Clinical trial NCT05924425: Daridorexant to Treat Insomnia in Patients With Mild Cognitive Impairment and Mild to Moderate Alzheimer Disease
Official title: Daridorexant to Treat Insomnia in Patients With Mild Cognitive Impairment and Mild to Moderate Alzheimer Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Alzheimer Disease
Insomnia Disorder
Sleep
Keywords: Orexin
Daridorexant
Cognition
Alzheimer
Sleep
Insomnia
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
Collaborators: name: Idorsia Pharmaceuticals Ltd.
First posted: 2023-06-29
Enrollment: 62
Sex: ALL
Minimum age (years): 60
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: During Period A, 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 will be followed by a one-week (range 5-12 days) washout period at home. During the second period (Period B), these patients will receive the placebo.

During Period A, 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 will be followed by a one-week (range 5-12 days) washout period at home. During the second period (Period B), these patients will receive the daridorexant 50 mg.
Primary purpose: TREATMENT

Brief 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.

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).

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 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

Primary outcomes:
measure: Change in Total Sleep Time (TST).
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
Secondary outcomes:
measure: Change in the wake time after sleep onset (WASO)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Change in Latency to Persistent Sleep (LPS)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Measure of sleep time at stage 1-2 during polysomnography
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Measure of sleep time at stage 3 during polysomnography
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Measure of number of wake bouts on the whole night
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Measure of number of wake bouts per quarter of the night
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Changes in sleep and wake duration
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Changes in sleep and wake duration
timeFrame: from baseline to Month 6
measure: Changes in sleep and wake duration
timeFrame: from baseline to Month 12
measure: Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI)
timeFrame: from baseline to Month 6
measure: Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI)
timeFrame: from baseline to Month 12
measure: Variations in the results of self-reported questionnaires administered to patients - Epworth Sleepiness Scale (ESS)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of self-reported questionnaires administered to patients - ESS
timeFrame: from baseline to Month 6
measure: Variations in the results of self-reported questionnaires administered to patients - Epworth Sleepiness Scale (ESS)
timeFrame: from baseline to Month 12
measure: Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ)
timeFrame: from baseline to Month 6
measure: Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ)
timeFrame: from baseline to Month 12
measure: Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries
timeFrame: from baseline to Month 6
measure: Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries
timeFrame: from baseline to Month 12
measure: Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI)
timeFrame: from baseline to Month 6
measure: Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI)
timeFrame: from baseline to Month 12
measure: Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI)
timeFrame: from baseline to Month 6
measure: Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI)
timeFrame: from baseline to Month 12
measure: Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D)
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D)
timeFrame: from baseline to Month 6
measure: Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D)
timeFrame: from baseline to Month 12
measure: Change in cognition
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Change in cognition
timeFrame: from baseline to Month 6
measure: Change in cognition
timeFrame: from baseline to Month 12
measure: Change in blood pressure
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Change in blood pressure
timeFrame: from baseline to Month 6
measure: Change in blood pressure
timeFrame: from baseline to Month 12
measure: Change in blood AD biomarkers and proinflammatory cytokines levels
timeFrame: from baseline to the end of each period A/B (Month1/Month2)
measure: Change in blood AD biomarkers and proinflammatory cytokines levels
timeFrame: from baseline to Month 6
measure: Change in blood AD biomarkers and proinflammatory cytokines levels
timeFrame: from baseline to Month 12
measure: Concentration of CSF AD biomarkers and proinflammatory cytokines
timeFrame: baseline
measure: Concentration of CSF orexinA/hypocretin
timeFrame: baseline
measure: Percentage of Serious Adverse Events Occurring
timeFrame: between baseline and 12 months
Other outcomes:
Locations:
city: Montpellier
country: France
facility: University Hospital, Montpellier
Study officials:
affiliation: University Hospital, Montpellier
name: Yves Dauvilliers, MD
role: PRINCIPAL_INVESTIGATOR
References: