Clinical trial NCT04827056: Effect of Sublingual Formulation of Dexmedetomidine HCl (BXCL501) - Alcohol Interaction Study
Official title: Effect of Sublingual Formulation of Dexmedetomidine HCl (BXCL501) on Ethanol in Heavy Drinkers With PTSD - Alcohol Interaction Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alcohol Use Disorder (AUD)
Post Traumatic Stress Disorder (PTSD)
Keywords: Alcohol Used Disorder (AUD)
Post Traumatic Stress Disorder
Alcohol Use
Heavy Drinkers
Dexmedetomidine HCl (BXCL501)
Lead sponsor: Pharmacotherapies for Alcohol and Substance Use Disorders Alliance
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
name: Congressionally Directed Medical Research Programs
name: RTI International
name: VA Connecticut Healthcare System
name: BioXcel Therapeutics Inc
name: Yale University
First posted: 2021-04-01
Enrollment: 10
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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).
Primary purpose: OTHER

Brief 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female, Veterans and non-Veterans, ages 21 to 65;
2. Able to read and write in English and sign the informed consent;
3. Willing to comply with all study procedures and be available for the duration of the study;
4. ECG that demonstrates no clinically significant conduction issues or arrhythmias;
5. Have no clinically significant contraindications, in the judgement of the PI/study physician, for study participation (based on self-reported medical history and brief physical examination);
6. Have a current diagnosis of Alcohol use disorder (AUD) (mild, moderate, or severe) as determined by MINI-5
7. Have a traumatic event in their lifetime that meets Criterion A for PTSD;
8. Must have \> 1 heavy drinking episodes (\>4 standard drink units (SDU) for men; \>3 SDU for women) in the last 30 days (assessed by the Timeline Follow Back (TLFB)).
9. Not be treatment seeking for AUD
10. Females of childbearing potential (not surgically sterilized (tubal ligation/hysterectomy) or not post-menopausal (no menstrual period for \> 6 months) must be willing to use a medically acceptable and effective birth control method for 3 months before the study and while participating in the study. Medically acceptable methods of contraception that may be used by the participant include abstinence, birth control pills or patches, birth control implants, diaphragm, intrauterine device (IUD), or condoms.

Exclusion Criteria:

1. Current bipolar disorder or psychotic disorders as determined by MINI-5;
2. Current diagnosis of a substance use disorder (other than alcohol, nicotine, or marijuana) as determined by MINI-5;
3. Females who are pregnant, nursing, or planning to become pregnant during study participation;
4. Current physiological alcohol dependence requiring a higher level of care (e.g. detox) as determined by study physician conducting physical examination and CIWA score. Tolerance to alcohol will be allowed.
5. Recent history of complicated alcohol withdrawal, alcohol withdrawal seizures, or delirium tremens (DTs);
6. Score \> 4 on Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) at randomization;
7. History of major medical illnesses including liver disease, heart disease, chronic pain or other medical conditions that the physician investigator deems contraindicated for the participant to be in the study;
8. Clinically significant history of cardiac disease including (a) chronic hypertension (even if adequately controlled by antihypertensive medications); (b) history of syncope or other syncopal attacks; (c) current evidence of orthostatic hypotension (defined as a decrease in systolic BP of 20 mm Hg or decrease in diastolic BP of 10mm Hg within 3 minutes); (d) resting heart rate of \<60 beats per minute; (e) systolic blood pressure \<110mmHg or diastolic BP \<70mmHg; or (f) participants with a QTC interval \>440msec (males) or \>460msec (females).
9. Clinically significant medical conditions including hepatic ascites (bilirubin \>10% above the upper limit of normal \[ULN\] or liver function tests \[LFT\] \>3 × ULN);
10. Renal impairment as measured by BUN/Creatinine;
11. Currently taking the following medications: a) medications for alcoholism (e.g. naltrexone, disulfiram, topiramate, acamprosate); b) psychotropic medications that promote sedation including sedative/hypnotics, barbiturates, antihistamines, sedative antidepressants (e.g. doxepin, mirtazapine, trazodone), and triptans (e.g., sumatriptan); c) antihypertensive medications; d) alpha-2-adrenergic agonists (clonidine, guanfacine, lofexidine); or adrenergic agents prescribed for other reasons are excluded (prazosin). (Permitted Concomitant Medications: The concomitant medications allowed in the study include non-sedative antidepressants used to treat PTSD);
12. History of allergic reactions to dexmedetomidine or known allergy to dexmedetomidine;
13. Participation in a clinical trial of a pharmacological agent within 30 days prior to screening;
14. Any finding that, in the view of the principal investigator, would compromise the subject's ability to fulfill the study visit schedule or requirements

Primary outcomes:
measure: Change in anxiety, as measured by blood pressure (systolic and diastolic), by treatment group during stress reactivity conditions.
timeFrame: On each Test Day (1-3), from baseline (prior to stress condition) to the end of the PTSD stress reactivity conditions
measure: Change in anxiety, as measured by heart rate, by treatment group during stress reactivity conditions.
timeFrame: On each Test Day (1-3), from baseline (prior to stress condition) to the end of the PTSD stress reactivity conditions .
measure: Change in anxiety, as measured by the State Trait Anxiety Inventory (STAI-6), by treatment group during stress reactivity conditions.
timeFrame: On each Test Day (1-3), from baseline (prior to stress condition) to the end of the PTSD stress reactivity conditions.
measure: Change in alcohol craving, as measured by the Yale Craving Scale (YCS), by treatment group during stress reactivity conditions.
timeFrame: On each Test Day (1-3), from baseline (prior to stress condition) to the end of the PTSD stress reactivity conditions.
measure: Change in mood disturbance, as measured by Drugs Effects Questionnaire (DEQ), by treatment group during stress reactivity conditions.
timeFrame: On each Test Day (1-3), from baseline (prior to stress condition) to the end of the PTSD stress reactivity conditions.
measure: Change in mood disturbance, as measured by Visual Analog Scale (VAS), by treatment group during stress reactivity conditions.
timeFrame: On each Test Day (1-3), from baseline (prior to stress condition) to the end of the PTSD stress reactivity conditions.
measure: Change in anxiety, as measured by blood pressure (systolic and diastolic), by treatment group during alcohol cue induced craving.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol reactivity conditions) to assessments conducted immediately after the alcohol reactivity conditions.
measure: Change in anxiety, as measured by heart rate, by treatment group during alcohol cue induced craving.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol reactivity conditions) to assessments conducted immediately after the alcohol reactivity conditions.
measure: Change in anxiety, as measured by the State Trait Anxiety Inventory (STAI-6), by treatment group during alcohol cue induced craving.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol reactivity conditions) to assessments conducted immediately after the alcohol reactivity conditions.
measure: Change in alcohol craving, as measured by the Yale Craving Scale (YCS), by treatment group during alcohol cue induced craving.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol reactivity conditions) to assessments conducted immediately after the alcohol reactivity conditions.
measure: Change in mood disturbance, as measured by Drugs Effects Questionnaire (DEQ), by treatment group during alcohol cue induced craving.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol reactivity conditions) to assessments conducted immediately after the alcohol reactivity conditions.
measure: Change in mood disturbance, as measured by Visual Analog Scale (VAS), by treatment group during alcohol cue induced craving.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol reactivity conditions) to assessments conducted immediately after the alcohol reactivity conditions.
measure: Evaluate whether pretreatment with BXCL501 alters subjective effects, as measured by the Biphasic Alcohol Effects Scale (BAES), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion start) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters subjective effects, as measured by the Number of Drinks Scale (NDS), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion start) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters subjective effects, as measured by the State Trait Anxiety Inventory (STAI-6), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion start) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters subjective effects, as measured by the Drug Effects Questionnaire (DEQ), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion start) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters subjective effects, as measured by the Yale Craving Scale (YCS), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion start) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters subjective effects, as measured by the Visual Analog Scale (VAS), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion start) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters motor impairment, as measured by the Grooved Pegboard (GPB), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to drug administration) to assessments conducted immediately after the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters cognitive functioning, as measured by the Rapid Information Processing Task (RVIP), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to drug administration) to the RVIP assessment conducted immediately after the targeted BAL is reached during the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters cognitive functioning, as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to drug administration) to the HVLT-R assessment conducted immediately after the targeted BAL is reached during the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 alters cognitive functioning, as measured by the Go No-Go Task, in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to drug administration) to the Go No-Go assessment conducted immediately after the targeted BAL is reached during the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 increases side effects, as measured by blood pressure (systolic and diastolic), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion) to the blood pressure measurement taken after completion of the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 increases side effects, as measured by heart rate, in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion) to the heart rate measurement taken after completion of the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 increases side effects, as measured by the Richmond Agitation Sedation Scale (RASS), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion) to the RASS measurement taken after completion of the alcohol infusion.
measure: Evaluate whether pretreatment with BXCL501 increases side effects, as measured by the Agitation-Calmness Evaluation Scale (ACES), in the presence of ethanol.
timeFrame: On each Test Day (1-3), from baseline (prior to alcohol infusion) to the ACES measurement taken after completion of the alcohol infusion.
Secondary outcomes:
Other outcomes:
Locations:
city: West Haven
country: United States
facility: VA Connecticut Healthcare System
state: Connecticut
Study officials:
affiliation: VA Connecticut Healthcare System
name: Ismene Petrakis, MD
role: PRINCIPAL_INVESTIGATOR
References: