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

Alzheimer Disease Clinical Trial

— DARIDOR-ALZ  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05924425
• Other study ID #: RECHMPL22_0529
• Status: Recruiting
• Phase: Phase 4
• Start date: March 13, 2024
• Est. completion date: March 13, 2027

Study information

• Verified date: June 2023
• Source: University Hospital, Montpellier
• Contact: Yves Dauvilliers, MD
• Phone: +33467336361
• Email: y-dauvilliers[@]chu-montpellier.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 62
• Est. completion date: March 13, 2027
• Est. primary completion date: May 13, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 85 Years

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 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, 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

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Insomnia Disorder
• Sleep
• Sleep Initiation and Maintenance Disorders

Intervention

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

Behavioral:
• Neuropsychological assessment
A full neuropsychological assessment will be performed at inclusion, M1, M2
• 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.
• 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 (Aß42, Aß40, 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

Locations

Country	Name	City	State
France	University Hospital, Montpellier	Montpellier

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Montpellier	Idorsia Pharmaceuticals Ltd.

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Total Sleep Time (TST).	TST is defined as the total sleep time in minutes. The total sleep time is the total amount of sleep time scored during the total recording time. The TST is measured during polysomnography.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Change in the wake time after sleep onset (WASO)	WASO is defined as the time to wake after initial sleep onset. WASO is measured during overnight sleep laboratory (PSG) assessment and defined as the duration of wakefulness from the onset of persistent sleep.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Change in Latency to Persistent Sleep (LPS)	LPS is the time in minutes from 'lights out' that marks the starting of total recording time to the first epoch recorded as sleep. The LPS is measured during polysomnography.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Measure of sleep time at stage 1-2 during polysomnography	Time spent in stage 1-2 sleep measured in hours and minutes during polysomnography.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Measure of sleep time at stage 3 during polysomnography	Time spent in stage 3 sleep measured in hours and minutes during polysomnography.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Measure of number of wake bouts on the whole night	The number of wake bouts on the whole night will be measured by polysomnography.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Measure of number of wake bouts per quarter of the night	The number of wake bouts per quarter of the night will be measured by polysomnography.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Changes in sleep and wake duration	Average sleep duration (in hours and minutes) over a 7-day period from inclusion to each visit measured by actimetry.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Changes in sleep and wake duration	Average sleep duration (in hours and minutes) over a 7-day period from inclusion to each visit measured by actimetry.	from baseline to Month 6
Secondary	Changes in sleep and wake duration	Average sleep duration (in hours and minutes) over a 7-day period from inclusion to each visit measured by actimetry.	from baseline to Month 12
Secondary	Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire ISI.; The Insomnia Severity Index (ISI) is a 7-item self-report questionnaire assessing the nature, severity of both nighttime and daytime components of insomnia, and impact of insomnia.; Each item is scored 0 (no problem) - 4 (very big problem) with total between 0-28 (absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire ISI.; The Insomnia Severity Index (ISI) is a 7-item self-report questionnaire assessing the nature, severity of both nighttime and daytime components of insomnia, and impact of insomnia.; Each item is scored 0 (no problem) - 4 (very big problem) with total between 0-28 (absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).	from baseline to Month 6
Secondary	Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire ISI.; The Insomnia Severity Index (ISI) is a 7-item self-report questionnaire assessing the nature, severity of both nighttime and daytime components of insomnia, and impact of insomnia.; Each item is scored 0 (no problem) - 4 (very big problem) with total between 0-28 (absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).	from baseline to Month 12
Secondary	Variations in the results of self-reported questionnaires administered to patients - Epworth Sleepiness Scale (ESS)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire ESS.; The Epworth Sleepiness Scale (ESS) is a self-report measure of daytime sleepiness in various situations and consists of eight questions. ESS score can range from 0 to 24 (1 to 6 points: Normal sleep; 7 to 8 points: Average sleepiness: 9 to 24 points: Abnormal (possibly pathologic) sleepiness).	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of self-reported questionnaires administered to patients - ESS	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire ESS.; The Epworth Sleepiness Scale (ESS) is a self-report measure of daytime sleepiness in various situations and consists of eight questions. ESS score can range from 0 to 24 (1 to 6 points: Normal sleep; 7 to 8 points: Average sleepiness: 9 to 24 points: Abnormal (possibly pathologic) sleepiness).	from baseline to Month 6
Secondary	Variations in the results of self-reported questionnaires administered to patients - Epworth Sleepiness Scale (ESS)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire ESS.; The Epworth Sleepiness Scale (ESS) is a self-report measure of daytime sleepiness in various situations and consists of eight questions. ESS score can range from 0 to 24 (1 to 6 points: Normal sleep; 7 to 8 points: Average sleepiness: 9 to 24 points: Abnormal (possibly pathologic) sleepiness).	from baseline to Month 12
Secondary	Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire IDSIQ.; The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a patient-reported outcome instrument that assesses daytime functioning in patients with insomnia.; It consists of 14 items (each using a numeric rating scale from 0 to 10) grouped into 3 domains : Alert/Cognition, Mood, and Sleepiness domain reflecting daytime impairment of insomnia.; The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire IDSIQ.; The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a patient-reported outcome instrument that assesses daytime functioning in patients with insomnia.; It consists of 14 items (each using a numeric rating scale from 0 to 10) grouped into 3 domains : Alert/Cognition, Mood, and Sleepiness domain reflecting daytime impairment of insomnia.; The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.	from baseline to Month 6
Secondary	Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ)	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire IDSIQ.; The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a patient-reported outcome instrument that assesses daytime functioning in patients with insomnia.; It consists of 14 items (each using a numeric rating scale from 0 to 10) grouped into 3 domains : Alert/Cognition, Mood, and Sleepiness domain reflecting daytime impairment of insomnia.; The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.	from baseline to Month 12
Secondary	Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire Sleep diaries.; Participants will completed a daily sleep diary (sleep onset latency, wake after sleep onset, early morning awakening, total wake time, total sleep time, and sleep efficiency).	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire Sleep diaries.; Participants will completed a daily sleep diary (sleep onset latency, wake after sleep onset, early morning awakening, total wake time, total sleep time, and sleep efficiency).	from baseline to Month 6
Secondary	Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries	Values and variations from baseline of patient-reported outcomes including self-reported questionnaire Sleep diaries.; Participants will completed a daily sleep diary (sleep onset latency, wake after sleep onset, early morning awakening, total wake time, total sleep time, and sleep efficiency).	from baseline to Month 12
Secondary	Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI)	The nocturnal agitation will be assessed by using the Neuropsychiatric Inventory (NPI) agitation/aggression domain.; The Neuropsychiatric Inventory (NPI), which consists of 12 items scored with questions, sub-questions, and frequency and severity ratings, is used to assess behavioral changes in Alzheimer disease and other neurodegenerative disorders. The agitation/aggression domain will be evaluated at each visit.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI)	The nocturnal agitation will be assessed by using the Neuropsychiatric Inventory (NPI) agitation/aggression domain.; The Neuropsychiatric Inventory (NPI), which consists of 12 items scored with questions, sub-questions, and frequency and severity ratings, is used to assess behavioral changes in Alzheimer disease and other neurodegenerative disorders. The agitation/aggression domain will be evaluated at each visit.	from baseline to Month 6
Secondary	Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI)	The nocturnal agitation will be assessed by using the Neuropsychiatric Inventory (NPI) agitation/aggression domain.; The Neuropsychiatric Inventory (NPI), which consists of 12 items scored with questions, sub-questions, and frequency and severity ratings, is used to assess behavioral changes in Alzheimer disease and other neurodegenerative disorders. The agitation/aggression domain will be evaluated at each visit.	from baseline to Month 12
Secondary	Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI)	Values and variations from baseline of patient-reported outcomes including health assessment questionnaire BDI.; The Beck Depression Inventory (BDI) contains 21 items on a 4-point scale from 0 (symptom absent) to 3 (severe symptoms). The minimum score is 0 and the maximum score is 63, with a higher score indicating more severe depressive symptoms.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI)	Values and variations from baseline of patient-reported outcomes including health assessment questionnaire BDI.; The Beck Depression Inventory (BDI) contains 21 items on a 4-point scale from 0 (symptom absent) to 3 (severe symptoms). The minimum score is 0 and the maximum score is 63, with a higher score indicating more severe depressive symptoms.	from baseline to Month 6
Secondary	Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI)	Values and variations from baseline of patient-reported outcomes including health assessment questionnaire BDI.; The Beck Depression Inventory (BDI) contains 21 items on a 4-point scale from 0 (symptom absent) to 3 (severe symptoms). The minimum score is 0 and the maximum score is 63, with a higher score indicating more severe depressive symptoms.	from baseline to Month 12
Secondary	Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D)	Values and variations from baseline of patient-reported outcomes including health assessment questionnaire EQ5D.; The EuroQol 5-dimensional descriptive system (EQ5D) is a Health Assessment Scale quality of life questionnaire evaluating: mobility, washing and dressing, daily activities, pain and anxiety. Each question has 3 levels of answers: No problem, some problems and important problems. Lower score indicate better outcomes.; The questionnaire also includes a visual analog scale in which the patient quantifies his or her perception of quality of life using a score ranging from the worst imaginable state of health (0) to the best imaginable state of health (100).	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D)	Values and variations from baseline of patient-reported outcomes including health assessment questionnaire EQ5D.; The EuroQol 5-dimensional descriptive system (EQ5D) is a Health Assessment Scale quality of life questionnaire evaluating: mobility, washing and dressing, daily activities, pain and anxiety. Each question has 3 levels of answers: No problem, some problems and important problems. Lower score indicate better outcomes.; The questionnaire also includes a visual analog scale in which the patient quantifies his or her perception of quality of life using a score ranging from the worst imaginable state of health (0) to the best imaginable state of health (100).	from baseline to Month 6
Secondary	Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D)	Values and variations from baseline of patient-reported outcomes including health assessment questionnaire EQ5D.; The EuroQol 5-dimensional descriptive system (EQ5D) is a Health Assessment Scale quality of life questionnaire evaluating: mobility, washing and dressing, daily activities, pain and anxiety. Each question has 3 levels of answers: No problem, some problems and important problems. Lower score indicate better outcomes.; The questionnaire also includes a visual analog scale in which the patient quantifies his or her perception of quality of life using a score ranging from the worst imaginable state of health (0) to the best imaginable state of health (100).	from baseline to Month 12
Secondary	Change in cognition	The Alzheimer's Disease Cooperative Study - Preclinical Alzheimer Cognitive (ADCS-PACC) scale score will be based on scores from the Mini Mental State Examination (MMSE) (range from 0-30 points), Free and Cued Selective Reminding Test - FCSRT (range from 0-48 points), the Digit Substitution Symbol Test, the Wechsler Intelligence Scale for Adults (WAIS-IV) (range from 0-93 points), the Clinical Dementia Rating Scale (CDR) (range from 0-18 points), and the 2-minute Verbal Fluency Test.; The ADCS-PACC will be measured at each visit. Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Z Scores could range from -5 to +5 with higher scores indicating less deficit and lower scores indicating greater deficit.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Change in cognition	The Alzheimer's Disease Cooperative Study - Preclinical Alzheimer Cognitive (ADCS-PACC) scale score will be based on scores from the Mini Mental State Examination (MMSE) (range from 0-30 points), Free and Cued Selective Reminding Test - FCSRT (range from 0-48 points), the Digit Substitution Symbol Test, the Wechsler Intelligence Scale for Adults (WAIS-IV) (range from 0-93 points), the Clinical Dementia Rating Scale (CDR) (range from 0-18 points), and the 2-minute Verbal Fluency Test.; The ADCS-PACC will be measured at each visit. Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Z Scores could range from -5 to +5 with higher scores indicating less deficit and lower scores indicating greater deficit.	from baseline to Month 6
Secondary	Change in cognition	The Alzheimer's Disease Cooperative Study - Preclinical Alzheimer Cognitive (ADCS-PACC) scale score will be based on scores from the Mini Mental State Examination (MMSE) (range from 0-30 points), Free and Cued Selective Reminding Test - FCSRT (range from 0-48 points), the Digit Substitution Symbol Test, the Wechsler Intelligence Scale for Adults (WAIS-IV) (range from 0-93 points), the Clinical Dementia Rating Scale (CDR) (range from 0-18 points), and the 2-minute Verbal Fluency Test.; The ADCS-PACC will be measured at each visit. Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Z Scores could range from -5 to +5 with higher scores indicating less deficit and lower scores indicating greater deficit.	from baseline to Month 12
Secondary	Change in blood pressure	Decrease in blood pressure variability (Systolic and Diastolic) 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.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Change in blood pressure	Change in 24-hour blood pressure (Systolic and Diastolic) monitoring dipping pattern from baseline to the month 6 with daridorexant 50 mg.	from baseline to Month 6
Secondary	Change in blood pressure	Change in 24-hour blood pressure (Systolic and Diastolic) monitoring dipping pattern from baseline to the month 12 with daridorexant 50 mg.	from baseline to Month 12
Secondary	Change in blood AD biomarkers and proinflammatory cytokines levels	Determination of blood AD biomarkers (Aß42, Aß40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.	from baseline to the end of each period A/B (Month1/Month2)
Secondary	Change in blood AD biomarkers and proinflammatory cytokines levels	Determination of blood AD biomarkers (Aß42, Aß40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.	from baseline to Month 6
Secondary	Change in blood AD biomarkers and proinflammatory cytokines levels	Determination of blood AD biomarkers (Aß42, Aß40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.	from baseline to Month 12
Secondary	Concentration of CSF AD biomarkers and proinflammatory cytokines	Determination of AD biomarkers (Aß42, Aß40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in cerebrospinal fluid (CSF).	baseline
Secondary	Concentration of CSF orexinA/hypocretin	Determination orexinA/hypocretin in cerebrospinal fluid (CSF)	baseline
Secondary	Percentage of Serious Adverse Events Occurring	Safety: rates of serious adverse events between baseline and 12 months.	between baseline and 12 months