Impact of Daridorexant on Sleep, Daytime Alertness, and Smoking

Official title

Impact of Daridorexant on Sleep, Daytime Alertness, and Smoking During Abstinence

Overview

Tobacco use is the leading cause of preventable death in the U.S., with 480,000 deaths per year and 7.7 million deaths globally. A major clinical symptom associated with abstinence from both licit and illicit drugs is insomnia, which is a clinically verified, major risk factor for relapse. Roughly half of the 40 million smokers in the U.S. attempt to quit annually, with very low rates of success. One major hurdle is poor sleep quality during abstinence. Compounding the problem is that some pharmaceuticals to help reduce smoking can increase insomnia. Poor sleep is recognized as a major impediment to maintaining abstinence from several drugs of abuse, including nicotine. Blockers of orexin have recently been proposed as a promising therapy for smoking cessation. Insomnia has been reported in up to 40% of smokers, and 80% report regular sleep disturbances, which can be amplified during abstinence. A new orexin blocker, daridorexant, was FDA approved within the past two years for the treatment of insomnia, and while it has been tested in healthy individuals with insomnia, it has not been tested in smokers, who suffer from insomnia, particularly during the withdrawal phase when trying to quit. Daridorexant has an improved profile of beneficial effects for those with insomnia, the most notable advantage being its shorter duration of action that promotes daytime alertness, which is problematic for both active smokers and smokers during withdrawal. Poor sleep leads to daytime sleepiness, which often leads to smoking to maintain alertness.

Detailed description

The investigators will use a randomized, double-blind placebo-controlled design to determine how daridorexant given over 3 weeks of smoking abstinence will alter sleep, daytime alertness, and smoking behavior and craving for cigarettes. Sleep will be monitored using a sleep-tracking device, a sleep diary, and daytime alertness will be monitored using a performance metric (psychomotor vigilance task) three times per week for the 3 week study. Participants will also complete several other questionnaires related to smoking behaviors, craving, withdrawal, daytime sleepiness, and mood.

Interventions

• Drug Daridorexant 50 mg
  Active daridorexant vs placebo comparator in smokers with insomnia
• Other Placebo
  Placebo in Smokers

Primary outcome measures

• Sleep Quality [Time frame: 2 days + 3 weeks study: 2 days to assess sleep prior to taking daridorexant followed by 3 weeks of daily daridorexant administration.]
• Daytime alertness [Time frame: Assessed 3 times per day (morning, midday, evening), 3 times per week for 3 weeks.]
• Insomnia Severity Index [Time frame: Assess at prescreening and on last day of the study (3 weeks and 2 days)]
• Sleep Quality-sleep diary [Time frame: Assessed 2 days prior to taking daridorexant and daily for 3 weeks during daily daridorexant administration.]
• Pittsburgh Sleep Quality Index [Time frame: 2 days before beginning study medication.]
• PROMIS Sleep-Short Form 8a [Time frame: 2 days before beginning study medication and last day of weeks 1, 2, 3.]
• Karolinska Sleepiness Scale [Time frame: Given 3X/day on days 3, 5, 7 of weeks 1, 2, 3.]

Secondary outcome measures (5)

• Fagerstrom [Time frame: Measure at pre-screening and at the end of each week for 3 weeks.]
• Smoking History and Habits [Time frame: Measure at pre-screening.]
• Minnesota Scale Withdrawal from Nicotine [Time frame: 2 days before beginning study medication, end of day on days 3, 5, 7 of weeks 1, 2, and 3.]
• QSU Brief Smoking Desire [Time frame: End of day on days 3, 5, 7 of weeks 1, 2, and 3.]
• Number of cigarettes/vape products smoked [Time frame: Reported daily for entire study (2 days + 3 weeks).]

Eligibility criteria

INCLUSION

• Adult participants who are cigarette smokers, 18-55 years of age.
• Smokers: greater than 10 cigarettes/day.
• Smoking for 1 year or longer.
• Willingness to try to reduce or stay abstinent from cigarettes, smoking cessation aides (including nicotine gum or patches), smokeless tobacco, or electronic cigarettes for 3 weeks during the study.
• Willingness to monitor sleep at home with an external device and maintain a simple sleep and smoking diary for 3 weeks.
• Willingness to take a 5-min, mobile-based test 3X/day for 3 days/week during the 3 weeks.
• Ability to travel to three Study Visits.
• Are willing to abstain from consuming grapefruit products during the study.
• Have an iPhone, best with iOS 17 or newer.

EXCLUSION:

• Are currently taking any pharmaceutical drugs for smoking cessation, including: Nicotine patch or nicotine gum, buproprion (Wellbutrin, Zyban), varenicline (Chantix, Champix), other behavioral interventions such as cognitive behavioral therapy for smoking.
• Are currently using cannabis or alcohol for sleep. Are currently taking any pharmaceutical drugs for insomnia, such as eszopiclone (Lunesta), zaleplon (Sonata) or zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist) benzodiazepines, or opioids.
• Are currently taking stimulants commonly used for ADHD, such as methylphenidate (Ritalin Concerta, Daytrana) or amphetamines (Adderall, Dexedrine, Vyvanse).
• Are currently taking anti-seizure drugs, including lamotrigine, pregabalin (Lyrica), or gabapentin (Neurontin, Horizant, or Gralise).
• Have non-nicotine substance dependence (diagnosed with substance use disorder, including alcohol or cannabis use disorder (current cannabis use is acceptable, and past illicit drug use is acceptable if greater than 2 months prior to testing and does not meet current criteria for substance use disorders (SUDs) according to DSM-5).
• Have a major neurological disorder such as Parkinson's disease, epilepsy, Alzheimer's disease, multiple sclerosis, or any other serious neurological disorder.
• Have a history of serious psychiatric disorders including bipolar disorder, schizophrenia, or suicidality.
• Had a stroke or head injury which caused loss of consciousness for longer than three minutes in the past 1 year.
• Are pregnant or breastfeeding.
• Have been diagnosed with sleep apnea or other diagnosed sleep disorders such as narcolepsy.
• Have been diagnosed with thyroid problems.
• Have been diagnosed with COPD.
• Have been doing variable shift work in the past 1 month or traveled more than 1 time zone in past month.
• Are currently taking the following medications, supplements, or food: Daridorexant can interact with strong inhibitors of CYP3A4, which should be discussed with The Study Doctor's office (some of these include clarithromycin, diltiazem, erythromycin, itraconzale, ketoconazole, ritonavir, and verapamil).
• Have a BMI of 33 or higher.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Legacy Research Institute — Portland

Publications

• Mauries S, Rolland B, Mallevays M, Catoire S, Zehani F, Sauvage K, Davido G, Lejoyeux M, Geoffroy PA. Conditions of sleep restoration after smoking cessation: A systematic review. Sleep Med Rev. 2025 Apr;80:102041. doi: 10.1016/j.smrv.2024.102041. Epub 2024 Dec 9. PMID 39893864
• Fietze I, Bassetti CLA, Mayleben DW, Pain S, Seboek Kinter D, McCall WV. Efficacy and Safety of Daridorexant in Older and Younger Adults with Insomnia Disorder: A Secondary Analysis of a Randomised Placebo-Controlled Trial. Drugs Aging. 2022 Oct;39(10):795-810. doi: 10.1007/s40266-022-00977-4. Epub 2022 Sep 13. PMID 36098936
• Fragale JE, James MH, Avila JA, Spaeth AM, Aurora RN, Langleben D, Aston-Jones G. The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System. Front Neurol Neurosci. 2021;45:117-127. doi: 10.1159/000514965. Epub 2021 May 28. PMID 34052815
• Hamidovic A. Dual Orexin Receptor Antagonists (DORAs) as an Adjunct Treatment for Smoking Cessation. CNS Drugs. 2022 May;36(5):411-417. doi: 10.1007/s40263-022-00918-0. Epub 2022 Apr 22. PMID 35451800
• Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, Pain S, Kinter DS, Roth T; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022 Feb;21(2):125-139. doi: 10.1016/S1474-4422(21)00436-1. PMID 35065036

Identifiers

NCT: NCT07328594 · 2233 · 750140603

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗