Targeting Orexin to Treat Nicotine Dependence

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.

Study Overview

• Status: Recruiting
• Conditions: Nicotine Dependence
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Suvorexant 10 mg; Drug: Suvorexant 20 mg

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: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Amy Janes, PhD; Phone Number: (617)855-3244; Email: ajanes@mclean.harvard.edu
• Study Contact Backup: Name: Nathan Krantz, BA; Phone Number: (617) 855-2429‬; Email: nkrantz@mclean.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Belmont, Massachusetts, United States, 02478
      • Recruiting
      • McLean Hospital
      • Contact: Amy C Janes, PhD; Phone Number: 617-855-3244; Email: ajanes@mclean.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nicotine Craving	Total average value on the Questionnaire of Smoking Urges (QSU): and average values for Factors 1 and 2	approximately 4 hours post drug administration and following exposure to visual smoking cues
Nicotine withdrawal	Wisconsin Smoking Withdrawal Scale: Total average value	approximately 4 hours post drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Somnolence	Stanford Sleepiness Scale (SSS)	approximately 4 hours post drug administration

Collaborators and Investigators

• Sponsor: Mclean Hospital
• Investigators: Principal Investigator: Amy Janes, PhD, McLean Hospital

Publications and helpful links

General Publications

• Brandon TH, Tiffany ST, Obremski KM, Baker TB. Postcessation cigarette use: the process of relapse. Addict Behav. 1990;15(2):105-14. doi: 10.1016/0306-4603(90)90013-n.
• 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.
• Hall SM, Humfleet GL, Reus VI, Munoz RF, Hartz DT, Maude-Griffin R. Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry. 2002 Oct;59(10):930-6. doi: 10.1001/archpsyc.59.10.930.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2019
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 16, 2019
• First Submitted That Met QC Criteria: June 25, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Suvorexant
• Other Study ID Numbers: Orexin and Nicotine

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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