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Sublingual Dexmedetomidine for Treating Opioid Withdrawal

Primary Purpose

Opioid Use Disorder, Opioid Withdrawal

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
BXCL501 (180 micrograms)
BXCL501 (240 micrograms)
Placebo
Lofexidine (Positive Control)
Sponsored by
New York State Psychiatric Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Opioid Use Disorder

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Capable of understanding and complying with the protocol. 18 years of age or older but less than 60 years old. Has opioid use disorder moderate-to-severe (304.00) as per DSM-V, and physiological dependence on opioids. Females agree to use an acceptable method of contraception for the duration of the study. Exclusion Criteria: Positive urine or serum pregnancy test at screening, after admission, planning to become pregnant during the course of the trial, or currently breast feeding. Clinically significant history of cardiac disease, including syncope, bradycardia, conduction abnormalities, orthostatic hypotension or blood pressure disorders. Heart rate and blood pressure at screening and baseline of < 50 beats per minute or systolic blood pressure <105, >150 mmHg or diastolic BP <70, >90 mmHg. Clinically significant medical condition or observed abnormalities (including: physical examination, hypotension, laboratory evaluation, and/or urinalysis findings). Clinically significant abnormal ECG such as second- or third-degree heart block, uncontrolled arrhythmia, or QTc interval > 450 msec for males, and > 470 msec for females. Evidence of hepatic abnormalities, including: ascites, bilirubin >10% above upper limit of normal and/or esophageal variceal disease, active hepatitis/aspartate aminotransferase, alanine aminotransferase >3x the upper limit of normal. Any psychiatric disorder that would compromise ability to complete study requirements [e.g. severe acute depression, active mania, or suicidality with specific plan and intent (assessed using the CSSRS)]. Not being able to provide a negative urine for methadone or buprenorphine at screening. Use of oral naltrexone for ≥7 consecutive days within 60 days prior to screening. Need for alcohol or benzodiazepine detoxification. Participation in a clinical trial of a pharmacological agent within 30 days prior to screening. Use of any concomitant medication at screening or anticipated/required use during the study period that the investigators feel may impact participant safety or interfere with the aims of the trial (e.g., daily licit or illicit benzodiazepine use). 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. Investigator-site personnel or immediate family of investigator-site personnel.

Sites / Locations

  • Yale UniversityRecruiting
  • ClinilabsRecruiting
  • New York State Psychiatric Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Active Comparator

Placebo Comparator

Arm Label

BXCL501 (180 micrograms)

BXCL501 (240 micrograms)

Lofexidine (Positive Control)

Placebo

Arm Description

The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.

The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.

The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.

The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.

Outcomes

Primary Outcome Measures

Adverse Events: BXCL501 versus Placebo and Lofexidine (Positive Control)
Establish the safety of BXCL501 relative to placebo and lofexidine in subjects with OUD who are physically dependent on opioids as measured by adverse events.

Secondary Outcome Measures

Full Information

First Posted
January 24, 2023
Last Updated
August 18, 2023
Sponsor
New York State Psychiatric Institute
Collaborators
BioXcel Therapeutics Inc, Yale University, Clinilabs, Inc., National Institute on Drug Abuse (NIDA)
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1. Study Identification

Unique Protocol Identification Number
NCT05712707
Brief Title
Sublingual Dexmedetomidine for Treating Opioid Withdrawal
Official Title
Phase 1B Study of Sublingual Dexmedetomidine, an Alpha 2 Adrenergic Agonist, for Treating Opioid Withdrawal
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 28, 2023 (Actual)
Primary Completion Date
January 30, 2025 (Anticipated)
Study Completion Date
April 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
New York State Psychiatric Institute
Collaborators
BioXcel Therapeutics Inc, Yale University, Clinilabs, Inc., National Institute on Drug Abuse (NIDA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
A major challenge to seeking treatment for opioid use disorder (OUD) is the withdrawal symptoms associated with cessation of opioid use. The signs and symptoms of the opioid withdrawal include irritability, anxiety, muscular and abdominal pains, chills, nausea, diarrhea, yawning, runny eyes and nose, sweating, sneezing, weakness, and insomnia. The current gold standard of treatment involves gradual reduction of the opioid drug dosage (tapering). However, as all opioids have potential for abuse and require careful dosing due to side effects (e.g., respiratory depression), a non-opioid medication to facilitate withdrawal severity would be of great value. Commonly used non-opioid medications like lofexidine have concerning side effects including sedation and low blood pressure. BioXcel Therapeutics has developed BXCL501 (dexmedetomidine: sublingual film) to reduce symptoms associated with opioid withdrawal. Dexmedetomidine is currently used as an intravenous anesthetic for its anxiety-reducing, sedative, and painrelief properties. The current study will seek to compare the safety and efficacy of BXCL501 relative to lofexidine and placebo in subjects with OUD who are physically dependent on opioids. Throughout a 7-day inpatient withdrawal period, opioid-dependent participants will receive sublingual BXCL501, placebo, or lofexidine. In comparison to lofexidine, dexmedetomidine is expected to have a superior safety profile with limited adverse effects on blood pressure and heart rhythm. Three sites will participate in this study: NYSPI, Clinilabs, Inc., and Yale University, but only NYSPI and Clinilabs will be governed by the NYSPI IRB.
Detailed Description
A major challenge to seeking treatment for OUD is the withdrawal syndrome associated with cessation of opioid use. Withdrawal symptoms include irritability, anxiety, muscular and abdominal pains, chills, nausea, diarrhea, yawning, lacrimation, sweating, sneezing, rhinorrhea, general weakness, and insomnia. The intensity of withdrawal symptoms is one of the most common barriers to entering and completing treatment for patients, particularly those who may be interested in maintenance therapy with naltrexone, an opioid antagonist, or buprenorphine, an opioid partial agonist. Because of the short half-life of most illicitly used opioid drugs, such as heroin, withdrawal symptoms reach peak intensity within two to four days after last use, and the duration of withdrawal symptoms usually lasts 7-12 days (Antoine et al., 2021; Cook, 2021). Currently, there are 2 major strategies to treat withdrawal symptoms after stopping opioid use: Gradual tapering using an opioid drug substitute (methadone or buprenorphine) and amelioration of withdrawal symptoms using alpha-2-adrenergic agonists and other non-opioid medications (benzodiazepines, nonsteroidal anti-inflammatory drugs, etc.) The current gold standard involves gradual reduction of the opioid drug dosage (tapering). The most common opioid withdrawal method is substituting and tapering with methadone or buprenorphine (Srivastava et al., 2020). These are opioid medications with longer half-lives than street opioids and result in more manageable withdrawal symptoms after stopping their use. However, buprenorphine and methadone can be diverted for illicit use, and is associated with adverse events such as respiratory depression, which could be further aggravated by concomitant drug and alcohol use in this population. Furthermore, discontinuation of opioid medications can lead to withdrawal symptoms. A non-opioid medication to facilitate withdrawal suppression from opioid discontinuation in OUD would be of great value. For over four decades, studies have demonstrated that norepinephrine regulates activity of locus coeruleus neurons, the same neurons that are affected by opioid drugs (Maze et al., 1988). In 1978, several groups reported early successful experience with the use of the alpha-2a-adrenergic agonist clonidine to treat symptoms of opioid withdrawal (Cedarbaum & Aghajanian, 1977; Gold et al., 1978), which has led to their widespread use for this indication. Opioid physical dependence and withdrawal are mediated at least in part by the interaction of mu-opioid receptors with neurons that contain the neurotransmitter norepinephrine. Activation of mu-opioid receptors normally suppresses the release of norepinephrine from the locus coeruleus. When opioid use is discontinued or blocked, the locus coeruleus releases excess norepinephrine, and this excess norepinephrine causes many of the withdrawal symptoms noted above. By administering an alpha-2a-adrenergic agonists (like lofexidine, clonidine and dexmedetomidine), hyperactivity of locus coeruleus neurons can be blocked and withdrawal symptoms reduced. Lofexidine is currently approved in the U.S. for the mitigation of withdrawal symptoms during discontinuation from use of opioids under the brand name Lucemyra. In a recent clinical trial of lofexidine, only 41.5% of the participants taking lofexidine and 27.8% of patients on placebo completed the trial (FDA Approval 2018; Fishman et al., 2019). As a result, patients seeking treatment for illicit opioid use only have an ~4 in 10 chance of completing treatment with the only currently available non-opioid medication, lofexidine. Dexmedetomidine possesses superior pharmacological properties within the alpha-2-adrenergic agonist class. Dexmedetomidine is a full agonist with higher affinity for alpha-2a-adrenergic receptors compared to lofexidine and may be expected to produce a higher level of efficacy (Peltonen et al., 1998, Ouchi & Sugiyama, 2016; Zhang et al., 2013). *BXCL501 (120 and 180 mcg: IgalmiTM) was recently FDA approved for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.* Few direct comparisons have been made between dexmedetomidine and lofexidine, but a recent metaanalysis comparing peri-operative adverse events related to dexmedetomidine versus clonidine showed that hypotension was similar for the 2 medications pre- and post-operatively but dexmedetomidine appeared to be protective against hypertension and tachycardia during surgery (Demiri et al., 2019).Furthermore, a trial directly comparing dexmedetomidine (n=144) and clonidine (n=142) in older adults undergoing cardiac surgery showed that dexmedetomidine had superior outcomes with regard to risk and duration of delirium, duration of mechanical ventilation, length of stay in the intensive care unit, mortality rate, and morphine consumption (Shokri & Ali, 2019). In summary, sublingual dexmedetomidine (BXCL501) is expected to be superior safety and efficacy to other alpha-2a-adrenergic agonists in the treatment of opioid withdrawal. This study will be first direct comparison of BXCL501 to lofexidine on these outcomes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Opioid Use Disorder, Opioid Withdrawal

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Throughout the 7-day inpatient study (Figure 1; Table 1), participants will receive sublingual BXCL501 or placebo twice daily and lofexidine or placebo 4 times daily using a double-blind,double-dummy design.
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo. The goal is to establish the safety and efficacy of BXCL501 relative to lofexidine and placebo in subjects with OUD who are physically dependent on opioids.
Allocation
Randomized
Enrollment
160 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
BXCL501 (180 micrograms)
Arm Type
Experimental
Arm Description
The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.
Arm Title
BXCL501 (240 micrograms)
Arm Type
Experimental
Arm Description
The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.
Arm Title
Lofexidine (Positive Control)
Arm Type
Active Comparator
Arm Description
The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
The current study is a randomized, double-blind, double-dummy inpatient study comparing BXCL501 (180 and 240 ug BID), lofexidine (as a positive control), and placebo.
Intervention Type
Drug
Intervention Name(s)
BXCL501 (180 micrograms)
Intervention Description
Throughout the 7-day inpatient study (Figure 1; Table 1), participants will receive sublingual BXCL501 or placebo twice daily and lofexidine or placebo 4 times daily using a double-blind, double-dummy design.
Intervention Type
Drug
Intervention Name(s)
BXCL501 (240 micrograms)
Intervention Description
Throughout the 7-day inpatient study (Figure 1; Table 1), participants will receive sublingual BXCL501 or placebo twice daily and lofexidine or placebo 4 times daily using a double-blind, double-dummy design.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Throughout the 7-day inpatient study (Figure 1; Table 1), participants will receive sublingual BXCL501 or placebo twice daily and lofexidine or placebo 4 times daily using a double-blind, double-dummy design.
Intervention Type
Other
Intervention Name(s)
Lofexidine (Positive Control)
Intervention Description
Throughout the 7-day inpatient study (Figure 1; Table 1), participants will receive sublingual BXCL501 or placebo twice daily and lofexidine or placebo 4 times daily using a double-blind, double-dummy design.
Primary Outcome Measure Information:
Title
Adverse Events: BXCL501 versus Placebo and Lofexidine (Positive Control)
Description
Establish the safety of BXCL501 relative to placebo and lofexidine in subjects with OUD who are physically dependent on opioids as measured by adverse events.
Time Frame
Study Days 1-7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Capable of understanding and complying with the protocol. 18 years of age or older but less than 60 years old. Has opioid use disorder moderate-to-severe (304.00) as per DSM-V, and physiological dependence on opioids. Females agree to use an acceptable method of contraception for the duration of the study. Exclusion Criteria: Positive urine or serum pregnancy test at screening, after admission, planning to become pregnant during the course of the trial, or currently breast feeding. Clinically significant history of cardiac disease, including syncope, bradycardia, conduction abnormalities, orthostatic hypotension or blood pressure disorders. Heart rate and blood pressure at screening and baseline of < 50 beats per minute or systolic blood pressure <105, >150 mmHg or diastolic BP <70, >90 mmHg. Clinically significant medical condition or observed abnormalities (including: physical examination, hypotension, laboratory evaluation, and/or urinalysis findings). Clinically significant abnormal ECG such as second- or third-degree heart block, uncontrolled arrhythmia, or QTc interval > 450 msec for males, and > 470 msec for females. Evidence of hepatic abnormalities, including: ascites, bilirubin >10% above upper limit of normal and/or esophageal variceal disease, active hepatitis/aspartate aminotransferase, alanine aminotransferase >3x the upper limit of normal. Any psychiatric disorder that would compromise ability to complete study requirements [e.g. severe acute depression, active mania, or suicidality with specific plan and intent (assessed using the CSSRS)]. Not being able to provide a negative urine for methadone or buprenorphine at screening. Use of oral naltrexone for ≥7 consecutive days within 60 days prior to screening. Need for alcohol or benzodiazepine detoxification. Participation in a clinical trial of a pharmacological agent within 30 days prior to screening. Use of any concomitant medication at screening or anticipated/required use during the study period that the investigators feel may impact participant safety or interfere with the aims of the trial (e.g., daily licit or illicit benzodiazepine use). 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. Investigator-site personnel or immediate family of investigator-site personnel.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gabriela Madera
Phone
646-774-6119
Email
Gabriela.Madera@nyspi.columbia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Jermaine Jones, Ph.D
Phone
646-774-6613
Email
jermaine.jones@nyspi.columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sandra Comer, Ph.D
Organizational Affiliation
Columbia University / New York State Psychiatric Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gustavo A Angarita, M.D.
Phone
203-974-7536
Email
gustavo.angarita@yale.edu
First Name & Middle Initial & Last Name & Degree
Henrique Oliva
Email
henrique.oliva@yale.edu
Facility Name
Clinilabs
City
Eatontown
State/Province
New Jersey
ZIP/Postal Code
07724
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gary Zammit, Ph.D.
Email
gzammit@clinilabs.com
First Name & Middle Initial & Last Name & Degree
Ronni Spanola
Email
rspanola@clinilabs.com
Facility Name
New York State Psychiatric Institute
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Active, not recruiting

12. IPD Sharing Statement

Citations:
PubMed Identifier
32572978
Citation
Antoine D, Huhn AS, Strain EC, Turner G, Jardot J, Hammond AS, Dunn KE. Method for Successfully Inducting Individuals Who Use Illicit Fentanyl Onto Buprenorphine/Naloxone. Am J Addict. 2021 Jan;30(1):83-87. doi: 10.1111/ajad.13069. Epub 2020 Jun 23.
Results Reference
background
PubMed Identifier
32563380
Citation
Srivastava AB, Mariani JJ, Levin FR. New directions in the treatment of opioid withdrawal. Lancet. 2020 Jun 20;395(10241):1938-1948. doi: 10.1016/S0140-6736(20)30852-7.
Results Reference
background
PubMed Identifier
2908485
Citation
Maze M, Segal IS, Bloor BC. Clonidine and other alpha2 adrenergic agonists: strategies for the rational use of these novel anesthetic agents. J Clin Anesth. 1988;1(2):146-57. doi: 10.1016/0952-8180(88)90034-7.
Results Reference
background
PubMed Identifier
330174
Citation
Cedarbaum JM, Aghajanian GK. Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol. 1977 Aug 15;44(4):375-85. doi: 10.1016/0014-2999(77)90312-0. No abstract available.
Results Reference
background
PubMed Identifier
30531234
Citation
Fishman M, Tirado C, Alam D, Gullo K, Clinch T, Gorodetzky CW; CLEEN-SLATE Team. Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial. J Addict Med. 2019 May/Jun;13(3):169-176. doi: 10.1097/ADM.0000000000000474.
Results Reference
background
PubMed Identifier
31668468
Citation
Shokri H, Ali I. A randomized control trial comparing prophylactic dexmedetomidine versus clonidine on rates and duration of delirium in older adult patients undergoing coronary artery bypass grafting. J Clin Anesth. 2020 May;61:109622. doi: 10.1016/j.jclinane.2019.09.016. Epub 2019 Oct 23.
Results Reference
background

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Sublingual Dexmedetomidine for Treating Opioid Withdrawal

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