatment of OUD, and reduces 
illicit opioid use and related morbidities associated with opioid use disorders. The recovery 
coaching intervention may provide benefit to the study participants by increasing their likelihood 
of remaining in treatment, reducing their illicit opioid use, and reduce hospital readmissions. 

12 
 
 
This study will generate valuable information about the effect of combining recovery 
coaches with buprenorphine initiated during hospitalization. The results will help inform the 
direction needed to take in developing effective strategies to improve the care of hospitalized 
OUD patients. Given the potential public health impact, and the minimal risk associated with 
participation, we believe that the risk to participants is reasonable.  
 
 
IX. Monitoring and quality assurance:  
1. Data Quality and Management 
a. Description of plan for data quality and management: The PI or study staff will 
review all data collection forms on an ongoing basis for data completeness and 
accuracy as well as protocol. To minimize any conflicts of interest, a physician 
from Brigham and Women’s Hospital familiar with clinical research who is not a 
collaborator or investigator on the proposed project, nor a close colleague, will 
serve as an independent individual to monitor the data and safety. 
b. Frequency of review: The candidate will complete reports every 3 months 
detailing the study progress and subjects’ status, any adverse events, and any 
protocol deviations, which will be submitted to the independent individual for 
review. 
2. Subject Accrual and Compliance 
a. Measurement and Reporting of Subject Accrual, Compliance with 
inclusion/exclusion criteria: Review of the rate of subject accrual and compliance 
with inclusion/exclusion criteria will occur every 3 months to ensure that a 
sufficient number of participants are being enrolled and that they meet eligibility 
criteria and the targeted ethnic diversity goals outlined in the proposal. 
b. Measurement and reporting of participant adherence to treatment protocol: Data 
on adherence to the treatment protocol will be collected weekly by research staff 
and reviewed quarterly by the PI. Fidelity to the treatment manual will be 
reviewed by the candidate each week with the recovery coaches.  
3. Justification of sample size: In a study of a care management intervention for patients 
with substance use disorder in primary care, individuals receiving the intervention were 
more likely to remain in treatment at 24 weeks (40% vs 10%). While this study is entirely 
community based, no other comparable studies have been conducted with OUD patients 
on buprenorphine. Based on this effect size, we plan to screen 145 participants, 
assuming a 60% attrition due to screening failure, allowing for a sample size of 58 
available for analysis, evenly divided between the control and intervention arm. This will 
yield a statistical power of 0.8 and 95% confidence level to detect differences in 
proportions of participants who remain in treatment at 24 weeks, as confirmed by the 
BWH-affiliated clinic. The study will not be powered to detect smaller effect sizes, but will 
be helpful in providing important information about effect sizes to adequately power 
future studies. 
4. Stopping rules: This study will be stopped prior to its completion if: (1) the intervention 
is associated with adverse effects that call into question the safety of the intervention; 
(2) difficulty in study recruitment or retention will significantly impact the ability to 
evaluate the study endpoints; (3) any new information becomes available during the trial 
that necessitates stopping the trial; or (4) other situations occur that might warrant 
stopping the trial 
5. Designation of an independent monitor: To minimize any conflicts of interest, a 
physician from Brigham and Women’s Hospital familiar with clinical research who is not 
a collaborator or investigator on the proposed project, nor a close colleague, will serve 
as an independent individual to monitor the data and safety. 

13 
 
6. Safety Review Plan: Study progress and safety will be reviewed monthly (and more 
frequently if needed). Progress reports, including patient recruitment, retention/attrition, 
and AEs, will be provided to the Independent Monitor following each of the monthly 
reviews. An Annual Report will be compiled and will include a list and summary of AEs. 
In addition, the Annual Report will address (1) whether AE rates are consistent with pre-
study assumptions; (2) reason for dropouts from the study; (3) whether all participants 
met entry criteria; (4) whether continuation of the study is justified on the basis that 
additional data are needed to accomplish the stated aims of the study; and (5) conditions 
whereby the study might be terminated prematurely. 
7. Study report outline for the independent monitor: Study Report tables will be 
generated only from aggregate (not by group assignment) baseline and aggregate safety 
data for the study population. A separate Closed Safety Report, with masked group 
baseline and safety data, will be generated for the Independent Monitor(s) by a 
designated unmasked member of the team but will not be reviewed by the study team. 
8. Informed consent: The subject (if applicable, parent/guardian) will be asked to review 
the study consent form. The PI or Co-Investigator (Co-I) will meet with the subject to 
review the form, to confirm the subject’s understanding of the study, and to answer any 
questions the subject might have.Once the subject demonstrates understanding of the 
study and agrees to participate in the study, the consent will be signed in the presence 
of the PI (or Co-I) and a witness 
9. This study does not involve any medications or devices and carries no risk of harm from 
such medications or devices. 
 
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