Extended-Release Naltrexone and Monthly Extended-Release Buprenorphine for Cocaine Use Disorder (CURB-2)
Study Details
Study Description
Brief Summary
This is an 8-week, double-blind, randomized placebo-controlled trial of the efficacy of a combination of extended-release naltrexone (XR-NTX) and extended-release buprenorphine (XR-BUP) compared to matched placebo injections (PBO-Inj) for the treatment of cocaine use disorder (CUD).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
The primary objective of this study is to assess the efficacy of XR-NTX plus XR-BUP as a combination pharmacotherapy for CUD. Approximately four hundred and twenty-six adults will be randomized into the study at 8-12 sites in the U.S. Eligibility will be determined during a maximum 21-day screening period. To document current ongoing cocaine use, participants must submit at least 2 urine samples positive for cocaine of a possible 3 tests to occur within a 10-day period during which clinic visits occur with at least 2 days between visits. In addition, participants must meet diagnostic criteria for moderate or severe CUD per DSM-5 (4 or more criteria) at screening. After screening/baseline is completed and eligibility is confirmed, participants will be randomized and begin the 1-week medication induction phase followed by the 8-week medication phase of the trial.
Participants will be randomized in a 1:1 ratio to either 1) XR-NTX + XR-BUP arm and receive injections of extended-release naltrexone (XR-NTX; as Vivitrol®) and extended-release buprenorphine (XR-BUP; as SublocadeTM), or to 2) PBO-Inj matching the timeline and delivery methods of injections for the XR-NTX + XR-BUP arm. XR-NTX or PBO-Inj injections will be provided on the day of randomization and in Weeks 3 and 6. XR-BUP or PBO-Inj injections will be provided on days 3-5 following randomization and in week 4. During the 1-week induction phase and the 8-week medication phase, participants will be asked to attend clinic twice weekly for collection of urine samples and to complete assessments as indicated on the schedule of assessments. Following the 8-week medication phase, participants will be asked to attend clinic weekly for the follow-up phase during Weeks 9-12.
Participants will be involved in the study for approximately 16 weeks, including a screening/baseline period of up to 3 weeks (i.e., 21 days), 1 week for randomization and medication induction, 8 weeks of medication, and 4 weeks of follow-up. The screening phase may differ by participant in the length of time needed to complete preliminary eligibility assessments. Confirmation of opioid-free status (urine drug screen) will take place after confirmation of eligibility and before randomization. Randomization and medication induction visit may take approximately 2 hours. Twice-weekly visits during the medication phase will range from about 20 to 90 minutes in length depending on scheduled assessments. Medication administration visits may require an additional 2 hours. Visits in the follow-up phase will take place approximately 30-60 minutes to complete. An 8-week medication period was selected based on expected time for group differences to emerge and for pragmatic issues related to medication dosing.
Enrollment is expected to take place over a period of approximately 13 months, with an approximate total of 16 months of study visits.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Drug intervention (XR-NTX+XR-BUP) The study intervention is three doses of 380mg XR-NTX (Weeks 0, 3 and 6) and two doses of 300mg XR-BUP (Weeks 0, 4). Drug: XR-NTX XR-NTX: 3 intramuscular injections administered Week 0, 3, 6. Other Names: Extended Release Injectable Naltrexone Arm: Experimental Drug: XR-BUP XR-BUP: 2 subcutaneous injections administered Week 0, 4. Other Names: Extended Release Injectable Buprenorphine Arm: Experimental |
Drug: Extended-Release Naltrexone
XR-NTX (Extended-Release Naltrexone) doses of 380mg (Weeks 0, 3 and 6) via intramuscular (IM) injections in the gluteus.
Other Names:
Drug: Extended Release Buprenorphine
Extended-Release buprenorphine (XR-BUP) two doses of 300mg XR-BUP (Weeks 0, 4) via subcutaneous injections in the abdomen. Option for 100mg at Weeks 3 and 6 (if needed to alleviate side effects).
Other Names:
|
| Placebo Comparator: Placebo Matched placebo injections (PBO-Inj) for the treatment of cocaine use disorder (CUD). Drug: Placebo (PLB) Injectable Placebo: 3 intramuscular injections administered Week 0, 3, 6. Other Names: Injectable matching (to XR-NTX) placebo Arm: Placebo Comparator - matched Placebo (PLB) Drug: Placebo (PLB) Injectable Placebo: 2 subcutaneous injections administered Week 0, 4. Other Names: Injectable matching (to XR-BUP) placebo Arm: Placebo Comparator - matched Placebo (PLB) |
Drug: Placebo (PLB) Injectable
3 doses of intramuscular injections (Week 0, 3, 6)
Other Names:
Drug: Placebo (PLB) Injectable
2 doses of subcutaneous injections (Week 0, 4)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Proportion of Cocaine-negative UDS [Week 5 up to Week 8]
The primary outcome measure is the proportion of cocaine-negative UDS obtained during Weeks 5 through 8 of the medication phase as measured for the XR-NTX + XR-BUP and PBO-Inj conditions. The primary outcome (UDS) has been chosen because it is an objective measure of cocaine use and was the outcome showing significant improvement over placebo in the original CURB trial.
Secondary Outcome Measures
- Number of participants who Self-report cocaine use [8 Weeks]
Self-report elicited through Timeline Followback (TLFB) on days of cocaine use during Weeks 0-8;
- Mean self reported cocaine craving score [8 Weeks]
Cocaine craving as measured by the Visual Analog Craving Scales (VAS) during Weeks 0-8. Possible scores range from 0 to 100, with higher scores indicating worse craving.
- Measures of safety (adverse events) [8 weeks]
Number and severity of adverse events reported during Weeks 0-8; Number and outcomes (non-fatal and fatal) of overdose events during Weeks 0-8
- Mean self reported overall functioning [Week 8]
Self-report overall functioning as measured by the Treatment Effectiveness Assessment (TEA) at Week 8. Possible scores range from 1 to 10 for each of the 4 domains, with higher scores indicating better outcome.
Eligibility Criteria
Criteria
Inclusion Criteria:
Individuals must meet all of the inclusion criteria in order to be eligible to participate in the study:
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Be 18 to 65 years of age;
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Be interested in reducing or stopping cocaine use;
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Meet DSM-5 criteria for moderate or severe CUD (4 or more criteria);
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Provide at least 2 urine samples positive for cocaine (out of a possible 3 samples) within a 10-day period collected over a maximum 21 days during screening with at least 2 days between visits;
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Self-report cocaine use on 18 or more days in the 30-day period prior to consent using the Timeline Follow-Back (TLFB);
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If female, agree to use acceptable birth control methods and have periodic urine pregnancy testing done during participation in the study unless unable to conceive (e.g., hysterectomy, post-menopause);
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Provide a urine sample negative for opioids and self-report no opioid use in the past 7 days on the TLFB and Prior and Concomitant Medications (PCM) assessment prior to XR-NTX induction;
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Be willing to comply with all study procedures and medication instructions.
Exclusion Criteria:
- Have a psychiatric condition that, in the judgement of the site medical clinician, would make study participation unsafe or which would prevent adherence to study procedures;
Examples include:
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Suicidal or homicidal ideation requiring immediate attention
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Severe inadequately-treated mental health disorder (e.g., active psychosis, uncontrolled bipolar disorder);
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Have evidence of second- or third-degree heart block, atrial fibrillation, atrial flutter, prolongation of the QTc, or any other finding on the screening electrocardiogram (ECG) that, in the opinion of the site medical clinician, would preclude safe participation in the study;
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Have a medical condition that, in the judgement of the site medical clinician, would make study participation unsafe or which would make treatment compliance difficult. Medical conditions that may compromise participant safety or study conduct include, but are not limited to, allergy/sensitivity to study medications or diluents and the following results on clinical labs assessed during baseline/screening:
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AST or ALT greater than 5 times the upper limit of normal
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Total bilirubin greater than 2 times the upper limit of normal
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Platelet count <100 x 103/μL
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Have a body habitus that precludes gluteal intramuscular injection of XR-NTX or abdominal SQ injection of XR-BUP in accordance with the administration equipment (needle) and procedures;
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Have been in a prior study of pharmacological or behavioral treatment for CUD within 6 months of study consent;
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Have taken an investigational drug in another study within 30 days of study consent;
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Have been prescribed and taken naltrexone or buprenorphine within 30 days of study consent;
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Be currently enrolled in formal treatment studies or addiction treatment services (behavioral or pharmacological);
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Be at significant clinical risk for development of serotonin syndrome with buprenorphine treatment as determined by the site medical clinician;
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Have a current pattern of alcohol, benzodiazepine, or other sedative hypnotic use which would preclude safe participation in the study as determined by the site medical clinician;
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Have a surgery planned or scheduled or otherwise medically require the use of opioid-containing medications (e.g., opioid analgesics) during the study period;
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Be currently in jail, prison or any inpatient overnight facility as required by court of law or have pending legal action or other situation (e.g., unstable living arrangements) in the judgement of the site investigator that could prevent participation in the study or in any study activities;
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If female, be currently pregnant, breastfeeding, or planning on conception;
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Have any condition for which, in the opinion of the site investigator or designee, study participation would not be in their best interest (including but not limited to cognitive impairment, unstable general medical condition, active psychosis) or that could prevent, limit, or confound the protocol-specified assessments.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- University of Texas Southwestern Medical Center
- National Institute on Drug Abuse (NIDA)
Investigators
- Principal Investigator: Madhukar Trivedi, MD, UT Southwestern Medical Center
- Study Director: Geoffrey Obel, DrPh, UT Southwestern Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
- Center for Behavioral Health Statistics and Quality. 2019 National Survey on Drug Use and Health (NSDUH): CAI Specifications for Programming (English Version). Substance Abuse and Mental Health Services Administration, editor. Rockville, MD; 2018.
- Czoty PW, Stoops WW, Rush CR. Evaluation of the "Pipeline" for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research. Pharmacol Rev. 2016 Jul;68(3):533-62. doi: 10.1124/pr.115.011668. Review.
- dela Cruz AM, Bernstein IH, Greer TL, Walker R, Rethorst CD, Grannemann B, Carmody T, Trivedi MH. Self-rated measure of pain frequency, intensity, and burden: psychometric properties of a new instrument for the assessment of pain. J Psychiatr Res. 2014 Dec;59:155-60. doi: 10.1016/j.jpsychires.2014.08.003. Epub 2014 Aug 27.
- Kariisa M, Scholl L, Wilson N, Seth P, Hoots B. Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential - United States, 2003-2017. MMWR Morb Mortal Wkly Rep. 2019 May 3;68(17):388-395. doi: 10.15585/mmwr.mm6817a3.
- Ling W, Farabee D, Liepa D, Wu LT. The Treatment Effectiveness Assessment (TEA): an efficient, patient-centered instrument for evaluating progress in recovery from addiction. Subst Abuse Rehabil. 2012 Jan 1;3(1):129-136.
- Ling W, Hillhouse MP, Saxon AJ, Mooney LJ, Thomas CM, Ang A, Matthews AG, Hasson A, Annon J, Sparenborg S, Liu DS, McCormack J, Church S, Swafford W, Drexler K, Schuman C, Ross S, Wiest K, Korthuis PT, Lawson W, Brigham GS, Knox PC, Dawes M, Rotrosen J. Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. Addiction. 2016 Aug;111(8):1416-27. doi: 10.1111/add.13375. Epub 2016 Apr 21.
- Nasser AF, Heidbreder C, Liu Y, Fudala PJ. Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers. Clin Pharmacokinet. 2015 Aug;54(8):837-49. doi: 10.1007/s40262-015-0238-6.
- Pettinati HM, Kampman KM, Lynch KG, Suh JJ, Dackis CA, Oslin DW, O'Brien CP. Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence. J Subst Abuse Treat. 2008 Jun;34(4):378-90. Epub 2007 Jul 30.
- Trivedi MH, Wisniewski SR, Morris DW, Fava M, Kurian BT, Gollan JK, Nierenberg AA, Warden D, Gaynes BN, Luther JF, Rush AJ. Concise Associated Symptoms Tracking scale: a brief self-report and clinician rating of symptoms associated with suicidality. J Clin Psychiatry. 2011 Jun;72(6):765-74. doi: 10.4088/JCP.11m06840.
- Whitfield TW Jr, Schlosburg JE, Wee S, Gould A, George O, Grant Y, Zamora-Martinez ER, Edwards S, Crawford E, Vendruscolo LF, Koob GF. κ Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake. J Neurosci. 2015 Mar 11;35(10):4296-305. doi: 10.1523/JNEUROSCI.1978-13.2015.
- Winhusen TM, Kropp F, Lindblad R, Douaihy A, Haynes L, Hodgkins C, Chartier K, Kampman KM, Sharma G, Lewis DF, VanVeldhuisen P, Theobald J, May J, Brigham GS. Multisite, randomized, double-blind, placebo-controlled pilot clinical trial to evaluate the efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. J Clin Psychiatry. 2014 Jul;75(7):757-64. doi: 10.4088/JCP.13m08862.
- STU-2021-0223
- UG1DA020024