Evaluation of the O'Neil Long Acting Naltrexone Implant in Opioid Dependent Persons

Study Overview
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Brief Summary
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This study will examine the safety and efficacy of the O'Neil Long Acting Naltrexone Implant (OLANI) in persons with opioid dependency who are seeking relapse-prevention treatment. All participants will be treated in an open label manner. No randomization will occur. The OLANI is a long-acting biodegradable form of naltrexone which is implanted in the abdominal region. It is hypothesized that the OLANI will produce blood levels sufficient to block the effects of opioids for an extended period allowing patients to engage in psychosocial treatment and recovery over the long term. After the initial set of implants, participants will be offered a second set of implants after 13-24 weeks.

Detailed Description
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This is a Phase II, multi-center, open-label study designed to evaluate the safety profile and the efficacy of the OLANI when used in participants who meet the diagnosis of opioid use disorder (OUD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and who will be voluntarily seeking relapse-prevention treatment using the naltrexone (NTX) implant. Participants eligible for the study have diagnosed OUD, have completed withdrawal from opioids, and are no longer physically dependent at the time of study enrollment. After completing the informed consent process for the study, all participants will receive their initial OLANI set (two implants) implanted subcutaneously by a study surgeon and will be followed by a medical and surgical research team, receiving medical management intervention and blood draws to measure levels of NTX and its metabolite, 6-beta-naltrexol (6BN). For interested participants, a second implant set will be offered, with placement 13-24 weeks after the initial procedure, after which all participants will be followed for an additional 24 weeks.

Official Title
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A Phase II Multi-Center Safety Study Examining the Use of the O'Neil Long Acting Naltrexone Implant (OLANI) in Opioid Dependent Persons Receiving Repeat Dosing

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: naltrexone implant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women between 18 and 65 (inclusive) years old Meet criteria for a current (within the previous 12-months) DSM-5 diagnosis of OUD at screening, and voluntarily seeking relapse-prevention treatment with NTX implant Completed opioid withdrawal as demonstrated by a negative naloxone challenge test (i.e., has tolerated naloxone 0.8 mg) Individuals currently treated with NTX will be eligible to receive the implant at the end of the dosing interval of either Vivitrol or oral NTX Have no medical or psychiatric contraindications to treatment either with NTX or with the OLANI, as determined by the site clinician and based on medical history and current health status Able to sufficiently speak and understand English and understand study procedures Able and willing to provide written informed consent Able and willing to provide detailed contact information for both self and for close contact(s) on the locator form Able and willing to comply with the requirements and procedures of the protocol, including tolerating a minor surgical procedure with local anesthetic for placement of the implant sets into the subcutaneous tissue of the abdomen Have an initial weight between 45.3 and 130 kg (inclusive) or have a BMI of 18.5 to 35.0 (inclusive) For female participants of childbearing potential, a willingness to practice an effective method of birth control for the duration of participation in the study. Acceptable methods of birth control are specified on the data collection form and in the Manual of Procedures (MOP), and methods other than those specified are not permitted, except in combination with a study-acceptable method; and willingness to complete urine pregnancy testing to confirm non-pregnant status, as per the study schedule and as requested by the site clinician. Exclusion Criteria: Has a condition, disease state, previous medical history, or observed abnormality(ies) (including physical examination, electrocardiogram [ECG], laboratory evaluation, or urinalysis finding) identified during screening that, in the opinion of the site clinician, would preclude safe participation in the study, would affect the ability of the participant to adhere to the protocol, or would interfere with the study assessments, including, but not limited to the following: A significant neurological (including cognitive and psychiatric disorders), hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematologic, or metabolic disease, unless currently controlled and stable using protocol-allowed medication(s) for the 30 days immediately preceding the proposed administration of OLANI Has had significant suicidal ideation or behavior within the past year Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value more than three times the upper limit of normal, or a different indicator of clinically significant liver cirrhosis (e.g., bilirubin and albumin will also be assessed) Has a condition (e.g., chronic pain) that requires ongoing treatment with opiate based medication Has any contraindicated medical condition per the approved labelling for NTX containing products Has physiological dependence on alcohol and/or sedative-hypnotics that require medical detoxification If female, is currently pregnant or breastfeeding, is planning to conceive during the period of study engagement, has a positive blood pregnancy test, or is unwilling to practice effective contraception during study participation Has a known hypersensitivity to NTX Is not able to provide blood samples due to extensive vein damage Has a known hypersensitivity to polylactic acid based materials, including disposable sutures or implants Has a known hypersensitivity to local anesthesia Is prone to skin rashes, skin irritation, or has a diagnosed or observed skin condition (e.g., recurrent eczema) Is tattooed in the proposed implantation area or demonstrates any abnormal skin tissue in the proposed implantation area Currently confined or detained in a penal institution or sentenced to such an institution under a criminal or civil statute or detained in other facilities by virtue of statutes. Any additional condition(s) that, in the investigator's opinion, would prohibit the participant from completing the study or that would not be in the best interest of the participant.

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OLANI (naltrexone implant)<br>2 OLANI implants containing 60% naltrexone (3.6 g total NXT) administered at Day 0 with repeat dosing at Week 13 to 24 | Drug: naltrexone implant<br>* 3.6 g per implant set each containing 60% naltrexone<br>* Other names: O'Neil Long Acting Naltrexone Implant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Emergent Adverse Events (TEAEs) | Incidence and Severity of TEAEs | time from from placement of first implant set until immediately before placement of the second implant set (or 24 weeks after first implant set) | 
| Treatment Emergent Adverse Events (TEAEs) | Incidence and Severity of TEAEs | 24 weeks after second implant set | 
| Treatment Emergent Adverse Events (TEAEs) | Incidence and Severity of TEAEs | through Week 48 | 
| Adverse Events of Special Interest (AESI) | Incidence of AESIs related to the surgical procedure and local reaction to the implant over time | time from from placement of first implant set until immediately before placement of the second implant set (or 24 weeks after first implant set) | 
| Adverse Events of Special Interest (AESI) | Incidence of AESIs related to the surgical procedure and local reaction to the implant over time | 24 weeks after second implant set | 
| Adverse Events of Special Interest (AESI) | Incidence of AESIs related to the surgical procedure and local reaction to the implant over time | through Week 48 | 
| Deaths | Incidence of study deaths | through Week 48 | 
| Serious Adverse Events (SAEs) | Incidence of SAEs | time from from placement of first implant set until immediately before placement of the second implant set (or 24 weeks after first implant set) | 
| Serious Adverse Events (SAEs) | Incidence of SAEs | 24 weeks after second implant set | 
| Serious Adverse Events (SAEs) | Incidence of SAEs | through Week 48 | 
| Adverse events (AEs) causing study discontinuation | AEs that lead to study discontinuation | through Week 48 | 
| Opioid overdose events | Incidence of opioid overdose events | time from placement of first implant set until immediately before placement of the second implant set (or 24 weeks after first implant set) | 
| Opioid overdose events | Incidence of opioid overdose events | 24 weeks after second implant set | 
| Opioid overdose events | Incidence of opioid overdose events | through Week 48 | 
| Laboratory abnormalities | Incidence and Severity of lab abnormalities | through Week 48 | 
| Suicidality | incidence of suicidal ideation and suicidal behavior captured with the Columbia-Suicide Severity Rating Scale (C-SSRS) | through Week 48 | 
| Concomitant medications | Proportion of participants who initiate concomitant medications | through Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t of naltrexone | area under the plasma concentration-time curve from 0 to the time of last measurable concentration (AUC0-t) | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| AUC0-t of 6-beta-naltrexol | area under the plasma concentration-time curve from 0 to the time of last measurable concentration (AUC0-t) | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| AUC0-infinity of naltrexone | area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity) | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| AUC0-infinity of 6-beta-naltrexol | area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity) | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| Cmax of naltrexone | Single-dose pharmacokinetic (PK) measurement of the plasma naltrexone concentration (Cmax) after dosing on Day 1 | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| Cmax of 6-beta-naltrexol | Single-dose PK measurement of the plasma 6-beta-naltrexol concentration (Cmax) after dosing on Day 1 | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| Tmax of naltrexone | Single-dose PK measurement of the time to reach the maximum plasma naltrexone concentration (Tmax) after dosing on Day 1 | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| Tmax of 6-beta-naltrexol | Single-dose PK measurement of the time to reach the maximum plasma naltrexone concentration (Tmax) after dosing on Day 1 | collected before each implant administration (pre-dose), and 3 hours, 7 days, 14 days, 28 days, then every 14 days after implant administration until second implant procedure or Week 24 | 
| Proportion of participants that maintain a minimum plasma concentration (13 weeks) | Proportion of participants who maintain NTX blood levels of ≥2 ng/mL for ≥13 weeks | up to Week 48 | 
| Proportion of participants that maintain a minimum plasma concentration (24 weeks) | Proportion of participants who maintain NTX blood levels of ≥2 ng/mL for ≥24 weeks | up to Week 48 | 
| Abstinence from drugs of abuse by UDS | Proportion of participants who maintain abstinence from opioids, benzodiazepines; barbiturates; cocaine; amphetamine; methamphetamine; phencyclidine (PCP); ecstasy (MDMA); and marijuana (THC) as measured through a urine drug screen (UDS) | pre-dose (prior to each implant procedure), Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Abstinence from drugs of abuse by Timeline Followback (TLFB) | Proportion of participants who maintain abstinence from opioids, benzodiazepines; barbiturates; cocaine; amphetamine; methamphetamine; phencyclidine (PCP); ecstasy (MDMA); and marijuana (THC) as measured through a urine drug screen (UDS) | Baseline, Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Abstinence from alcohol | Proportion of participants who maintain abstinence from alcohol as measured using and alcohol breathalyzer | pre-dose (prior to each implant procedure), Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Opioid craving (VAS) | The craving for opioids will be measured using a horizontal visual analog scale (VAS), which ranges from 0 (no craving) to 10 (most intense craving possible). | Baseline, pre-dose prior to implant (Day 0), Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Opioid withdrawal (SOWS) | The SOWS is a 16-item questionnaire designed to measure the severity of opioid withdrawal symptoms. The participant rates the intensity of symptoms using a 5-point scale; with 0 representing not at all and 4 representing extremely. | pre-dose prior to implant (Day 0), Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Opioid withdrawal (COWS) | The COWS is a questionnaire designed to measure 11 common opioid withdrawal signs and symptoms. The summed score provides information about the severity of opioid withdrawal and the level of physical dependence on opioids. Total scores range from 0 to 47, and withdrawal is classified as mild (5-12), moderate (13-24), moderately severe (25-36), or severe (>36) | pre-dose prior to implant (Day 0), Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Hamilton Depression Rating Scale (HDRS) | Assessment of Depression/Mood via the HDRS, is a clinician-administered instrument, useful for following both depression and suicidal ideation, and for following typical symptoms of subacute withdrawal (e.g., low appetite, fatigue, poor sleep). A score of 1 or more to item 3 (suicidality) prompts a clinician assessment for suicide risk before leaving the clinic. | Baseline, Day 7, Day 14, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Brief Symptom Inventory 18 (BSI-18) | Assessment of Depression/Mood via the BSI-18; comprising 18 items (ranging from 0 = not at all to 4 = extremely), assesses psychiatric symptoms in three distinct domains: depression, anxiety, and somatization. The total score ranges from 0 to 72 with higher scores indicating higher symptom severity. | Baseline, Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Quality of Life Score (QoL) | Quality of life as measured through Quality of Life Enjoyment and Satisfaction Questionnaire (short form). is a 16 item self-administered questionnaire that captures life satisfaction over the past week. Each question is rated on a 5 point scale from 1 (Very Poor) to 5 (Very Good). Scores from the individual items are added together and reported as percentage maximum possible score. The Total Score is reported as percentage maximum possible % Max = Raw-minimum score/maximum score-minimum score. (Raw score minus the minimum possible raw score divided by the maximum possible raw score minus the minimum possible raw score). If items are left blank the maximum and minimum scores must be modified to reflect the number of items scored. | Day 28, Day 42, Day 56, then every 28 days until second implant procedure or Week 48 | 
| Treatment Satisfaction (TSQM-14) | The TSQM-14 is comprised of 14 questions that provide scores on four scales: effectiveness (3 items), side effects (5 items), convenience (3 items) and global satisfaction (3 items). With the exception of item 4 (presence of side effects; yes or no), all items have five or seven responses, scored from one (least satisfied) to five or seven (most satisfied). Item scores are summed to give four domain scores, which are in turn transformed to a scale of 0-100 | Before second implant and Week 37 to 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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naltrexone, opioids, OLANI implant, opioid use disorder, opioid dependence, opioid receptor antagonist