The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults Study

Официальное название

The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults (ESSENTIAL) Study

Обзор

The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL) study is a 5-year, multicenter randomized open-label trial that will screen 400 cognitively normal older adults recruited from well-established sleep clinics at 4 academic medical centers, with newly diagnosed moderate-severe OSA. An expected 200 OSA patients will be then randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI4%\< 10/hour and AHI3A\<20/hour (see below); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Both groups will continue follow-up for 24 months on stable therapy to determine if sustained improvements in sleep are associated with improvement in cognitive function and AD biomarkers.

Подробное описание

The prevalence of Alzheimer disease (AD) is high and projected to increase. While there are multiple risk factors for AD, epidemiological data suggests that \~15% of AD risk may be attributed to sleep problems. Obstructive sleep apnea (OSA) is common among the elderly (30-55%), and the investigators have shown that cognitively normal older women with OSA have nearly double the risk of developing mild cognitive impairment (MCI) or dementia over 5 years. Further, the investigators have shown that in normal elderly, OSA predicts longitudinal increases in AD biomarkers. Our preliminary data also show that after positive airway pressure (PAP) withdrawal, OSA patients treated with PAP experienced significant overnight increases in plasma neurofilament light (NfL), a marker of neural injury. The present study is designed to overcome challenges identified in previous trials of treatment of OSA to slow cognitive decline and progression to AD. First, the most effective treatment for OSA, PAP therapy, has poor adherence (typically only 50% are adequately treated). Other common therapies include oral appliance therapy (OAT) which tends to be better tolerated but less effective. The investigators have piloted and propose for this study a rapid multimodal therapy initiation (RMMT) which ensures subjects will have effective therapy for their OSA that reduces OSA severity to AHI4%\<10/hour and AHI3A (AKA pRDI) \< 20/hour within 4 months. Second, most prior OSA treatment trials have focused primarily on symptomatic older adults (e.g. patients with MCI recruited from memory clinics), whereas early intervention in pre-symptomatic individuals may have stronger impact in preventing progression to AD. The investigators propose to enroll cognitively normal adults with newly diagnosed moderate-severe OSA (AHI4% \>20/hour or AHI3A \> 40/hour). Finally, selection of cognitive outcomes most responsive to OSA therapy has proved challenging. The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL) study is a 5-year, multicenter randomized open-label trial that will screen 400 cognitively normal older adults (MoCA≥24, Clinical Dementia Rating \[CDR\]=0), ages 55-75, recruited from well-established sleep clinics at 4 academic medical centers, with newly diagnosed moderate-severe OSA (AHI4% \>20/hour or AHI3A \> 40/hour). An expected 200 OSA patients will be then randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI4%\< 10/hour and AHI3A\<20/hour (see below); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Both groups will continue follow-up for 24 months on stable therapy to determine if sustained improvements in sleep are associated with improvement in cognitive function and AD biomarkers. Both arms will include PSG and actigraphy, sleep-dependent memory and other cognitive evaluations, and blood draws at baseline, 3 and 24 months, with cognitive evaluation only at 12 months. Structural brain MRI will be performed at baseline. Because the investigators anticipate that 150 of 200 subjects will be well treated at 24 months, and 50 will not be, the investigators will additionally recruit \~50 subjects (on average 13 subjects per clinical site) with the same inclusion criteria who refuse treatment. These 50 subjects will perform baseline (blood draw and cognitive evaluations), 12-month (cognitive evaluation only), and 24-month (blood draw and cognitive evaluations) visits, allowing for a 24-month comparison of \~150 subjects with adequate treatment over 24 months to 100 subjects with inadequate treatment over 24 months. Our aims are: 1) To compare 3-month change in plasma AD biomarkers (NfL, p-tau, Aβ) in those randomized to OSA treatment and wait-list control groups (via both intention-to-treat and per-protocol analyses); 2) To test differences at 3 months in sleep-dependent declarative memory and cognitive scores (PACC and sub-domains) between the OSA treatment and wait-list control groups (via both intention-to-treat and per-protocol analyses); 3) To compare 24-month changes in AD biomarkers (NfL, p-tau, Aβ) and cognition in all successfully treated subjects and untreated controls.

Вмешательства

• Устройство Positive airway pressure
  Positive airway pressure (PAP) therapy is a sleep apnea treatment that uses a stream of compressed air to support the airway during sleep. With PAP therapy, a mask is worn during sleep and a portable machine gently blows pressurized room air from into your upper airway through a tube connected to the mask. This positive airflow helps keep the airway open, preventing the collapse that occurs during apnea, thus allowing normal breathing.
• Устройство Oral appliance therapy
  Oral appliance therapy involves the use of a dental appliance or oral mandibular advancement device that prevents the tongue from blocking the throat and/or advances the lower jaw forward. These devices help keep the airway open during sleep.
• Устройство Positional therapy
  A NightShift Sleep Positioner (Advanced Brain Monitoring) is a neck vibration device, FDA approved to treat positional sleep apnea. The device detects patient supine position and delivers a small vibratory signal to the back of the neck to prompt position change.

Первичные конечные точки

• Change in overnight memory retention on the A-B verbal paired associates task [Срок оценки: 3 months]
• Change in overnight memory retention on the A-B verbal paired associates task [Срок оценки: 12 months]
• Change in overnight memory retention on the A-B verbal paired associates task [Срок оценки: 24 months]
• Change in Aβ42/ Aβ40 ratio [Срок оценки: 3 months]
• Change in Aβ42/ Aβ40 ratio [Срок оценки: 24 months]
• Change in Plasma P-tau181 [Срок оценки: 3 months]
• Change in Plasma P-tau181 [Срок оценки: 24 months]
• Change in P-tau217 [Срок оценки: 3 months]
• Change in P-tau217 [Срок оценки: 24 months]
• Change in Neurofibrilary light (NfL) [Срок оценки: 3 months]

Вторичные конечные точки (12)

• Change in Task-switching Accuracy [Срок оценки: 3 months]
• Change in Task-switching Accuracy [Срок оценки: 12 months]
• Change in Task-switching Accuracy [Срок оценки: 24 months]
• Change in Task-switching Reaction Time [Срок оценки: 3 months]
• Change in Task-switching Reaction Time [Срок оценки: 12 months]
• Change in Task-switching Reaction Time [Срок оценки: 24 months]
• Change in Psychomotor Vigilance Task (PVT) lapses [Срок оценки: 3 months]
• Change in Psychomotor Vigilance Task (PVT) lapses [Срок оценки: 12 months]
• Change in Psychomotor Vigilance Task (PVT) lapses [Срок оценки: 24 months]
• Change in Psychomotor Vigilance Task (PVT) reaction time [Срок оценки: 3 months]
• Change in Psychomotor Vigilance Task (PVT) reaction time [Срок оценки: 12 months]
• Change in Psychomotor Vigilance Task (PVT) reaction time [Срок оценки: 24 months]

Критерии участия

Критерии включения

• Cognitively normal (TiCS ≥29)
• Age 55-85 years
• Moderate - severe OSA defined as AHI4 ≥20 events/hour or AHI3A>40/hr using a hypopnea criterion of a 4% oxygen desaturation (AHI4) or 3% oxygen desaturation and/or EEG arousal (AHI3A), or equivalent based on in-home testing - Testing must have been completed in past 12 months or confirmed by repeat test
• Not currently on therapy for OSA and has not received treatment for OSA for at least 6months
• Able and willing to be treated for OSA (Treatment group)
• Fluency in English or Spanish

Критерии исключения

• Documented diagnosis of chronic insomnia, or sleep onset insomnia based on Insomnia Severity Index - an answer of severe or very severe in the screening form
• Documented diagnosis of circadian rhythm disorder
• Any current use of supplemental oxygen
• Other sleep-related breathing disorders (central sleep apnea, etc) based on AASM criteria
• Current shift work involving night shift (regular work between 12am and 6am or night shift) within the past 6 mo
• Anticipated scheduled bariatric surgery within the next 3 months
• Chronic regular (> 2 nights per week) of cannabis for sleep
• Chronic regular use (> 2 nights per week) of sedatives/hypnotics for sleep
• Diagnosis of uncontrolled psychiatric disease in the last six months , and/or history of schizophrenia or bipolar disorder. Controlled conditions will include major depressive disorder, panic disorder, generalized anxiety disorder, OCD, substance use disorders, and alcohol abuse/dependence. Personality disorders and neurodevelopmental disorders (e.g. autism, ADHD) are allowed if cognition is within normal limits.
• Taking methylphenidate for ADHD. Unless on stable dose which will be reviewed by the PI to determine.
• Taking GLP-1 agonist semaglutide (Ozempic, Wegovy, Rybelsus), or tirzepatide (Mounjaro, Zepbound), or similar for weightloss, and planning to lose an additional 20lbs or more at the time of enrollment. PI Discretion for determination of why they are taking the drug based on conversation with subject and medical chart, will be documented in form of Note-to-file in the subject's records
• Presence of other comorbid condition that would lead to inability to complete the study protocol (including follow-up for 2 years), or that would affect cognition (e.g. clinically relevant endocrine or hematological conditions).
• Does not have a regular sleeping environment (i.e., sleeps in a different setting > 2 nights per week).
• Currently pregnant or planning to become pregnant.
• Prior diagnosis of a Central nervous system (CNS) disease, such as multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, a loss of consciousness > 24 hours, or traumatic brain injury as identified by the Cumulative Illness Rating Scale for Geriatrics (CIRS). Participants who are diagnosed with MCI or Alzheimer's disease based on neuropsychological testing will be excluded. Delirium in the last 12 months.
• Near-miss or prior automobile accident "due to sleepiness" within the past 12 months.
• Employed as a commercial driver during the study (for example, bus drivers, train engineers, airplane pilots).
• Any use of neuroleptics, benzodiazepines, barbiturates, opiates or anti-amyloid therapies.
• Use of other cognitive enhancing drugs will also be excluded if initiated in the last 3 months, or not on stable dose.
• Consumption of >14 alcohol drinks per week, unless alcohol consumption can be reduced if initiated in the last 3 months.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 4 центра

• University of Arizona — Tucson
• New York University — New York
• Mount Sinai — New York
• University of Pittsburgh — Pittsburgh

Идентификаторы

NCT: NCT05988385 · AG080609

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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