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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: Sublingual buprenorphine with naloxone
* Drug: Injectable subcutaneous buprenorphine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sublingual Arm<br>The sublingual buprenorphine contains naloxone in a ratio of 4:1 and will be prescribed. Consistent with the SAMHSA TIP 40 guidelines 75, before SL-BUP/NLX is prescribed, participants will be evaluated for recent (within 24 hours) drug use and associated symptoms. The randomization dose will be determined based on the maintenance dose identified during the induction period, with a target dose of 16-24mg that is standard practice. While the target dose is 16-24mg, doses may go as low as 8mg as occasionally patients prefer lower doses. SL-BUP/NLX will be prescribed at the randomization visit (28-day supply), then every 4 weeks until week 48. | Drug: Sublingual buprenorphine with naloxone<br>* 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.<br>|
| Experimental: Injectable Arm<br>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. The target dose is 300mg, there is the option to use 100mg dose. The final study dose of injectable buprenorphine will be given at Week 48. | Drug: Injectable subcutaneous buprenorphine<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| Patient Health Questionnaire (PHQ-9) | A measure of depressive symptoms (overall) and suicidality (item 9) | Assessed at baseline, weeks 12, 24, 36, and 52 | 
| PTSD Checklist for DSM-5 | A measure of PTSD symptoms | Assessed at baseline, weeks 12, 24, 36, and 52 | 
| Texas Christian University Criminal Justice Form | A measure of incarceration, arrests, criminal activity. | Assessed at baseline, weeks 12, 24, 36, and 52 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Buprenorphine, Veterans, Clinical Trial, Abstinence