Effect of Sublingual Formulation of Dexmedetomidine HCl (BXCL501) - Alcohol Interaction Study

NCT ID: NCT04827056

Last Updated: 2023-10-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-09
• Study Completion Date: 2023-06-02

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.

Conditions

Alcohol Use Disorder (AUD); Post Traumatic Stress Disorder (PTSD)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 40µg

BXCL501 is a thin film formulation of dexmedetomidine (DEX) for sublingual (SL) administration. The product is a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to solubilize in the SL space within 1-3 minutes. At the time of dosing, subjects will be verbally instructed on how to take the investigational product sublingually, and that they should retain the investigational product in the sublingual cavity until dissolved.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Placebo will be administered orally, as individual films in the SL space.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 40µg

Intervention Type: DRUG

BXCL 501 40µg will be administered orally, as individual films in the SL space.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 80µg

Intervention Type: DRUG

BXCL 501 80µg will be administered orally, as individual films in the SL space.

Ethanol Infusion

Intervention Type: PROCEDURE

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%).

PTSD Reactivity Condition

Intervention Type: BEHAVIORAL

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).

Alcohol Cue Reactivity

Intervention Type: BEHAVIORAL

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.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 80µg

BXCL501 is a thin film formulation of dexmedetomidine (DEX) for sublingual (SL) administration. The product is a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to solubilize in the SL space within 1-3 minutes. At the time of dosing, subjects will be verbally instructed on how to take the investigational product sublingually, and that they should retain the investigational product in the sublingual cavity until dissolved.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Placebo will be administered orally, as individual films in the SL space.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 40µg

Intervention Type: DRUG

BXCL 501 40µg will be administered orally, as individual films in the SL space.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 80µg

Intervention Type: DRUG

BXCL 501 80µg will be administered orally, as individual films in the SL space.

Ethanol Infusion

Intervention Type: PROCEDURE

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%).

PTSD Reactivity Condition

Intervention Type: BEHAVIORAL

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).

Alcohol Cue Reactivity

Intervention Type: BEHAVIORAL

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.

Placebo

Placebo and study drug will look exactly the same in order to maintain the double-blind; study drug and placebo are administered exactly the same.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo will be administered orally, as individual films in the SL space.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 40µg

Intervention Type: DRUG

BXCL 501 40µg will be administered orally, as individual films in the SL space.

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 80µg

Intervention Type: DRUG

BXCL 501 80µg will be administered orally, as individual films in the SL space.

Ethanol Infusion

Intervention Type: PROCEDURE

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%).

PTSD Reactivity Condition

Intervention Type: BEHAVIORAL

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).

Alcohol Cue Reactivity

Intervention Type: BEHAVIORAL

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.

Interventions

Placebo

Placebo will be administered orally, as individual films in the SL space.

Intervention Type: DRUG

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 40µg

BXCL 501 40µg will be administered orally, as individual films in the SL space.

Intervention Type: DRUG

Dexmedetomidine (DEX) for sublingual (SL) administration (BXCL501) - 80µg

BXCL 501 80µg will be administered orally, as individual films in the SL space.

Intervention Type: DRUG

Ethanol Infusion

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%).

Intervention Type: PROCEDURE

PTSD Reactivity Condition

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).

Intervention Type: BEHAVIORAL

Alcohol Cue Reactivity

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.

Intervention Type: BEHAVIORAL

Other Intervention Names

BXCL501 40µg; BXCL501 80µg

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

Congressionally Directed Medical Research Programs

FED

Sponsor Role: collaborator

RTI International

OTHER

Sponsor Role: collaborator

VA Connecticut Healthcare System

FED

Sponsor Role: collaborator

BioXcel Therapeutics Inc

INDUSTRY

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: collaborator

Pharmacotherapies for Alcohol and Substance Use Disorders Alliance

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ismene Petrakis, MD

Role: PRINCIPAL_INVESTIGATOR

VA Connecticut Healthcare System

Locations

VA Connecticut Healthcare System

West Haven, Connecticut, United States

Countries

United States

Other Identifiers

W81XWH1820044

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

AS170014-A7

Identifier Type: -

Identifier Source: org_study_id