Clinical trial NCT06983769: The CRESCENDO Trial
Official title: Cognition Recovery in Sleep Apnea Patients With Cardiovascular Risk by Evaluating Nasal CPAP Versus Dental Oral Appliance
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Obstructive Sleep Apnea (OSA)
Mild Cognitive Impairment
Keywords: Sleep, Cognition, Mandibular advancement device, CPAP, Clinical trial,
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: National University of Singapore
name: Ng Teng Fong General Hospital
name: Alexandra Hospital
name: National University Heart Centre, Singapore
name: The University of Sydney, Sydney, Australia
First posted: 2025-05-21
Enrollment: 260
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Obstructive sleep apnea (OSA) is a prevalent condition that significantly impacts the sleep health and overall well-being of millions of adults worldwide. It is characterized by breathing difficulties during sleep caused by an obstructed upper airway, leading to fragmented sleep, oxygen deprivation, and increased sympathetic activity. OSA and its associated health problems contribute to an annual economic burden exceeding $150 billion in the United States. Studies have shown that individuals with OSA are 26% more likely to develop cognitive impairment compared to those without the condition. However, despite the effectiveness of continuous positive airway pressure (CPAP) therapy, many patients struggle with acceptance and adherence to this treatment. As an alternative, mandibular advancement devices (MADs) have gained acceptance among OSA patients by improving upper airway anatomy through repositioning of the jaw and tongue, thus reducing collapsibility. This non-invasive approach shows promise, particularly in addressing the unique craniofacial features commonly found in East Asian OSA patients.

To further investigate the efficacy of MAD versus CPAP therapy, a multi-center, randomized clinical trial is proposed. The trial aims to evaluate cognitive function using established assessment tools and explore the relationship between different Asian ethnicities and changes in cognitive function, ambulatory blood pressure, and cerebral oxygen saturation. Additionally, brain MRI will be utilized to examine whether baseline brain structure and function can predict treatment response in OSA patients. Participants diagnosed with moderate-to-severe OSA will be randomly assigned to either the MAD or CPAP group in a 1:1 ratio. Baseline assessments, along with six-month and one-year follow-ups, will be conducted to assess the impact of the interventions. This trial seeks to provide valuable insights into the effectiveness of MAD versus CPAP therapy in Asian populations, specifically focusing on their effects on cognitive function and other relevant outcomes in individuals with OSA.

Detailed description: Aim #1: The primary objective is to compare the effectiveness of MAD and CPAP in improving cognitive function in participants with OSA and cardiovascular risk. The key endpoints of the trial will include cognitive function using the Montreal Cognitive Assessment (MoCA) and the National Institute of Health (NIH) Toolbox Cognition Battery.23 Participants diagnosed with moderate-to-severe OSA, mild cognitive impairment, and cardiovascular risk will be randomly assigned to either the MAD or CPAP group (1:1). Baseline assessments, along with six- and twelve-month follow-ups, will include the administration of the MoCA and NIH Toolbox Cognition Battery. The analysis of covariance (ANCOVA) will be used to compare the between-group differences in the changes observed in various measures of cognitive function. We hypothesize that MAD is non-inferior to CPAP in improving cognitive function.

Aim #2: The second objective is to examine whether brain structural and functional integrity at baseline can predict cognitive recovery after OSA treatment. Besides traditional brain macrostructural measures (grey matter volume, cortical thickness, and white matter hyperintensity), we hypothesize that brain microstructural and functional measures at baseline capturing individual differences in cerebral blood flow (via perfusion), cerebrovascular damage (via diffusion-derived freewater in both grey matter and white matter), functional network in higher-order cognitive networks (via task-free fMRI), and blood-brain barrier integrity (diffusion-prepared perfusion) will predict post-treatment cognition in OSA patients (see Preliminary work).

Aim #3: To understand the relative contribution of the complex disease pathophysiology of OSA and its treatment in cognitive function. We aim to understand the relative contribution of the complex disease pathophysiology of OSA and its treatment in cognitive function. We will explore the relationship between improvement in MoCA score from baseline to 12 months follow-up and the following parameters (1) OSA pathophysiology: Epworth Sleepiness Scale, apnea-hypopnea index, oxygen desaturation index, time with SpO2\<90% (T90), arousal index. (2) OSA treatment with CPAP/MAD: CPAP/MAD device adherence

Eligibility criteria: Inclusion Criteria:

Age of at least 50 Chinese, Malay, Indian or Thai residing in Singapore or Thailand Referred to the sleep clinics of the CRESCENDO participating centers for suspected OSA, underwent a clinically indicated level 1 polysomnography, and diagnosed to have moderate-to-severe OSA (AHI ≥ 15 events/hour) At least one of the following cardiovascular risk factors: hypertension, diabetes, smoking, or obesity (BMI \>27.5 kg/m2)- cutoff for obesity among Asians Mild cognitive impairment: MoCA score \<27 (for those with \>10 years of education) and \<26 (for those with ≤10 years of education) Agree to follow the study protocol

Exclusion Criteria:

Known OSA and already on regular treatment Severe cognitive impairment (MoCA \<10) Severe hypoxemia on polysomnography ODI \>60 or min SpO2 \<60% Known schizophrenia, bipolar disorder, severe depression, drug abuse or alcohol abuse Contraindications to MAD: less than six teeth in each arch; inability to advance the mandible and open the jaw widely. Pre-existing temporomandibular joint problems, severe bruxism, and advanced periodontal disease Limited life expectancy (\< one year) Cardiac or cerebrovascular events leading to hospitalization in the past three months Complex cardiovascular diseases: cyanotic congenital heart disease, moderate to severe pulmonary hypertension On regular medications that could affect the neurocognitive function and/or alertness

Primary outcomes:
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline, 6 months and 12 months
Secondary outcomes:
measure: NIH Toolbox Cognition Battery
timeFrame: Baseline, 6 months and 12 months
measure: Epworth Sleepiness Scale
timeFrame: Baseline, 6 months and 12 months
measure: Sleep Apnea Quality of Life Index (SAQLI)
timeFrame: Baseline, 6 months and 12 months
measure: SF-36
timeFrame: Baseline, 6 months and 12 months
Other outcomes:
Locations:
Study officials:
affiliation: National University Heart Centre, Singapore
name: Chi-Hang Ronald Lee, MBBS, MD
role: PRINCIPAL_INVESTIGATOR
References: