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

Summary

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.

Interventions

• Daridorexant 50 mg · DRUG

  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.

• Placebo · DRUG

  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.

• Polysomnography · PROCEDURE

  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 recording). The advantages of this video-polysomnography are based on the evaluation of sleep architecture, micro-arousals, respiratory events and nocturnal motor behavior.

• Neuropsychological assessment · BEHAVIORAL

  A full neuropsychological assessment will be performed at inclusion, M1, M2

• Questionnaires on sleep and behavioural problems · BEHAVIORAL

  Questionnaires on sleep and behavioural problems will be performed at inclusion, M1, M2

• Actimetrics · PROCEDURE

  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.

• 24-hour Ambulatory Blood Pressure Monitoring (ABPM · PROCEDURE

  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

• Biomarker assay · OTHER

  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

Published eligibility criteria

Verbatim from the registry. Only the site can decide how these apply to a specific patient.

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

Sites (1)

• University Hospital, Montpellier, Montpellier, France · RECRUITING