Dexmedetomidine in the Treatment of Symptoms Of Acute Opioid Withdrawal
Condition: Opioid Withdrawal
MeSH terms: Substance Withdrawal Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Dexmedetomidine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Sublingual Film of Dexmedetomidine; Sublingual Placebo film
Other intervention name(s): BXCL501; Placebo comparator
Intervention MeSH terms: Dexmedetomidine
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Opioid; Opioid Addiction; Opioid Dependance; Opioid Withdrawal Symptoms; Opioid Withdrawal Syndrome; 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; 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