Daridorexant to treat insomnia in patients with mild cognitive impairment and mild to moderate Alzheimer disease.

INTERVENTION: Product Name: Placebo matching daridorexant is provided as identitical‐looking oral tablets, formulated with the same inactive ingredients (excipients) as the active tablets.,Product Code: N/A,Pharmaceutical Form: N/A,Other descriptive name: N/A,Strength: N/A,Pharmaceutical form of the placebo: N/A,Product Name: QUVIVIQ 50 mg film‐coated tablets,Product Code: PRD9668426,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: ,Strength: Daridorexant 50mg CONDITION: Insomnia Disorder; SLEEP; Alzheimer Disease ; MedDRA version: 20.0Level: LLTClassification code: 10078083Term: Insomnia disorderSystem Organ Class: 10037175 MedDRA version: 20.0Level: LLTClassification code: 10078083Term: Insomnia disorderSystem Organ Class: 10037175 Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] 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 Aß42 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, gala PRIMARY OUTCOME: Main Objective:To evaluate the efficacy of oral administration of daridorexant 50 mg on the total sleep time (TST) duration as assessed via polysomnography from baseline to post‐baseline, in outpatients with MCI and mild‐to‐moderate AD, with insomnia disorder. Primary end point(s):The change in Total Sleep Time (TST) from baseline to the end of each period (Month 1/Month 2) as assessed by polysomnography comparing daridorexant 50 mg with placebo. Secondary Objective:To evaluate the efficacy of the oral administration of daridorexant 50 mg on a second objective sleep parameter, the wake time after sleep onset (WASO), as assessed by polysomnography from baseline to post‐baseline, in patients with MCI and mild‐to‐moderate AD with insomnia disorder.,To evaluate the efficacy of the oral administration of daridorexant 50 mg on other objective sleep quantity parameters as assessed by polysomnography (latency to persistent sleep (LPS), percentage of sleep stages, wake bouts on the whole night and per quarter of the night) from baseline to post‐baseline.,To evaluate the efficacy of the oral administration of daridorexant 50 mg on sleep/wake parameters (sleep and wake duration, sleep efficiency) as assessed by actigraphy from baseline to post‐baseline.,To evaluate the efficacy of the oral administration of daridorexant 50 mg from baseline to post‐baseline on self‐reported sleep questionnaire total scores for insomnia severity (assessed by the Insomnia Severity Index (ISI) scale and TST reported subjectively), daytime sleepiness and functioning (Epworth Sleepiness Scale (ESS) total score, Insomnia Daytime Symptoms and Impacts (IDSIQ) total score, sleepiness, mood, and alerts/cognition domain scores), depression (Beck Depressive Inventory (BDI)), and quality of life (EQ‐5D) completed by patients and/or caregivers.,To evaluate the efficacy of the oral administration of daridorexant 50 mg from baseline to post‐baseline on cognition (episodic memory, executive function, verbal fluency…) and nocturnal agitation using the Neuropsychiatric Inventory (NPI) agitation/aggression domain.,To evaluate the efficacy of the oral administration of daridorexant 50 mg on beat‐to‐beat blood pressure and nocturnal heart rate during polysomnography and during 24‐hour ambulatory blood pressure monitoring from baseline to post‐baseline.,To evaluate the efficacy of the oral administration of daridorexant 50 mg on serum levels of AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) from baseline to post‐baseline.,To evaluate changes in objective sleep parameters as assessed by polysomnography according to baseline CSF AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and Orexin levels.,To evaluate the concordance of CSF AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and CSF proinflammatory cytokines (TNFa, IL6) with serum AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and serum proinflammatory cytokines (TNFa, IL6) at baseline.,To evaluate the safety and tolerability of treatment during the trial. SECONDARY OUTCOME: Secondary end point(s):Change in depression (using the Beck Depression Inventory – BDI) and quality of life (using the EuroQol 5‐Dimensional Descriptive System – EQ‐5D) from baseline to the end of each period (Month 1/Month 2) with daridorexant 50 mg compared to placebo. Secondary end point(s):Change in the wake time after sleep onset (WASO) from baseline to the end of each period (Month 1/Month 2) as assessed by polysomnography comparing daridorexant 50 mg with placebo. Secondary end point(s):Changes in blood AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):Changes in cognition (episodic memory, executive function, verbal fluency…) and nocturnal agitation using the Neuropsychiatric Inventory (NPI) agitation/aggression domain from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):Changes in objective sleep parameters as assessed by polysomnography (LPS, percentage of sleep stages, wake bouts on the whole night and per quarter of the night) from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):Changes in objective sleep parameters as assessed by polysomnography according to baseline CSF AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and Orexin levels from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):Changes in self‐reported sleep parameters (sleep questionnaires such as TST, insomnia on ISI, and excessive daytime sleepiness on ESS, IDSIQ total score, sleepiness, mood, and alert/cognition domain scores) from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):Changes in sleep/wake parameters (sleep and wake duration, sleep efficiency) as assessed by actigraphy from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):CSF AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and CSF proinflammatory cytokines (TNFa, IL6) levels according to serum AD biomarkers (Aß42, Aß40, Tau, P‐Tau, neurofilament) and serum proinflammatory cytokines (TNFa, IL6) levels at baseline. Secondary end point(s):Decrease in blood pressure variability during polysomnography and increase in 24‐hour blood pressure monitoring dipping pattern from baseline to the end of each period (Month 1/Month 2) comparing daridorexant 50 mg with placebo. Secondary end point(s):Rates of serious adverse events with treatment intake from baseline to the end of trial.