Dexmedetomidine in the Treatment of Symptoms Of Acute Opioid Withdrawal

NCT04470050 | Completed Phase 1 Results FDA Drug

• 1 other identifier: BXCL501-201
• Study Type: interventional
• Target: 225
• Locations: 1 country
• Sites: 3

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.

Conditions

Opioid Withdrawal

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

Outcome Measures

Primary Outcomes (1)

• Peak SOWS Scores at Baseline and Over Time

  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.

  Baseline (pre-dose day 6) and at days 6, 7, 8, 9, 10, 11, 12, 13, and 14 post-dose

Secondary Outcomes (6)

• 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

• 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

• 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

• Time to Drop-out After Discontinuation of Opioid Maintenance Phase

  Day 6 through Day 14

• Number and Percentage of Subject Drop-out After Discontinuation of Opioid Maintenance Phase Maintenance Within Each Treatment Group

  Day 6 through Day 14

Study Arms (6)

Cohort 1- Dexmedetomidine (30 Micrograms) vs. Placebo

EXPERIMENTAL

Sublingual film containing 30 Micrograms Dexmedetomidine or Placebo Sublingual film

Drug: Dexmedetomidine; Drug: Placebo

Cohort 2- Dexmedetomidine (60 Micrograms) vs. Placebo

EXPERIMENTAL

Sublingual film containing 60 Micrograms Dexmedetomidine or Placebo Sublingual film

Drug: Dexmedetomidine; Drug: Placebo

Cohort 3- Dexmedetomidine (90 Micrograms) vs. Placebo

EXPERIMENTAL

Sublingual film containing 90 Micrograms Dexmedetomidine or Placebo Sublingual film

Drug: Dexmedetomidine; Drug: Placebo

Cohort 4- Dexmedetomidine (120 Micrograms) vs. Placebo

EXPERIMENTAL

Sublingual film containing 120 Micrograms Dexmedetomidine or Placebo Sublingual film

Drug: Dexmedetomidine; Drug: Placebo

Cohort 5- Dexmedetomidine (180 Micrograms) vs. Placebo

EXPERIMENTAL

Sublingual film containing 180 Micrograms Dexmedetomidine or Placebo Sublingual film

Drug: Dexmedetomidine; Drug: Placebo

Cohort 6- Dexmedetomidine (240 Micrograms) vs. Placebo

EXPERIMENTAL

Sublingual film containing 240 Micrograms Dexmedetomidine or Placebo Sublingual film

Drug: Dexmedetomidine; Drug: Placebo

Interventions

Dexmedetomidine DRUG

Sublingual Film of Dexmedetomidine

Also known as: BXCL501

Cohort 1- Dexmedetomidine (30 Micrograms) vs. Placebo; Cohort 2- Dexmedetomidine (60 Micrograms) vs. Placebo; Cohort 3- Dexmedetomidine (90 Micrograms) vs. Placebo; Cohort 4- Dexmedetomidine (120 Micrograms) vs. Placebo; Cohort 5- Dexmedetomidine (180 Micrograms) vs. Placebo; Cohort 6- Dexmedetomidine (240 Micrograms) vs. Placebo

Placebo DRUG

Sublingual Placebo film

Also known as: Placebo comparator

Cohort 1- Dexmedetomidine (30 Micrograms) vs. Placebo; Cohort 2- Dexmedetomidine (60 Micrograms) vs. Placebo; Cohort 3- Dexmedetomidine (90 Micrograms) vs. Placebo; Cohort 4- Dexmedetomidine (120 Micrograms) vs. Placebo; Cohort 5- Dexmedetomidine (180 Micrograms) vs. Placebo; Cohort 6- Dexmedetomidine (240 Micrograms) vs. Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects who are 18 years of age to less than 65 years of age.
• Meets criteria for moderate to severe opioid use disorder as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) with physiological dependence as evidenced by a Clinical Opiate Withdrawal (COWS) score of \>5 or a positive naloxone challenge upon admission on Day 1.
• Subjects who can read, understand, and provide written informed consent. Women of childbearing potential must have a negative pregnancy test and agree to be abstinent or use an acceptable method of contraception for the duration of the study.

You may not qualify if:

• Positive urine pregnancy test at screening or when tested or currently breast feeding.
• Clinically significant history of cardiac disease, screening and baseline heart rate of \<55 beats per minutes or systolic blood pressure \<110 mmHg or diastolic blood pressure \<70 mmHg.
• History or presence of a significant medical disease or disorder which, in the opinion of the investigator, increases the risk or may confound the interpretation of study measures, as confirmed by screening laboratory results.
• Hepatic dysfunction (marked by ascites, or bilirubin \>10% above the upper limit of normal \[ULN\] or liver function tests \>3 x ULN) at the screening visit.
• Acute active Hepatitis B or C as evidenced by positive serology and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2 x ULN.
• Clinically significant abnormal ECG findings such as second- or third-degree heart block, uncontrolled arrhythmia, or QTcF (Fridericia correction formula) interval \>450 msec for males, and \>470 msec for females at screening or prior to dosing.
• Any psychiatric disorder that would compromise ability to complete study requirements.
• Currently meets DSM-5 criteria for substance abuse disorder, moderate or severe for any substance other than opioids, caffeine, or nicotine and/or current physical dependence on drugs that pose risk of withdrawal that requires medical management such as alcohol or benzodiazepines.
• History of suicidal behavior within the last 1 year prior to screening.
• Participation in a clinical trial of a non-FDA-approved pharmacological agent within 30 days prior to screening.
• Use of any excluded medication at screening or anticipated/required use during the study period.
• Subjects with a history of intolerance to morphine.
• Any finding that, in the view of the principal investigator, would compromise the subject's ability to fulfill the protocol visit schedule or visit requirements.

Sponsors & Collaborators

• BioXcel Therapeutics Inc: lead
• Cognitive Research Corporation: collaborator

Study Sites (3)

BioXcel Clinical Research Site

Miami Lakes, Florida, 33016, United States

Location

BioXcel Clinical Research Site

Marlton, New Jersey, 08053, United States

Location

BioXcel Clinical Research Site

New York, New York, 10032, United States

Location

Related Publications (1)

• Jones JD, Rajachandran L, Yocca F, Risinger R, De Vivo M, Sabados J, Levin FR, Comer SD. Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial. Am J Drug Alcohol Abuse. 2023 Jan 2;49(1):109-122. doi: 10.1080/00952990.2022.2144743. Epub 2023 Jan 11.

  PMID: 36630319 BACKGROUND

MeSH Terms

Conditions

Opioid-Related Disorders; Morphine Dependence; Psychomotor Agitation

Interventions

Dexmedetomidine

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Vice President Head of Clinical Operations
• Organization: Bioxcel Therapeutics

cgommoll@bioxceltherapeutics.com

(475) 355 5177

Study Officials

• Robert Risinger, MD

  Chief Medical Officer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Phase 1b: morphine maintenance, blinded to BXCL501 sublingual treatment (placebo). Phase 2: Randomized, Double-blind, placebo-controlled (4:1, active to placebo ratio, respectively). Follow-On portion of Phase 2: Double-blind, placebo-controlled (treatment with morphine-placebo capsules and BXCL501-placebo sublingual films as administered during phase 1b)
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 1, 2020
• First Posted: July 14, 2020
• Study Start: June 9, 2020
• Primary Completion: February 18, 2021
• Study Completion: February 18, 2021
• Last Updated: October 26, 2023
• Results First Posted: October 26, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)