Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment

• ClinicalTrials.gov Identifier: NCT02032433
• Recruitment Status: Completed
• First Posted: January 10, 2014
• Results First Posted: January 19, 2018
• Last Update Posted: August 13, 2020
• Sponsor: NYU Langone Health
• Collaborators: National Institute on Drug Abuse (NIDA); The Emmes Company, LLC
• Information provided by (Responsible Party): NYU Langone Health

Tracking Information

• First Submitted Date: December 30, 2013
• First Posted Date: January 10, 2014
• Results First Submitted Date: November 24, 2017
• Results First Posted Date: January 19, 2018
• Last Update Posted Date: August 13, 2020
• Actual Study Start Date: January 29, 2014
• Actual Primary Completion Date: January 25, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 5, 2018)

• Time to Relapse (Intent to Treat Population) [ Time Frame: Weeks 3-24 ]
  Relapse occurs if the participant is using any non-protocol prescribed opioids regularly starting at day 21 post-randomization or thereafter. Operationally, relapse is defined as either: (a) four consecutive opioid use weeks, or (b) seven consecutive days of use by self-report. A use week is defined as any week during which a participant self-reports at least one day of use during that week, provides a urine sample positive for non-protocol opioids, or fails to provide a urine sample. Self-report of opioid (heroin or prescription opioids) and other substance use is ascertained at each weekly study visit using the Timeline Follow-Back for each day leading back to the previous visit. Urine is collected at each study visit and tested for opioids. A missed UDS counts as a use week.
• Time to Relapse (Per Protocol Population) [ Time Frame: Weeks 3-24 ]
  Relapse occurs if the participant is using any non-protocol prescribed opioids regularly starting at day 21 post-randomization or thereafter. Operationally, relapse is defined as either: (a) four consecutive opioid use weeks, or (b) seven consecutive days of use by self-report. A use week is defined as any week during which a participant self-reports at least one day of use during that week, provides a urine sample positive for non-protocol opioids, or fails to provide a urine sample. Self-report of opioid (heroin or prescription opioids) and other substance use is ascertained at each weekly study visit using the Timeline Follow-Back for each day leading back to the previous visit. Urine is collected at each study visit and tested for opioids. A missed UDS counts as a use week.

Original Primary Outcome Measures (submitted: January 8, 2014)

Time to relapse [ Time Frame: Days 21 - 167 ]

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.

Current Secondary Outcome Measures (submitted: July 30, 2020)

• Number Successfully Inducted Onto Assigned Study Medication [ Time Frame: Weeks 0-24 ]
  Binary Y/N assessment of whether the participant was or was not able to initiate their assigned study medication.
• Adverse Events Related to Study Medications [ Time Frame: Weeks 0-36 ]
  Adverse events reported by participants and assessed by clinical staff for relatedness to study medication. These determinations were reviewed by the study medical monitor.
• Opioid Abstinence Over Time While on Study Medication (Subjective) [ Time Frame: Weeks 0-24 ]
  Self report of opioid use by participants using the TLFB. At each visit, the TLFB was completed for dates going back to the last participant encounter.
• Alcohol Use Over Time, Drinks Per Day, Past 30 Days, W0 [ Time Frame: Week 0 ]
  Alcohol use over time, drinks per day, past 30 days, at week 0
• Cigarette Smoking, W0, 10 or Less [ Time Frame: Week 0 ]
  Participants average cigarettes/day, in past 4 weeks, at week 0, equals 10 or less.
• Opioid Craving Over Time W0 [ Time Frame: Week 0 ]
  Opioid craving over time via VAS at week 0
• Score of Subacute Withdrawal Symptoms Subscale Within Hamilton Depression (HAM-D) Rating Scale [ Time Frame: Week 0 ]
  The Subacute Withdrawal Symptoms Subscale consists of 6 symptoms. Classification of symptoms can be scored as: 0 - absent, 1 - doubtful or trivial, 2 - present. The total range of scores is 0 - 12, and the higher the total score the more severe the depression.
• Score of Alcohol Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 0 ]
  The Alcohol Subscale within ASI is one question that asks how bothered one has been by alcohol problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Sexual Behavior Subscale Within HIV Risk-Taking Behavior Scale (HRBS) [ Time Frame: Week 0 ]
  The Sexual Behavior Subscale consists of 5 questions. Each question is scored from 0-5, for a total score range of 0-25. Higher scores indicate a greater degree of risk-taking behavior.
• Score on Trail Making Test Part A [ Time Frame: Week 0 ]
  Trail Making Test Part A consists of 25 circles distributed over a sheet of paper. The circles are number 1-25, and the patient is asked to draw lines to connect the numbers in ascending order. The patient is instructed to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Higher scores reveal greater impairment.
• Opioid Abstinence Over Time While on Study Medication (Objective) [ Time Frame: Weeks 0-24 ]
  A urine sample was obtained and tested for opioids at each in person visit; screening, prior to induction onto study medication, weekly through week 24 and at each of the follow up visits.
• Cigarette Smoking, W0 0 [ Time Frame: Week 0 ]
  Participants average cigarettes/day, in past 4 weeks, at week 0, equals none
• Cigarette Smoking, W0 11-20 [ Time Frame: Week 0 ]
  Participants average cigarettes/day, in past 4 weeks, at week 0, equals 11-20.
• Cigarette Smoking, W0 21-30 [ Time Frame: Week 0 ]
  Participants average cigarettes/day, in past 4 weeks, at week 0, equals 21-30
• Cigarette Smoking, W0 31 or More [ Time Frame: Week 0 ]
  Participants average cigarettes/day, in past 4 weeks, at week 0, equals 31 or more
• Cigarette Smoking, W24 0 [ Time Frame: Week 24 ]
  Participants average cigarettes/day, in past 4 weeks, at week 24, equals none
• Cigarette Smoking [ Time Frame: Week 24 ]
  Participants average cigarettes/day, in past 4 weeks, at week 24, equals 10 or less.
• Cigarette Smoking, W24 11-20 [ Time Frame: Week 24 ]
  Participants average cigarettes/day, in past 4 weeks, at week 24, equals 11-20.
• Cigarette Smoking, W24 21-30 [ Time Frame: Week 24 ]
  Participants average cigarettes/day, in past 4 weeks, at week 24, equals 21-30
• Cigarette Smoking, W24 31 or More [ Time Frame: Week 24 ]
  Participants average cigarettes/day, in past 4 weeks, at week 24, equals 31 or more
• Score on Opioid Craving Scale (OCS) [ Time Frame: Week 24 ]
  OCS is a brief 3-item measure used to measure opioid craving. The scale consists of 3 items rated on a visual analogue scale (VAS) from 1-10. The total range of score is 0-30, and a higher score indicates a stronger craver / desire to use opiates.
• Score of Subacute Withdrawal Symptoms Subscale Within Hamilton Depression (HAM-D) Rating Scale [ Time Frame: Week 24 ]
  The Subacute Withdrawal Symptoms Subscale consists of 6 symptoms. Classification of symptoms can be scored as: 0 - absent, 1 - doubtful or trivial, 2 - present. The total range of scores is 0 - 12, and the higher the total score the more severe the depression.
• Score on Subjective Opiate Withdrawal Scale (SOWS) [ Time Frame: Week 0 ]
  The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It contains 16 symptoms whose intensity the patient rates on a scale of 0 (not at all) to 4 (extremely). The total range of scores is 0-64; the higher the score, the more intense the withdrawal.
• Score on Subjective Opiate Withdrawal Scale (SOWS) [ Time Frame: Week 24 ]
  The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It contains 16 symptoms whose intensity the patient rates on a scale of 0 (not at all) to 4 (extremely). The total range of scores is 0-64; the higher the score, the more intense the withdrawal.
• Score of Sexual Behavior Subscale Within HIV Risk-Taking Behavior Scale (HRBS) [ Time Frame: Week 24 ]
  The Sexual Behavior Subscale consists of 5 questions. Each question is scored from 0-5, for a total score range of 0-25. Higher scores indicate a greater degree of risk-taking behavior.
• Score of Condom Use Subscale Within HIV Risk-Taking Behavior Scale (HRBS) [ Time Frame: Week 0 ]
  The Sexual Behavior Subscale consists of 3 questions. Each question is scored from 0-5, for a total score range of 0-15. Higher scores indicate a greater degree of risk-taking behavior.
• Score of Condom Use Subscale Within HIV Risk-Taking Behavior Scale (HRBS) [ Time Frame: Week 24 ]
  The Sexual Behavior Subscale consists of 3 questions. Each question is scored from 0-5, for a total score range of 0-15. Higher scores indicate a greater degree of risk-taking behavior.
• Score on Trail Making Test Part A [ Time Frame: Week 24 ]
  Trail Making Test Part A consists of 25 circles distributed over a sheet of paper. The circles are number 1-25, and the patient is asked to draw lines to connect the numbers in ascending order. The patient is instructed to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Higher scores reveal greater impairment.
• Score on Trail Making Test Part B [ Time Frame: Week 0 ]
  Part B consists of 25 circles distributed over a sheet of paper. In Part B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern, by alternating between the numbers and letters. Results are reported as the number of seconds required to complete the task.
• Score on Trail Making Test Part B [ Time Frame: Week 24 ]
  Part B consists of 25 circles distributed over a sheet of paper. In Part B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern, by alternating between the numbers and letters. Results are reported as the number of seconds required to complete the task.
• Score on Word Card of Stoop Test [ Time Frame: Week 0 ]
  The "word card" of the Stoop Test has the names of colors printed in black and white (100 items to be named). The patient's basic score is the total time he/she takes to utter the 100 words on the card.
• Score on Word Card of Stoop Test [ Time Frame: Week 24 ]
  The "word card" of the Stoop Test has the names of colors printed in black and white (100 items to be named). The patient's basic score is the total time he/she takes to utter the 100 words on the card.
• Score on Color Card of Stoop Test [ Time Frame: Week 0 ]
  The "color card" contains 100 patches of between 3-5 different colors. The patient's task is to utter the names of the colored patches as rapidly as possible, scanning the rows from left to right. The score is the total time (in seconds) it takes to utter the 100 colors.
• Score on Color Card of Stoop Test [ Time Frame: Week 24 ]
  The "color card" contains 100 patches of between 3-5 different colors. The patient's task is to utter the names of the colored patches as rapidly as possible, scanning the rows from left to right. The score is the total time (in seconds) it takes to utter the 100 colors.
• Score on Color Word Card of Stoop Test [ Time Frame: Week 0 ]
  The "color-word card" contains the printed names of colors, but printed in an ink of a conflicting color (e.g. the word RED might be printed in green, yellow, or blue). The patient is required to name the colors of the inks while ignoring the conflicting printed color names. The basic score is the total time (in seconds) to utter the 100 colors.
• Score on Color Word Card of Stoop Test [ Time Frame: Week 24 ]
  The "color-word card" contains the printed names of colors, but printed in an ink of a conflicting color (e.g. the word RED might be printed in green, yellow, or blue). The patient is required to name the colors of the inks while ignoring the conflicting printed color names. The basic score is the total time (in seconds) to utter the 100 colors.
• Score of Alcohol Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 24 ]
  The Alcohol Subscale within ASI is one question that asks how bothered one has been by alcohol problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Drug Use Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 0 ]
  The Drug Use Subscale within ASI is one question that asks how bothered one has been by drug use problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Drug Use Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 24 ]
  The Drug Use Subscale within ASI is one question that asks how bothered one has been by drug use problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Social Relationship Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 0 ]
  The Social Relationship Subscale within ASI contains 2 questions that ask how bothered one has been by family or social problems. The total range of the subscale is 0-8. The higher the score, the bigger the problem.
• Score of Family / Social Relationship Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 24 ]
  The Family / Social Relationship Subscale within ASI contains 2 questions that ask how bothered one has been by family or social problems. The total range of the subscale is 0-8. The higher the score, the bigger the problem.
• Score of Legal Status Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 0 ]
  The Legal Status Subscale within ASI is one question that asks how bothered one has been by legal problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Legal Status Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 24 ]
  The Legal Status Subscale within ASI is one question that asks how bothered one has been by legal problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Medical Status Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 0 ]
  The Medical Status Subscale within ASI is one question that asks how bothered one has been by medical problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Medical Status Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 24 ]
  The Medical Status Subscale within ASI is one question that asks how bothered one has been by medical problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Psychiatric Status Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 0 ]
  The Psychiatric Status Subscale within ASI is one question that asks how bothered one has been by psychiatric or emotional problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score of Psychiatric Status Subscale Within Addiction Severity Index (ASI) Scale [ Time Frame: Week 24 ]
  The Psychiatric Status Subscale within ASI is one question that asks how bothered one has been by psychiatric or emotional problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.
• Score on EuroQOL EQ-5D Questionnaire [ Time Frame: Week 0 ]
  Problems related to drug abuse is assessed through this questionnaire, which consists of 5 conditions. Each condition is scored from 0-2 for a total score range of 0-10. The higher the score, the more problems.
• Score on EuroQOL EQ-5D Questionnaire [ Time Frame: Week 24 ]
  Problems related to drug abuse is assessed through this questionnaire, which consists of 5 conditions. Each condition is scored from 0-2 for a total score range of 0-10. The higher the score, the more problems.
• Alcohol Use Over Time, Drinks Per Day [ Time Frame: Week 24 ]
  Alcohol use over time, drinks per day
• Other Drug Use Over Time, Cannabis, W0 [ Time Frame: week 0 ]
  Other drug use over time measuring cannabis at week 0
• Other Drug Use Over Time, Cannabis, W24 [ Time Frame: week 24 ]
  Other drug use over time measuring cannabis at week 24
• Other Drug Use Over Time, Cocaine, W0 [ Time Frame: week 0 ]
  Other drug use over time measuring cocaine at week 0
• Other Drug Use Over Time, Cocaine, W24 [ Time Frame: week 24 ]
  Other drug use over time measuring cocaine at week 0
• Other Drug Use Over Time, Stimulant, W0 [ Time Frame: week 0 ]
  Other drug use over time measuring stimulant (cocaine, crack and amphetamine) at week 0
• Other Drug Use Over Time, Stimulant, W24 [ Time Frame: week 24 ]
  Other drug use over time measuring stimulant (cocaine, crack and amphetamine) at week 24

Original Secondary Outcome Measures (submitted: January 8, 2014)

• Proportion successfully inducted onto assigned study medication (binary: did or did not receive first dose of XR-NTX, or achieve maintenance dose of BUP-NX) [ Time Frame: Days 0 - 10 ]
  Hypothesis: BUP-NX will produce higher rate of successful induction than XR-NTX Significance/Rationale: XR-NTX induction requires completion of detoxification, whereas BUP-NX induction only requires onset of withdrawal symptoms. Thus XR-NTX may have more dropouts after randomization but prior to XR-NTX induction.
• Adverse Events related to study medications [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX and BUP-NX will produce equivalent rates of SAEs, and equivalent rates of AEs, though AE pattern will differ somewhat (e.g. injection site reactions with XR-NTX) Significance/Rationale: Careful documentation of SAEs and AEs, including overdose episodes, would be considered essential safety data, and important component of a comparative effectiveness trial.
• Opioid abstinence over time while on study medication (Weekly TLFB, confirmed by urine drug screens) [ Time Frame: Days 0 - 167 ]
  Hypothesis: XR-NTX will produce greater opioid abstinence than BUP-NX Significance/Rationale: XR-NTX produces complete blockade of opioid effects, so that during treatment with monthly injections, opioid use can be expected to be minimal. In contrast BUP-NX may not produce complete blockade, or patients may reduce or stop doses for a few days and substitute other opioids (heroin, prescription opioids).
• Alcohol and other drug use, over time (TLFB and UDS) [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX will be superior to BUP-NX in producing abstinence from alcohol and other drugs Significance/Rationale: Clinical trials show XR-NTX is effective for treatment of alcohol dependence, and naltrexone has some evidence of efficacy for stimulant dependence.
• Cigarette smoking (FTND, Tobacco Use Questionnaire, VAS nicotine craving) [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX will reduce cigarette smoking compared to BUP-NX Significance/Rationale: Naltrexone has been studied as a treatment for nicotine dependence, with some support from clinical trials, although inconsistent. Given high morbidity and mortality associated with nicotine dependence, a comparative advantage of one or the other of these treatments at reducing smoking would be valuable to examine.
• Opioid Craving (VAS) over time [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX will be superior to BUP-NX in reducing opioid craving Significance/Rationale: Krupitsky et al (Lancet 2011) pivotal XR-NTX trial showed, surprisingly, that XR-NTX reduced craving substantially compared to placebo.
• Subacute withdrawal symptoms over time (HAM-D, SOWS) [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX will produce greater severity of subacute withdrawal symptoms than BUP-NX during the first month after randomization, but will be equivalent to BUP-NX in months 2 to 6 Significance/Rationale: Low-grade withdrawal-like symptoms (dubbed "naltrexone flu" by the Columbia group, and consisting typically of insomnia, fatigue, and anorexia, though not drug craving) have been observed in some patients in the 1 to 4 weeks after naltrexone initiation, resolving gradually. Further characterization of this syndrome would be important for developing treatment guidelines.
• Problems related to drug abuse (ASI-Lite and EQ-5D) [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX will be superior to BUP-NX Significance/Rationale: Greater opioid and non-opioid abstinence on XR-NTX will result in fewer problems associated with active drug abuse.
• HIV risk behavior over time (RAB and other HIV risk measures) [ Time Frame: Days 0 - 279 ]
  Hypothesis: XR-NTX and BUP-NX will be equivalent Significance/Rationale: The opioid-dependent population is at high risk for HIV, both from injection drug use and from unsafe sexual practices. Effective treatment for the opioid dependence may reduce HIV risk behavior. Given the high morbidity and mortality associated with HIV, a comparative advantage of one or the other of these treatments would be valuable to examine.
• Cognitive function (Trails Making Test Parts A and B, Stroop) [ Time Frame: Days 0 - 195 ]
  Hypothesis: XR-NTX and BUP-NX will be equivalent Significance/Rationale: Some providers and policy-makers are concerned that patients maintained on BUP-NX will have opioid-agonist-related cognitive impairment.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment
• Official Title: CTN-0051: Extended-Release Naltrexone vs. Buprenorphine for Opioid 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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Opioid Use Disorder

Intervention

• Drug: Extended-Release Naltrexone
  Extended-Release Naltrexone (Vivitrol®)
  Other Name: Vivitrol®
• Drug: Buprenorphine-Naloxone
  Buprenorphine-Naloxone (Suboxone®)
  Other Name: Suboxone®

Study Arms

• Active Comparator: Extended-Release Naltrexone
  Extended-Release Naltrexone (Vivitrol)
  Intervention: Drug: Extended-Release Naltrexone
• Active Comparator: Buprenorphine-Naloxone
  Buprenorphine-Naloxone (Suboxone)
  Intervention: Drug: Buprenorphine-Naloxone

Publications *

• Nielsen S, Tse WC, Larance B. Opioid agonist treatment for people who are dependent on pharmaceutical opioids. Cochrane Database Syst Rev. 2022 Sep 5;9(9):CD011117. doi: 10.1002/14651858.CD011117.pub3.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 5, 2018): 570
• Original Estimated Enrollment (submitted: January 8, 2014): 1200
• Actual Study Completion Date: January 31, 2017
• Actual Primary Completion Date: January 25, 2017 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02032433
• Other Study ID Numbers: 12-03133; UG1DA013035 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Data from this study will be available to researchers on the website, http://datashare.nida.nih.gov/ after the study is complete and the data analyzed. This website will not include information that can identify individual study participants.

• Current Responsible Party: NYU Langone Health
• Original Responsible Party: John Rotrosen, NYU Langone Health, Lead Investigator
• Current Study Sponsor: NYU Langone Health
• Original Study Sponsor: Same as current

Collaborators

• National Institute on Drug Abuse (NIDA)
• The Emmes Company, LLC

Investigators

• Principal Investigator: John Rotrosen, MD; NYU Langone Health

• PRS Account: NYU Langone Health
• Verification Date: July 2020