Clinical trial NCT02032433: Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment
Official title: CTN-0051: Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Opioid Use Disorder
Keywords: extended-release naltrexone (Vivitrol)
buprenorphine-naloxone (Suboxone)
comparative effective
relapse prevention
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
name: The Emmes Company, LLC
First posted: 2014-01-10
Enrollment: 570
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: CTN-0051 assesses the comparative effectiveness of extended release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery.

The study is conducted in 8 NIDA Clinical Trials Network affiliated community based treatment programs. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid).

The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e.., loss of persistent abstinence) during the 6-month trial. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, and (2) explore demographic and, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient).), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments.

Detailed description: For opioid-dependent patients in the U.S. and most of the rest of the world, detoxification or detoxification followed by short term residential treatment, with the goal of achieving long-term abstinence from opioid misuse is a mainstay of treatment. Nonetheless, the majority of patients treated in this way will relapse to opioid misuse, leading to a costly and ineffectual cycle of readmission for repeated detoxifications.

The overarching goal of CTN-0051 is to foster adoption of new relapse-prevention pharmacotherapies in community-based treatment programs (CTPs) where these could have a substantial public health impact. To this end CTN-0051 assesses the comparative effectiveness of extended release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery.

The study is conducted in 8 CTN-affiliated CTPs that provide or partner with detoxification services (inpatient/residential) which have the capacity to maintain participants opioid-free for approximately 3-7 days, have the capacity to provide medication-assisted therapy, and can provide a minimum of one group or individual counseling session per week during the 24-week treatment period. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid). To maximize generalizability, the point of randomization is flexible, from shortly after program admission until just prior to program discharge. A data analysis modification (assessment of whether the early vs. late randomizers have a differential treatment effect and if so, time to relapse will be estimated for early and late randomizers separately) will occur if differential treatment initiation is a problem for cases randomized prior to completing detoxification (i.e., significantly fewer early randomizers are able to complete detoxification and XR-NTX induction).

The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e., loss of persistent abstinence) during the 6-month trial. The primary outcome measure will be the time to the event, with the event called relapse. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, and (2) explore demographic and, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments.

Toward the end of the 24-week treatment period, participants are referred for follow-up care in the community (which could include pharmacotherapy if desired and available), and follow-up outcomes are assessed at week 28 and week 36 after randomization. For participants receiving BUP-NX, who do not wish to continue, or for whom community resources are not available, the study provides a two-week BUP-NX taper.

In an ancillary genetics study we plan to study functional variants in three genes (OPRM1, OPRK1 and PDYN), known to affect the dynamic response to opioid receptor ligands. These variants will be evaluated in CTN-0051 for their contribution to treatment retention, abstinence, and depression. Blood collection for DNA extraction will occur at the same time that blood is collected for medical safety and liver function evaluation, precluding the need for an additional needle-stick. Coded blood samples for the genetics studies will be sent to the NIDA Center for Genetics Repository.

Eligibility criteria: Inclusion Criteria

* Male or female
* 18 years of age and older
* Meet DSM-5 criteria for opioid-use disorder (heroin and/or prescription opioids)
* Have used opioids other than as specifically prescribed within thirty days prior to consent
* Seeking treatment for opioid dependence and willing to accept "agonist-based" or "antagonist-based" therapy
* In good-enough general health, as determined by the study physician on the basis of medical history, review of systems, physical exam and laboratory assessments, to permit treatment with XR-NTX or BUP-NX
* Able to provide written informed consent
* Able to speak English sufficiently to understand the study procedures and provide written informed consent to participate in the study
* If female of childbearing potential, be willing to practice an effective method of birth control for the duration of participation in the study

Exclusion Criteria

* Serious medical, psychiatric or substance use disorder that, in the opinion of the study physician, would make study participation hazardous to the participant, or compromise study findings or would prevent the participant from completing the study. Examples include:

  1. Disabling or terminal medical illness (e.g., uncompensated heart failure, cirrhosis or end-stage liver disease) as assessed by medical history, review of systems, physical exam and/or laboratory assessments;
  2. Severe, untreated or inadequately treated mental disorder (e.g., active psychosis, uncontrolled manic-depressive illness) as assessed by history and/or clinical interview;
  3. Current severe alcohol, benzodiazepine, or other depressant or sedative hypnotic use likely to require a complicated medical detoxification (routine alcohol and sedative detoxifications may be included)
* LFTs (ALT, AST) greater than 5 times upper limit of normal
* Suicidal or homicidal ideation that requires immediate attention
* Known allergy or sensitivity to buprenorphine, naloxone, naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or other components of the Vivitrol® diluent
* Maintenance on methadone at doses of 30mg or greater at the time of signing consent
* Presence of pain of sufficient severity as to require ongoing pain management with opioids
* Pending legal action or other reasons that might prevent an individual from completing the study
* If female, currently pregnant or breastfeeding, or planning on conception
* Body habitus that, in the judgment of the study physician, precludes safe intramuscular injection of XR-NTX (e.g., BMI\>40, excess fat tissue over the buttocks, emaciation)

Primary outcomes:
measure: Time to Relapse (Intent to Treat Population)
timeFrame: Weeks 3-24
measure: Time to Relapse (Per Protocol Population)
timeFrame: Weeks 3-24
Secondary outcomes:
measure: Number Successfully Inducted Onto Assigned Study Medication
timeFrame: Weeks 0-24
measure: Adverse Events Related to Study Medications
timeFrame: Weeks 0-36
measure: Opioid Abstinence Over Time While on Study Medication (Subjective)
timeFrame: Weeks 0-24
measure: Alcohol Use Over Time, Drinks Per Day, Past 30 Days, W0
timeFrame: Week 0
measure: Cigarette Smoking, W0, 10 or Less
timeFrame: Week 0
measure: Opioid Craving Over Time W0
timeFrame: Week 0
measure: Score of Subacute Withdrawal Symptoms Subscale Within Hamilton Depression (HAM-D) Rating Scale
timeFrame: Week 0
measure: Score of Alcohol Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 0
measure: Score of Sexual Behavior Subscale Within HIV Risk-Taking Behavior Scale (HRBS)
timeFrame: Week 0
measure: Score on Trail Making Test Part A
timeFrame: Week 0
measure: Opioid Abstinence Over Time While on Study Medication (Objective)
timeFrame: Weeks 0-24
measure: Cigarette Smoking, W0 0
timeFrame: Week 0
measure: Cigarette Smoking, W0 11-20
timeFrame: Week 0
measure: Cigarette Smoking, W0 21-30
timeFrame: Week 0
measure: Cigarette Smoking, W0 31 or More
timeFrame: Week 0
measure: Cigarette Smoking, W24 0
timeFrame: Week 24
measure: Cigarette Smoking
timeFrame: Week 24
measure: Cigarette Smoking, W24 11-20
timeFrame: Week 24
measure: Cigarette Smoking, W24 21-30
timeFrame: Week 24
measure: Cigarette Smoking, W24 31 or More
timeFrame: Week 24
measure: Score on Opioid Craving Scale (OCS)
timeFrame: Week 24
measure: Score of Subacute Withdrawal Symptoms Subscale Within Hamilton Depression (HAM-D) Rating Scale
timeFrame: Week 24
measure: Score on Subjective Opiate Withdrawal Scale (SOWS)
timeFrame: Week 0
measure: Score on Subjective Opiate Withdrawal Scale (SOWS)
timeFrame: Week 24
measure: Score of Sexual Behavior Subscale Within HIV Risk-Taking Behavior Scale (HRBS)
timeFrame: Week 24
measure: Score of Condom Use Subscale Within HIV Risk-Taking Behavior Scale (HRBS)
timeFrame: Week 0
measure: Score of Condom Use Subscale Within HIV Risk-Taking Behavior Scale (HRBS)
timeFrame: Week 24
measure: Score on Trail Making Test Part A
timeFrame: Week 24
measure: Score on Trail Making Test Part B
timeFrame: Week 0
measure: Score on Trail Making Test Part B
timeFrame: Week 24
measure: Score on Word Card of Stoop Test
timeFrame: Week 0
measure: Score on Word Card of Stoop Test
timeFrame: Week 24
measure: Score on Color Card of Stoop Test
timeFrame: Week 0
measure: Score on Color Card of Stoop Test
timeFrame: Week 24
measure: Score on Color Word Card of Stoop Test
timeFrame: Week 0
measure: Score on Color Word Card of Stoop Test
timeFrame: Week 24
measure: Score of Alcohol Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 24
measure: Score of Drug Use Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 0
measure: Score of Drug Use Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 24
measure: Score of Social Relationship Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 0
measure: Score of Family / Social Relationship Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 24
measure: Score of Legal Status Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 0
measure: Score of Legal Status Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 24
measure: Score of Medical Status Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 0
measure: Score of Medical Status Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 24
measure: Score of Psychiatric Status Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 0
measure: Score of Psychiatric Status Subscale Within Addiction Severity Index (ASI) Scale
timeFrame: Week 24
measure: Score on EuroQOL EQ-5D Questionnaire
timeFrame: Week 0
measure: Score on EuroQOL EQ-5D Questionnaire
timeFrame: Week 24
measure: Alcohol Use Over Time, Drinks Per Day
timeFrame: Week 24
measure: Other Drug Use Over Time, Cannabis, W0
timeFrame: week 0
measure: Other Drug Use Over Time, Cannabis, W24
timeFrame: week 24
measure: Other Drug Use Over Time, Cocaine, W0
timeFrame: week 0
measure: Other Drug Use Over Time, Cocaine, W24
timeFrame: week 24
measure: Other Drug Use Over Time, Stimulant, W0
timeFrame: week 0
measure: Other Drug Use Over Time, Stimulant, W24
timeFrame: week 24
Other outcomes:
Locations:
city: Tarzana
country: United States
facility: Tarzana Treatment Centers
state: California
city: Jacksonville
country: United States
facility: Gateway Community Services, Inc.
state: Florida
city: Rockville
country: United States
facility: Avery Road Treatment Center
state: Maryland
city: Fall River
country: United States
facility: Stanley Street Treatment and Resources
state: Massachusetts
city: Albuquerque
country: United States
facility: Turquoise Lodge Hospital
state: New Mexico
city: New York
country: United States
facility: Bellevue Hospital Center
state: New York
city: Columbus
country: United States
facility: Maryhaven
state: Ohio
city: Seattle
country: United States
facility: Evergreen Treatment Services
state: Washington
Study officials:
affiliation: NYU Langone Health
name: John Rotrosen, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Tsui JI, Campbell ANC, Pavlicova M, Choo TH, Lee JD, Cook RR, Shulman M, Nunes EV, Rotrosen J. Methamphetamine/amphetamine use over time among persons with opioid use disorders treated with buprenorphine/naloxone versus extended-release naltrexone. Drug Alcohol Depend. 2022 Jul 1;236:109469. doi: 10.1016/j.drugalcdep.2022.109469. Epub 2022 Apr 21.
citation: Jelovac A, McLoughlin DM. Twelve-Month Outcomes for Remitters Following Electroconvulsive Therapy for Depression. J Clin Psychiatry. 2022 Apr 18;83(3):21lr14371. doi: 10.4088/JCP.21lr14371. No abstract available.
citation: Na PJ, Scodes J, Fishman M, Rotrosen J, Nunes EV. Co-occurring Depression and Suicidal Ideation in Opioid Use Disorder: Prevalence and Response During Treatment With Buprenorphine-Naloxone and Injection Naltrexone. J Clin Psychiatry. 2022 Apr 18;83(3):21m14140. doi: 10.4088/JCP.21m14140.
citation: Rudolph KE, Shulman M, Fishman M, Diaz I, Rotrosen J, Nunes EV. Association between dynamic dose increases of buprenorphine for treatment of opioid use disorder and risk of relapse. Addiction. 2022 Mar;117(3):637-645. doi: 10.1111/add.15654. Epub 2021 Oct 1.
citation: Nunes EV Jr, Scodes JM, Pavlicova M, Lee JD, Novo P, Campbell ANC, Rotrosen J. Sublingual Buprenorphine-Naloxone Compared With Injection Naltrexone for Opioid Use Disorder: Potential Utility of Patient Characteristics in Guiding Choice of Treatment. Am J Psychiatry. 2021 Jul;178(7):660-671. doi: 10.1176/appi.ajp.2020.20060816. Epub 2021 Jun 25.
citation: Fishman M, Wenzel K, Scodes J, Pavlicova M, Campbell ANC, Rotrosen J, Nunes E. Examination of Correlates of OUD Outcomes in Young Adults: Secondary Analysis From the XBOT Trial. Am J Addict. 2021 Sep;30(5):433-444. doi: 10.1111/ajad.13176. Epub 2021 Jun 1.
citation: Shulman M, Choo TH, Scodes J, Pavlicova M, Wai J, Haenlein P, Tofighi B, Campbell ANC, Lee JD, Rotrosen J, Nunes EV. Association between methadone or buprenorphine use during medically supervised opioid withdrawal and extended-release injectable naltrexone induction failure. J Subst Abuse Treat. 2021 May;124:108292. doi: 10.1016/j.jsat.2021.108292. Epub 2021 Jan 16.
citation: Lee JD, Nunes EV Jr, Novo P, Bachrach K, Bailey GL, Bhatt S, Farkas S, Fishman M, Gauthier P, Hodgkins CC, King J, Lindblad R, Liu D, Matthews AG, May J, Peavy KM, Ross S, Salazar D, Schkolnik P, Shmueli-Blumberg D, Stablein D, Subramaniam G, Rotrosen J. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018 Jan 27;391(10118):309-318. doi: 10.1016/S0140-6736(17)32812-X. Epub 2017 Nov 14.
citation: Lee JD, Nunes EV, Mpa PN, Bailey GL, Brigham GS, Cohen AJ, Fishman M, Ling W, Lindblad R, Shmueli-Blumberg D, Stablein D, May J, Salazar D, Liu D, Rotrosen J. NIDA Clinical Trials Network CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT): Study design and rationale. Contemp Clin Trials. 2016 Sep;50:253-64. doi: 10.1016/j.cct.2016.08.004. Epub 2016 Aug 10.