A Study Comparing Oral Buprenorphine and Injectable Buprenorphine for the Treatment of Opioid Use Disorder

Opioid Use Disorder Clinical Trial

— VA-BRAVE  

Official title:

CSP #2014 - Comparative Effectiveness of Two Formulations of Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04375033
• Other study ID #: 2014
• Status: Recruiting
• Phase: Phase 4
• Start date: November 3, 2020
• Est. completion date: November 4, 2025

Study information

• Verified date: February 2024
• Source: VA Office of Research and Development
• Contact: Avron Spiro, PhD MS
• Phone: (857) 364-2888
• Email: avron.spiro[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

VA-BRAVE will determine whether a 28-day long-acting injectable sub-cutaneous (in the belly area) formulation of buprenorphine at a target dose of 300mg is superior in retaining Veterans in opioid treatment and in sustaining opioid abstinence compared to the daily sublingual (under the tongue) buprenorphine formulation at a target dose of 16-24 mg (standard of care). This is an open-label, randomized, controlled trial including 952 Veterans with opioid use disorder (OUD) recruited over 3 years and followed actively for 52 weeks. There are a number of secondary objectives that will be studied as well and include: comorbid substance use, both non-fatal and fatal opioid overdose, HIV and Hepatitis B (HBV) and C (HCV) testing results and risk behaviors, incarceration, quality of life, psychiatric symptoms of depression and posttraumatic stress disorder, housing status, dental health and utilization, and cost-effectiveness.

Description:

CSP2014 is the first direct long-term comparison of monthly injectable versus daily SL buprenorphine. In addition to its impact on the care of Veterans, the results of VA-BRAVE will provide critical data to guide effective treatment of opioid use disorder throughout the United States. The CSP2014 study population is Veterans aged 18 years diagnosed with moderate to severe opioid use disorder (OUD)by Diagnostic and Statistical Manual (DSM)-5th edition criteria. Veterans must be entering a new episode of opioid use disorder care prior to study start. There are two primary outcomes that address key Veterans Health Administration (VHA) clinical issues related to opioid use disorder treatment. The first is retention on protocol-directed medication treatment (sublingual or injectable sub-cutaneous buprenorphine). The second primary outcome is opioid abstinence using the systematic Timeline Followback method of self-report and corresponding urine toxicology screens. VA-BRAVE includes a 52-week intervention and 52-week active assessment period, and up to a 10-year passive follow-up for the duration of the study. Participants are inducted on daily SL buprenorphine using SAMHSA guidelines and dosed upward for a target dose of 16-24 mg for 3 days (more than 3 days may be required if deemed clinically necessary; should not exceed 30 days). Once reaching the target dose, participants are randomized 1:1 and assigned to receive at each 28-day research visit either: 1) a 28-day take-home supply of SL buprenorphine, prescribed at the clinically determined dose, or 2) injectable sub-cutaneous buprenorphine administered in the clinic (target dose = 300mg; 100mg dose may be used for those who cannot tolerate 300mg). Participants also receive Medication Management intervention at these visits. Study visits for all participants occur at Weeks 1, 2, 3 and 4 post-randomization, and biweekly thereafter through Week 52. Self-reported abstinence and urine toxicology screens are obtained at biweekly visits. Following one year of active follow-up, administrative data will be used to follow participants for up to 10 years for early enrollees and up to 7 years for late enrollees. The recruitment expectation is 15 new participants per study year per study site. There will be 20 participating VA Medical Center sites.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 952
• Est. completion date: November 4, 2025
• Est. primary completion date: November 3, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has used opioids within 30 days prior to consent or within 30 days prior to entry into a supervised setting -- e.g., opioid use within the 30 days prior to recent (<30 days) incarceration, entry into a detoxification facility, or entry into an inpatient hospital setting
• Have started on MOUD via clinical induction on SL-BUP/NLX
• Meets DSM-5 criteria for moderate to severe OUD based on the Mini-International Neuropsychiatric Interview
• Referred to/seeking treatment for OUD and willing to accept "partial-agonist-based" therapy

Exclusion Criteria:

• Is a Veteran less than 18 years of age
• For Veterans of childbearing potential (a premenopausal person capable of becoming pregnant), pregnancy, breastfeeding, and/or failure to practice an effective method of birth control
• Taking a form of prescribed maintenance MOUD (e.g., methadone, buprenorphine or XR-NTX) continuously >30 days prior to consent.
• Taking a form of prescribed maintenance MOUD (e.g., methadone, buprenorphine or XR-NTX) continuously >45 days prior to randomization
• Has a history of significant adverse effects from buprenorphine and/or naloxone
• Has experienced (within the past 2 weeks) recent suicidal or homicidal ideation that requires acute treatment or hospitalization.
• Is unwilling or unable to provide consent
• Meets criteria for current (past month) DSM-5 severe sedative hypnotic use disorder based on the MINI SHUD module
• Is determined unsuitable for study participation based on the clinical judgement of the LSI or Co-I given results of a CIWA-Ar, physical exam, and/or liver or kidney function tests and/or blood tests
• Has any other medical, psychiatric, behavioral, or logistical condition which, in the judgement of the LSI or Co-I, makes it unlikely the participant can participate in or complete the 52-week active phase of the study
• Is actively participating in an interventional clinical trial for which a waiver of dual-enrollment with CSP#2014 has not been obtained

Related Conditions & MeSH terms

• Opioid Use Disorder
• Opioid-Related Disorders
• Substance-Related Disorders

Intervention

Drug:
• Sublingual buprenorphine with naloxone
The combination SL-containing buprenorphine contains naloxone in a ratio of 4:1 buprenorphine:naloxone. Participants will be given a 28-prescription at each 28-day visit.
• Injectable subcutaneous buprenorphine
Injectable buprenorphine consists of a depot injectable formulation in polymeric solution and releases buprenorphine over a 28-day (4-week) period by diffusion as the polymer biodegrades. The injection will be administered subcutaneously in the abdomen at each 28-day visit.

Locations

Country	Name	City	State
United States	Bay Pines VA Healthcare System, Pay Pines, FL	Bay Pines	Florida
United States	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts
United States	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio
United States	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas
United States	Dayton VA Medical Center, Dayton, OH	Dayton	Ohio
United States	North Florida/South Georgia Veterans Health System, Gainesville, FL	Gainesville	Florida
United States	Hampton VA Medical Center, Hampton, VA	Hampton	Virginia
United States	Huntington VA Medical Center, Huntington, WV	Huntington	West Virginia
United States	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California
United States	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin
United States	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota
United States	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California
United States	Philadelphia MultiService Center, Philadelphia, PA	Philadelphia	Pennsylvania
United States	Phoenix VA Health Care System, Phoenix, AZ	Phoenix	Arizona
United States	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania
United States	Providence VA Medical Center, Providence, RI	Providence	Rhode Island
United States	Salem VA Medical Center, Salem, VA	Salem	Virginia
United States	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah
United States	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California
United States	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington
United States	Tuscaloosa VA Medical Center, Tuscaloosa, AL	Tuscaloosa	Alabama
United States	CERC (VISN1, West Haven, CT)	West Haven	Connecticut
United States	VA Connecticut Healthcare System West Haven Campus, West Haven, CT	West Haven	Connecticut
United States	White River Junction VA Medical Center, White River Junction, VT	White River Junction	Vermont

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

References & Publications (1)

Petrakis I, Springer SA, Davis C, Ralevski E, Gu L, Lew R, Hermos J, Nuite M, Gordon AJ, Kosten TR, Nunes EV, Rosenheck R, Saxon AJ, Swift R, Goldberg A, Ringer R, Ferguson R. Rationale, design and methods of VA-BRAVE: a randomized comparative effectiveness trial of two formulations of buprenorphine for treatment of opioid use disorder in veterans. Addict Sci Clin Pract. 2022 Jan 31;17(1):6. doi: 10.1186/s13722-022-00286-6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Retention in Treatment Change	Measured by receipt of prescribed study drug (via prescription or admission) and assessed via local study team records. Retention-in-treatment is a highly sensitive indicator of effective treatment as discontinuation is strongly associated with recurrence of use to opioids and risk for accidental drug poisoning.	Approximately every 4 weeks until the first period of missed prescription medication coverage lasting at least 4 weeks through week 52
Primary	Opioid Abstinence	Measured by Timeline Followback (self-report measure of substance use) and urine toxicology free of opioids. Both Timeline Followback and urine toxicology must indicate non-use to indicate abstinence.	Approximately every 2 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase)
Secondary	Accidental Opioid Poisoning (overdose)	Self-reported non-fatal accidental opioid poisoning, hospital records, and CDC data on fatal accidental drug poisoning (by state) will be used to indicate fatal and non-fatal accidental opioid poisoning.	Approximately every 2 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase)
Secondary	Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) seroconversion	Assessment will indicate positive seroconversion for HIV, HBV, or HCV based on HIV-1 p24 antigen/antibody with reflex HIV RNA viral load, HBV sAB, sAG with reflex HBV viral load if HBV sAG positive only, and HCV AB with reflex HCV viral load. These tests are recommended as standard care for Veterans with OUD.	Assessed at baseline, week 24, week 52 (active phase) and via EMR review for up to 10 years (passive phase)
Secondary	Healthcare and Service Utilization	An indicator of healthcare and service utilization will be obtained using the Service Utilization Review Form (SURF) that assesses utilization of VHA inpatient and outpatient care clinics, SUD clinics, detoxification programs, and pharmacies located within the VHA and local hospitals. Participants' use of other treatments will be documented on the SURF; non-VA health services will also be captured using the SURF.	Assess from baseline approximately every 4 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase)
Secondary	Other Addictive Substances	Measured by Timeline Followback (self-report measure of substance use) and urine toxicology free of other addictive substances. Both Timeline Followback and urine toxicology must indicate non-use to indicate abstinence.	Approximately every 2 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase)
Secondary	Opioid Craving	Opioid craving will be measured on a 10-point Likert scale in response to the question "Please indicate how much you are craving opioids right now."	Approximately every 4 weeks through 52 weeks (active phase)
Secondary	HIV Sexual and Injection Risk Behaviors	HIV sexual and injection risk behaviors will be assessed using NIDA's HIV Risk Behavior tool.	Assessed at baseline, weeks 12, 24, 36, and 52
Secondary	Patient Health Questionnaire (PHQ-9)	A measure of depressive symptoms (overall) and suicidality (item 9)	Assessed at baseline, weeks 12, 24, 36, and 52
Secondary	PTSD Checklist for DSM-5	A measure of PTSD symptoms	Assessed at baseline, weeks 12, 24, 36, and 52
Secondary	Texas Christian University Criminal Justice Form	A measure of incarceration, arrests, criminal activity.	Assessed at baseline, weeks 12, 24, 36, and 52
Secondary	Dental Quality of Life Questionnaire	Self-report measure assessing oral/dental health and quality of life, salivary function, access to and use of dental healthcare.	Assessed at baseline, weeks 24 and 52