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出境医 / 临床实验 / Targeting Orexin to Treat Nicotine Dependence

Targeting Orexin to Treat Nicotine Dependence

Study Description
Brief Summary:
Tobacco smoking continues to be the primary cause of preventable mortality in the United States. Despite the availability of smoking cessation aids, the majority of those trying to quit smoking end up relapsing. Thus, there is a strong need to evaluate alternative treatment targets such as orexin antagonists, which have shown promise in preclinical models at reducing the motivational aspects of drug use.The current work will evaluate the influence of orexin antagonism on several factors impacting the motivation to smoke.

Condition or disease Intervention/treatment Phase
Nicotine Dependence Drug: Suvorexant 20 mg Drug: Suvorexant 10 mg Drug: Placebo oral tablet Phase 1

Detailed Description:
Tobacco use leads to ~440,000 deaths and a loss of $193 billion every year in the US. This public health and economic crisis continues as no interventions effectively prevent smoking relapse. Between 40-70% of smokers are unable to maintain abstinence and 75% of those who do attain abstinence will relapse within one-year. These relapse rates remain high even when using currently available cessation aids, which primarily target the cholinergic system, suggesting the need for medications with novel targets such as orexin. The current proposal will improve scientific knowledge and/or clinical practice by translating preclinical research on orexin into the clinical domain by indicating: 1) whether orexin antagonism attenuates motivational factors associated with smoking relapse, 2) whether suvorexant shows promise as a smoking cessation aid, or 3) whether suvorexant contributes too many unwanted side effects despite mitigating the motivation to smoke, thus confirming the role of orexin in nicotine dependence and indicating the need to develop more specific orexin antagonists.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: A single group will undergo three study visits where, on different days, they will receive placebo, 10 mg, or 20 mg lorcaserin.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: The order or medication/placebo administration will be randomized. The study staff and participant will be blinded to which medication they are receiving.
Primary Purpose: Basic Science
Official Title: Targeting Orexin to Treat Nicotine Dependence
Actual Study Start Date : September 26, 2019
Estimated Primary Completion Date : May 30, 2021
Estimated Study Completion Date : June 30, 2021
Arms and Interventions
Arm Intervention/treatment
Placebo Comparator: Placebo Drug: Placebo oral tablet
Placebo

Experimental: Suvorexant 10mg
Suvorexant 10mg oral dose
Drug: Suvorexant 10 mg
Suvorexant at a low dose (10 mg)

Experimental: Suvorexant 20mg
Suvorexant 20mg oral dose
Drug: Suvorexant 20 mg
Suvorexant at a high dose (20 mg)

Outcome Measures
Primary Outcome Measures :
  1. Nicotine Craving [ Time Frame: approximately 4 hours post drug administration and following exposure to visual smoking cues ]
    Total average value on the Questionnaire of Smoking Urges (QSU): and average values for Factors 1 and 2

  2. Nicotine withdrawal [ Time Frame: approximately 4 hours post drug administration ]
    Wisconsin Smoking Withdrawal Scale: Total average value


Secondary Outcome Measures :
  1. Somnolence [ Time Frame: approximately 4 hours post drug administration ]
    Stanford Sleepiness Scale (SSS)


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants will be male and female volunteers between the ages of 18-50
  • Participants must report daily smoking of at least 5 cigarettes per day over the last 6 months.
  • Participants must be nicotine dependent, having an FTND score greater than or equal to 4.
  • Participants must have an expired carbon monoxide level of 10 ppm or more on the screening day.
  • Participants must have an expired carbon monoxide level of no more than 10 ppm on the study visits.
  • Female participants must have a negative pregnancy test on all study days.

Exclusion Criteria:

  • Participants cannot meet DSM-5 criteria for lifetime and/or current psychotic disorders such as bipolar disorder, schizophrenia, schizoaffective disorder
  • Participants cannot meet DSM-5 criteria for current substance abuse disorders other than nicotine and marihuana and cannot meet criteria for current moderate or severe alcohol use disorder (as assessed by the SCID-5)
  • Participants cannot have positive drug and alcohol screen on each study visit other than for nicotine or marijuana.
  • Participants reporting marihuana use greater than 1-2 times per week will be excluded.
  • Participants must report no marihuana use within 24 hours of the study visit.
  • Participants cannot be taking any prescription medication that could impact brain function including medications that depress CNS function
  • Participants cannot have a history of major head trauma resulting in cognitive impairment, seizure, or other neurological disorders.
  • Participants cannot be pregnant or breastfeeding.
  • Participants must be able to read screening materials including consent form and give informed consent
  • Individuals with severe hepatic impairment will be excluded.
  • Participants cannot be obese as determined by a Body Mass Index (BMI) of 30 or greater.
  • Participants cannot be using a CYP3A inhibitor/inducer (metabolism by CYP3A is the major elimination pathway for suvorexant)
  • Participants cannot have a current cardiac disorder such as palpitations, tachycardia and/or use of the cardiac medication Digoxin
  • Participants cannot have narcolepsy
  • Participants cannot self-report complex sleep behaviors such as sleep driving, preparing and eating food or making phone calls
  • Participants cannot have compromised respiratory function such severe obstructive sleep apnea or severe chronic obstructive pulmonary disease
  • Participants cannot have current major depressive disorder (within the past 6 months) and/or indorse suicidal ideation on the Beck Depression Inventory.
Contacts and Locations

Contacts
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Contact: Amy Janes, PhD (617)855-3244 ajanes@mclean.harvard.edu
Contact: Nathan Krantz, BA (617) 855-2429‬ nkrantz@mclean.harvard.edu

Locations
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United States, Massachusetts
McLean Hospital Recruiting
Belmont, Massachusetts, United States, 02478
Contact: Amy C Janes, PhD    617-855-3244    ajanes@mclean.harvard.edu   
Sponsors and Collaborators
Mclean Hospital
Investigators
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Principal Investigator: Amy Janes, PhD Mclean Hospital
Tracking Information
First Submitted Date  ICMJE June 16, 2019
First Posted Date  ICMJE June 26, 2019
Last Update Posted Date February 21, 2020
Actual Study Start Date  ICMJE September 26, 2019
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2019)
  • Nicotine Craving [ Time Frame: approximately 4 hours post drug administration and following exposure to visual smoking cues ]
    Total average value on the Questionnaire of Smoking Urges (QSU): and average values for Factors 1 and 2
  • Nicotine withdrawal [ Time Frame: approximately 4 hours post drug administration ]
    Wisconsin Smoking Withdrawal Scale: Total average value
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2019)
Somnolence [ Time Frame: approximately 4 hours post drug administration ]
Stanford Sleepiness Scale (SSS)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Targeting Orexin to Treat Nicotine Dependence
Official Title  ICMJE Targeting Orexin to Treat Nicotine Dependence
Brief Summary Tobacco smoking continues to be the primary cause of preventable mortality in the United States. Despite the availability of smoking cessation aids, the majority of those trying to quit smoking end up relapsing. Thus, there is a strong need to evaluate alternative treatment targets such as orexin antagonists, which have shown promise in preclinical models at reducing the motivational aspects of drug use.The current work will evaluate the influence of orexin antagonism on several factors impacting the motivation to smoke.
Detailed Description Tobacco use leads to ~440,000 deaths and a loss of $193 billion every year in the US. This public health and economic crisis continues as no interventions effectively prevent smoking relapse. Between 40-70% of smokers are unable to maintain abstinence and 75% of those who do attain abstinence will relapse within one-year. These relapse rates remain high even when using currently available cessation aids, which primarily target the cholinergic system, suggesting the need for medications with novel targets such as orexin. The current proposal will improve scientific knowledge and/or clinical practice by translating preclinical research on orexin into the clinical domain by indicating: 1) whether orexin antagonism attenuates motivational factors associated with smoking relapse, 2) whether suvorexant shows promise as a smoking cessation aid, or 3) whether suvorexant contributes too many unwanted side effects despite mitigating the motivation to smoke, thus confirming the role of orexin in nicotine dependence and indicating the need to develop more specific orexin antagonists.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
A single group will undergo three study visits where, on different days, they will receive placebo, 10 mg, or 20 mg lorcaserin.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
The order or medication/placebo administration will be randomized. The study staff and participant will be blinded to which medication they are receiving.
Primary Purpose: Basic Science
Condition  ICMJE Nicotine Dependence
Intervention  ICMJE
  • Drug: Suvorexant 20 mg
    Suvorexant at a high dose (20 mg)
  • Drug: Suvorexant 10 mg
    Suvorexant at a low dose (10 mg)
  • Drug: Placebo oral tablet
    Placebo
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo oral tablet
  • Experimental: Suvorexant 10mg
    Suvorexant 10mg oral dose
    Intervention: Drug: Suvorexant 10 mg
  • Experimental: Suvorexant 20mg
    Suvorexant 20mg oral dose
    Intervention: Drug: Suvorexant 20 mg
Publications *
  • Brandon TH, Tiffany ST, Obremski KM, Baker TB. Postcessation cigarette use: the process of relapse. Addict Behav. 1990;15(2):105-14.
  • Centers for Disease Control and Prevention (CDC). Smoking-attributable mortality, years of potential life lost, and productivity losses--United States, 2000-2004. MMWR Morb Mortal Wkly Rep. 2008 Nov 14;57(45):1226-8.
  • Hajek P, Stead LF, West R, Jarvis M, Lancaster T. Relapse prevention interventions for smoking cessation. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003999. doi: 10.1002/14651858.CD003999.pub3. Review. Update in: Cochrane Database Syst Rev. 2013;8:CD003999.
  • Hall SM, Humfleet GL, Reus VI, Muñoz RF, Hartz DT, Maude-Griffin R. Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry. 2002 Oct;59(10):930-6.
  • Rohsenow DJ, Tidey JW, Martin RA, Colby SM, Swift RM, Leggio L, Monti PM. Varenicline versus nicotine patch with brief advice for smokers with substance use disorders with or without depression: effects on smoking, substance use and depressive symptoms. Addiction. 2017 Oct;112(10):1808-1820. doi: 10.1111/add.13861. Epub 2017 Jul 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 25, 2019)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2021
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participants will be male and female volunteers between the ages of 18-50
  • Participants must report daily smoking of at least 5 cigarettes per day over the last 6 months.
  • Participants must be nicotine dependent, having an FTND score greater than or equal to 4.
  • Participants must have an expired carbon monoxide level of 10 ppm or more on the screening day.
  • Participants must have an expired carbon monoxide level of no more than 10 ppm on the study visits.
  • Female participants must have a negative pregnancy test on all study days.

Exclusion Criteria:

  • Participants cannot meet DSM-5 criteria for lifetime and/or current psychotic disorders such as bipolar disorder, schizophrenia, schizoaffective disorder
  • Participants cannot meet DSM-5 criteria for current substance abuse disorders other than nicotine and marihuana and cannot meet criteria for current moderate or severe alcohol use disorder (as assessed by the SCID-5)
  • Participants cannot have positive drug and alcohol screen on each study visit other than for nicotine or marijuana.
  • Participants reporting marihuana use greater than 1-2 times per week will be excluded.
  • Participants must report no marihuana use within 24 hours of the study visit.
  • Participants cannot be taking any prescription medication that could impact brain function including medications that depress CNS function
  • Participants cannot have a history of major head trauma resulting in cognitive impairment, seizure, or other neurological disorders.
  • Participants cannot be pregnant or breastfeeding.
  • Participants must be able to read screening materials including consent form and give informed consent
  • Individuals with severe hepatic impairment will be excluded.
  • Participants cannot be obese as determined by a Body Mass Index (BMI) of 30 or greater.
  • Participants cannot be using a CYP3A inhibitor/inducer (metabolism by CYP3A is the major elimination pathway for suvorexant)
  • Participants cannot have a current cardiac disorder such as palpitations, tachycardia and/or use of the cardiac medication Digoxin
  • Participants cannot have narcolepsy
  • Participants cannot self-report complex sleep behaviors such as sleep driving, preparing and eating food or making phone calls
  • Participants cannot have compromised respiratory function such severe obstructive sleep apnea or severe chronic obstructive pulmonary disease
  • Participants cannot have current major depressive disorder (within the past 6 months) and/or indorse suicidal ideation on the Beck Depression Inventory.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Amy Janes, PhD (617)855-3244 ajanes@mclean.harvard.edu
Contact: Nathan Krantz, BA (617) 855-2429‬ nkrantz@mclean.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03999099
Other Study ID Numbers  ICMJE Orexin and Nicotine
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Amy C. Janes, Mclean Hospital
Study Sponsor  ICMJE Mclean Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amy Janes, PhD Mclean Hospital
PRS Account Mclean Hospital
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP