Lemborexant for the Treatment of Residual Insomnia in Major Depressive Disorder (MDD) (MDD)

Lemborexant for the Treatment of Residual Insomnia in Adequately Treated Major Depressive Disorder: A Pilot Randomized Controlled Trial

The goal of this clinical trial is to learn if Lemborexant works to treat residual insomnia in adults with depression that is being treated. It will also learn about how practical, tolerable, and effective Lemborexant is. The main questions it aims to answer are:

• Does Lemborexant help participants improve sleep and reduce insomnia symptoms?
• How practical is it to use Lemborexant (how many participants join, drop out, and follow the study rules)? How do participants feel about using it (based on surveys and interviews)?

Researchers will compare Lemborexant to a placebo (a look-alike substance that contains no drug) to see if Lemborexant works to treat residual insomnia in adequately treated major depressive disorder.

Participants will:

• Take Lemborexant or a placebo every day for 6 weeks (2 weeks at 5 mg then 4 weeks at 10 mg)
• Complete clinical assessments and in-person study visits
• Maintain a digital sleep diary and complete daily and weekly self-report ecological momentary assessments (EMAs)
• Use a wearable device which will be used to collect and monitor physiological data

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder(MDD); Insomnia Comorbid to Psychiatric Disorder
• Intervention / Treatment: Drug: Lemborexant; Other: Placebo

Detailed Description

Major Depressive Disorder (MDD) is often accompanied by persistent residual insomnia which does not resolve, even after adequate MDD treatment. Lemborexant is an orexin receptor antagonist involved in the regulation of sleep-wake cycles with a favourable safety profile compared to other sleep medications. There are currently no trials evaluating the feasibility and clinical efficacy of Lemborexant as a treatment for residual insomnia in patients with adequately treated MDD. This pilot study will investigate the feasibility, tolerability, and efficacy of Lemborexant in adults with adequately-treated MDD and residual insomnia.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Venkat Bhat, MD, MSc; Phone Number: 76404 416-360-4000; Email: venkat.bhat@unityhealth.to

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • Recruiting
      • St. Michael's Hospital, Unity Health Toronto
      • Contact: Gyu Hee Lee, HBSc; Phone Number: 76404 416-360-4000; Email: lemborexant@unityhealth.to
      • Principal Investigator: Venkat Bhat Dr., MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18 to 70 (inclusive), with a self-reported body mass index (BMI) between 19 and 30 kg/m2 (inclusive);
2. Meet criteria for primary MDD diagnosis without psychotic symptoms, as defined by the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5)2, and currently in a MDE, confirmed by the MINI International Neuropsychiatric Interview (MINI)3;
3. Have not failed more than 2 trials of antidepressant treatments in the current MDE, and have a history of adequate response (clinical outcome rating score of 1 or 2) to at least 1 antidepressant treatment during the current MDE as determined by the Antidepressant Treatment History Form-Short Form (ATHF-SF)4;
4. Are outpatients;
5. Did not take non-psychotropic or non-central nervous system (CNS) medications suspected to affect sleep-wake function for at least 4 weeks before starting the study.
6. Self-reported subjective total sleep time (sTST) ≤ 6.5 hours, subjective sleep onset latency (sSOL) ≥ 30 minutes, and subjective wake after sleep onset (sWASO) ≥ 45 minutes per night. Time spent in bed (either sleeping or attempting to sleep) must be between 7 and 10 hours per night. Self-reported regular bedtime (i.e., the time the participant gets in bed) between 21:00 and 01:00 and regular wake time (i.e., the time the participant wakes and does not go back to sleep) between 05:00 and 10:00;
7. Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed on at least 7 consecutive mornings (minimum 5 of 7 for eligibility), such that sSOL ≥ 30 minutes on at least 3 of the 7 nights and/or sWASO ≥ 45 minutes on at least 3 of the 7 nights;
8. Confirmation of sufficient duration of time spent in bed, as determined from responses on the Sleep Diary on the 7 most recent mornings before the visit, such that there are no more than 2 nights with time spent in bed of duration < 7 hours or > 10 hours;
9. Confirmation of regular bedtime (i.e., the time the participant gets in bed) between 21:00 and 01:00 on at least 5 of the 7 preceding nights, and regular wake time (i.e., the time the participant wakes and does not go back to sleep) between 05:00 and 10:00 on at least 5 of the 7 preceding nights.
10. Have a medically responsible physician (family doctor or psychiatrist) during their enrollment and participation in the trial;
11. Current 17-Item Hamilton Depression Rating Scale (HAM-D-17)30 score ≥ 8 and reporting an insomnia score of ≥15 on ISI1;
12. Are able to understand and comply with the requirements of the study, as judged by the investigator(s);
13. Provide written informed consent before initiation of any study-related procedures;
14. Own a smartphone and have reliable access to the internet and a browser on which to complete questionnaires.

Exclusion criteria:

1. Have taken or participated in any clinical trial of lemborexant and other drugs with the same mechanism (e.g., daridorexant), regardless of treatment outcome;
2. Have any known sensitivity to lemborexant or their excipients;
3. A lifetime history (current or previous) of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or psychotic symptoms as determined by the MINI;
4. Women who are pregnant or lactating (documented by a positive beta-human chorionic gonadotropin [beta-hCG] or human chorionic gonadotropin [hCG] urine test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG or hCG);
5. Women who are not using an approved and effective method of contraception or family planning during the study. For example, combined estrogen- and progestogen-containing hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion and ligation, vasectomized partner, sexual abstinence, or two forms of contraception with any barrier method or oral hormones (ie.g., condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives plus spermicide or condom).
6. Positive toxicology screening results;
7. If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions or the therapeutic focus 4 weeks before screening and the entire duration of participation;
8. Have active suicidal intent as determined by a score of 3 (severe suicidality with a clear plan and/or intent) or 4 (very severe: suicidal attempts) on item #3 on the HAM-D-17;
9. Have had a course of electroconvulsive therapy or intravenous ketamine therapy in the current episode or any previous episode;
10. Medical history of insomnia associated with another sleep disorder or any condition known to impact sleep. This includes any lifetime diagnosis of sleep-related breathing disorder, periodic limb movement disorder, restless legs syndrome, nightmare disorder, sleep terror disorder, sleepwalking disorder, rapid eye movement (REM) behaviour disorder, narcolepsy, or comorbid nocturia that is causing or exacerbating insomnia;
11. STOP-Bang5 scores ≥ 5; International Restless Legs Scale (IRLS)6 scores ≥ 16,Epworth Sleepiness Scale (ESS)⁷ ≥ 11
12. Habitual naps 4 or more days a week, occurring in the late afternoon or evening;
13. Transmeridian travel across more than 3 time zones in the 2 weeks before screening, or between screening and study baseline, or plans to travel across more than 3 time zones during the study;
14. Used any modality of treatment for insomnia, including cognitive-behavioural therapy within 2 weeks before screening;
15. Excessive caffeine use, defined as consuming more than 400 mg of caffeine per day (approximately 4 cups of brewed coffee), or habitual consumption of caffeine after 6:00 p.m., which in the investigator's opinion may contribute to insomnia;
16. Reports habitually consuming more than 14 drinks containing alcohol per week (females) or more than 21 drinks containing alcohol per week (males);
17. Used prohibited prescriptions or over-the-counter concomitant medications, or used any medication or sleep aid with known effects on sleep within 2 weeks before screening;
18. Report a history of sleep-related violent behaviour, or sleep driving, or any other complex sleep-related behaviour (e.g., making phone calls, preparing and eating food);
19. Diagnosis of substance dependence or abuse within the last 3 months as determined by MINI3;
20. Have a concomitant major unstable medical illness, cardiac pacemaker, or implanted medication pump;
21. Have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of seizure except a febrile seizure of infancy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes;
22. A history of risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or the use of concomitant medications that prolonged the QTcF interval;
23. Scheduled for major surgery during the study;
24. Have a clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina);
25. Have uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 30 days prior to enrolment;
26. Have any other condition that, in the opinion of the investigator(s), would adversely affect the subject's ability to complete the study or its measures.
27. Non-English-speaking individuals because the ability to communicate study information, answer questions accurately and completely about the study, and obtain consent are necessary.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lemborexant; Participants will take a 5 mg pill of lemborexant daily for two weeks, followed by a dosage increase to 10 mg daily for the next four weeks (6 weeks total).	Drug: Lemborexant; Dayvigo (lemborexant compound) is an orexin antagonist that acts on the arousal and sleep neural networks of the brain to regulate sleep-wake cycles and is used in the treatment of insomnia characterized by difficulties with sleep.; Other Names: Dayvigo
Placebo Comparator: Placebo; Participants will take a 5 mg of placebo pill daily for 2 weeks then 10 mg daily for 4 weeks (total of 6 weeks).	Other: Placebo; The placebo is an inactive sugar pill that looks and tastes identical to the lemborexant pill.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility Outcomes	Feasibility will be measured by the recruitment rate, withdrawal rate, data completion rate, and adherence rate. Recruitment rate will be quantified by the percentage of eligible participants enrolled relative to the number of participants contacted. Feasibility will be marked as a minimum of 1-2 participants enrolled per month. Withdrawal/dropout rate will be quantified by the percentage of participants who drop out of the study. The upper limit of the 95% confidence interval (CI) for dropout rate should not exceed 20%. Adherence and data completion will bhe proportion of participants who strictly follow the study protocol (the "per-protocol group") will be estimated with a 95% CI. This includes adherence to treatment (taking the medication correctly for six weeks), study completion (attending all required visits), and providing complete data. To be considered feasible, the lower limit of this 95% CI must be greater than 80%.	13 weeks
Tolerability Outcomes	Tolerability will be measured by the frequency and nature of adverse events and medication adherence (i.e., missed dosage).	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary Clinical Parameters	Changes in insomnia symptoms will be measured using the Insomnia Severity Index (ISI) Score. ISI score reduction will be compared between allocation and treatment end for participants randomized to receive Lemborexant and those receiving placebo.	6 weeks
Within-person Correlations	Within-person changes in insomnia symptoms will be measured by within-person correlations of baseline and follow-up ISI scores. The ISI assesses the severity of insomnia symptoms, such as the impact of sleep on daytime functioning, difficulties with sleep onset, and sleep maintenance. Each item is rated on a scale from 0 (mild) to 4 (very severe), with a higher overall score indicating more severe insomnia presentations.	10 weeks
Standard Deviation	Within and between participant variability in insomnia symptoms will be measured by standard deviation of ISI scores. This measure will be separate for each group (treatment and placebo).	13 weeks
Change in Physiological Biometrics (Oura Ring Metrics)	Physiological biometrics will be captured using the Oura Ring and analyzed as a composite measure of changes across multiple parameters. Individual metrics will be reported separately and summarized as part of an overall physiological profile. The measured parameters include daily activity (step count (steps/day) and energy expenditure (METs)), heart rate metrics (resting heart rate (beats per minute) and heart rate variability (milliseconds)), body temperature (average nightly body temperature deviation (degrees Celsius), sleep quality (sleep latency, total time in bed, sleep staging (light, deep, REM sleep in minutes)), wake onset (minutes), and Oura composite scores (sleep, activity, and readiness scores (0-100 scale)). Statistical analyses will assess changes in each metric individually, as well as aggregated trends across sleep, activity, and recovery domains.	13 weeks
Patient Health Questionnaire-9 (PHQ-9)	This questionnaire assesses the severity of depression, with questions probing the frequency and severity of symptoms such as mood, energy, sleep, and concentration. Each item is scored from 0 (not at all) to 3 (nearly every day), with a higher total score indicating more severe depression presentations.	13 weeks
Insomnia Severity Index (ISI-7)	This questionnaire assesses the severity of insomnia symptoms, such as the impact of sleep on daytime functioning, difficulties with sleep onset, and sleep maintenance. Each item is rated on a scale from 0 (mild) to 4 (very severe), with a higher overall score indicating more severe insomnia presentations.	13 weeks
Generalized Anxiety Disorder-7 (GAD-7)	This questionnaire assesses the severity of anxiety symptoms, such as excessive worry, restlessness, and irritability. Each question is scored ranging from 0 (not at all) to 3 (nearly every day), with a higher overall score indicating more severe presentations of anxiety.	13 weeks
World Health Organization Well-being Index (WHO-5)	This questionnaire is a self-report measure that evaluates subjective well-being, with statements probing mood, vitality, and mental well-being. Participants rate their responses from 0 (at no time) to 5 (all the time), with a higher overall score indicating positive well-being.	13 weeks
Montgomery-Åsberg Depression Rating Scale (MADRS)	This clinician-administered scale assesses the severity and changes in depression symptoms over time. Each item is rated from 0 (no symptoms) to 6 (very severe symptoms), with a higher overall score indicating more severe depression.	13 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Perspectives	Subjective patient experiences, thoughts, beliefs, and attitudes towards the digital health monitoring platforms (REDCap and Oura Ring) will be assessed using the user experience survey and semi-structured exit interviews. Open-ended feedback for considerations of future trials and digital intervention design will be considered.	13 weeks

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: Centre for Addiction and Mental Health; University of Toronto; Toronto Metropolitan University
• Investigators: Principal Investigator: Venkat Bhat, MD, MSc, Unity Health Toronto

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: January 21, 2025
• First Submitted That Met QC Criteria: February 18, 2025
• First Posted (Actual): February 24, 2025

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Placebo-controlled; Lemborexant; Feasibility trial; Pilot study; Major depressive disorder (MDD); Wearable devices; Residual Insomnia; Ecological momentary assessments (EMA); Remote measurement-based care; Digital health monitoring
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Neurotransmitter Agents; Hypnotics and Sedatives; lemborexant
• Other Study ID Numbers: 24-133; 68425v4 (Other Grant/Funding Number: Eisai Inc.)

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.: No