Daridorexant to Treat Insomnia in Patients With Mild Cognitive Impairment and Mild to Moderate Alzheimer Disease
- Conditions
- Insomnia DisorderAlzheimer DiseaseSleep
- Interventions
- Drug: PlaceboProcedure: PolysomnographyBehavioral: Neuropsychological assessmentBehavioral: Questionnaires on sleep and behavioural problemsProcedure: ActimetricsProcedure: 24-hour Ambulatory Blood Pressure Monitoring (ABPMOther: Biomarker assay
- Registration Number
- NCT05924425
- Lead Sponsor
- University Hospital, Montpellier
- 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).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 62
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Daridorexant 50 mg Daridorexant 50 mg Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Placebo-controlled arm Questionnaires on sleep and behavioural problems Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B). Daridorexant 50 mg Polysomnography Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Daridorexant 50 mg Actimetrics Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Daridorexant 50 mg Neuropsychological assessment Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Placebo-controlled arm Placebo Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B). Daridorexant 50 mg Questionnaires on sleep and behavioural problems Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Daridorexant 50 mg Biomarker assay Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Placebo-controlled arm Polysomnography Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B). Placebo-controlled arm Neuropsychological assessment Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B). Placebo-controlled arm Actimetrics Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B). Placebo-controlled arm 24-hour Ambulatory Blood Pressure Monitoring (ABPM Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B). Daridorexant 50 mg 24-hour Ambulatory Blood Pressure Monitoring (ABPM Patients will receive daridorexant 50 mg during one month (Period A or Period B). Daridorexant is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. Placebo-controlled arm Biomarker assay Patients will receive a placebo matching to daridorexant 50 mg during one month (Period A or Period B).
- Primary Outcome Measures
Name Time Method Change in Total Sleep Time (TST). from baseline to the end of each period A/B (Month1/Month2) 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.
- Secondary Outcome Measures
Name Time Method Change in cognition from baseline to Month 12 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.Measure of sleep time at stage 1-2 during polysomnography from baseline to the end of each period A/B (Month1/Month2) Time spent in stage 1-2 sleep measured in hours and minutes during polysomnography.
Measure of number of wake bouts on the whole night from baseline to the end of each period A/B (Month1/Month2) The number of wake bouts on the whole night will be measured by polysomnography.
Change in the wake time after sleep onset (WASO) from baseline to the end of each period A/B (Month1/Month2) 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.
Changes in sleep and wake duration from baseline to Month 12 Average sleep duration (in hours and minutes) over a 7-day period from inclusion to each visit measured by actimetry.
Variations in the results of self-reported questionnaires administered to patients - Epworth Sleepiness Scale (ESS) from baseline to Month 12 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).Variations in the results of self-reported questionnaires administered to patients - Insomnia Daytime Symptoms and Impacts (IDSIQ) from baseline to Month 12 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.Variations in the results of self-reported questionnaires administered to patients - Sleep Diaries from baseline to Month 12 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).Variations in the results of health assessment questionnaires administered to patients - Beck Depression Inventory (BDI) from baseline to Month 12 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.Change in blood pressure from baseline to Month 12 Change in 24-hour blood pressure (Systolic and Diastolic) monitoring dipping pattern from baseline to the month 12 with daridorexant 50 mg.
Change in blood AD biomarkers and proinflammatory cytokines levels from baseline to Month 12 Determination of blood AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.
Concentration of CSF AD biomarkers and proinflammatory cytokines baseline Determination of AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in cerebrospinal fluid (CSF).
Concentration of CSF orexinA/hypocretin baseline Determination orexinA/hypocretin in cerebrospinal fluid (CSF)
Change in Latency to Persistent Sleep (LPS) from baseline to the end of each period A/B (Month1/Month2) 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.
Measure of sleep time at stage 3 during polysomnography from baseline to the end of each period A/B (Month1/Month2) Time spent in stage 3 sleep measured in hours and minutes during polysomnography.
Measure of number of wake bouts per quarter of the night from baseline to the end of each period A/B (Month1/Month2) The number of wake bouts per quarter of the night will be measured by polysomnography.
Variations in the results of self-reported questionnaires administered to patients - Insomnia Severity Index (ISI) from baseline to Month 12 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).Variations in the results of self-reported questionnaires administered to patients - ESS from baseline to Month 6 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).Variations in the results of health assessment questionnaires administered to patients - Neuropsychiatric Inventory (NPI) from baseline to Month 12 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.Variations in the results of health assessment questionnaires administered to patients - EuroQoL-5D (EQ5D) from baseline to Month 12 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).Percentage of Serious Adverse Events Occurring between baseline and 12 months Safety: rates of serious adverse events between baseline and 12 months.
Trial Locations
- Locations (1)
University Hospital, Montpellier
🇫🇷Montpellier, France