Auricular Neurostimulation for Opioid Use Disorder
(RESTORE Trial)
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Spark Biomedical, Inc.
Must be taking: Opioid antagonists
Must not be taking: Long-acting opioids
Disqualifiers: Uncontrolled conditions, Epilepsy, Neurological diseases, others
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?The primary objective of this trial is to determine whether tAN can improve relapse prevention beyond that seen with extended-release injectable naltrexone during Phase II.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does exclude those using long-acting opioids like methadone or buprenorphine for five or more consecutive days before joining. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug for opioid use disorder?
Research shows that extended-release injectable naltrexone (XR-NTX) is effective for treating opioid use disorder by reducing opioid use and increasing adherence due to its once-a-month administration, which helps overcome the compliance issues seen with daily oral naltrexone.
12345Is extended-release injectable naltrexone safe for humans?
Extended-release injectable naltrexone (Vivitrol) is generally well tolerated in humans, with studies showing it has a stable safety profile. It has been used for treating alcohol and opioid dependence, and while there are concerns about overdose risk after stopping the treatment, it is considered safe when used as directed.
12678How is the drug extended-release injectable naltrexone unique for treating opioid use disorder?
Extended-release injectable naltrexone is unique because it is given as a once-a-month injection, which helps improve patient adherence compared to daily oral naltrexone. This formulation maintains stable levels of the drug in the body, reducing the rewarding effects of opioids and helping prevent relapse.
123910Eligibility Criteria
This trial is for adults aged 18-65 with current opioid dependence, experiencing mild to moderate withdrawal. They must be English-speaking, able to consent and participate fully in the study. Excluded are those not switching to opioid antagonist medication post-detox, with neurological issues or ear problems, on long-term opioids like methadone, pregnant or breastfeeding women without proper contraception, and anyone at risk due to other health conditions.Inclusion Criteria
I can understand and agree to the study's requirements.
Participant shows signs of current opioid dependence; prescription or non-prescription
Participant COWS score is ≥ 8 or in the opinion of the investigator the participant is in mild to moderate withdrawal at the baseline assessment
+2 more
Exclusion Criteria
Participant has recent suicide attempt leading to current hospital admission or continued expressed suicidal ideation
I have an ear infection or my ear structure is not typical.
Participant has any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase I: Acute Detoxification
Participants undergo acute detoxification in a residential detox center with different treatment groups for 7 days.
1 week
Daily visits in residential setting
Phase II: Relapse Prevention
Participants are re-randomized into treatment groups and receive extended-release injectable naltrexone or active tAN + naltrexone. Weekly visits for 90 days.
13 weeks
Weekly visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests if transcutaneous auricular neurostimulation (tAN) can better prevent relapse in opioid addiction when added to extended-release injectable naltrexone treatment. Participants will also receive Sparrow Ascent Therapy System and Lofexidine during Phase II of the study.
6Treatment groups
Experimental Treatment
Active Control
Placebo Group
Group I: Active tAN + extended-release injectable naltrexoneExperimental Treatment2 Interventions
Extended-release injectable naltrexone will be administered according to the clinical site's standard of care. Participants will be provided with a Spark Sparrow Ascent Therapy System and instructed to administer therapy according to the specified frequencies:
* Month 1 (Days 1 - 28): a minimum of 2 hours per day at least 5 days a week
* Month 2 (Days 29 - 56): a minimum of 2 hours per day at least 3 days a week
* Month 3 (Days 57 - 90: a minimum of 2 hours per day at least 1 day per week
Group II: Active tAN + lofexidineActive Control2 Interventions
tAN will be delivered at a duty cycle of for 5 minutes ON and 10 seconds OFF for up to 168 hours (7 days) therapy duration. Stimulation intensity will be customized to the participants comfort level and within range of therapeutic effectiveness. Participants will receive 3 lofexidine 0.18 mg/tablets four times per day (daily dose of 2.16 mg) for 7 days.
Group III: Sham tAN + placeboActive Control1 Intervention
Participants will have the earpiece applied and the cable connected to the Patient Controller, but tAN stimulation will not be turned on. Participants will receive 3 placebo pills four times per day for 7 days. The placebo will appear similar to lofexidine in size, shape, color, and smell to lofexidine.
Group IV: extended-release injectable naltrexoneActive Control1 Intervention
Extended-release injectable naltrexone will be administered according to the clinical site's standard of care.
Group V: Sham tAN + lofexidinePlacebo Group1 Intervention
Participants will have the earpiece applied and the cable connected to the Patient Controller, but tAN stimulation will not be turned on. Participants will receive 3 lofexidine 0.18 mg/tablets four times per day (daily dose of 2.16 mg) for 7 days.
Group VI: Active tAN + placeboPlacebo Group1 Intervention
tAN will be delivered at a duty cycle of for 5 minutes ON and 10 seconds OFF for up to 168 hours (7 days) therapy duration. Stimulation intensity will be customized to the participants comfort level and within range of therapeutic effectiveness. Participants will receive 3 placebo pills four times per day for 7 days. The placebo will appear similar to lofexidine in size, shape, color, and smell to lofexidine.
Extended-release injectable naltrexone is already approved in United States for the following indications:
🇺🇸 Approved in United States as Vivitrol for:
- Prevention of relapse to opioid dependence following opioid detoxification
- Alcohol dependence
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Gaudenzia, Inc.Baltimore, MD
Gaudenzia, Inc.Crownsville, MD
Hazelden Betty Ford FoundationRancho Mirage, CA
Hazelden Betty Ford FoundationCenter City, MN
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Who Is Running the Clinical Trial?
Spark Biomedical, Inc.Lead Sponsor
Hazelden Betty Ford FoundationCollaborator
Gaudenzia, Inc.Collaborator
References
Extended-release injectable naltrexone for opioid use disorder: a systematic review. [2019]Label="AIMS">To review systematically the published literature on extended-release naltrexone (XR-NTX, Vivitrol® ), marketed as a once-per-month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR-NTX; (2) what are adherence rates to XR-NTX; and (3) does XR-NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined.
The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence. [2019]Oral naltrexone, a nonselective opioid antagonist, is approved for the treatment of alcohol and opioid dependence. However, the efficacy of oral naltrexone is limited by poor patient compliance. To overcome this limitation, attempts have been made to develop an injectable extended-release formulation of naltrexone, including encapsulation into biodegradable polymer microspheres (e.g. Medisorb Naltrexone, Vivitrex (naltrexone long acting injection)). In 1980, NIDA established development goals that they considered optimal for an extended-release formulation. At Alkermes, different formulations were tested with in vitro assays and in vivo models to select a lead formulation. Pharmacokinetic studies in rats confirmed that the principle formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately one month following a single injection. The pharmacodynamic effects (antagonism of morphine analgesia) of extended-release naltrexone corresponded well with the pharmacokinetic profile from the same animals. While brain mu-opioid receptor density was found to increase over time in these rats, it did not appear to affect the ability of naltrexone to suppress morphine analgesia. Finally the pharmacokinetic profile of extended-release naltrexone in monkeys confirmed long duration of elevated plasma concentrations of naltrexone. Both naltrexone and the PLG polymer matrix in which it is encapsulated are well tolerated. Clinical trials of Vivitrex are currently ongoing in alcohol dependent patients.
Naltrexone extended-release injection: an option for the management of opioid abuse. [2021]The United States Food and Drug Administration (FDA) approved naltrexone, a synthetic competitive antagonist at opioid receptors, in oral form in 1984 for use in the management of opioid abuse and addiction. Because naltrexone and its major metabolite, 6-β-naltrexone, are both competitive antagonists at opioid receptors - and thereby inhibit opioid agonist-induced effects including those desired by abusers - it was hypothesized that once maintained on naltrex-one, opioid-induced desirable effects would be diminished to the point that relapse to illicit use would decline because it was no longer rewarding. However, good medication compliance is a requisite for such a strategy to be effective and a systematic review of oral naltrexone concluded that this method of treatment was not superior for any outcomes measured (ie, retention, abstinence, or side effects) to placebo, psychotherapy, benzodiazepines, or buprenorphine treatment. In addition, the retention rate on oral naltrexone was very low (less than 30%). Recently, the FDA approved an extended-release formulation (intramuscular depot injection) of naltrexone for prevention of relapse to opioid dependence following opioid detoxification and to be used along with counseling and social support. Since it needs to be administered only monthly, as opposed to the daily administration required for the oral formulation, naltrexone injection has the potential for increasing adherence and retention rates. Concerns include liver damage at high doses (oral formulation) and possible opioid overdose if an attempt is made to surmount receptor antagonism by taking higher doses of an opioid agonist or if opioid receptors become "sensitized" under long-term antagonism. The focus of the present review is the current information regarding the safety and efficacy of naltrexone extended-release therapy.
Patient characteristics associated with initiation of XR-naltrexone for opioid use disorder in clinical trials. [2023]Extended-release injectable naltrexone (XR-naltrexone) is effective for treatment of patients with opioid use disorder (OUD), but initiation remains a barrier due to the challenge of tolerating opioid withdrawal prior to administration. Understanding factors associated with successful initiation of XR-naltrexone could facilitate its implementation through patient-treatment matching.
Opioid use and dropout from extended-release naltrexone in a controlled trial: implications for mechanism. [2022]Extended-release formulations of naltrexone have emerged as effective treatment options for opioid use disorder. This post-hoc analysis examined the temporal relationship between episodes of opioid use and subsequent dropout in a placebo-controlled trial of extended-release injection naltrexone (XR-NTX) to draw inferences about the mechanism by which extended blockade of opioid receptors translates into clinical effectiveness.
[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. [2016]To evaluate efficacy and safety of injectable extended-release naltrexone (XR-NTX, Vivitrol), an opioid receptor antagonist, in the treatment of opioid dependence, we carried out a 1-year open-label extension study.
Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. [2019]Label="INTRODUCTION">An extended-release injectable naltrexone suspension (Vivitrol®) was approved in USA in 2010 for the prevention of relapse to opioid dependence. Concerns, raised at the time of approval, about rebound overdose risk following the last dose, have not been adequately studied. We sought to determine the time period of concern for fatal overdose associated with Vivitrol.
Long-acting injectable naltrexone for the treatment of alcohol dependence. [2013]Combining pharmacotherapy with psychosocial and behavioral interventions has helped improve the treatment of alcohol dependence. However, the clinical use of effective medications, such as naltrexone, is limited by poor adherence to a daily oral regimen. Recently, a once monthly extended-release injectable formulation of naltrexone (Vivitrol, Alkermes, Inc.) became the first FDA-approved long-acting formulation of naltrexone for alcohol dependence. Compared with the oral preparation, extended-release naltrexone shows reduced peaks and minimal fluctuations in plasma levels that may possibly lead to a more benign adverse-event profile. The administration of long-acting naltrexone in conjunction with psychosocial support has been associated with significant improvement in drinking outcome measures, especially among patients who are abstinent entering treatment. Additional studies are warranted to increase the knowledge on the clinical applications of long-acting naltrexone in other addictive disorders and to compare extended-release naltrexone with other long-acting formulations that are in development. The clinical availability of extended-release naltrexone has the potential to enhance treatment outcomes for alcohol and other drug dependence disorders.
A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence. [2018]Naltrexone implants are used to treat opioid dependence, but their safety and efficacy remain poorly understood. We systematically reviewed the literature to assess the safety and efficacy of naltrexone implants for treating opioid dependence.
Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats. [2015]While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [(3)H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [(3)H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.