Surmounting Withdrawal to Initiate Fast Treatment With Naltrexone

Study Overview
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Brief Summary
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This study compares two methods of initiating treatment with extended-release naltrexone (XR-NTX) when implemented at community-based inpatient or residential programs. The primary goal of this hybrid effectiveness-implementation study is to determine whether the Rapid Method (5-7 day long) is non-inferior to a Standard Method (13-day long) on the primary effectiveness outcome of successful initiation of XR-NTX (receiving the first injection). Secondary objectives include comparing Rapid versus Standard method on: time from admission to first dose of XR-NTX and time to dropout, craving, withdrawal severity, retention, abstinence, and safety measures, as measured during the inpatient induction process and the first two months of post-induction XR-NTX maintenance. Other exploratory outcomes include predictors of initiation success, and economic analyses. The implementation goal is to operationalize an implementation facilitation strategy that will be used to train clinical sites on the XR-NTX initiation method, to capture fidelity to the rapid induction process, and to study barriers and facilitators to implementation and refine the implementation facilitation strategy accordingly.

Detailed Description
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The overarching objective of the SWIFT trial (CTN-0097) is to foster widespread adoption of a regimen for rapid initiation of treatment with extended-release injection naltrexone (XR-NTX) at inpatient or residential Community Treatment Programs (CTPs). If widely adopted, such a regimen would have a substantial public health impact by expanding medication treatment options offered to patients with OUD to include XR-NTX. In multi-site, randomized (subject level) trials, XR-NTX, once initiated, has been found to have similar effectiveness to sublingual buprenorphine on clinical outcomes of retention in treatment and abstinence from opioids. However, initiation of naltrexone often involves a significant (up to 2 weeks) delay, which is a clinical hurdle that impedes the widespread adoption of XR-NTX as a treatment option. Initiation of naltrexone in patients actively using opioids requires that a patient be detoxified first, and the official prescribing information for XR-NTX recommends an additional 7- to 10-day waiting period after last dose of opioid before administering XR-NTX. This standard initiation regimen, involving a brief period of agonist, usually buprenorphine, taper followed by a 7- to 10-day waiting period, takes approximately two weeks. During this time, patients are vulnerable to drop out and relapse; further, this waiting period is problematic in the face of funding restrictions on the duration of inpatient stays. In a single-site randomized trial, a Rapid naltrexone induction method utilizing minimal buprenorphine, non-opioid medications to treat withdrawal symptoms, and upward titration of oral naltrexone starting with small doses, XR-NTX initiation was accomplished in 5 to 7 days and was found superior to the standard 14-day approach on the proportion of patients initiating XR-NTX. The primary goal of this hybrid effectiveness-implementation study is to determine whether the Rapid method of initiating treatment with XR-NTX is non-inferior to a standard method on the primary effectiveness outcome of successful initiation of XR-NTX (receiving the first injection) when implemented at community-based inpatient or residential programs. Secondary objectives include comparing rapid versus standard method of XR-NTX initiation on: time from admission to first dose of XR-NTX and time to dropout, craving, withdrawal severity, retention, abstinence, and safety measures, as measured during the inpatient initiation process and the first two months post XR-NTX induction. Other exploratory outcomes include predictors of initiation success, and economic analyses. The implementation goal is to operationalize an implementation facilitation strategy that will be used to train clinical sites on the XR-NTX initiation method, to capture fidelity to the rapid induction process, and to study barriers and facilitators to implementation and refine the implementation facilitation strategy accordingly.

Official Title
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Surmounting Withdrawal to Initiate Fast Treatment With Naltrexone: Improving the Real-World Effectiveness of Injection Naltrexone for Opioid Use Disorder (SWIFT)

Conditions
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Opioid-use Disorder

Intervention / Treatment
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* Other: Standard Induction Procedure (SP)
* Other: Rapid Induction Procedure (RP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older. Meets current Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for opioid use disorder. Seeking treatment for opioid use disorder, willing to accept treatment with XR- NTX and, in the judgment of the treating physician, is a good candidate for naltrexone- based treatment. Willing and 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, willing to practice an effective method of birth control for the duration of participation in the study. Exclusion Criteria: 1. Serious medical, psychiatric or substance use disorder that, in the opinion of the study physician, would make a detoxification and naltrexone initiation, or maintenance treatment with XR-NTX, hazardous (relative contra-indications) or requires a different level of care. Examples include: Disabling or terminal medical illness (e.g., uncompensated heart failure, severe acute hepatitis, cirrhosis or end-stage liver disease) as assessed by medical history and/or review of systems. Severe, untreated or inadequately treated mental disorder (e.g., active psychosis, uncontrolled manic-depressive illness) as assessed by history and/or clinical interview. 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). 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. 3. Maintenance treatment with methadone. 4. Maintenance treatment with buprenorphine unless the patient is determined to have a poor treatment response (in the form of buprenorphine non-adherence with or without the use of illicit opioids), warranting change to XR-NTX treatment. 5. Presence of pain of sufficient severity as to require ongoing pain management with opioids. 6. Circumstances (legal, personal, occupational) that would threaten the feasibility of XR- NTX treatment or make another treatment (e.g. buprenorphine or methadone) a better choice. 7. 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. 8. If female, currently pregnant or breastfeeding, or planning on conception. 9. 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). 10. Admitted to the inpatient detoxification or residential rehabilitation unit more than 3 days prior to consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The proposed study is an open-label, multi-center, stepped-wedge cluster randomized trial. As part of the stepped-wedge design proposed for this trial, one site, randomly chosen, will start implementing the Rapid procedure (RP) and will remain in this arm for the rest of the study. The next 4 sites randomly chosen will first implement the Standard procedure (SP), to establish the within-site comparison condition, and then at selected staggered time-points (steps) will switch to implementing only the RP. The 6th site (after 5 sites have been randomized to RP) will remain in the SP procedure arm throughout the whole duration of the study. Implementation of RP at study sites will be staggered by 14 weeks and the order in which sites will cross-over from SP to RP will be randomly chosen.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Induction Method<br>The Standard Method (13-day long) includes 5-days of buprenorphine taper followed by 7-day washout period | Other: Standard Induction Procedure (SP)<br>* SP includes stabilization on buprenorphine (6-8 mg) on Day 1 followed by a taper over the subsequent 4 days. After the completion of buprenorphine taper, participants will enter a washout period of at least 8 days. On the last day of the washout period, participants will be evaluated for eligibility to receive XR-NTX injection. Once found eligible, an XR-NTX injection will be given.<br>|
| Experimental: Rapid Induction Method<br>The Rapid Method includes one day of buprenorphine followed by a day of washout and 3-4 days of oral naltrexone titration with adjunctive medications | Other: Rapid Induction Procedure (RP)<br>* RP includes 1 day of buprenorphine 6-8 mg, followed by a day of washout and 4 days of oral naltrexone titration. If the participant is able to tolerate the last dose of the naltrexone titration, an XR-NTX injection will be given<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Patients Who Receive the First XR-NTX Injection (Dichotomous: Did or Did Not Receive First Dose of XR-NTX) | The primary goal of the study is to show RP is non-inferior to SP XR-NTX induction method. | Induction Phase: 1-30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean for Time From Admission to First XR-NTX Injection by Treatment Group. | Time to receipt of first injection of XR-NTX from day of admission for participants that receive first injection of XR-NTX. | Induction Phase: 1-30 days | 
| Mean of Individual Participant's Opioid Craving Measured by Visual Analog Scales (VAS) During Induction Phase | Craving for opioids measured by Visual Analog Scales (VAS). Scale 0-100, 0 no craving and 100 Most intense craving possible | Induction Phase: 1-30 days | 
| Mean of Individual Participant's Opioid Craving Measured by Visual Analog Scales (VAS) During Post-induction Weeks 1 Through 8 | Craving for opioids measured by Visual Analog Scales (VAS). Scale 0-100, 0 no craving and 100 Most intense craving possible | Post Induction Phase: 1-8 weeks | 
| Mean of Individual Participant's Opioid Withdrawal Measured by Subjective Opioid Withdrawal Scale (SOWS) During Induction Phase | Opioid withdrawal symptoms as measured by the Subjective Opioid Withdrawal Scale (SOWS). Scale 0-64, with the higher score representing greater withdrawal severity. | Induction Phase: 1-30 days | 
| Mean of Individual Participant's Opioid Withdrawal Measured by Subjective Opioid Withdrawal Scale (SOWS) During Post-induction Weeks 1 Through 4 | Opioid withdrawal symptoms as measured by the Subjective Opioid Withdrawal Scale (SOWS). Scale 0-64, with the higher score representing greater withdrawal severity. | Post Induction Phase: 1 - 4 weeks | 
| Mean of Individual Participant's Opioid Withdrawal Measured by Clinical Opioid Withdrawal Scale (COWS) During Induction Phase | Opioid withdrawal symptoms as measured by the Clinical Opiate Withdrawal Scale (COWS). Scale 0-59, with the higher score representing greater withdrawal severity. | Induction Phase: 1-30 days | 
| Mean of Individual Participant's Opioid Craving Measured by Clinical Opioid Withdrawal Scale (COWS) During Post-induction Weeks 1 Through 4 | Opioid withdrawal symptoms as measured by the Clinical Opiate Withdrawal Scale (COWS). Scale 0-59, with the higher score representing greater withdrawal severity. | Post Induction Phase: 1 - 4 weeks | 
| Mean for Individual Participant's Patient Health Questionnaire (PHQ-9) Score During Induction Phase | Other depressive, anxiety, and subacute withdrawal symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9). Scale 0-27, with the higher score representing greater severity. | Induction Phase: 1-30 days | 
| Mean for Individual Participant's Patient Health Questionnaire (PHQ-9) Score During Post-induction Weeks 1 Through 8 | Other depressive, anxiety, and subacute withdrawal symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9). Scale 0-27, with the higher score representing greater severity. | Post Induction Phase: 1 - 8 weeks | 
| Mean for Individual Participant's General Anxiety Disorder (GAD-7) Score During Induction Phase | Other depressive, anxiety, and subacute withdrawal symptoms as measured by the General Anxiety Disorder-7 (GAD-7). Scale 0-21, with the higher score representing greater severity. | Induction Phase: 1-30 days | 
| Mean for Individual Participant's General Anxiety Disorder (GAD-7) Score During Post-induction Weeks 1 Through 8 | Other depressive, anxiety, and subacute withdrawal symptoms as measured by the General Anxiety Disorder-7 (GAD-7). Scale 0-21, with the higher score representing greater severity. | Post Induction Phase: 1 - 8 weeks | 
| Frequency of Targeted Safety Events Related to Study Medication and Any Serious Adverse Events During Induction Period and During Eight Weeks of Post-induction Treatment | Safety, as measured by targeted safety events and serious adverse events. | Induction Phase- 1 - 30 days, Post Induction Phase- 1-8 weeks | 
| Number of Medical Visits and Therapy Completed During Follow up Treatment. | Engagement with medical visits and therapy (based on medical management log, XR- NTX dose log, Psychosocial log). | Post Induction Phase: 1 - 8 weeks | 
| Percent of Patients Reporting Continued Treatment With Medication for Opioid Use Disorder (MOUD) at Week 8 | Use of medication for opioid use disorder (MOUD) as measured by patient self-report on Timeline Followback (TLFB). | Post Induction Phase: Week 8 | 
| Percent of Participants Positive for Opioids Using Weekly TLFB During Eight Weeks of Post-induction | Opioid abstinence, as measured by the Timeline Followback (TLFB) (self-report days using opioids) | Post Induction Phase: 1 - 8 weeks | 
| Percent of Participants Positive for Opioids Using Urine Drug Screens at Week 4 and 8 | Opioid abstinence, as measured by the proportion of opioid-positive urine tests. | Post Induction Phase: Week 4 and Week 8 | 
| Percent of Participants Positive for Cocaine, Sedatives, Alcohol, Cannabis, and Tobacco Using Weekly TLFB During Eight Weeks of Post- Induction | Use of alcohol and other drugs of abuse (e.g., cocaine, other stimulants, cannabis, benzodiazepines), by self-report | Post Induction Phase: 1 - 8 weeks | 
| Percent of Participants Positive for Cocaine, Sedatives, Alcohol, Cannabis, and Tobacco Using Urine Drug Screens at Week 4 and 8 | Use of alcohol and other drugs of abuse (e.g., cocaine, other stimulants, cannabis, benzodiazepines), by urine drug screens. | Post Induction Phase: Week 4 and Week 8 | 
| Proportion of Participants That Receive Second and Third Injection of XR-NTX (at 1 Month and 2 Months, From First Injection) | Retention in the trial to receive the second and the third XR-NTX injections. | Post Induction Phase: Week 4 and Week 8 |