Auricular Neurostimulation for Opioid Use Disorder

(RESTORE Trial)

Recruiting at 4 trial locations

Overseen By Mary Lilly, RN

Age: 18+

Sex: Any

Trial Phase: Academic

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 This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

108 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 6 7 8}

How 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. ^{1 2 3 9 10}

Eligibility 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

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

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

Treatment Details

Interventions

• Extended-release injectable naltrexone
• Lofexidine
• Naltrexone Injection
• Sparrow Ascent Therapy System
• Sparrow Therapy System

Trial Overview 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.

Participant Groups

Group I: Active tAN + extended-release injectable naltrexone Experimental Treatment 2 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 + lofexidine Active Control 2 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 + placebo Active Control 1 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 naltrexone Active Control 1 Intervention

Extended-release injectable naltrexone will be administered according to the clinical site's standard of care.

Group V: Sham tAN + lofexidine Placebo Group 1 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 + placebo Placebo Group 1 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

Who Is Running the Clinical Trial?

Spark Biomedical, Inc.

Lead Sponsor

Trials

14

Recruited

560+

Hazelden Betty Ford Foundation

Collaborator

Trials

3

Recruited

220+

Gaudenzia, Inc.

Collaborator

Trials

1

Recruited

170+

Findings from Research

Induction success for extended-release naltrexone (XR-NTX) is significantly lower in individuals requiring opioid detoxification (62.6%) compared to those already detoxified (85.0%), indicating that detoxification status is crucial for treatment initiation.

Adherence to XR-NTX is relatively low, with only 44.2% of individuals completing all scheduled injections, and adherence rates are notably higher in controlled research settings compared to routine care, which limits the overall effectiveness of XR-NTX in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release injectable naltrexone for opioid use disorder: a systematic review. Jarvis, BP., Holtyn, AF., Subramaniam, S., et al.[2019]

Injectable extended-release naltrexone, developed using biodegradable polymer microspheres, maintains stable plasma levels for about one month after a single injection, which could improve patient compliance compared to oral formulations.

Pharmacokinetic studies in rats and monkeys showed that this formulation effectively antagonizes morphine analgesia without affecting the brain's mu-opioid receptor density, indicating its potential safety and efficacy in treating alcohol and opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence. Dean, RL.[2019]

The FDA-approved extended-release formulation of naltrexone, administered as a monthly injection, may improve adherence and retention rates in treating opioid dependence compared to the oral form, which has low compliance (less than 30%).

While naltrexone effectively reduces the rewarding effects of opioids to prevent relapse, there are safety concerns, including potential liver damage at high doses and risks of opioid overdose if individuals attempt to overcome the drug's antagonistic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone extended-release injection: an option for the management of opioid abuse. Taylor, R., Raffa, RB., Pergolizzi, JV.[2021]

In a study of 409 patients with opioid use disorder, 56% successfully initiated extended-release injectable naltrexone (XR-naltrexone), with higher success rates in inpatient settings (62%) compared to outpatient settings (48%).

Patients using more severe forms of opioids, such as heroin or speedballs, had significantly better initiation rates in inpatient settings, suggesting that this environment may be more effective for those with greater severity of addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient characteristics associated with initiation of XR-naltrexone for opioid use disorder in clinical trials. Shulman, M., Hu, MC., Sullivan, MA., et al.[2023]

In a 24-week trial involving 250 adults with opioid use disorder, extended-release naltrexone (XR-NTX) significantly reduced the risk of treatment dropout after episodes of opioid use compared to placebo, indicating its effectiveness in maintaining treatment adherence.

Patients receiving XR-NTX had a higher completion rate without positive urine drug tests (31%) compared to those on placebo (20%), suggesting that XR-NTX may help sustain abstinence, although the difference was not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioid use and dropout from extended-release naltrexone in a controlled trial: implications for mechanism. Nunes, EV., Bisaga, A., Krupitsky, E., et al.[2022]

In a 1-year open-label extension study involving 114 patients, injectable extended-release naltrexone (XR-NTX) demonstrated long-term efficacy, with 50.9% of participants remaining abstinent from opioids throughout the study.

The treatment was generally safe, with only 21.1% of patients reporting adverse events and no severe adverse events noted, although 16.7% experienced elevated liver function tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. Krupitsky, EM., Nunes, EV., Ling, W., et al.[2016]

A review of 263 cases related to Vivitrol (extended-release naltrexone) found that 84.6% of fatal overdoses occurred within two months after the last injection, highlighting a critical period for overdose risk.

The study suggests that there may be a link between Vivitrol discontinuation and increased overdose risk, indicating the need for further investigation and monitoring during this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. Saucier, R., Wolfe, D., Dasgupta, N.[2019]

The FDA-approved extended-release injectable formulation of naltrexone (Vivitrol) offers a promising alternative to daily oral medication for alcohol dependence, potentially improving adherence and treatment outcomes.

When combined with psychosocial support, long-acting naltrexone has shown significant improvements in drinking outcomes, particularly for patients who are abstinent at the start of treatment, suggesting its efficacy in managing alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting injectable naltrexone for the treatment of alcohol dependence. Mannelli, P., Peindl, K., Masand, PS., et al.[2013]

Naltrexone implants were found to be more effective than placebo and oral naltrexone in reducing opioid use, based on a systematic review of 5 randomized trials involving 576 participants.

However, the overall quality of evidence regarding the safety and efficacy of naltrexone implants is low, and no significant difference in opioid use was found when compared to methadone maintenance, indicating a need for better-designed studies before widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence. Larney, S., Gowing, L., Mattick, RP., et al.[2018]

The extended-release formulation of naltrexone (Vivitrex) provides stable plasma levels for about one month after injection, which could improve adherence and efficacy in treating alcohol and opiate dependencies.

In rat studies, this formulation effectively blocked morphine analgesia for 28 days, demonstrating its long-lasting antagonistic effects, while also increasing mu-opioid receptor density, suggesting a potential mechanism for its sustained action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats. Bartus, RT., Emerich, DF., Hotz, J., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Extended-release injectable naltrexone for opioid use disorder: a systematic review. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence. [2019]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Naltrexone extended-release injection: an option for the management of opioid abuse. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

Patient characteristics associated with initiation of XR-naltrexone for opioid use disorder in clinical trials. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Opioid use and dropout from extended-release naltrexone in a controlled trial: implications for mechanism. [2022]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. [2016]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Long-acting injectable naltrexone for the treatment of alcohol dependence. [2013]

9. Australia pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats. [2015]