Efficacy of Daridorexant in Treating Insomnia in Patients with Mild Cognitive Impairment and Mild to Moderate Alzheimer's Disease

The primary objective of this study is 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 mild cognitive impairment (MCI) and mild-to-moderate Alzheimer disease (AD) who have insomnia disorder. This is clinically relevant as improving TST can significantly enhance the quality of life and cognitive function in patients with insomnia associated with MCI and AD.

Secondary objectives include: - Evaluating the efficacy of daridorexant on wake time after sleep onset (WASO) and other sleep parameters such as latency to persistent sleep (LPS), percentage of sleep stages, and wake bouts, using polysomnography. - Assessing sleep/wake parameters like sleep and wake duration and sleep efficiency via actigraphy. - Analyzing self-reported sleep questionnaire scores for insomnia severity, daytime sleepiness, functioning, depression, and quality of life. - Investigating the impact on cognition and nocturnal agitation using the Neuropsychiatric Inventory. - Monitoring beat-to-beat blood pressure and nocturnal heart rate during polysomnography and 24-hour ambulatory blood pressure monitoring. - Measuring serum levels of AD biomarkers and proinflammatory cytokines. - Evaluating changes in sleep parameters according to baseline cerebrospinal fluid (CSF) AD biomarkers and Orexin levels. - Assessing the concordance of CSF and serum AD biomarkers and proinflammatory cytokines. - Evaluating the safety and tolerability of the treatment during the trial.

The clinical trial involves a study population comprising both **male** and **female** participants aged between 60 and 85 years. The participants are outpatients diagnosed with mild cognitive impairment (MCI) and mild-to-moderate **Alzheimer's disease** (AD), who also suffer from **insomnia disorder**. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on specific criteria, including dissatisfaction with sleep quality or quantity, with a total sleep time of less than 6 hours, causing significant distress or impairment in daytime functioning. The trial population includes individuals with a Clinical Dementia Rating (CDR) of 0.5 to 2 and a Mini-Mental State Examination (MMSE) score ranging from 12 to 26. The study considers lifestyle factors such as the stability of central nervous system (CNS) drug use, allowing for the inclusion of participants on stable doses of anticholinesterase drugs or memantine for at least three months. The trial targets a vulnerable population, focusing on those with early-stage AD and MCI, as defined by the National Institute on Aging (NIA) diagnosis criteria, including positive biomarkers for CSF Aβ42 and evidence of neuronal injury.

The clinical trial is designed to evaluate the efficacy of **daridorexant** 50 mg in treating **insomnia disorder** in patients with mild cognitive impairment and mild to moderate **Alzheimer disease**. This study employs a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either the active treatment or a placebo, with both groups receiving identical-looking oral tablets to maintain blinding. The trial is expected to last until May 2026, with recruitment having commenced in May 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (60-85 years), outpatient status, and specific sleep-related complaints. Baseline assessments will include polysomnography to measure total sleep time (TST) and wake time after sleep onset (WASO). Follow-up visits will occur monthly, with primary endpoints focusing on changes in TST from baseline to the end of each period (Month 1/Month 2), as assessed by polysomnography. Secondary endpoints will evaluate changes in WASO, sleep parameters, self-reported sleep quality, depression, quality of life, cognition, and blood biomarkers.

The expected length of participant involvement is up to 12 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. The end-of-study visit will involve final assessments to compare the effects of daridorexant with placebo, ensuring comprehensive data collection for analysis. This trial aims to provide valuable insights into the therapeutic potential of daridorexant for improving sleep in patients with cognitive impairments and Alzheimer's disease.

The clinical trial involves the administration of **daridorexant**, marketed under the name QUVIVIQ, as the experimental medication. QUVIVIQ is provided in the form of **film-coated tablets** containing 50 mg of the active substance, daridorexant. The tablets are administered orally. The maximum daily dose is 50 mg, and the treatment period extends up to 12 weeks. The study product is identical to the commercial product in terms of quality, but it is presented without debossing to maintain blinding. The primary objective of the trial is to evaluate the efficacy of daridorexant in increasing total sleep time in patients with insomnia associated with mild cognitive impairment and mild to moderate Alzheimer's disease.

The trial also includes a **placebo** group for comparison. The placebo is designed to match the daridorexant tablets in appearance and is formulated with the same inactive ingredients (excipients) as the active tablets. The placebo is administered orally in the same manner as the active treatment, ensuring that the study remains double-blind. The use of a placebo allows for the assessment of the true efficacy of daridorexant by providing a baseline for comparison against the active treatment group.

The efficacy of **daridorexant** in treating insomnia in patients with mild cognitive impairment and mild to moderate Alzheimer's disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in Total Sleep Time (TST) from baseline to the end of each period (Month 1/Month 2), as measured by polysomnography, comparing **daridorexant** 50 mg with placebo. Secondary endpoints include changes in wake time after sleep onset (WASO), objective sleep parameters such as latency to persistent sleep (LPS), percentage of sleep stages, and wake bouts, all assessed via polysomnography. Additionally, sleep/wake parameters like sleep and wake duration and sleep efficiency will be evaluated using actigraphy.

Self-reported sleep parameters will be collected through sleep questionnaires, including the Insomnia Severity Index (ISI) and the Epworth Sleepiness Scale (ESS), along with assessments of mood and cognition. Depression and quality of life will be measured using the Beck Depression Inventory (BDI) and the EuroQol 5-Dimensional Descriptive System (EQ-5D), respectively. Cognitive function and nocturnal agitation will be evaluated using the Neuropsychiatric Inventory (NPI). Changes in blood pressure variability and 24-hour blood pressure monitoring will also be assessed. Biomarker analysis will include blood and cerebrospinal fluid (CSF) levels of Alzheimer's disease biomarkers and proinflammatory cytokines. The study will also monitor the rates of serious adverse events throughout the trial duration.