Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (RDD)

Study Overview
=================
Brief Summary
-----------------
This is a two phase study investigating combinations of pharmacological and behavioral interventions to optimize the treatment of Opioid Use Disorder (OUD). The Retention Phase will assess strategies for improving retention on buprenorphine (BUP) and extended-release injectable naltrexone (XR-NTX). The Discontinuation Phase will assess which approaches are most likely to lead to long-term success (absence of relapse), and what characteristics of participants distinguish those who can safely discontinue Medications for Opioid Use Disorder (MOUD) from those who remain at risk of relapse and should not discontinue.

Detailed Description
-----------------
The main objectives of this study are: To test strategies to improve retention in treatment on medications for opioid use disorder (MOUD), among patients initiating treatment for OUD. To test strategies to improve outcomes among patients who have achieved stable remission on MOUD and want to discontinue MOUD. To develop models to predict who is able to discontinue MOUD without relapse, based on patient characteristics, including duration of MOUD prior to discontinuation. The study will have a multicenter, randomized, pragmatic non-blinded design. The study has two phases, a Retention Phase and a Discontinuation Phase.

Official Title
-----------------
NIDA-CTN-0100: Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (RDD)

Conditions
-----------------
Opioid Use Disorder (OUD)

Intervention / Treatment
-----------------
* Drug: SL-BUP
* Drug: XR-BUP
* Drug: XR-NTX
* Behavioral: MM
* Behavioral: MMR
* Behavioral: MMD


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for Retention Phase: 18 years of age or older; Meet DSM-5 criteria for current opioid use disorder (heroin, fentanyl or other synthetic opioids, and/or prescription opioids); Seeking treatment for opioid use disorder and choosing either buprenorphine (BUP) or extended-release injection naltrexone (XR-NTX); If choosing buprenorphine, willing to be randomized to SL-BUP-16mg, SL-BUP-32mg, or XR-BUP; Willing to be randomized to either MM (standard Medical Management plus counseling treatment as usual available at the site) or MMR (MM plus usual counseling and access to an app delivering CM + CBT); In good-enough general health (meaning good enough health to be in outpatient treatment) as determined by the study medical clinician on the basis of medical history, review of systems, and physical/mental status exam, to permit treatment with XR-NTX or BUP; Willing and able to provide written informed consent; Able to speak English sufficiently to understand the study procedures; If female of childbearing potential, willing to practice an effective method of birth control for the duration of participation in the study (participants who become pregnant during the study will continue to be followed; treatment may be modified consistent with pregnancy). Exclusion Criteria for Retention Phase: Serious medical, psychiatric, or co-occurring substance use disorder or concomitant medication that, in the opinion of the study medical clinician, makes the patient not appropriate for outpatient treatment with buprenorphine or XR-NTX, but instead requires a higher or different level of care. Examples include: 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; Severe, untreated or inadequately treated psychiatric condition (e.g., active psychosis, uncontrolled bipolar disorder) as assessed by history and/or clinical interview, requiring a different level of care (e.g., hospitalization); Current severe alcohol, benzodiazepine, or other depressant or sedative hypnotic use, requiring a different level of care (e.g., hospitalization); Suicidal or homicidal ideation or behavior requiring a different level of care (e.g., hospitalization); Known allergy or sensitivity to preferred medication or its components; Maintenance on methadone at the time of signing consent; For those preferring XR-NTX, presence of pain of sufficient severity as to require ongoing pain management with opioids; For those preferring XR-NTX, 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); If female, currently pregnant or breastfeeding or planning on conception; Are currently in jail, prison or other overnight facility as required by court of law or have pending legal action that could prevent participation in study activities; Have used the reSET-O or CHESS Connections mHealth apps in the 3 months prior to consent; Other major reasons that might prevent an individual from participating in the study (e.g., a planned move out of the area). Inclusion Criteria for Discontinuation Phase: 18 years of age or older; Have been receiving buprenorphine for OUD for at least the past year or XR-NTX pharmacotherapy for OUD for at least the past 6 months prior to consent for the Discontinuation Phase; Express the desire to discontinue MOUD after a shared decision-making discussion with the treating provider; Meet stability criteria, i.e., have abstained from opioids (other than buprenorphine), cocaine, methamphetamine, and non-prescribed benzodiazepines for the past ≥12 weeks, and do not meet DSM-5 criteria for current (≥12 weeks) alcohol use disorder (participants with cannabis use will be eligible); If currently taking buprenorphine, are willing to take either SL-BUP or XR-BUP if randomized to that condition; Willing to be randomized to either MM or to MMD; Able to provide written informed consent after discussion with their provider regarding the risks of discontinuation; Able to speak English sufficiently to understand the study procedures; If female of childbearing potential, willing to practice an effective method of birth control while in the study and taking study medication (participants who become pregnant during the study will continue to be followed; treatment may be modified consistent with pregnancy). Exclusion Criteria for Discontinuation Phase: Serious medical or psychiatric disorder or concomitant medication that, in the opinion of the study medical clinician, would make study participation hazardous to the participant or compromise study findings or would prevent the participant from completing the study. Examples include: 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; Severe, untreated, or inadequately treated psychiatric condition (e.g., active psychosis, uncontrolled bipolar disorder) as assessed by history and/or clinical interview, requiring a different level of care (e.g., hospitalization); Suicidal or homicidal ideation or behavior requiring a different level of care (e.g., hospitalization); For participants entering the study taking buprenorphine, presence of pain requiring or likely requiring ongoing pain management with buprenorphine or other opioids; If female, currently pregnant or breastfeeding or planning on conception; Use of opioids (other than buprenorphine), cocaine, methamphetamine, or non-prescribed benzodiazepines in the past 12 weeks; Meets current DSM-5 criteria for any current alcohol use disorder; Are currently in jail, prison or other overnight facility as required by court of law or have pending legal action that could prevent participation in study activities; Have used the Connections mHealth app in the 3 months prior to consent (other than Connections in the Retention Phase); Other major reasons that might prevent an individual from participating in the study (e.g., a planned move out of the area.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Retention Phase: 3x2 for BUP; 1x2 for XR-NTX; Discontinuation Phase: 2x2 for SL-BUP; 1x2 for XR-BUP; 1x2 for XR-NTX
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Retention: SL-BUP standard dose + MM<br>Standard dose sublingual buprenorphine-naloxone (SL-BUP) 16mg/day target plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: SL-BUP<br>* Daily dosing of sublingual buprenorphine-naloxone<br>* Other names: Suboxone;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Retention: SL-BUP high dose + MM<br>High dose sublingual buprenorphine-naloxone (SL-BUP) 32mg/day target plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: SL-BUP<br>* Daily dosing of sublingual buprenorphine-naloxone<br>* Other names: Suboxone;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Retention: XR-BUP + MM<br>Extended-release injectable buprenorphine (XR-BUP) plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: XR-BUP<br>* Weekly/monthly dosing of extended-release injectable buprenorphine<br>* Other names: Brixadi;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Retention: XR-NTX + MM<br>Extended-release injectable naltrexone (XR-NTX) plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: XR-NTX<br>* Monthly dosing of extended-release injectable naltrexone<br>* Other names: Vivitrol;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Retention: SL-BUP standard dose + MMR<br>Standard dose sublingual buprenorphine-naloxone (SL-BUP) 16mg/day target plus MMR, consisting of Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: SL-BUP<br>* Daily dosing of sublingual buprenorphine-naloxone<br>* Other names: Suboxone;Behavioral: MMR<br>* MMR consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Retention: SL-BUP high dose + MMR<br>High dose sublingual buprenorphine-naloxone (SL-BUP) 32mg/day target plus MMR, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: SL-BUP<br>* Daily dosing of sublingual buprenorphine-naloxone<br>* Other names: Suboxone;Behavioral: MMR<br>* MMR consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Retention: XR-BUP + MMR<br>Extended-release injectable buprenorphine (XR-BUP) plus MMR, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: XR-BUP<br>* Weekly/monthly dosing of extended-release injectable buprenorphine<br>* Other names: Brixadi;Behavioral: MMR<br>* MMR consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Retention: XR-NTX + MMR<br>Extended-release injectable naltrexone (XR-NTX) plus MMR, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: XR-NTX<br>* Monthly dosing of extended-release injectable naltrexone<br>* Other names: Vivitrol;Behavioral: MMR<br>* MMR consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Discontinuation: Discontinue SL-BUP with SL-BUP + MM<br>Start on SL-BUP, taper with SL-BUP, plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: SL-BUP<br>* Daily dosing of sublingual buprenorphine-naloxone<br>* Other names: Suboxone;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Discontinuation: Discontinue SL-BUP with XR-BUP + MM<br>Start on SL-BUP, taper with XR-BUP, plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: XR-BUP<br>* Weekly/monthly dosing of extended-release injectable buprenorphine<br>* Other names: Brixadi;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Discontinuation: Discontinue XR-BUP with XR-BUP + MM<br>Start on XR-BUP, taper with XR-BUP, plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: XR-BUP<br>* Weekly/monthly dosing of extended-release injectable buprenorphine<br>* Other names: Brixadi;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Discontinuation: Discontinue XR-NTX with XR-NTX + MM<br>Start on XR-NTX, taper with XR-NTX, plus MM, consisting of standard Medical Management and usual counseling at the treatment program. | Drug: XR-NTX<br>* Monthly dosing of extended-release injectable naltrexone<br>* Other names: Vivitrol;Behavioral: MM<br>* MM consists of standard Medical Management and the usual counseling at the treatment program.<br>|
| Experimental: Discontinuation: Discontinue SL-BUP with SL-BUP + MMD<br>Start on SL-BUP, taper with SL-BUP, plus MMD, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: SL-BUP<br>* Daily dosing of sublingual buprenorphine-naloxone<br>* Other names: Suboxone;Behavioral: MMD<br>* MMD consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Discontinuation: Discontinue SL-BUP with XR-BUP + MMD<br>Start on SL-BUP, taper with XR-BUP, plus MMD, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: XR-BUP<br>* Weekly/monthly dosing of extended-release injectable buprenorphine<br>* Other names: Brixadi;Behavioral: MMD<br>* MMD consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Discontinuation: Discontinue XR-BUP with XR-BUP + MMD<br>Start on XR-BUP, taper with XR-BUP, plus MMD, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: XR-BUP<br>* Weekly/monthly dosing of extended-release injectable buprenorphine<br>* Other names: Brixadi;Behavioral: MMD<br>* MMD consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|
| Experimental: Discontinuation: Discontinue XR-NTX with XR-NTX + MMD<br>Start on XR-NTX, taper with XR-NTX, plus MMD, consisting of standard Medical Management and usual counseling, plus a technology-based behavioral component. | Drug: XR-NTX<br>* Monthly dosing of extended-release injectable naltrexone<br>* Other names: Vivitrol;Behavioral: MMD<br>* MMD consists of Medical Management and usual counseling, plus a technology-based behavioral component.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retention: Continuous retention in MOUD treatment at 26 weeks | Binary (yes/no). Continuously enrolled in maintenance treatment on one or more of the evidence-based MOUD modalities (e.g., SL-BUP, XR-BUP, XR-NTX, or methadone maintenance) with no more than a 28-day gap in MOUD over the 26-week period. | Retention: at week 26 | 
| Discontinuation: Completed Discontinuation without Relapse | Binary (yes/no). Discontinuing MOUD during the taper period, no return to MOUD, and no relapse to opioid use, either during the taper (up to 48 weeks for those entering on BUP or 24 weeks for those entering on XR-NTX) or during the 24 weeks after MOUD is discontinued. | Discontinuation: at week 24 follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retention KS1: Weekly opioid abstinence | Weekly opioid abstinence (measured by Timeline Followback, not contradicted by toxicology test). Repeated yes/no measure for each of weeks 3 through 26. | Retention: through week 26 | 
| Retention KS2: Treatment effectiveness | Retention treatment effectiveness, measured by the Treatment Effectiveness Assessment (TEA, Ling et. al, 2012); a brief instrument to assess patient progress in treatment and recovery along 4 domains (substance use, health, lifestyle and community) at week 26. | Retention: at week 26 | 
| Discontinuation KS1: Other discontinuation outcomes | Participants who did not meet the criteria for the primary outcome (Completed Discontinuation without Relapse), will be subcategorized into 3 other outcome categories: 1) Did not Complete Discontinuation (i.e., MOUD is continued or discontinued and then restarted within the next 24 weeks) and did not Relapse; 2) Completed Discontinuation followed by Relapse; or 3) Did not Complete Discontinuation and Relapse (i.e., relapse while on MOUD). | Discontinuation: at week 24 follow up | 
| DSK2: Treatment effectiveness | Discontinuation treatment effectiveness, measured by the Treatment Effectiveness Assessment (TEA, Ling et. al, 2012); a brief instrument to assess patient progress in treatment and recovery along 4 domains (substance use, health, lifestyle and community) at week 24. Measured at the end of taper (EOT): up to 24 weeks for tapers with XR-NTX and up to 48 weeks for tapers with BUP; and at the week 24 follow up (primary outcome timepoint). | Discontinuation: week 24 follow up |