Ignite Creation Date:
2024-05-06 @ 6:35 PM
Last Modification Date:
2024-10-26 @ 2:50 PM
Study NCT ID:
NCT05712707
Status:
RECRUITING
Last Update Posted:
2024-06-14
First Post:
2023-01-24
Brief Title:
Sublingual Dexmedetomidine for Treating Opioid Withdrawal
Sponsor:
New York State Psychiatric Institute
Organization:
New York State Psychiatric Institute
Study Overview
Official Title:
Phase 1B Study of Sublingual Dexmedetomidine an Alpha 2 Adrenergic Agonist for Treating Opioid Withdrawal
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 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 a gradual reduction of the opioid drug dosage tapering However as all opioids have potential for abuse and require careful dosing due to side effects eg 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 analgesic 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 using a methadone taper 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
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 US 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 415 of the participants taking lofexidine and 278 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 meta-analysis 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 n144 and clonidine n142 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
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 US 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 415 of the participants taking lofexidine and 278 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 meta-analysis 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 n144 and clonidine n142 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| UG3DA056247-01 | NIH | None | httpsreporternihgovquickSearchUG3DA056247-01 |