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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Montpellier

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

14 Dec 2023 → ongoing

Decision date (initial)

2023-06-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Idorsia Pharmaceuticals Ltd

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

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.

Secondary objectives 10

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. To evaluate the efficacy of the oral administration of daridorexant 50 mg on serum levels of AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and proinflammatory cytokines (TNFa, IL6) from baseline to post-baseline.
8. To evaluate changes in objective sleep parameters as assessed by polysomnography according to baseline CSF AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and Orexin levels.
9. To evaluate the concordance of CSF AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and CSF proinflammatory cytokines (TNFa, IL6) with serum AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and serum proinflammatory cytokines (TNFa, IL6) at baseline.
10. To evaluate the safety and tolerability of treatment during the trial.

Conditions and MedDRA coding

Insomnia Disorder; SLEEP; Alzheimer Disease

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age [60-85] years old.
2. Outpatients
3. 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 was below 6 hours, on at least 3 nights per week and for at least 1 month before screening
4. Baseline PSG (at randomization) assessed TST < 6 hours and WASO > 1 hour
5. 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 Aβ42 and neuronal injury (hippocampal and/or temporal atrophy by MRI))
6. MMSE from 12 to 26
7. Clinical Dementia Rating CDR from 0.5 to 2
8. Possible of CNS drugs if stable dose for at least 3 months: anticholinesterase drugs (rivastigmine, donepezil, galantamine) or memantine

Exclusion criteria 20

1. Patients significantly dependent on caregivers
2. Institutionalized patients
3. Analphabetism or subjects unable to read or/and write
4. Patients unable to perform the neuropsychological tests
5. Patients unable to complete the study instruments (sleep diary)
6. Planned longer stay outside the region that prevents compliance with the visit schedule
7. Patients who cannot be followed up for at least 2 months
8. History of narcolepsy and/or cataplexy
9. History of drug or alcohol abuse or addiction
10. History of depression or suicidal ideation/attempt or other psychiatric conditions
11. Moderate and severe liver failure
12. PSG baseline evidence of significant/severe sleep-related breathing disorder (defined as >30 apnea/hypopnea episodes per hour)
13. Treatments interfering with sleep-wake patterns
14. Psychotropic drugs (antidepressants and hypnotics)
15. Hypersensitivity to the active substance or to any of the excipients listed in the Summary of Product Characteristics (SmPC)
16. Forbidden and restricted concomitant medications: • Concomitant CNS-depressant medicinal products • CYP3A4 inhibitors • CYP3A4 inducers
17. Participation in another clinical trial or administration of an investigational product
18. Protected population according to articles of the French Public Health Code (e.g. patients under law protection, prisoners). Patients under guardianship/curatorship are accepted
19. Subjects not covered by public health insurance
20. Failure to obtain written informed consent after a reflection period

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 11

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Changes in blood AD biomarkers (Aβ42, Aβ40, 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.
9. Changes in objective sleep parameters as assessed by polysomnography according to baseline CSF AD biomarkers (Aβ42, Aβ40, 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.
10. CSF AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and CSF proinflammatory cytokines (TNFa, IL6) levels according to serum AD biomarkers (Aβ42, Aβ40, Tau, P-Tau, neurofilament) and serum proinflammatory cytokines (TNFa, IL6) levels at baseline.
11. Rates of serious adverse events with treatment intake from baseline to the end of trial.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Montpellier

Sponsor organisation

Centre Hospitalier Universitaire De Montpellier

Address

191 Avenue Du Doyen Gaston Giraud

City

Montpellier Cedex 5

Postcode

34295

Country

France

Scientific contact point

Organisation

University Hospital Of Montpellier

Contact name

DAUVILLIERS YVES

Public contact point

Organisation

University Hospital Of Montpellier

Contact name

DAUVILLIERS YVES

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications