Dexmedetomidine in the Treatment of Symptoms Of Acute Opioid Withdrawal
- Registration Number
- NCT04470050
- Lead Sponsor
- BioXcel Therapeutics Inc
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 225
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1- Dexmedetomidine (30 Micrograms) vs. Placebo Placebo Sublingual film containing 30 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 1- Dexmedetomidine (30 Micrograms) vs. Placebo Dexmedetomidine Sublingual film containing 30 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 2- Dexmedetomidine (60 Micrograms) vs. Placebo Placebo Sublingual film containing 60 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 3- Dexmedetomidine (90 Micrograms) vs. Placebo Placebo Sublingual film containing 90 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 4- Dexmedetomidine (120 Micrograms) vs. Placebo Dexmedetomidine Sublingual film containing 120 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 4- Dexmedetomidine (120 Micrograms) vs. Placebo Placebo Sublingual film containing 120 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 5- Dexmedetomidine (180 Micrograms) vs. Placebo Dexmedetomidine Sublingual film containing 180 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 5- Dexmedetomidine (180 Micrograms) vs. Placebo Placebo Sublingual film containing 180 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 6- Dexmedetomidine (240 Micrograms) vs. Placebo Dexmedetomidine Sublingual film containing 240 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 6- Dexmedetomidine (240 Micrograms) vs. Placebo Placebo Sublingual film containing 240 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 2- Dexmedetomidine (60 Micrograms) vs. Placebo Dexmedetomidine Sublingual film containing 60 Micrograms Dexmedetomidine or Placebo Sublingual film Cohort 3- Dexmedetomidine (90 Micrograms) vs. Placebo Dexmedetomidine Sublingual film containing 90 Micrograms Dexmedetomidine or Placebo Sublingual film
- Primary Outcome Measures
Name Time Method Peak SOWS Scores at Baseline and Over Time Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose 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.
- Secondary Outcome Measures
Name Time Method Average COWS Scores at Baseline and Over Time Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose 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.
Number and Percentage of Subject Drop-out After Discontinuation of Opioid Maintenance Phase Maintenance Within Each Treatment Group Day 6 through Day 14 Number and Percentage of Subject Drop-out after Discontinuation of Opioid Maintenance Phase Within Each Treatment Group Between Days 6-14.
Average SOWS at Baseline and Over Time Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose 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.
Time to Drop-out After Discontinuation of Opioid Maintenance Phase Day 6 through Day 14 Time to drop-out during double-blind treatment phase after discontinuation of opioid maintenance Phase.
Peak COWS Score at Baseline and Over Time Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose 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.
Total ACES Total Score Over Time - 2 hr. Post-First Dose Post-Dose Day 6 to Day 12 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.
Trial Locations
- Locations (1)
BioXcel Clinical Research Site
🇺🇸New York, New York, United States