Clinical trial NCT05988385: The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults Study
Official title: The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults (ESSENTIAL) Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obstructive Sleep Apnea
Cognitive Decline
Keywords: Obstructive Sleep Apnea
OSA
Cognitive decline
Alzheimer Disease
AD
AD biomarkers
Positive Airway Pressure
PAP
CPAP
Oral appliance therapy
OAT
Positional therapy
Sleep-dependent memory
Lead sponsor: California Pacific Medical Center Research Institute
Sponsor class: OTHER
Collaborators: name: Icahn School of Medicine at Mount Sinai
name: New York University
name: University of Arizona
name: University of Pittsburgh
name: National Institute on Aging (NIA)
First posted: 2023-08-14
Enrollment: 200
Sex: ALL
Minimum age (years): 55
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Approximately 250 total patients (\~63 per site) will be enrolled. In the 3-month wait-list control randomized trial, 200 patients will be 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" AHI3a\<15 (rapid multi-modal treatment RMMT); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. The remaining 50, plus an additional \~50 (n\~100 total) participants who declined treatment and were not interested in being randomized for the 3-month trial, or who have tried but failed treatment in the past, will serve as the "control" group for the 24-month follow-up period.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Cognitively normal (TiCS\>29
* 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 12 months
* Able and willing to be treated for OSA
* Fluency in English or Spanish

Exclusion Criteria:

* Documented diagnosis of chronic insomnia.
* Severe or very severe difficulty falling asleep.
* 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
* Chronic regular (\> 2 nights per week) use of any sedative, stimulant, neuroleptic drugs, or other medications limiting validity of cognitive tests. This includes regular use of alcohol or cannabis for sleep. Melatonin is ok.
* 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. (medical record/EHR). Personality disorders and neurodevelopmental disorders (e.g. autism, ADHD) are allowed if cognition is within normal limits.
* Taking methylphenidate for ADHD.
* Presence of other critical comorbid conditions 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).

Primary outcomes:
measure: Change in overnight memory retention on the A-B verbal paired associates task
timeFrame: 3 months
measure: Change in overnight memory retention on the A-B verbal paired associates task
timeFrame: 12 months
measure: Change in overnight memory retention on the A-B verbal paired associates task
timeFrame: 24 months
measure: Change in Aβ42/ Aβ40 ratio
timeFrame: 3 months
measure: Change in Aβ42/ Aβ40 ratio
timeFrame: 24 months
measure: Change in Plasma P-tau181
timeFrame: 3 months
measure: Change in Plasma P-tau181
timeFrame: 24 months
measure: Change in P-tau217
timeFrame: 3 months
measure: Change in P-tau217
timeFrame: 24 months
measure: Change in Neurofibrilary light (NfL)
timeFrame: 3 months
measure: Change in Neurofibrilary light (NfL)
timeFrame: 24 months
measure: Preclinical Cognitive Composite Score
timeFrame: 3 months
measure: Preclinical Cognitive Composite Score
timeFrame: 12 months
measure: Preclinical Cognitive Composite Score
timeFrame: 24 months
Secondary outcomes:
measure: Change in Task-switching Accuracy
timeFrame: 3 months
measure: Change in Task-switching Accuracy
timeFrame: 12 months
measure: Change in Task-switching Accuracy
timeFrame: 24 months
measure: Change in Task-switching Reaction Time
timeFrame: 3 months
measure: Change in Task-switching Reaction Time
timeFrame: 12 months
measure: Change in Task-switching Reaction Time
timeFrame: 24 months
measure: Change in Psychomotor Vigilance Task (PVT) lapses
timeFrame: 3 months
measure: Change in Psychomotor Vigilance Task (PVT) lapses
timeFrame: 12 months
measure: Change in Psychomotor Vigilance Task (PVT) lapses
timeFrame: 24 months
measure: Change in Psychomotor Vigilance Task (PVT) reaction time
timeFrame: 3 months
measure: Change in Psychomotor Vigilance Task (PVT) reaction time
timeFrame: 12 months
measure: Change in Psychomotor Vigilance Task (PVT) reaction time
timeFrame: 24 months
Other outcomes:
measure: Cognitive Impairment Severity
timeFrame: Baseline
measure: Cognitive Impairment Severity
timeFrame: 24 months
measure: Clinical Dementia Rating (CDR) Scale (0-3)
timeFrame: Baseline
measure: Sleepiness Score
timeFrame: Baseline
measure: Sleepiness Score
timeFrame: 3 months
measure: Sleepiness Score
timeFrame: 24 months
measure: Insomnia Severity
timeFrame: Baseline
measure: Insomnia Severity
timeFrame: 3 months
measure: Insomnia Severity
timeFrame: 24 months
measure: Psychiatric Symptom Questionnaires: Geriatric Depression Scale (GDS)
timeFrame: Baseline
measure: Psychiatric Symptom Questionnaires: Hamilton Anxiety Rating Scale (HAM-A)
timeFrame: Baseline
measure: Psychiatric Symptom Questionnaires: Clinician-Administered PTSD Scale (CAPS)
timeFrame: Baseline
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: California Pacific Medical Center Research Institute
name: Katie L Stone, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: New York University
name: Ricardo Osorio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Andrew Varga, MD
role: PRINCIPAL_INVESTIGATOR
References: