Effect of Sublingual Formulation of Dexmedetomidine HCl (BXCL501) - Alcohol Interaction Study
Condition: Alcohol Use Disorder (AUD); Post Traumatic Stress Disorder (PTSD)
MeSH terms: Alcoholism; Stress Disorders, Traumatic; Alcohol Drinking; Stress Disorders, Post-Traumatic
Study type: Interventional
Phase: Phase 1

Summary: 
      The overall objective of the proposed study is to determine if Dexmedetomidine HCl (BXCL501)
      is safe for treatment of alcohol use disorder (AUD) with comorbid posttraumatic stress
      disorder (PTSD) and also shows potential signals of efficacy thereby supporting the conduct
      of later phase clinical trials. Safety endpoints will be compared following an alcohol
      challenge without and concurrent with BXCL501 treatment.
    

Detailed description: 
      BXCL501 is a sublingual film containing dexmedetomidine. Dexmedetomidine is an alpha-2
      adrenergic receptor agonist and has higher intrinsic activity and is more potent in vitro
      than either clonidine or lofexidine. The drug has a high free brain to free plasma ratio
      after dosing in rats that persists after plasma concentrations are cleared. Dexmedetomidine
      does not depress respiratory function. It is not predicted to have abuse potential. BXCL501
      will bypass 1st pass metabolism and produce fewer problems in participants with compromised
      liver function.

      This laboratory study is a phase 1, double-blind, placebo-controlled, within subjects study.
      This study will consist of 3 laboratory test sessions following pretreatment with
      BXCL501/placebo for 10 heavy drinker participants with comorbid PTSD. Participants (n=10)
      will participate in a laboratory study with 3 test days (minimum of 2 days, but no longer
      than 2 weeks between each test session); for each test day they will be assigned to receive
      sublingual BXCL501 40µg, 80µg and placebo in a randomized fashion. Test sessions will be
      conducted to evaluate stress (PTSD) reactivity and alcohol cue reactivity. Participants will
      also receive IV ethanol administered via "clamp methodology" to assess for the effects of
      BXCL501 in combination with ethanol.

      Since this is the first time BXCL501 is being tested in combination with alcohol
      administration, the study team will be using a modified randomization where participants will
      not receive the 80µg dose until they have received the 40µg dose.
    

Intervention name(s): Placebo; Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 40µg; Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 80µg; Ethanol Infusion; PTSD Reactivity Condition; Alcohol Cue Reactivity
Intervention type(s): Drug; Drug; Drug; Procedure; Behavioral; Behavioral
Intervention description(s): Placebo will be administered orally, as individual films in the SL space.; BXCL 501 40µg will be administered orally, as individual films in the SL space.; BXCL 501 80µg will be administered orally, as individual films in the SL space.; Study team will be using a modified alcohol-IV clamp procedure developed and standardized by Subramanian and colleagues (Subramanian, Heil et al. 2002). The infusion will be performed using a 6% ethanol solution in 0.9% saline. The computer assisted administration program automatically calculates and corrects the infusion rate based on real-time BrAC data entry by staff, based on the pharmacokinetic profile of each subject (targeting a breath alcohol concentration (BrAC) of 100 mg%).; Participants will be exposed to two conditions in random order: PTSD cues and neutral cues. The cues will consist of a 5 minute presentation of the stimulus (trauma or neutral) followed by immediate evaluation of craving and anxiety. There will be a relaxation procedure between each condition. The imagery scripts are developed based on the scene construction questionnaire developed by Lang et al (Lang, Kozak et al. 1980, Lang, Levin et al. 1983) using a standardized format designed by Sinha (Sinha 2001).; Participants will be exposed to two conditions: a neutral cue (water) followed by an alcohol cue. Individuals will be instructed that they may smell and handle the beverage, but they cannot consume the beverage. Following the presentation, the research assistant takes the beverage and leaves the room, while the subject completes the anxiety and alcohol craving assessments.
Other intervention name(s): BXCL501 40µg; BXCL501 80µg
Intervention MeSH terms: Ethanol; Dexmedetomidine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: All participants will be randomized to receive BXCL501 40µg, 80µg or placebo in a modified crossover randomization scheme in which all participants will receive each possible study drug assignment but must receive 40µg before receiving the higher dose (80µg).
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Other
Keywords: Alcohol Used Disorder (AUD); Post Traumatic Stress Disorder; Alcohol Use; Heavy Drinkers; Dexmedetomidine HCl (BXCL501)