Daridorexant to Treat Insomnia in Patients With Mild Cognitive Impairment and Mild to Moderate Alzheimer Disease

Overview

DARIDOR-ALZ is a phase IV clinical trial designed to evaluate both the efficacy and safety of daridorexant, a selective dual orexin receptor antagonist that blocks the actions of the orexin neuropeptides at both orexin-1 and orexin-2 receptors, in selected populations of MCI and mild-to-moderate AD patients with insomnia complaints.

Detailed description

This Phase IV clinical trial is a monocentric, randomized, double-blind, placebo-controlled, 2 way-crossover study (with two periods of one month separated by a washout period range from 5 to 12 days).The study population includes MCI and mild-to-moderate AD patients aged between 60 and 85 years old, with insomnia complaints.

A single-night baseline polysomnography recording will be performed from 11 pm to 7 am at the Montpellier Sleep Unit. After a baseline PSG that assessed TST \< 6 hours and WASO \> 1 hour, treatment will be assigned using an interactive response technology system.

A randomization list will be generated and will remain confidential until the database is locked. Participants, investigators, and site personnel will be unaware of treatment allocation during the two crossover periods. Patients will be randomized (1:1) to receive daridorexant 50 mg or placebo, without titration, every evening within 30 minutes of going to bed during both treatment periods (Treatment Period A and B) of one-month duration each. Each treatment period will be followed by a one-week (range 5-12 days) washout period at home.

A ten-month open-label (OL) study with daridorexant 50 mg will be proposed to all participants after completing the second treatment period. Based on the experience with another DORA study in patients with mild-to-moderate probable Alzheimer's disease, the investigators would need to recruit 62 patients (including drop-outs).

Interventions

• Drug Daridorexant 50 mg
  Patients randomized in the experimental group will receive the treatment every evening within 30 minutes of going to bed during one month. The treatment period (Period A or Period B) will be followed by a one-week (range 5-12 days) washout period at home.
• Drug Placebo
  Patients randomized in the control group will receive the placebo every evening within 30 minutes of going to bed during one month. The treatment period (Period A or Period B) will be followed by a one-week (range 5-12 days) washout period at home.
• Procedure Polysomnography
  A full-night polysomnography recording with blood pressure and heart rate monitoring will be performed at night in the Sleep Laboratory from 11 p.m. to 7 a.m. at baseline (before the randomization) and at the end of each period (Period A/M1, Period B/M2). The recording procedure consists of an electroencephalogram, two electrooculograms, an electromyogram, an electrocardiogram, and a videographic recording. This examination is painless (the sensors are glued to the skin for the duration of the r
• Behavioral Neuropsychological assessment
  A full neuropsychological assessment will be performed at inclusion, M1, M2
• Behavioral Questionnaires on sleep and behavioural problems
  Questionnaires on sleep and behavioural problems will be performed at inclusion, M1, M2
• Procedure Actimetrics
  Measurement of actimetrics for seven days in average (with a minimum of three nights required) prior to the inclusion visit, M1 visit and M2 visit.
• Procedure 24-hour Ambulatory Blood Pressure Monitoring (ABPM
  Evaluation of the 24-hour hemodynamic profile of a patient by multiple and regular blood pressure and heart rate measurements. The ABP will be monitored at inclusion, M1 and M2
• Other Biomarker assay
  Determination of AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) in serum and cerebrospinal fluid (CSF) and dosage of Orexin-A/hypocretin-1 in the CSF

Primary outcome measures

• Change in Total Sleep Time (TST). [Time frame: from baseline to the end of each period A/B (Month1/Month2)]

Secondary outcome measures (12)

• Change in the wake time after sleep onset (WASO) [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Change in Latency to Persistent Sleep (LPS) [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Measure of sleep time at stage 1-2 during polysomnography [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Measure of sleep time at stage 3 during polysomnography [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Measure of number of wake bouts on the whole night [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Measure of number of wake bouts per quarter of the night [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Changes in sleep and wake duration [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Changes in sleep and wake duration [Time frame: from baseline to Month 6]
• Changes in sleep and wake duration [Time frame: from baseline to Month 12]
• Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI) [Time frame: from baseline to the end of each period A/B (Month1/Month2)]
• Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI) [Time frame: from baseline to Month 6]
• Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI) [Time frame: from baseline to Month 12]

Eligibility criteria

Inclusion criteria

• Age \[60-85\] years old
• Outpatients
• Pre-screening:

• Complaints of dissatisfaction with sleep quantity or quality, despite adequate opportunity for sleep, at least 3 nights per week and for at least 3 months, and
• Total sleep time causes clinically significant distress or impairment in daytime functioning, and
• Total sleep time estimated by interview was below 6 hours, on at least 3 nights per week and for at least 1 month before screening
• Baseline PSG (at randomization) assessed TST < 6 hours and WASO > 1 hour
• Diagnosis of MCI and AD patients at an early stage according to the NIA diagnosis criteria (core clinical criteria for MCI, positive CSF Aβ42 and/or positive plasma biomarker, and neuronal injury (hippocampal and/or temporal atrophy by MRI))
• MMSE from 12 to 26
• Clinical Dementia Rating CDR from 0.5 to 2
• Use of CNS-active medications is permitted provided the dose has been stable for at least 3 months, including: anticholinesterase drugs (rivastigmine, donepezil, galantamine) or memantine, antidepressants SSRI (e.g. fluoxetine, sertraline, paroxetine…), SNRI (e.g. venlafaxine, duloxetine), neuroleptics (e.g. clozapine, olanzapine, aripiprazole...) or drug for pain level 2 (codeine, tramadol).
• For a male subject who is not sterilized and is sexually active with a female partner of childbearing potential, no contraceptive methods are needed

Non inclusion criteria :

• Patients significantly dependent on caregivers
• Institutionalized patients
• Analphabetism or subjects unable to read or/and write
• Patients unable to perform the neuropsychological tests
• Patients unable to complete the study instruments (sleep diary)
• Planned longer stay outside the region that prevents compliance with the visit schedule
• Patients who cannot be followed up for at least 2 months
• History of narcolepsy and/or cataplexy
• History of drug or alcohol abuse or addiction
• History of diagnosed and characterized psychiatric disorders (DSM-5), cured or stabilized (with or without the same treatment for at least 3 months) and excluding any current characterized psychiatric disorder (DSM-5), the diagnosis of which is established by a psychiatrist trained in geriatric psychiatry
• Moderate and severe liver failure
• PSG baseline evidence of significant/severe sleep-related breathing disorder (defined as >30 apnea/hypopnea episodes per hour)
• Treatments interfering with sleep-wake patterns
• Use of hypnotics (benzodiazepines, zolpidem, zopiclone) or drug for pain level 3 (morphine and derivatives)
• Hypersensitivity to the active substance or to any of the excipients listed in the Summary of Product Characteristics (SmPC)
• Forbidden and restricted concomitant medications:

• Concomitant CNS-depressant medicinal products
• CYP3A4 inhibitors
• CYP3A4 inducers
• Participation in another clinical trial or administration of an investigational product
• Protected population according to articles of the French Public Health Code (e.g. patients under law protection, prisoners, pregnant, parturient or lactating women, and patients under guardianship/curatorship).
• Subjects not covered by public health insurance
• Failure to obtain written informed consent after a reflection period

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

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 1 center

• University Hospital, Montpellier — Montpellier

Identifiers

NCT: NCT05924425 · RECHMPL22_0529

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗