Impact of Daridorexant on Sleep, Daytime Alertness, and Smoking

NCT07328594 | Not Yet Recruiting Phase 4 FDA Drug

• 2 other identifiers: 2233750140603
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Tobacco; Insomnia; Sleep; Smoking; Nicotine; Addiction; Substance Use Disorders

Keywords

Insomnia; Daridorexant; Smoking; Nicotine; Tobacco; Sleep; Addiction; Substance use disorders

Outcome Measures

Primary Outcomes (7)

• Sleep Quality

  Sleep device to assess: latency to sleep, number of awakenings during the night, and sleep stages.

  2 days + 3 weeks study: 2 days to assess sleep prior to taking daridorexant followed by 3 weeks of daily daridorexant administration.

• Daytime alertness

  Assess daytime alertness using a 5 min psychomotor vigilance task. Higher score indicates lower alertness.

  Assessed 3 times per day (morning, midday, evening), 3 times per week for 3 weeks.

• Insomnia Severity Index

  Assesses extent of insomnia. Range is 0-28. Higher score indicates high level of insomnia.

  Assess at prescreening and on last day of the study (3 weeks and 2 days)

• Sleep Quality-sleep diary

  Daily sleep diary to assess self-reported sleep

  Assessed 2 days prior to taking daridorexant and daily for 3 weeks during daily daridorexant administration.

• Pittsburgh Sleep Quality Index

  Assesses sleep quality (duration, disturbance, latency) over last 1 month. Range is 0-21; higher score indicates worse sleep quality.

  2 days before beginning study medication.

• PROMIS Sleep-Short Form 8a

  Assesses sleep quality over last 7 days. Range is 8-40, higher score indicates worse sleep/low alertness.

  2 days before beginning study medication and last day of weeks 1, 2, 3.

• Karolinska Sleepiness Scale

  Assesses daytime alertness - single question. Range is 1-10. Higher score indicates lower alertness.

  Given 3X/day on days 3, 5, 7 of weeks 1, 2, 3.

Secondary Outcomes (5)

• Fagerstrom

  Measure at pre-screening and at the end of each week for 3 weeks.

• Smoking History and Habits

  Measure at pre-screening.

• Minnesota Scale Withdrawal from Nicotine

  2 days before beginning study medication, end of day on days 3, 5, 7 of weeks 1, 2, and 3.

• QSU Brief Smoking Desire

  End of day on days 3, 5, 7 of weeks 1, 2, and 3.

• Number of cigarettes/vape products smoked

  Reported daily for entire study (2 days + 3 weeks).

Other Outcomes (4)

• Morningness/Eveningness questionnaire

  2 days before beginning study medication

• GAD-67 Anxiety

  2 days before beginning study medication and last day of the study (3 weeks, 2 days).

• Patient Health Questionnaire 9 (PHQ 9 Depression)

  2 days before beginning study medication and last day of the study (3 weeks, 2 days).

Study Arms (2)

Treatment

ACTIVE COMPARATOR

Drug: Daridorexant 50 mg

No treatment

PLACEBO COMPARATOR

Other: Placebo

Interventions

Daridorexant 50 mg DRUG

Active daridorexant vs placebo comparator in smokers with insomnia

Treatment

Placebo OTHER

Placebo in Smokers

No treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Legacy Health System: lead
• Washington State University: collaborator

Study Sites (1)

Legacy Research Institute

Portland, Oregon, 97232, United States

Location

Related Publications (5)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Smoking; Behavior, Addictive; Substance-Related Disorders; Sleep Initiation and Maintenance Disorders

Interventions

daridorexant

Condition Hierarchy (Ancestors)

Behavior; Compulsive Behavior; Impulsive Behavior; Chemically-Induced Disorders; Mental Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Central Study Contacts

Barbara A. Sorg, PhD

CONTACT

503-413-1934; bsorg@downeurobiology.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Medical Monitor will remain blinded unless adverse event.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dow Neurobiology Chair

Study Record Dates

• First Submitted: December 30, 2025
• First Posted: January 9, 2026
• Study Start: February 10, 2026
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: January 9, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)