Buprenorphine to Improve HIV Care Engagement and Outcomes: A Randomized Trial (BRAVO)
Phase: PHASE4
Conditions: HIV, Substance Related Disorders
Sponsor: Oregon Health and Science University

BRAVO Protocol Version 6– April 27, 2020 
 
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BRAVO 
 
Buprenorphine to Improve HIV Care Engagement 
and Outcomes: A Randomized Trial 
 
 
 
 
 
Lead Investigator:      
Todd Korthuis, MD MPH 
 
 
Co-Investigators:        
Le Minh Giang, PD, PhD 
Nguyen Kim Viet, PhD 
Gavin Bart, MD PhD 
Thuan Nguyen, PhD 
Doan Ha, PhD 
 
 
Project Manager: 
Lynn E. Kunkel, MS CCRP 
 
 
Scientific Advisory Board: 
Walter Ling, MD 
Dennis McCarty, PhD 
Rick Rawson, PhD 
Kevin Mulvey, PhD 
 
 
 
 
 
NCT 01936857 
 
 
 
 
 
 
 April 27, 2020 
 
Protocol Version: 6 
 
 

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Introduction and Background 
Opioid dependence worsens HIV transmission and outcomes across the continuum of 
HIV care.  
Heroin injection drug use (IDU) is the main driver of HIV transmission in Vietnam and a 
recalcitrant source of new HIV infections worldwide.5-6 In Vietnam, HIV prevalence among IDUs 
ranges from 20% to 56%7. Needle sharing among HIV-infected IDU ranges from 7% to 37%, 
contributing to ongoing transmission.7 In addition to risk behavior-related transmission, opioid 
use amplifies transmission due to lack of HIV viral suppression in IDU who do not fully access 
HIV care. IDU adversely impacts engagement across the continuum of HIV care: being 
diagnosed with HIV in a timely manner, linking to HIV care, receiving and adhering to ART, and 
staying in HIV care.3, 8-9 Successful engagement throughout this continuum is required for 
achieving sustained HIV viral suppression.3 Interventions to close the gaps in engagement in 
HIV care are urgently needed in the U.S. and worldwide. In Vietnam, only 29% of those 
estimated to be living with HIV are linked to care (Figure 3).1, 3, 10 National data regarding HIV 
viral suppression are limited in Vietnam (* in Figure 3). A large cohort study demonstrated 72% 
of ART-naïve participants achieved viral suppression at 12 months,2 which extrapolates to 14% 
of all HIV-infected Vietnamese. As in the U.S., IDU are less likely to be linked to care, receive 
antiretroviral treatment (ART), stay in HIV care, or achieve viral suppression compared with 
non-users.2, 4 
 
 
Access to opioid dependence treatment for HIV-infected IDU is limited.  
While engagement in methadone maintenance therapy (MMT) is effective for decreasing opioid 
use and HIV transmission, access to substance abuse treatment is limited for many HIV-
infected participants in the U.S.11-12 Barriers to MMT include requirements for observed dosing, 
lack of transportation13, inflexible dosing schedules14, legal problems15-17, perceived 
discrimination and cost.15, 17-19 Treatment of heroin dependence in Vietnam has historically 
involved compulsory commitment to rehabilitation detention centers for re-education where 
relapse rates exceeded 90% in 2011.20 MMT scale-up has been highly successful since being 
introduced in 2008, with 62 treatment centers nationwide and plans for 28 new clinics in 2013. 
Many HIV-infected IDU in Vietnam, however, experience barriers to MMT as in the U.S. and 
other countries. Twenty-five percent of HIV-infected participants at participating Vietnam HIV 
clinics have untreated, active heroin dependence (Table 1). New treatment delivery models are 
urgently needed to augment MMT scale-up and improve access to treatment. A 2012 change in 
Vietnamese government policy encourages voluntary and community-based addiction treatment 

BRAVO Protocol Version 6– April 27, 2020 
 
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as an alternative to compulsory rehabilitation, and opens the door for testing addiction treatment 
models that better engage HIV-infected IDU at all levels of the HIV care continuum (Vietnam 
Government Decree 96 modification, 2012). 
 
Clinic-based BUP/NX: potential for improving engagement in the HIV care continuum. 
Training HIV providers to manage opioid dependence with buprenorphine/naloxone (BUP/NX) 
during HIV clinic visits has the potential to expand access to opioid dependence treatment while 
increasing engagement in HIV care. Buprenorphine/naloxone (BUP/NX), a partial opioid agonist 
recently available in Vietnam, has few drug-drug interactions with HIV or TB treatment 
medications, low overdose risk, no requirement for daily observed dosing and avoids the 
administrative requirements of MMT, making it highly feasible for use in busy HIV clinics.21-23 As 
in other countries, HIV providers in Vietnam’s 320 HIV clinics are well-positioned to adopt new 
treatments and successfully manage both HIV and opioid dependence as two interrelated 
chronic, but treatable illnesses. Studies of BUP/NX in HIV care settings are limited, however. 
Two U.S. pilot studies of BUP/NX suggest it is safe and feasible and reduces opioid use in HIV 
care, but were limited by lack of a comparison group21-22, and small sample size.24 In both 
studies, the majority of participants were already on ART with high baseline rates of viral 
suppression, limiting the capacity to assess the effect of BUP/NX on HIV outcomes. Assessing 
the effectiveness of clinic-based BUP/NX with a high proportion of participants new to care, as 
we propose, provides the opportunity for assessing its ability to close gaps in the HIV care 
cascade in real-world HIV clinic settings. 
Clinic-based BUP/NX: potential for decreasing HIV transmission. Treating IDU for opioid 
dependence decreases risky injection and sexual HIV transmission risk behaviors as well as 
opioid use.25-26 In a recent meta-analysis of 12 studies that examined the association between 
opioid agonist therapy (OAT) for opioid dependence and HIV incidence, OAT reduced new HIV 
infections by 54% (rate ratio 0.45; 95% CI 0.32, 0.67).27 Likewise, treating HIV-infected persons 
for HIV decreases HIV viral load—the main host determinant of HIV transmission—and 
decreases transmission apart from change in risk behavior.28 Combining ART and MMT for IDU 
in Vancouver, British Columbia decreased new HIV infections both among IDU and in the 
community, overall.29-30 BUP/NX delivered in a primary care setting decreased HIV transmission 
risk behaviors in one single-center, observational study.26 HIV viral load is the primary driver of 
infectivity. If our proposed trial of clinic-based BUP/NX is effective in increasing viral 
suppression, fewer new HIV infections will occur among the sexual and drug using partners of 
opioid dependent individuals.28-30 
 
Clinic-based BUP/NX is an innovative addiction treatment delivery model in much of the 
world. 
 Healthcare settings are traditionally underutilized as potential sites for expanding addiction 
treatment, both in the U.S. and other countries. Within Vietnam and developing and middle-
income countries, our work is innovative because it tests a novel services delivery model for 
medication-assisted treatment of opioid dependence in healthcare settings that are already 
seeing large numbers of participants with opioid dependence. The dominant treatment for 
heroin dependence in Vietnam is compulsory commitment to a 2-year government rehabilitation 
center for re-education, administered by the Ministry of Labor, Invalids and Social Affairs 
(MOLISA) with relapse rates of 70- 90% in 201120. MMT programs have expanded rapidly since 
2008, but access remains limited, as in much of the rest of the world.29-30 Integrating addiction 
treatment into clinic-based settings is an alternative treatment model with the potential for 
efficiently expanding access to other medication-assisted treatments for addiction. 
 
 

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Objectives 
The primary objective of this proposal is to add to the palette of treatment options by comparing 
the effect of two opioid dependence treatment delivery models on improving the HIV care 
engagement and outcomes in Vietnam. We propose a multisite, open-label, randomized, 
flexible-dose noninferiority trial of buprenorphine/naloxone (BUP/NX) (n=225) versus 
methadone maintenance therapy (MMT) referral (n=225) for treatment of opioid dependence in 
HIV-infected participants in 6 Vietnam HIV clinic research sites. The study is conducted in 
partnership with colleagues at Hanoi Medical University (HMU), the Provincial AIDS Control 
(PAC) authorities of Hanoi, Thanh Hoa, and Bac Giang, the Vietnam National Institute of Mental 
Health, and Oregon Health & Science University.  
 
Study sites are 4 HIV clinics in Hanoi, 1 in Thanh Hoa, and 1 in Bac Giang; epicenters of 
Vietnam’s HIV and heroin epidemics, all of which are associated with MMT and HIV testing and 
counseling centers. A research coordinating center at HMU provides additional outreach, 
recruitment, non-medication-related study procedures and links participants to participating HIV 
clinic sites for clinical management.  HIV providers will be trained to manage opioid dependence 
using BUP/NX.  
 
Participants are HIV-infected participants with opioid dependence new to HIV care, recruited 
from HIV clinics, MMTs, and associated HIV testing centers. Participants randomized to 
BUP/NX will receive BUP/NX after successful completion of medication induction and 
stabilization. Participants randomized to BUP/NX will receive a taper after 12 months of study 
drug exposure, with referral for MMT. Participants randomized to MMT will receive usual care, 
which is case-manager-assisted referral to MMT. All participants receive clinic-based individual 
counseling and HIV care.  
 
The primary outcome of HIV-1 viral load will be measured at baseline, 6, and 12 months.  
Secondary outcomes, including self-reported drug use, urine drug screens (UDS), and 
measures of HIV care engagement (adherence, retention) will be assessed quarterly through 12 
months follow-up. Qualitative interviews with participants, family members of participants, and 
providers in years 1 through 4 will identify lessons-learned for scale-up of HIV clinic-based 
BUP/NX.  
 
 
 
There are three specific aims in this protocol: 
Aim 1: Assess effect of clinic-based BUP/NX versus MMT referral on HIV treatment 
engagement and outcomes in HIV-infected participants with opioid dependence. The associated 
hypotheses are: 
 H1a: Participants randomized to BUP/NX will have noninferior rates of HIV viral 
suppression (HIV-1 RNA < 200 copies/mL) on 12 month blood draw compared with 
MMT referral. 

BRAVO Protocol Version 6– April 27, 2020 
 
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 H1b: Participants randomized to BUP/NX will have greater (Antiretroviral Therapy) 
ART initiation, adherence, and retention in HIV care at 12 months versus MMT 
referral. 
 
Aim 2: Assess effect of clinic-based BUP/NX versus MMT referral on opioid use in HIV-infected 
participants with opioid dependence. The associated hypothesis is: 
 H2: Participants randomized to BUP/NX will have a lower proportion of positive 
assessments for opioid use (self-report + UDS) at 12 months versus MMT referral 
 
Aim 3: Assess BUP/NX implementation experience to inform national scale-up of clinic-based 
BUP/NX. 
 
Conceptual Model 
Substance use disorders impair participant engagement and retention in HIV care, contributing 
to gaps in the HIV care cascade.3, 34 The current study seeks to compare clinic-based BUP/NX 
versus referral for MMT for treating opioid dependence in HIV-infected participants to improve 
engagement and retention in HIV treatment that leads to HIV viral suppression (Figure 2). 
Virologic suppression reduces HIV associated morbidity, prolongs survival, restores and 
preserves immunologic function and decreases HIV transmission 35. As shown in the conceptual 
model below, decreased use of opioids (Aim 2) and uptake of and adherence to ART (Aim 1B) 
are proximal outcomes that contribute to virologic suppression (Aim 1A). HIV-infected Injection 
Drug Users (IDU) who initiate ART should be able to achieve virologic suppression within 6-12 
months if they continue in HIV care and adhere to ART.36-38 In this model, successful treatment 
of opioid dependence is hypothesized as an important moderator of HIV care engagement and 
subsequent viral suppression. HIV-infected IDU who receive treatment for substance use are 
more likely to use HIV care and receive ART.39-41 Participant and provider attitudes toward 
treatment and organizational characteristics, assessed in Aim 3, influence adoption of new 
treatment modalities and provide lessons learned for wide-scale implementation.42 The 
Consolidated Framework for Implementation Research (CFIR)43-44 suggests that participant, 
provider, and organizational factors are key inputs to adoption of new evidence-based 
technologies in healthcare (Aim 3). 
 
 
Setting 
Hanoi, Thanh Hoa, and Bac Giang are epicenters of the Vietnam HIV epidemic with high 
numbers of HIV-infected heroin users. Care innovations in these provinces often serve as 
models for others to follow. Six outpatient HIV clinics (OPC) will participate in the clinical trial as 
clinical research sites: 4 clinics in Hanoi (Tu Liem, Long Bien, Hoang Mai and Dong Da), 1 clinic 
in Thanh Hoa (Thanh Hoa PAC OPC), and 1 clinic in Bac Giang (Bac Giang PAC OPC). A 

BRAVO Protocol Version 6– April 27, 2020 
 
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research coordinating center at HMU provides additional outreach, recruitment, non-medication-
related study procedures and links participants to participating HIV clinic sites for clinical 
management.  HIV clinics were selected based on the prevalence of untreated active opioid 
dependence among new participants with a history of IDU, ability to enroll at least 120 
participants over the course of the study, availability of methadone maintenance, and support of 
local authorities.  Medical directors at participating sites estimate that < 5% of participants with 
active heroin use currently access MMT. All HIV clinic sites have on-site counseling, case 
management, phlebotomists and pharmacy services on-site, and are affiliated with Voluntary 
Counseling and HIV Testing (VCT) services and MMT programs in their surrounding 
communities that have capacity for accepting new MMT referrals. 
 
Study Design and Procedures 
450 Participants (225 BUP/NX and 225 MMT) HIV-infected participants with active opioid 
dependence will be enrolled in the study across participating sites. Outreach activities will seek 
to identify patients new to HIV care or registered for care at participating HIV clinics but not on 
ART, though participants are not required to be ART treatment-naïve. Participants will be 
enrolled in the study for approximately 12 months, with 6 research visits total.  
 
Inclusion Criteria:   
 
HIV positive 
 
Have a current moderate to severe DSM-5 opioid use disorder 
 
Urine drug screen positive for opioids  
 
Interested in receiving treatment for opioid dependence 
 
Are age 18 or greater 
 
Are willing to practice effective method of birth control, if female  
 
Exclusion Criteria:  
 
Have a known hypersensitivity to buprenorphine or naloxone 
 
Have an AST & ALT > 5x upper limit 
 
Are currently pregnant or breastfeeding 
 
Have a serious medical or psychiatric illness in past 30 days (e.g. opportunistic infection, 
psychosis) that precludes safe participation in the opinion of study physician 
 
Have received methadone maintenance treatment within 30 days of consent 
 
Known vulnerable populations will be excluded from participation; this includes children, 
pregnant women, decisionally-impaired adults, and prisoners.  
 
Prisoners:  
Groups and organizations that work with newly-released prisoners will also be included but will 
not approach individuals who are currently detained as prisoners.  There is no probation or 
parole program in Vietnam. Researchers will meet with staff and volunteers, provide study 
information, and provide referral information only. No direct contact between newly-released 
individuals and research staff will occur.  
 
Research staff at each clinic and at HMU have been instructed on procedures related to 
participants who become incarcerated during enrollment. During incarceration, no research 
procedures will be conducted. If a participant is released during the twelve-month study period, 
research procedures may be resumed.  
 

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Participants will be given wallet cards with instructions to the police that they contact the 
research site for more information. In Vietnam, a suspected drug user will not be detained if he 
is voluntarily receiving treatment. Participants will be instructed on how to use the wallet card.   
 
Recruitment Methods 
Recruitment will occur through HIV clinics that will collaborate with their associated Voluntary 
Counseling and Testing Centers (VCTs) and MMTs to identify newly diagnosed participants. 
Local community groups (e.g. charity, non-profit, international organizations, self-help, peer 
educators, etc) and other governmental agencies, groups, and clinics will be contacted and 
provided with study information so that they can refer HIV+ and/or opioid dependent individuals 
to the clinic. Research staff will distribute flyers describing the study and provide contact 
information. Research staff will also participate in traditional outreach methods and offer HIV 
rapid testing (finger-prick) within the IDU community and will perform pre-screen activities 
outside of the clinic. These pre-screening activities will include HIV rapid testing and urine drug 
screening as location allows. Location of “outside of the clinic” could refer to anyplace; including 
parks, peer meetings, non-research clinics, etc. Anybody pre-screening as eligible will be given 
detailed instructions for referral. This type of recruitment will not only increase enrollment 
numbers but will increase the public health awareness of HIV and substance use screening.  
 
Groups and organizations that work with newly-released prisoners will also be included but will 
not approach individuals who are currently detained as prisoners. Detailed instructions will be 
provided to Vietnamese colleagues about the distinction. Researchers will meet with staff and 
volunteers, provide study information, and referral information only. 
 
HIV clinic staff will screen participants at intake for study eligibility. HMU research coordinating 
center research staff and peer educators will approach people from community-based “hot-
spots” and from people participating in existing observational research studies to offer study 
participation.  Potential participants with a history of MMT within the past 30 days will be 
excluded and encouraged to follow-up with their MMT program, in order to avoid creating an 
incentive for participants already engaged in MMT to switch to BUP/NX. HIV clinic and research 
staff will approach potential participants and assess inclusion and exclusion criteria. 
 
Consent process 
Participation in the study is completely voluntary.  
 
HIV clinic research staff will review study procedures with potential participants and collect 
informed consent. Study procedures will comply with International and U.S. requirements for 
human participant protections. Consent forms will be approved by Institutional Review Boards at 
OHSU and HMU, and by the Vietnam Ministry of Health Ethics Review. All consent forms will be 
presented to candidates in Vietnamese and will be administered by Vietnamese-speaking 
research staff.  
 
There are four consents used in this study:  
1. Pilot testing of study measurements 
2. Pre-Screening  
3. Full Study 
4. Qualitative Interviews (participants, family members, providers and administrators (staff)) 
 
 
 
 

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Compensation 
All participants will be compensated for their time and effort in this study, using culturally-
appropriate amounts. All compensation will be in cash and provided at the end of each visit so 
no pro-rating will be necessary. The following schedule will be used. 
 
Table 1. Compensation Schedule 
Visit 
Amount in Vietnamese Dong 
Amount in American Dollars 
(approximate as of October 2016) 
Pre-Screening 
50,000₫ 
$2.24 
Screening 
200,000₫ 
$8.97 
Baseline 
200,000₫ 
$8.97 
3 Month  
250,000₫ 
$11.21 
6 Month  
300,000₫ 
$13.46 
9 Month 
350,000₫ 
$15.7 
12 Month 
450,000₫ 
$20.19 
TOTAL 
1,800,000₫ 
$80.70 
 
Those who participate in pilot testing receive a one-time amount of 100,000₫. Those who 
participate in the qualitative interviews will receive 200,000₫ for each interview.  
 
Travel reimbursement will be provided for research visits only (not medication induction or other 
medication dispensing visits) at the rate of 3,000₫ per kilometer.  
 
Participants will not pay for the following research-associated laboratory testing:  
 
Screening: CBC, AST/ALT, CD4 
 
Baseline: Hepatitis B, Hepatitis C, tuberculosis screening (PPD test), HIV viral 
load, HIV confirmatory testing when only rapid test results available, HIV 
genotype resistance for participants on ART and who have viral loads > 200. 
 
6 Month: CD4 and HIV viral load 
 
12 Month: CD4, HIV viral load, HIV genotype resistance for participants on ART 
and who have viral loads > 200 
 
Referral Compensation 
 
Participants can refer individuals to the study, and upon successful completion of 
randomization, receive 100,000₫. 
 
Community outreach groups (peer educators, self-help, etc) can refer individuals to the 
study, and upon successful completion of randomization, receive 300,000₫. Outreach 
workers will receive 50,000 for each person pre-screened, regardless of randomization. 
 
Insurance Payments 
Beginning January 1st, 2017, the government of Vietnam is requiring health insurance for HIV-
infected patients. For those unable to obtain other insurance, the study will pay for insurance 
premiums while they are enrolled in the study. This will be coordinated with Hanoi Medical 
University and Hanoi PAC (Provincial AIDS Center) and payments will be directly made to the 
insurance companies, not to participants. Currently, this is expected to cost about 680,000 VND 
($30 US dollars) per year but could be change per national or local policy. Without the study 
paying for insurance, some participants would likely become ineligible to receive antiretroviral 
therapy, thus biasing the study’s secondary outcomes as well as jeopardizing retention rates.  
 

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Randomization 
Participants are randomized to clinic-based BUP/NX vs. referral for MMT. This is a non-blinded 
study. Randomization will be conducted by computer generated random number sequence in 
blocks of 10 prepared by statisticians at OHSU. Allocation assignments will be maintained in 
sealed, sequentially numbered envelopes by the Vietnam Research Coordinating Center (RCC) 
at Hanoi Medical University. HIV clinic site research assistants will call the RCC to receive 
allocation assignment when a participant is deemed eligible for study participation.  
 
Pilot Data Collection and Assessments 
The data collection instruments were pilot-tested with participants at four additional sites: Bac 
Giang PAC OPC; Bac Giang Provincial Hospital OPC; Viet Tri, Phu Tho PAC OPC; and Phu 
Tho Town Community Health Center OPC. 
 
 
 
 

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Table 2: Table of Assessments 
 
Pre-Screening 
Screening 
Baseline 
3 Month 
6 Month 
9 Month 
12 Month 
As 
Needed 
Only 
Visit Window 
-- 
60 days after Pre-
Screening 
+/- 14 
days 
 
+/- 14 
days 
+/- 14 
days 
-14 
days/+30 
days 
-- 
Pre-Screening Consent 
Form 
X 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Informed Consent Quiz 
 
X 
 
 
 
 
 
 
Progress Note 
 
X 
X 
X 
X 
X 
X 
X 
Visit Checklist 
X 
X 
X 
X 
X 
X 
X 
 
Locator Form 
X 
X 
X 
X 
X 
X 
X 
 
Master Enrollment Log 
X 
X 
X 
 
 
 
 
 
Communication Log 
 
 
 
 
 
 
 
X 
Compensation 
 
Log 
 
Receipt 
 
X 
X 
X 
X 
X 
X 
 
Data Collection Forms 
Inclusion/Exclusion Criteria 
(Eligibility Checklist) 
 
 
X 
 
 
 
 
 
Pre-Screening Survey 
X 
 
 
 
 
 
 
 
Screening Survey 
 
X 
 
 
 
 
 
 
Baseline Survey 
 
 
X 
 
 
 
 
 
3 Month Survey 
 
 
 
X 
 
 
 
 
6 Month Survey 
 
 
 
 
X 
 
 
 
9 Month Survey 
 
 
 
 
 
X 
 
 
12 Month Survey 
 
 
 
 
 
 
X 
 
ASI-lite Table 
 
 
X 
X 
X 
X 
X 
 
Randomization Form 
 
 
X 
 
 
 
 
 
Physical Exam 
 
 
X 
 
 
 
 
 
Dosing Form 
 
BUP/NX 
 
MMT 
 
 
 
X 
X 
X 
X 
 
HIV Care Utilization Form 
 
 
 
X 
X 
X 
X 
 
Fatal Overdose Form 
 
 
 
 
 
 
 
X 

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Table 2: Table of Assessments 
 
Pre-Screening 
Screening 
Baseline 
3 Month 
6 Month 
9 Month 
12 Month 
As 
Needed 
Only 
Pregnancy and Birth Control 
Assessment 
 
Includes Urine Test 
 
X 
X 
X 
X 
X 
X 
 
Confirmed Pregnancy Test 
 
 
 
 
 
 
 
X 
Early End of BUP/NX 
 
 
 
 
 
 
 
X 
HIV Viral Load 
 
 
X 
 
X 
 
X 
 
CD4* 
 
X* 
 
 
X* 
 
X* 
 
HIV genotype resistance 
testing (as necessary) 
 
 
X 
 
 
 
X 
 
HIV confirmatory testing (as 
necessary) 
 
X 
 
 
 
 
 
 
HIV rapid testing 
X 
 
 
 
 
 
 
 
Tuberculosis (PPD Skin 
Test)* 
 
 
X* 
 
 
 
 
 
Hepatitis B/C* 
 
 
X* 
 
 
 
 
 
Safety Labs* 
 
CBC 
 
AST/ALT 
 
 
 
X* 
 
 
 
 
 
 
UDS 
 
Morphine 
 
Methadone 
 
Methamphetamine 
 
Amphetamine 
 
Buprenorphine 
X 
X 
 
X 
X 
X 
X 
 
Adverse Events 
 
Paper Log 
 
eCRF 
 
Serious Adverse Events 
eCRF 
 
 
 
 
 
 
 
X 
Protocol Deviation 
 
Paper Log 
 
eCRF 
 
 
 
 
 
 
 
X 

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Table 2: Table of Assessments 
 
Pre-Screening 
Screening 
Baseline 
3 Month 
6 Month 
9 Month 
12 Month 
As 
Needed 
Only 
Study Termination Form 
 
 
 
 
 
 
X 
X (if ppt 
ends early) 
*chart abstraction possible       
 

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Visit Procedures 
Survey Data 
Research assistants will administer participant surveys in a confidential setting using real-time, 
secure, web-based electronic data entry. All survey measures have been translated into 
Vietnamese and been field tested and adapted for cultural appropriateness and feasibility for 
electronic data collection in Vietnam during previous research.  
 
Survey data measurements include:  
 
Demographics 
 
Drug and alcohol use 
 
Addiction treatment 
 
HIV treatment 
 
Co-morbid conditions including physical and mental health  
 
Quality of life 
 
Medical Chart Data 
Research assistants will review participant HIV clinic and MMT medical charts quarterly to 
inform outcome measures including receipt of ART, retention in care, and adherence to study 
treatment condition (buprenorphine, methadone dosing, counseling visits). Medical charts will 
be reviewed at Baseline to establish diagnoses of Hepatitis B, Hepatitis C, and Tuberculosis. If 
not available in medical chart, research staff will obtain testing as necessary.  
 
Biologic Data  
Urine samples for pregnancy and urine drug screens (morphine, methamphetamine, 
methadone, amphetamine, buprenorphine) will be collected and processed in the HIV clinic 
using point of care testing.  
 
Viral load specimens will be drawn at baseline, 6, and 12 months, and processed for transport 
at HIV clinic, then transported to the National Hospital for Tropical Disease for centralized lab 
testing. HIV viral load testing (the primary outcome) is performed with Real-time RT-PCR on 
Real-time ABI 7500 machine with reagents and primers made by Invitrogen.110 The current viral 
load technique is certified for a lower limit of HIV-1 RNA detection of 55 copies/mL.  
 
All other phlebotomy measurements (Safety Labs, and CD4) will be either drawn at the 
appropriate times following the above schedule or will be chart-abstracted as required. They will 
be drawn and processed for analysis at the HIV clinic locally.  
 
Study physicians will conduct baseline physical exams to assess for medical appropriateness 
for participation.  
 
Qualitative Data 
Annual in-depth interviews with a purposefully-driven sample of participants, family members, 
providers, and administrators will be conducted by research assistants in years 1-4. During 
annual site visits (years 1-4), we will conduct audio-recorded qualitative interviews with: 
1. Providers (n=5 per site) including HIV clinic physicians, nurses, counselors, and 
pharmacists responsible for the care of participants at the clinic and for referral and 
treatment for substance use disorders 
2. Administrators (n=2 per site)  who lead the clinics and local HIV prevention authorities, 
3. Participants (n=10 per site, five per randomization arm) to document their experience 
with care. 

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4. Family Members (n=10 per site), identified as a support person by the participant   
 
Site visits observe practices for BUP/NX clinical procedures, counseling, and referrals for MMT. 
The study team will complete site visits each year (years 1-4) completing approximately 68 
interviews per year across all four sites. Interview guides use the Consolidated Framework 
Implementation Research (CFIR) framework to probe participant perceptions of the 
characteristics of the BUP/NX and referral (e.g., intervention quality, advantage, adaptability), 
outer setting (e.g., resources, external policies and incentives), inner setting (e.g., clinic 
organization, networks and communication, practice culture, and implementation climate), 
provider characteristics (e.g., knowledge and beliefs about BUP/NX and substance abuse and 
self-efficacy) and the implementation process (e.g., engaging, executing, evaluating).43-44 Not all 
questions will be asked of all informants based on interview responses. Interview guides are 
meant to guide the conversation.    
 
Randomization Arms 
Clinic-based BUP/NX   
HIV clinic providers and staff will be trained in BUP/NX management of opioid dependence. 
Participants randomized to clinic-based BUP/NX will be evaluated by the HIV clinic study 
physician for symptoms and signs of withdrawal using clinically available opioid withdrawal 
scales and induced onto BUP/NX when in moderate withdrawal in order to avoid precipitated 
withdrawal (12-24 hours after last dose of short-acting opiates like heroin, and 2-4 days after 
last dose of long-acting opioids. BUP/NX induction begins with a 2-4 mg test dose followed by 
additional doses on the day of induction to relieve withdrawal symptoms, and then titrated to a 
maintenance dose between 8-24 mg/day over 1 to 3 days. Participants will return for daily 
dosing until a stable maintenance dose is reached, as determined clinically by the HIV clinic 
study physician. Dosing will remain flexible to a maximum dose of 24mg. After a participant is 
stabilized on a maintenance daily dose for at least 2 weeks, they may switch to every-other-day 
dosing (4 times per week), doubling the maintenance dose to a maximum of 32mg prior to “skip” 
days. Participants will continue to receive BUP/NX for 12 months, followed by a 14-day taper 
and referral to MMT. The study will use BUP/NX in a 4:1 ratio combination sublingual tablet for 
treatment of opioid dependence.  
 
Referral for MMT 
Referral for MMT has become the standard of care for opioid dependence in Vietnam. 
Participants randomized to MMT referral will meet with an HIV clinic case manager who will 
facilitate referral to MMT. Methadone dosing will be managed by MMT staff, who dispense 
methadone according to Ministry of Health guidelines for MMT.98 
 
Study sites and dosing sites 
Participants will complete all research activities (consenting, surveys, and other data collection 
activities) at the six HIV clinics. Two HIV clinics (Tu Liem clinic and Long Bien clinic) will serve 
only as clinical management and medication dispensing sites, with non-medication study 
procedures being performed by Vietnam Research Coordinating Center (HMU) research staff.  
 
If a participant becomes unable to travel to the study clinic because of serious illness or injury, 
study staff or appointed clinic staff will be allowed to distribute buprenorphine as needed to 
ensure continued substance abuse treatment. Hospital or home dosing must continue to be 
approved on a case-by-case basis by the Principal Investigator to ensure clinical safety. 
Approval will also only be on a case-by-case basis to ensure that non-clinic dosing is only being 
used in the most serious of cases when there is no other option for a participant to remain on 
study drug. Current national buprenorphine guidelines allow for take-home dosing for those 

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unable to travel to clinic. Study staff will maintain current drug accountability procedures 
including completion of dosing logs and pill counts.  
 

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Risks and Benefits 
Risks 
In addition to the risks associated with the study medication (either arm), there are several 
general risks associated with participating in a clinical trial.  
 
Risk of Underlying Conditions 
Each of the participating HIV clinic research sites have established practices for managing 
medical emergencies, and the study staff will continue to utilize these procedures. Treatment 
providers at each research site will be responsible for monitoring participants for possible 
clinical deterioration or other problems, and for implementing appropriate courses of action. As 
this population will have significant ongoing health and substance use issues, events related to 
complications of HIV, substance use treatment or admission for substance detoxification, 
hospitalizations for medical and psychological reasons and deaths will be captured on study 
specific forms and not duplicate reported as an adverse or serious adverse event. These data 
will still be included in the reports to the DSMB at the regular meetings. 
 
Risks to Confidentiality 
There are also risks to confidentiality, particularly because information will be collected about 
substance use and abuse and other potentially illegal activities.  
 
Phlebotomy Risks  
Blood drawing may cause pain or bruising at the site and carries a small risk of infection. 
 
Buprenorphine/Naloxone 
The study will use BUP/NX in a 4:1 ratio combination sublingual tablet for treatment of opioid 
dependence. Potential adverse events related to BUP/NX include: death, which has been 
reported among people who abuse BUP in combination with benzodiazepines and other drugs; 
withdrawal, if BUP is taken while actively taking methadone or various other opioids; increased 
risk of opioid dependence with continued use of heroin or other opioids; and possible 
impairment of mental or physical abilities for at least 6 hours after taking BUP. 
 
Because it is a partial opioid agonist, BUP/NX has limited respiratory depressant effects, low 
toxicity even at high doses, and limited risk of overdose. At sufficient doses, BUP/NX blocks the 
effects of exogenous opioids and can both reduce illicit use and afford some level of protection 
against overdose. BUP/NX has abuse potential, though in contrast to full agonists like 
methadone, this is limited, likely also a consequence of partial agonist properties. 
Buprenorphine itself may cause physical dependence. It can also cause intoxication and mild 
respiratory depression, as evidenced by possible drowsiness and breathing that is slower and 
shallower. 
 
Common side effects from BUP may include headache, constipation, difficulty sleeping, 
weakness, sleepiness, nausea, vomiting, sweating, and dizziness. Elevated liver enzyme levels 
have been reported in participants with hepatitis who are treated with buprenorphine. 
 
If the participant attempts to dissolve and inject BUP, he/she may experience opioid withdrawal 
symptoms, including nausea, diarrhea, hot and cold sweats, hot flashes, muscle cramps, 
flushing, painful joints, yawning, restlessness, watery eyes, runny nose, chills, gooseflesh, 
sneezing, abdominal cramps, irritability, backache, tension and jitteriness, depression, 
sleepiness, shaking or tremor, sensitivity to noise, clammy or damp skin, or other unpleasant 

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effects. Use of other opioids while receiving the BUP tablet could also result in opioid withdrawal 
symptoms. 
 
Though BUP/NX is metabolized by cytochrome P-450 3A4, a prime pathway for antiretroviral 
metabolism, clinically significant drug-drug interactions with HIV or TB-related treatments are 
rare. Known P450 inhibitors such as erythromycin, ketoconazole, and the HIV protease inhibitor 
atazanavir can increase BUP levels. Despite this, there was no difference in mean BUP/NX 
dose and no episodes of over-sedation among the BHIVES clinical trial participants taking 
atazanavir versus a non-atazanavir regimen after 12 months of follow-up. Inducers include 
phenobarbital, carbamazepine, and phenytoin which could reduce BUP levels and lead to 
withdrawal symptoms though this has not been observed clinically, likely because the BUP 
metabolite nor-BUP also has partial agonist effects at the mu receptor. 
 
Methadone 
Methadone differs pharmacologically from BUP/NX in that it is a long-acting full agonist at the 
mu opioid receptor that produces cross-tolerance to superimposed opiates (e.g., heroin). As a 
full agonist, however, there is no clear ceiling effect to its respiratory suppressive effects and 
thus can cause overdose in opiate naïve people or when the rapidity of dose increase exceeds 
tolerance. To mitigate the risks of methadone exposure to opiate naïve individuals, methadone 
is highly regulated and directly observed daily dosing is required. 
 
Methadone has multiple clinically significant drug-drug interactions with ART and medications 
used for treatment of tuberculosis. Methadone decreases clearance of zidovudine which can 
lead to increased zidovudine toxicity (e.g., anemia). Other commonly prescribed ART increase 
methadone metabolism (e.g., efavirenz, nevirapine, and lopinavir/ritonavir), potentially requiring 
high doses of methadone to relieve withdrawal symptoms, and requiring methadone dose 
tapering to prevent unintentional overdose when ART is stopped. Nearly all HIV-infected 
participants in Vietnam are prescribed at least one ART medication that requires methadone 
dose adjustments. Rifampin, an anti-tuberculosis agent commonly prescribed in Vietnam, 
decreases methadone levels and may require increased methadone doses to avoid withdrawal 
symptoms. 
 
Potential Benefits  
Participants may benefit from participation in the proposed study by engaging in treatment for 
both HIV and opioid dependence. Both buprenorphine and methadone have a strong history of 
improving opioid dependence outcomes across many studies, worldwide. Individual findings 
may be helpful in participants’ clinical care if they wish the data to be shared with their clinicians. 
Involvement in the study may positively affect the chances of abstinence. 
 
 
Data Analysis 
Aim 1: Assess the effect of clinic-based BUP/NX (n=225) versus MMT referral (n=225) on HIV 
treatment engagement and outcomes in HIV-infected participants with opioid dependence. 
 
H1a: Participants randomized to BUP/NX will have noninferior rates of HIV viral suppression 
(HIV-1 RNA < 200 copies/mL) on 12 month blood draw compared with MMT referral. 
 
 
H1b: Participants randomized to BUP/NX will have greater ART initiation, adherence, and 
retention in HIV care at 12 months versus MMT referral. 
 

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Overview. Aim 1 assesses the effect of clinic-based BUP/NX on HIV treatment engagement and 
outcomes using the study procedures outlined in the Study Design and Procedures section.  
 
Dependent variables: The primary outcome for Aim 1 is HIV viral suppression at 12 months (lab 
data, binary). HIV viral suppression is defined as an HIV-1 RNA PCR test < 200 copies/mL, 
using the ultra-sensitive HIV real-time PCR assay available at the NHTD laboratory, consistent 
with current U.S. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and 
Adolescents.35 The rationale for this definition is to avoid the influence of “blips” in HIV RNA viral 
load which commonly occur at levels between 20 and 200 copies/mL using current PCR assays 
and which are of limited clinical significance 132-133. Secondary outcomes for Aim 1 include ART 
initiation at 12 months (binary, chart review); 100% ART adherence at 12 months (binary, self-
report), and retention in HIV care at 12 months (binary, chart review). 
 
Potential Covariates: We will consider participant demographics, alcohol and other drug use, 
HIV history, comorbid conditions, attitudes toward treatment services, and social support 
characteristics as potential covariates.  
 
Power Analysis: This study was initially conceived and powered as a superiority trial. Based on 
a desire to augment the existing treatment options rather than justify a preferred 
pharmacotherapy, the design was revised with approval from the study sponsor (see attached 
approval letter from sponsor). For reference, the original power analysis is below: 
 
Sample size calculations are based on the Aim 1 primary outcome of HIV viral 
suppression (HIV-1 RNA < 200 copies/mL). We estimate that 340 participants will be 
required (170 BUP/NX, 170 MMT) to detect a 15% difference in HIV viral suppression 
between the two study conditions at 12 months, assuming 80% power, alpha of .05, 
and a viral suppression of 50% in the referral for MMT group. We increase the sample 
size to 450 participants (225 BUP/NX, 225 MMT) to conservatively account for 
potential loss to follow-up of 20%. This sample size calculation is additionally 
conservative in that it does not account for multiple-time-point data that will be 
available from our longitudinal study. We favor a conservative estimate to off-set the 
complexity of our proposed mixed logistic model in the data analysis.  
 
Noninferiority Margin: For the primary outcome of viral suppression, we pre-specified a non-
inferiority margin of ≤13% in the risk difference (RD) comparing BUP to MMT. The noninferiority 
margin was selected based on margins ranging from 10% to 15% for noninferiority trials testing 
the effect of antiretrovirals on HIV viral suppression. After choosing the 13% margin, we 
conducted an informal survey of national HIV-addiction treatment experts who confirmed that it 
was clinically relevant and appropriate 
 
Data Analysis Plan: Univariate statistics will be used to describe participant characteristics and 
study outcomes using mean/SD for continuous variables and percentages for categorical 
variables. Independent samples T-tests will be used to test bivariate differences between the 
main independent variable (clinic-based BUP/NX versus MMT referral assignment) and baseline 
continuous variable participant characteristics (e.g., age, CD4 nadir, etc.). Chi-square/Fisher-
Exact test will be performed to assess differences between the main independent variable and 
categorical variables.  
 
The primary analysis for this study will be a mixed logistic regression model comparing BUP/NX 
versus MMT on viral suppression rates over time. Treatment comparisons will be performed 
under the Intent-to-Treat (ITT) criterion; participants will be analyzed in the arm to which they 

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were randomized regardless of subsequent events. In this mixed logistic model, each (binary) 
outcome serves as a dependent variable; treatment effect (BUP/NX versus MMT referral) and 
time effect (e.g., baseline, 6, and 12 months) will be considered main effects. An interaction 
between these two main effects, e.g., treatment*time, will be included in the model. Model-fitted, 
marginal risk and RD estimates will be obtained at each time by applying an inverse-logit 
transformation to coefficients from the logistic regression model, with standard errors estimated 
via the delta method. We will test the primary hypothesis of noninferiority by comparing the 
lower bound of a 95% confidence interval to the prespecified margin (i.e., 13%); if the lower 
confidence limit of the RD is greater than -13%, we will conclude that the BUP/NX is noninferior 
to MMT. The model will include subject-level random intercepts in order to account for repeated 
measurements within individuals. Attrition is unavoidable in a longitudinal study; in our study, we 
anticipate an attrition rate of 20%. The mixed model approach is a recommended strategy for 
handling missing data in clinical trials under the assumption that the data are missing at 
random. 
 
We will conduct three sensitivity analyses. First, we will assume data are missing not at random 
and use single imputation of unsuppressed for missing VL data. Participants who are lost to 
follow-up will be imputed as treatment failures (i.e., not suppressed). Death from any cause and 
dropout will also be considered equivalent to non-suppression for the purposes of this analysis. 
Second, we will use multiple imputation with Markov-Chain Monte Carlo methods and “auxiliary 
variables” (i.e., covariates that are not part of the main analysis, but may help predict data 
missingness) to address missing data. We will include covariates associated with missingness 
at any time-points (using a relaxed p-value of 0.2) as auxiliary variables in our multiple 
imputation model. Finally, for our third sensitivity analysis, we will conduct a per-protocol 
analysis among participants who received at least one dose of study medication in the 90 days 
before each visit. If sensitivity analysis results change the primary outcome findings, we will 
report the results alongside our main analysis. 
 
Secondary outcomes including binary ART initiation, ART adherence, and retention in HIV care 
will be analyzed using similar procedures. As these are superiority hypotheses, we will test them 
using two-tailed tests at an alpha level of .05.  
 
Aim 2: Assess effect of clinic-based BUP/NX versus MMT referral on opioid use in HIV-infected 
participants with opioid dependence. 
 
H2: We hypothesize that participants randomized to BUP/NX will have a lower proportion of 
positive assessments for opioid use (self-report + UDS) at 12 months versus MMT referral 
 
Overview. In Aim 2, we assess the effect of clinic-based BUP/NX on opioid use as measured by 
urine drug screens or any self-reported use in the last 30 days, assessed at 3, 6, 9, and 12 
months following randomization. 
 
Dependent variables. The primary dependent variable for Aim 2 will be the proportion of positive 
assessments for opioid use at 12 months, as measured by any self-reported opioid use or 
positive urine drug screen during the 12-month follow-up assessment (binary). We will consider 
secondary substance use outcomes including proportion of follow-up visits with a positive 
assessment for opioid use (proportion), and other illicit drug use (binary), and alcohol use 
(binary).   
 
Power Analysis: Since our primary outcome in this aim is opioid use, the power analysis is 
based on this outcome. With our proposed sample size (450 as the total, 225 for each treatment 
arm), we have gained the power of 91% to detect 15% in difference between the two groups at 

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the level of alpha 0.05, provided that the proportion of UDS positive for opioid at 12 months will 
be 65% for MMT referral. This power analysis is conservative due to not maximizing multiple-
time-point data from our longitudinal study. We anticipate the power is much higher to off-set the 
complexity of the mixed logistic model (adjusting for some covariates) we propose in the data 
analysis plan (see below). 
 
Data Analysis Plan: The primary (binary) outcome for Aim 2 is opioid use, collected at baseline, 
3, 6, 9, and 12 months. We will use an approach as in Aim 1.   
 
Aim 3: Assess BUP/NX implementation experience to inform national scale-up of clinic-based 
BUP/NX. 
 
Overview. We will conduct qualitative interviews with HIV providers, administrators, and opioid 
dependent participants, and their family members in participating HIV clinics annually during 
years 1 through 4 to document and describe formative implementation strategies, challenges, 
and best practices. Results inform policy-making for national scale-up of clinic-based BUP/NX in 
Vietnam. 
 
Qualitative Procedures and Analysis. The implementation aim documents the experience of 
providers and participants at clinics to further inform adoption of BUP/NX in Vietnam and guides 
planning efforts and policy-making. Data also monitor the performance of the sites and 
qualitative interviews provide critical detail for enhanced understanding of the findings from the 
trial (Aim 1 and 2). Using the Taxonomy of Mixed Method Designs 134-136, our design has a 
QUAN +Qual structure with simultaneous data collection and emphasis/weight placed on the 
quantitative efforts. The qualitative data provide complementary information to illuminate and 
expand the findings from Aims 1 and 2.    
 
The qualitative data (recurrent and salient themes extracted from interviews) document 
provider, organizational, and participant experiences over time to concurrently monitor clinic-
based BUP/NX and to examine these findings in parallel with outcomes data (i.e., opioid use, 
HIV viral suppression). The HIV clinics’ characteristics and provider attitudes (inner setting), as 
well as detail about the use of BUP/NX (intervention characteristics), and community 
awareness, linkage across service settings, and policy support (outer setting) help identify the 
full range of complex variables associated with implementation of clinic-based BUP/NX. This 
approach represents an innovative strategy to integrate available quantitative study results (Aim 
1 and 2) to examine the provider, participant, organizational, and policy-level changes that 
influence the uptake of BUP/NX in HIV clinics in Vietnam. Results are compared for 
convergence and the team examines concordance and discordance between study sites and 
across populations including providers, participants and administrators. Corresponding with the 
Consolidated Framework Implementation Research (CFIR) we identify individual, organizational 
and contextual characteristics that influence uptake of BUP/NX within the context of an RCT in 
HIV clinics in Vietnam.   
 
Qualitative Analysis. Data will be catalogued in a spreadsheet within one week of a site visit to 
assure that all files and documents have been collected. Field notes written on site are 
expanded and recorded electronically within 24 hours.137 Audio-recorded site visit interviews are 
professionally transcribed, reviewed and summarized. Transcriptions are password protected 
and stored on a secure network and uploaded into qualitative analysis software (Atlas.ti) which 
organizes data and facilitates coding and thematic analysis. The qualitative analysis will be 
completed in Vietnamese. Selected samples of the transcripts will be translated into English and 
sent to trained research staff so they can review and assist in developing codes. The qualitative 

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team creates a coding scheme, practices coding, and revises in an iterative group process that 
has been successfully implemented by the study team in other mixed-methods projects.47, 138-141 
Each transcript is coded and check-coding is completed with 20% of transcripts to ensure inter-
coder reliability. Selected texts for each code will be translated into English for review by the 
U.S. investigator. The analysis examines the implementation process and identifies specific 
characteristics that facilitate use of BUP/NX in HIV clinics within the framework of the RCT (Aim 
1 and 2). Iterative analyses assess convergence of CFIR participant, provider and 
organizational dimensions on study measures as well as the context of the policy subsystems, 
cross system interactions, and resource allocation. The team analyzes site visit products and 
identifies areas for additional data collection, assesses and ensures data quality, and produces 
summaries of findings shared with the Advisory Board to inform project implementation. A five 
phase strategy guides the analysis: describe themes, organize and structure data, connect 
codes and themes, corroborate and triangulate, and condense and summarize findings.142 
 
 
Privacy, Confidentiality, and Data Security 
Data will be stored in a manner intended to preserve participant confidentiality. All paper files 
that contain study data with PHI will be kept at the study sites in locked cabinets behind locked 
doors that only study staff have access to. Study files with names or other identifiers are kept in 
a separate locked cabinet than files with study data. The only file linking the unique identifier 
with the participant’s name is the Master Enrollment Log which is kept in separate locked 
cabinet than any study data. 
 
Data will be collected using the OHSU REDCap™ electronic data collection system. REDCap™ 
(Research Electronic Data Capture) is a secure, web-based database application designed to 
support traditional case report form data capture for research studies. Data files are securely 
maintained behind the OHSU firewall, and not shared with other institutions. REDCap™ also 
facilitates data quality assurance. 
 
Computers at each site connected to the internet will be used to collect data that is directly 
entered into the REDCap™ database. At no time is information stored on the study site 
computers. Only the PIs and and research staff will have access to study data. Each participant 
will have a unique participant ID number; participant names will not be included in the database. 
The PI will work with the study personnel to verify data accuracy via monthly internal data 
audits. 
 
Data and Safety Monitoring  
Safety monitoring will be performed by the study’s Scientific Advisory Board, who will oversee 
ongoing trial progress to assure protection of participants’ safety while maintaining that the 
study’s scientific goals are being met. The DSMB is responsible for conducting periodic reviews 
of accumulating safety and efficacy data. It will determine whether there is support for 
continuation of the trial, evidence that study procedures should be changed, or if the trial should 
be halted (for safety, efficacy, or recruitment or performance reasons). This process is intended 
to assure the IRBs, sponsor, and investigators that participants are provided with an accurate 
and ongoing risk evaluation when participating in research trials. 
 
Monitoring will begin with the initial review of the protocol during the study development process 
and continue throughout the study with meetings at least annually. Recommendations and 
reports from these reviews will be distributed to the site lead investigator for submission to their 
IRB. 

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The Study Coordinator will be responsible for reporting adverse events or unanticipated 
problems to the responsible PI within 24 hours, by telephone, for serious events (participant 
death, or breach of confidentiality). Other events or deviations are reportable to the PI by 
telephone or email within 5 working days of discovery. The PI will notify the IRB of reportable 
events according to IRB regulations. OHSU is the IRB of record and all reportable events will be 
submitted with the required timelines. HMU follows international standards for AEs and SEAs as 
set by the ICH.  
 
The Principal Investigator will review or provide consultation for each serious event as needed. 
These reviews will include an assessment of the severity and causality of the event to the study 
intervention (drug or therapy) or other study procedures. 
 
The study staff will be trained to monitor for and report Adverse Events and Serious Adverse 
Events. For the purposes of this study, all Serious Adverse Events will require reporting in the 
data system. Adverse Events that are determined to be Mild and Not Causally Related to Study 
Drug will not be reported in REDCap™ but will be tracked on a paper log at each site which the 
Quality Assurance monitors will review at all site visits.  
 
Local research assistants will be responsible for data collection. The PI and Quality Assurance 
Monitor will work with the study personnel to verify data accuracy via monthly internal data 
audits. 
 
See separate Data and Safety Monitoring Plan for more information.