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.
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).
Eligibility
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 and sleep diary was below 6 hours, on at least 3 nights per week and for at least 1 month before screening, and
- Insomnia Severity Scale ISI© score ≥ 15
- 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 biomarker for CSF Aβ42 and neuronal injury (hippocampal and/or temporal atrophy by MRI))
- MMSE from 12 to 26
- Clinical Dementia Rating CDR from 0.5 to 2
- Possible of CNS drugs if stable dose for at least 3 months: anticholinesterase drugs (rivastigmine, donepezil, galantamine) or memantine
- 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 depression or suicidal ideation/attempt or other psychiatric conditions
- 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
- Psychotropic drugs: antidepressants (SSRI (e.g. fluoxetine, sertraline, paroxetine…), SNRI (e.g. venlafaxine, duloxetine)), neuroleptics (e.g. clozapine, olanzapine, aripiprazole...), and hypnotics (benzodiazepines, zolpidem, zopiclone) or drug for pain (level 2 (e.g. codeine, tramadol), and 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