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.
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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
62
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.
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.
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.
A full neuropsychological assessment will be performed at inclusion, M1, M2
Questionnaires on sleep and behavioural problems will be performed at inclusion, M1, M2
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.
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
Determination of AD biomarkers (Aβ42, Aβ40, 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
University Hospital, Montpellier
Montpellier, France
RECRUITINGChange 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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
Measure of sleep time at stage 1-2 during polysomnography
Time spent in stage 1-2 sleep measured in hours and minutes during polysomnography.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
Measure of sleep time at stage 3 during polysomnography
Time spent in stage 3 sleep measured in hours and minutes during polysomnography.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
Measure of number of wake bouts on the whole night
The number of wake bouts on the whole night will be measured by polysomnography.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to Month 6
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.
Time frame: from baseline to Month 12
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).
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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).
Time frame: from baseline to Month 6
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).
Time frame: from baseline to Month 12
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).
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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).
Time frame: from baseline to Month 6
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).
Time frame: from baseline to Month 12
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to Month 6
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.
Time frame: from baseline to Month 12
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).
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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).
Time frame: from baseline to Month 6
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).
Time frame: from baseline to Month 12
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to Month 6
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.
Time frame: from baseline to Month 12
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to Month 6
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.
Time frame: from baseline to Month 12
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).
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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).
Time frame: from baseline to Month 6
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).
Time frame: from baseline to Month 12
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to Month 6
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.
Time frame: from baseline to Month 12
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.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
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.
Time frame: from baseline to Month 6
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.
Time frame: from baseline to Month 12
Change in blood AD biomarkers and proinflammatory cytokines levels
Determination of blood AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.
Time frame: from baseline to the end of each period A/B (Month1/Month2)
Change in blood AD biomarkers and proinflammatory cytokines levels
Determination of blood AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.
Time frame: from baseline to Month 6
Change in blood AD biomarkers and proinflammatory cytokines levels
Determination of blood AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in serum.
Time frame: from baseline to Month 12
Concentration of CSF AD biomarkers and proinflammatory cytokines
Determination of AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) levels in cerebrospinal fluid (CSF).
Time frame: baseline
Concentration of CSF orexinA/hypocretin
Determination orexinA/hypocretin in cerebrospinal fluid (CSF)
Time frame: baseline
Percentage of Serious Adverse Events Occurring
Safety: rates of serious adverse events between baseline and 12 months.
Time frame: between baseline and 12 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.