Delivering Transcutaneous Auricular Neurostimulation to Improve Relapse Prevention in Opioid Use Disorder

Study Overview
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Brief Summary
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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.

Detailed Description
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This is a prospective, randomized, controlled, multi-center, clinical trial in which participants with a history of dependence on prescriptive or non-prescriptive opioids will be randomized 2:1 into one of four treatment groups during Phase I (acute detoxification, 7 days): Group 1: Active tAN + placebo Group 2: Active tAN + lofexidine Group 3: Sham tAN + placebo Group 4: Sham tAN + lofexidine Phase I will occur during the participant's treatment in a residential detox center. Participants will have the option to continue into Phase II of the trial at the conclusion of their stay in the residential detox treatment program. In Phase II, participants will be re-randomized 1:1 into one of two treatment groups and will return weekly for 90 days: Group 1: Extended-release injectable naltrexone Group 2: Active tAN + extended-release injectable naltrexone

Official Title
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Delivering Transcutaneous Auricular Neurostimulation to Improve Relapse Prevention in Opioid Use Disorder

Conditions
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Opioid-use Disorder, Opioid Withdrawal

Intervention / Treatment
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* Device: Sparrow Ascent Therapy System
* Drug: Lofexidine
* Drug: Extended-release injectable naltrexone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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 Participant is between 18 and 65 years of age Participant is English proficient Participant is able to provide informed consent and function at an intellectual level sufficient for study requirements Exclusion Criteria Participant presents current evidence of an uncontrolled and/or clinically significant medical condition or psychiatric condition Participant has a history of epileptic seizures Participant has a history of neurological diseases or traumatic brain injury Participants using long-acting opioids such as methadone or buprenorphine for a period of five or more consecutive days prior to enrollment Participant has recent suicide attempt leading to current hospital admission or continued expressed suicidal ideation Participant has presence of devices, e.g., pacemakers, cochlear prosthesis, neurostimulators Participant has abnormal ear anatomy or ear infection present Participant is unwilling to transition to opioid antagonist medication following acute detox treatment Subject has significant current suicidal ideation within 30 days prior to Screening as evidenced by answering yes to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at Screening, that, in the opinion of the investigator, warrants exclusion from the trial Women of childbearing potential, not using adequate contraception as per investigator judgment or not willing to comply with contraception for the duration of the study Females who are pregnant or lactating 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: This is a prospective, randomized, controlled, multi-center, clinical trial in which participants with a history of dependence on prescriptive or non-prescriptive opioids will be randomized 2:1 into one of four treatment groups during Phase I (acute detoxification). Phase I will occur during the participant's treatment in a residential detox center. Participants will have the option to continue into Phase II of the trial at the conclusion of their stay in the residential detox treatment program. In Phase II, participants will be re-randomized 1:1 into one of two treatment groups.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Active tAN + placebo<br>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. | Device: Sparrow Ascent Therapy System<br>* Transcutaneous auricular neurostimulation (tAN)<br>|
| Active Comparator: Active tAN + lofexidine<br>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. | Device: Sparrow Ascent Therapy System<br>* Transcutaneous auricular neurostimulation (tAN)<br>Drug: Lofexidine<br>* Participants will receive 3 lofexidine 0.18 mg/tablets four times per day (daily dose of 2.16 mg) for 7 days.<br>|
| No Intervention: Sham tAN + placebo<br>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. | |
| Sham Comparator: Sham tAN + lofexidine<br>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. | Drug: Lofexidine<br>* Participants will receive 3 lofexidine 0.18 mg/tablets four times per day (daily dose of 2.16 mg) for 7 days.<br>|
| Active Comparator: extended-release injectable naltrexone<br>Extended-release injectable naltrexone will be administered according to the clinical site's standard of care. | Drug: Extended-release injectable naltrexone<br>* Participants will receive extended-release injectable naltrexone based on the clinical site's standard of care.<br>|
| Experimental: Active tAN + extended-release injectable naltrexone<br>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 | Device: Sparrow Ascent Therapy System<br>* Transcutaneous auricular neurostimulation (tAN)<br>Drug: Extended-release injectable naltrexone<br>* Participants will receive extended-release injectable naltrexone based on the clinical site's standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 14-Panel Urine Drug Screen | In Phase II, participants will provide a weekly urine sample to determine if opioids have been used in the past week (in conjunction with a self-report). A urine drug screen cup will be used to detect presence of: Amphetamines, Buprenorphine, Benzodiazepines, Cocaine, Ethyl Glucuronide, Fentanyl, Synthetic Marijuana, Ecstasy, Methamphetamines, Methadone, Opiates / Morphine, Oxycodone, Cannabinoid (Marijuana), and Tramadol. The urine drug screen cup also contains a temperature strip to confirm appropriate temperature of the sample and an adulteration panel for determination of sample tampering. | Weekly throughout Phase II (13 weeks) | 
| Self-Report of Drug Use | In Phase II, participants will be asked weekly to self-report any use of opioids to determine if opioids have been used in the past week (in conjunction with a UDS sample). | Weekly throughout Phase II (13 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Opiate Withdrawal Scale (COWS) | The Clinical Opiate Withdrawal Scale (COWS) is an 11-item scale designed to be administered by a clinician. This tool can be used in both inpatient and outpatient settings to reproducibly rate common signs and symptoms of opiate withdrawal and monitor these symptoms over time. The summed score for the complete scale can be used to help clinicians determine the stage or severity of opiate withdrawal and assess the level of physical dependence on opioids. Scores range between 0 and 48 where total score is the sum of all the items. A higher score indicates more severe withdrawal symptoms. Scores between 5 and 12 indicate mild withdrawal, scores between 13 and 24 indicate moderate withdrawal, scores between 25 and 36 indicate moderately severe withdrawal and scores greater than 36 indicate severe withdrawal. A COWS score reduction of 15% or greater for a given individual is considered clinically significant. | 60 minutes after treatment initiation (Day 1, Phase I) | 
| Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) | The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings. The scale was derived from the original 32-item Opiate Withdrawal Scale to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The assessment is a self-administered test used for the assessment of opiate withdrawal symptoms. The scale contains ten items: yawning, muscular tension, runny eyes, muscle twitching, pains, and aches, feeling of coldness, stomach cramps, insomnia, heart pounding, and feeling sick, making it easy and rapid to administer. The tool has a 4-point rating scale: 0 for 'none,' 1 for 'mild,' 2 for 'moderate,' and 3 for 'severe', with scores ranging from 0 to 30. | 60 minutes after treatment initiation (Day 1, Phase I) | 
| Clinical Opiate Withdrawal Scale (COWS) | The Clinical Opiate Withdrawal Scale (COWS) is an 11-item scale designed to be administered by a clinician. This tool can be used in both inpatient and outpatient settings to reproducibly rate common signs and symptoms of opiate withdrawal and monitor these symptoms over time. The summed score for the complete scale can be used to help clinicians determine the stage or severity of opiate withdrawal and assess the level of physical dependence on opioids. Scores range between 0 and 48 where total score is the sum of all the items. A higher score indicates more severe withdrawal symptoms. Scores between 5 and 12 indicate mild withdrawal, scores between 13 and 24 indicate moderate withdrawal, scores between 25 and 36 indicate moderately severe withdrawal and scores greater than 36 indicate severe withdrawal. A COWS score reduction of 15% or greater for a given individual is considered clinically significant. | 6 hours after treatment initiation (Day 1, Phase I) | 
| Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) | The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings. The scale was derived from the original 32-item Opiate Withdrawal Scale to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The assessment is a self-administered test used for the assessment of opiate withdrawal symptoms. The scale contains ten items: yawning, muscular tension, runny eyes, muscle twitching, pains, and aches, feeling of coldness, stomach cramps, insomnia, heart pounding, and feeling sick, making it easy and rapid to administer. The tool has a 4-point rating scale: 0 for 'none,' 1 for 'mild,' 2 for 'moderate,' and 3 for 'severe', with scores ranging from 0 to 30. | 6 hours after treatment initiation (Day 1, Phase I) | 
| Clinical Opiate Withdrawal Scale (COWS) | The Clinical Opiate Withdrawal Scale (COWS) is an 11-item scale designed to be administered by a clinician. This tool can be used in both inpatient and outpatient settings to reproducibly rate common signs and symptoms of opiate withdrawal and monitor these symptoms over time. The summed score for the complete scale can be used to help clinicians determine the stage or severity of opiate withdrawal and assess the level of physical dependence on opioids. Scores range between 0 and 48 where total score is the sum of all the items. A higher score indicates more severe withdrawal symptoms. Scores between 5 and 12 indicate mild withdrawal, scores between 13 and 24 indicate moderate withdrawal, scores between 25 and 36 indicate moderately severe withdrawal and scores greater than 36 indicate severe withdrawal. A COWS score reduction of 15% or greater for a given individual is considered clinically significant. | Daily on Days 2-7 of Phase I | 
| Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) | The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings. The scale was derived from the original 32-item Opiate Withdrawal Scale to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The assessment is a self-administered test used for the assessment of opiate withdrawal symptoms. The scale contains ten items: yawning, muscular tension, runny eyes, muscle twitching, pains, and aches, feeling of coldness, stomach cramps, insomnia, heart pounding, and feeling sick, making it easy and rapid to administer. The tool has a 4-point rating scale: 0 for 'none,' 1 for 'mild,' 2 for 'moderate,' and 3 for 'severe', with scores ranging from 0 to 30. | Daily on Days 2-7 of Phase I | 
| Opioid Craving Scale (OCS) | The 3-item Opioid Craving Scale was adapted from the 3-item Cocaine Craving Scale for use with opioids. The original 5-item version was found to be valid and unidimensional among cocaine-dependent individuals. Participants are asked to answer the following three questions with responses ranging from 0-10, where 0 = Not at all and 10 = Extremely. Total possible score ranges from 0 to 30 with greater scores indicating higher opioid craving. How much do you currently crave opiates? In the past week, please rate how strong your desire to use opiates has been when something in the environment has reminded you of opiates? Please imagine yourself in the environment in which you previously used opiates. If you were in this environment today and if it were the time of day that you typically used opiates, what is the likelihood that you would use opiates today? | Weekly throughout Phase II (13 weeks) | 
| Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) | The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings. The scale was derived from the original 32-item Opiate Withdrawal Scale to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The assessment is a self-administered test used for the assessment of opiate withdrawal symptoms. The scale contains ten items: yawning, muscular tension, runny eyes, muscle twitching, pains, and aches, feeling of coldness, stomach cramps, insomnia, heart pounding, and feeling sick, making it easy and rapid to administer. The tool has a 4-point rating scale: 0 for 'none,' 1 for 'mild,' 2 for 'moderate,' and 3 for 'severe', with scores ranging from 0 to 30. | Weekly throughout Phase II (13 weeks) | 
| Proportion of patients who receive and tolerate an XR-NTX injection after acute detox treatment (Phase I) |  | One hour after receiving first XR-NTX injection (Phase II Day 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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auricular neurostimulation, vagus nerve stimulation, transcutaneous, withdrawal symptoms, relapse prevention