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A Study Comparing Oral Buprenorphine and Injectable Buprenorphine for the Treatment of Opioid Use Disorder (VA-BRAVE)

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ClinicalTrials.gov Identifier: NCT04375033
Recruitment Status : Recruiting
First Posted : May 5, 2020
Last Update Posted : June 9, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief 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 900 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 C (HCV) testing results and risk behaviors, incarceration, quality of life, psychiatric symptoms of depression and posttraumatic stress disorder, housing status, and cost-effectiveness.

Condition or disease Intervention/treatment Phase
Opioid Use Disorder Drug: Sublingual buprenorphine with naloxone Drug: Injectable subcutaneous buprenorphine Phase 4

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: CSP #2014 - Comparative Effectiveness of Two Formulations of Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE)
Actual Study Start Date : November 3, 2020
Estimated Primary Completion Date : November 3, 2023
Estimated Study Completion Date : November 4, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sublingual Arm

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
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.

Experimental: Injectable Arm
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
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.




Primary Outcome Measures :
  1. Retention in Treatment Change [ Time Frame: Approximately every 4 weeks until the first period of missed prescription medication coverage lasting at least 4 weeks through week 52 ]
    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.

  2. Opioid Abstinence [ Time Frame: Approximately every 2 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase) ]
    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.


Secondary Outcome Measures :
  1. Accidental Opioid Poisoning (overdose) [ Time Frame: Approximately every 2 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase) ]
    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.

  2. Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) seroconversion [ Time Frame: Assessed at baseline, week 24, week 52 (active phase) and via EMR review for up to 10 years (passive phase) ]
    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.

  3. Quality of Life [ Time Frame: Assessed at baseline, weeks 12, 24, 36, and 52 ]
    Measure via the Veterans Rand-12, based on the 12-item Short Form Survey (SF12), a widely used measure of health-related quality of life. The VR-12 can be summarized resulting in a scale from 0 to 100, with higher scores indicating better quality of life.

  4. Healthcare and Service Utilization [ Time Frame: Assess from baseline approximately every 4 weeks through 52 weeks (active phase) and via EMR review for up to 10 years (passive phase) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • Meets 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
  • Has been taking a form of prescribed Medication-assisted treatment (MAT) continuously >30 days prior to time of consent
  • Has a history of significant adverse effects from buprenorphine and/or naloxone
  • Has experienced recent suicidal ideation that requires hospitalization.
  • Is unwilling or unable to provide consent
  • Meets criteria for sedative hypnotic use disorder based on the MINI (Sedative Hypnotic Use Disorder)
  • Has pending felony charges
  • 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, Liver function tests, kidney function tests, and CBC
  • Is determined unsuitable for study participation based on observed prolonged QTc interval on an electrocardiogram (EKG)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04375033


Contacts
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Contact: Cynthia R Davis, PhD (617) 483-5465 Cynthia.Davis8@va.gov
Contact: Melynn Nuite, RN BS CCRC (617) 232-9500 Melynn.Nuite@va.gov

Locations
Show Show 21 study locations
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Study Chair: Ismene L. Petrakis, MD VA Connecticut Healthcare System West Haven Campus, West Haven, CT
Study Chair: Sandra Ann Springer, MD VA Connecticut Healthcare System West Haven Campus, West Haven, CT
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT04375033    
Other Study ID Numbers: 2014
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: June 9, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by VA Office of Research and Development:
Buprenorphine
Veterans
Clinical Trial
Abstinence
Additional relevant MeSH terms:
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Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Buprenorphine
Naloxone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists