Dexmedetomidine in the Treatment of Symptoms Of Acute Opioid Withdrawal

Study Overview
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Brief Summary
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This Phase 1b/2 inpatient study assessed the safety, pharmacokinetics, and early signs of efficacy of escalating doses of BXCL501 versus placebo following discontinuation of morphine maintenance. The opioid (morphine) maintenance phase (Phase 1b) included Days 1-5; the randomized BXCL501/placebo phase (Phase 2) included Days 6-12. The randomized phase was followed by 2 sequential days, Days 13 and 14, utilizing treatment of BXCL501-placebo sublingual films and morphine-placebo capsules for all subjects who remained in the study.

Detailed Description
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This Study included two phases, Phase 1b and Phase 2. Phase 1b was the morphine maintenance phase, Days 1 through 5 and Phase 2 was the randomized, double-blind, placebo-controlled, ascending-dose study of BXCL501 sublingual films on Days 6-12 to treat symptoms of acute opioid withdrawal in patients with opioid use disorder who are/were physically dependent on opioids. Day 12 was followed by 2 sequential days (Days 13 and 14) of BXCL501 vs. placebo and morphine vs. placebo treatment for all subjects who remained in the study. After a 30-day screening period, eligible male and female adult subjects with Opioid Use Disorder (OID) who were physically dependent on opioids and were not seeking treatment for opioid withdrawal symptoms were admitted to an inpatient unit. The opioid maintenance phase of the study (Phase 1b, Days 1-5) began on Day 1 and continued through Day 5. Approximately 225 subjects were enrolled in the Phase 1b study in cohorts (approximately 25 subjects/cohort). All subjects enrolled in the Phase 1b portion of the study received oral morphine capsules. The total dose of morphine during the opioid maintenance phase varied at the discretion of the investigator, ranged between 120 mg and 150 mg per day, depending on patients abuse history and need for higher dose to stabilize withdrawal symptoms. In addition, these subjects received placebo sublingual films approximately 12 hours apart to simulate and thus blind treatment of BXCL501 during Phase 2 of the study (Days 6-12). Abrupt discontinuation of active morphine began on Day 6 (Phase 2) and subjects were randomized in a 4:1 ratio to receive either BXCL501 sublingual films or placebo sublingual films, respectively. 135 subjects enrolled/rolled over from the Phase 1b portion of the study into the randomized, double-blind, placebo-controlled portion of the study (Phase 2). Subjects were treated according to their assigned, randomized treatment from Day 6 through Day 12. Treatment was administered approximately 12 hours apart at approximately 8am (±30 minutes) and 8pm (±30 minutes); the 2nd dose (evening dose) was administered only to subjects that were hemodynamically stable, not hypotensive (must be greater than 110/70 diastolic/systolic), and not bradycardic (must be greater than 55 beats per minute (bpm)). Subjects were not given the second dose if they were orthostatic (a drop of 20 points in either systolic blood pressure (SBP) or 10 points in Diastolic Blood Pressure (DBP)) or if they were experiencing an Adverse Event (AE) that when assessed by the Investigator. If a subject experienced SBP <90 mmHg; or DBT <60 millimeters of mercury (mmHg); or Heart Rate (HR) <50 bpm, immediately prior to the next dose, administration of the study medication for that subject was withheld until resolution of the BP and HR parameters. The administration hold did not exceed 2 hours. Safety and tolerability were monitored continuously and summarized upon completion of each cohort by medical safety review. Studies of opioid withdrawal with placebo arms are likely to have high dropout rates, thus, the dropouts prior to Day 6 could be replaced to ensure enough sample size entering the treatment phase in Phase 2. Dropouts after Day 6 were not to be replaced. The study was intended to be flexible and adaptable, and as such, the dosing frequency, the doses, and the number of cohorts of BXCL501 allowed for change based on ongoing safety review and medical monitoring of safety, tolerability, and efficacy data after each dose-escalating cohort. Phase 2 evaluated 6 cohorts (n=25 subjects per cohort according to the 4:1 randomization ratio; n= 20 active BXCL501 and n=5 placebo). The following doses were administered: 30 µg (Cohort 1), 60 µg (Cohort 2), 90 µg (Cohort 3), 120 µg (Cohort 4), and 180 µg (Cohort 5). The dose for Cohort 6 (240 μg) was determined from data acquired from Cohorts 1-5 and Cohort 6 was activated prior to the end of the study. Other evaluations during the study included establishing the preliminary efficacy of multiple BXCL501 doses relative to placebo and evaluation of pharmacokinetics (PK) in subjects undergoing opiate withdrawal.

Official Title
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A Phase 1b/2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study of BXCL501 to Treat Symptoms of Acute Opioid Withdrawal in Patients With Opioid Use Disorder Who Are Physically Dependent on Opioids

Conditions
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Opioid Withdrawal

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male and female subjects who are 18 years of age to less than 65 years of age. Meets criteria for moderate to severe opioid use disorder as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) with physiological dependence as evidenced by a Clinical Opiate Withdrawal (COWS) score of >5 or a positive naloxone challenge upon admission on Day 1. Subjects who can read, understand, and provide written informed consent. Women of childbearing potential must have a negative pregnancy test and agree to be abstinent or use an acceptable method of contraception for the duration of the study. Exclusion Criteria Positive urine pregnancy test at screening or when tested or currently breast feeding. Clinically significant history of cardiac disease, screening and baseline heart rate of <55 beats per minutes or systolic blood pressure <110 mmHg or diastolic blood pressure <70 mmHg. History or presence of a significant medical disease or disorder which, in the opinion of the investigator, increases the risk or may confound the interpretation of study measures, as confirmed by screening laboratory results. Hepatic dysfunction (marked by ascites, or bilirubin >10% above the upper limit of normal [ULN] or liver function tests >3 x ULN) at the screening visit. Acute active Hepatitis B or C as evidenced by positive serology and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2 x ULN. Clinically significant abnormal ECG findings such as second- or third-degree heart block, uncontrolled arrhythmia, or QTcF (Fridericia correction formula) interval >450 msec for males, and >470 msec for females at screening or prior to dosing. Any psychiatric disorder that would compromise ability to complete study requirements. Currently meets DSM-5 criteria for substance abuse disorder, moderate or severe for any substance other than opioids, caffeine, or nicotine and/or current physical dependence on drugs that pose risk of withdrawal that requires medical management such as alcohol or benzodiazepines. History of suicidal behavior within the last 1 year prior to screening. Participation in a clinical trial of a non-FDA-approved pharmacological agent within 30 days prior to screening. Use of any excluded medication at screening or anticipated/required use during the study period. Subjects with a history of intolerance to morphine. Any finding that, in the view of the principal investigator, would compromise the subject's ability to fulfill the protocol visit schedule or visit requirements.

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
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1b: The blinded opioid maintenance phase (Days 1 to 5). Doses of morphine during Phase 1b varied at the discretion of the investigator, between 120-150 mg per day, depending on patients abuse history and need for a higher dose to stabilize withdrawal symptoms. In addition to morphine maintenance, all subjects received sublingual placebo films, approximately 12 hours apart, at 8 am and 8 pm (30min) during this period to simulate and thus blind treatment to BXCL501 sublingual films during Days 6 to 12 (Phase 2). Phase 2: The randomized BXCL501/placebo phase (both active and placebo administered as sublingual films) occurred on Days 6 to 12, followed by 2 days of BXCL501-placebo sublingual film and morphine-placebo capsule treatment for all remaining subjects on Days 13 and 14 following the dosing timeline as administered in the Phase 1b portion of the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1- Dexmedetomidine (30 Micrograms) vs. Placebo<br>Sublingual film containing 30 Micrograms Dexmedetomidine or Placebo Sublingual film | Drug: Dexmedetomidine<br>* Sublingual Film of Dexmedetomidine<br>* Other names: BXCL501;Drug: Placebo<br>* Sublingual Placebo film<br>* Other names: Placebo comparator;|
| Experimental: Cohort 2- Dexmedetomidine (60 Micrograms) vs. Placebo<br>Sublingual film containing 60 Micrograms Dexmedetomidine or Placebo Sublingual film | Drug: Dexmedetomidine<br>* Sublingual Film of Dexmedetomidine<br>* Other names: BXCL501;Drug: Placebo<br>* Sublingual Placebo film<br>* Other names: Placebo comparator;|
| Experimental: Cohort 3- Dexmedetomidine (90 Micrograms) vs. Placebo<br>Sublingual film containing 90 Micrograms Dexmedetomidine or Placebo Sublingual film | Drug: Dexmedetomidine<br>* Sublingual Film of Dexmedetomidine<br>* Other names: BXCL501;Drug: Placebo<br>* Sublingual Placebo film<br>* Other names: Placebo comparator;|
| Experimental: Cohort 4- Dexmedetomidine (120 Micrograms) vs. Placebo<br>Sublingual film containing 120 Micrograms Dexmedetomidine or Placebo Sublingual film | Drug: Dexmedetomidine<br>* Sublingual Film of Dexmedetomidine<br>* Other names: BXCL501;Drug: Placebo<br>* Sublingual Placebo film<br>* Other names: Placebo comparator;|
| Experimental: Cohort 5- Dexmedetomidine (180 Micrograms) vs. Placebo<br>Sublingual film containing 180 Micrograms Dexmedetomidine or Placebo Sublingual film | Drug: Dexmedetomidine<br>* Sublingual Film of Dexmedetomidine<br>* Other names: BXCL501;Drug: Placebo<br>* Sublingual Placebo film<br>* Other names: Placebo comparator;|
| Experimental: Cohort 6- Dexmedetomidine (240 Micrograms) vs. Placebo<br>Sublingual film containing 240 Micrograms Dexmedetomidine or Placebo Sublingual film | Drug: Dexmedetomidine<br>* Sublingual Film of Dexmedetomidine<br>* Other names: BXCL501;Drug: Placebo<br>* Sublingual Placebo film<br>* Other names: Placebo comparator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak SOWS Scores at Baseline and Over Time | Short Opiate Withdrawal Scale (SOWS)-Gossop: The SOWs scale is a validated 10-item patient-reported scale designed to measure the symptoms of withdrawal in subjects who are dependent on opioids. Each of the 10 items represents a symptom: feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, and insomnia/problems sleeping. Scores on the SOWS-Gossop can range from 0 to 30, with higher scores indicating greater severity of withdrawal symptoms. | Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak COWS Score at Baseline and Over Time | Clinical Opiate Withdrawal Scale (COWS): The COWS scale is a validated, 11-item questionnaire designed to quantify withdrawal symptoms. Symptoms evaluated include resting pulse rate, sweating, restlessness, pupil size, bone or joint aches, runny nose or tearing, gastrointestinal upset, tremor, yawning, anxiety or irritability, and gooseflesh. COWS total scores range from 0 to 48, with 5 to 12 indicating mild symptoms, 13 to 24 indicating moderate symptoms, 25 to 36 indicating moderately severe symptoms, and greater than 36 indicating severe symptoms. | Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose | 
| Average COWS Scores at Baseline and Over Time | Clinical Opiate Withdrawal Scale (COWS): The COWs scale is a validated, 11-item questionnaire designed to quantify withdrawal symptoms. Symptoms evaluated include resting pulse rate, sweating, restlessness, pupil size, bone or joint aches, runny nose or tearing, gastrointestinal upset, tremor, yawning, anxiety or irritability, and gooseflesh. COWS total scores range from 0 to 48, with 5 to 12 indicating mild symptoms, 13 to 24 indicating moderate symptoms, 25 to 36 indicating moderately severe symptoms, and greater than 36 indicating severe symptoms. | Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose | 
| Average SOWS at Baseline and Over Time | Short Opiate Withdrawal Scale (SOWS)-Gossop: The SOWs scale is a validated 10-item patient-reported scale designed to measure the symptoms of withdrawal in subjects who are dependent on opioids.5 Each of the 10 items represents a symptom: feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, and insomnia/problems sleeping. Scores on the SOWS-Gossop can range from 0 to 30, with higher scores indicating greater severity of withdrawal symptoms. | Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose | 
| Time to Drop-out After Discontinuation of Opioid Maintenance Phase | Time to drop-out during double-blind treatment phase after discontinuation of opioid maintenance Phase. | Day 6 through Day 14 | 
| Number and Percentage of Subject Drop-out After Discontinuation of Opioid Maintenance Phase Maintenance Within Each Treatment Group | Number and Percentage of Subject Drop-out after Discontinuation of Opioid Maintenance Phase Within Each Treatment Group Between Days 6-14. | Day 6 through Day 14 | 
| Total ACES Total Score Over Time - 2 hr. Post-First Dose | Overall Agitation-Calmness Evaluation Scale (ACES): The ACES scale is a single-item measure rating overall agitation and sedation, ranging from 1 (marked agitation) to 9 (unarousable). This outcome measures the total ACES total score over time at 2 hours, post-first dose. | Post-Dose Day 6 to Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Morphine Addiction, delta-opioid receptors, Inhibition of nociceptive afferent neurons (PNS System), Reduction of nociceptive transmission, Activation of descending inhibitory pathways (CNS System), Analgesic Opioids, Drug craving, μ-δ-opioid (Mu-Delta) receptor, Opioid, Opioid Addiction, Opioid Dependance, Opioid Withdrawal Symptoms, Opioid Withdrawal Syndrome, μ-binding (Mu receptors), afferents within laminae I and II, κ-opioid receptor (KOR), δ-opioid receptor (DOR) agonist, (+)-pentazocine, σ receptor antagonists, Downstream involvement of the σ receptor, Increase phosphorylation in p38 MAPK, IL-10, Activation of IL-12, IL-12 increase in T-cell immune response, pentacyclic 3°amine (alkaloid), stereogenic centers, tetrahydroisoquinoline reticuline, CPY2D6, benzylisoquinoline alkaloid, p38 MAPK-dependent pathway, kappa-opioid receptors, Short Opiate Withdrawal Scale (SOWS)-Gossop, Clinical Opiate Withdrawal Scale (COWS), Agitation and Calmness Evaluation Scale (ACES), Discontinuation of Morphine Maintenance