A Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling (CRESCENT)

The objective of this proposal is to evaluate whether mandibular advancement device (MAD) is non-inferior to continuous positive airway pressure (CPAP) in the treatment of obstructive sleep apnea (OSA) and blood pressure reduction. OSA and hypertension are highly prevalent disorders with profound impacts on health. Apart from improving quality of-life, an effective OSA treatment could improve cardiovascular risk partly through blood pressure reduction, particularly in patients with high cardiovascular risk in whom blood pressure control is often suboptimal. Although CPAP is useful, the high non-acceptance and non-adherence preclude its widespread use.

East Asians have a restrictive craniofacial phenotype that predisposes them to OSA and the associated cardiovascular stress. CPAP, while considered the first-line therapy for OSA, has failed to improve cardiovascular outcomes in randomized trials till date because it is poorly tolerated. MADs are oral appliances that correct the restrictive craniofacial phenotype present in East Asians by protruding the lower jaw to reduce upper airway collapsibility. MADs are better tolerated than CPAP, and this may be an important determinant of the overall effectiveness in treating OSA, and thus ameliorating the downstream adverse health outcomes. We hypothesize that MADs are non-inferior to CPAP in treating OSA and reducing cardiovascular risk by blood pressure reduction in East Asians.

We will recruit East Asian subjects with hypertension and high cardiovascular risk for polysomnography. Patients diagnosed with OSA (n=220) will be randomized to MAD or CPAP groups in a 1:1 ratio for a treatment duration of 6 months. The primary endpoint is the 24-hour mean blood pressure as determined by ambulatory monitoring. The secondary endpoints include sleep-time systolic BP, target blood pressure, cardiovascular biomarkers, and myocardial remodeling. Association between OSA and silent paroxysmal atrial fibrillation will also be determined. If MADs are shown to be effective, the next step is to evaluate our novel device- drug-eluting MAD that the team is developing.

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea; Hypertension,Essential
• Intervention / Treatment: Device: Continuous Positive Airway Pressure; Device: Mandibular Advancement Device

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • NUHS Cardiosleep research laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age of at least 40 years
2. Chinese (based on the Identity Card or other Identity Document if the subject is a non-Singapore citizen or permanent resident)
3. Physician diagnosed essential hypertension, on at least 1 medication for BP control
4. High cardiovascular risk, as defined by one or more of the following: (a) diabetes mellitus, (b) stroke, (c) significant coronary artery disease (at least one stenosis of >50% diameter in at least one major epicardial artery), (d) chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerular filtration rate of <60 ml/min/1.73m2, or (e) age of 75 years or older.

Exclusion Criteria:

1. Known OSA on treatment
2. Cheyne-Stokes breathing or predominantly central sleep apnea (>50%)
3. Known secondary hypertension: from renal (renal artery stenosis, chronic renal failure); endocrine (aldosterone excess, pheochromocytoma, cushing's syndrome, hyperthyroidism) or cardiac causes (aortic coarctation)
4. Contraindications to CMR: implantable devices, cerebral aneurysm clips, cochlear implants, renal impairment (GRF <30ml/min/1.73m2), claustrophobia and pregnant women
5. Contraindications to MAD: <6 to 10 teeth in each arch, inability to advance the mandible and open the jaw widely, pre-existing temporomandibular joint problems, severe bruxism
6. Limited life expectancy (< 1 year)
7. Hypertensive crisis, acute coronary syndromes or acute heart failure in the past 30 days
8. Known AF (not suitable for CMR and affects remodelling analysis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CPAP; Continuous Positive Airway Pressure	Device: Continuous Positive Airway Pressure; Continuous positive airway pressure (CPAP) is a form of positive airway pressure ventilator, which applies mild air pressure on a continuous basis to keep the airways continuously open in people with OSA
Experimental: MAD; Mandibular Advancement Device	Device: Mandibular Advancement Device; Mandibular advancement device (MAD) has been a novel method in the management of snoring and OSA. For mild to moderate sleep apnea, MADs have been a boon. A guideline published by American Academy of Sleep Medicine stated that MAD was indicated as first-line therapy for mild OSA and a second-line therapy for moderate to severe OSA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour mean BP (24MBP)	Difference in 24-hour mean BP (24MBP) between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour systolic BP (24SBP)	Difference in 24-hour systolic BP (24SBP) between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring.	6 months and 12 months
24-hour pulse pressure (24PP)	Difference in 24-hour pulse pressure (24PP) between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring.	6 months and 12 months
Nocturnal dipping	Difference in prevalence of nocturnal dipping between the patients in the MAD and CPAP groups as determined by 24-hour ambulatory BP monitoring.	6 months and 12 months
Ectopic beat	Difference in prevalence of ectopic beats between the patients in the MAD and CPAP groups as determined by continuous ECG monitoring	12 months
Myocardial remodeling	Difference in LV and LA dimensions between the patients in the MAD and CPAP groups as determined by cardiac MRI	12 months
Epworth Sleepiness Scale (ESS) score	Difference in change in ESS score between the MAD and CPAP groups	6 months and 12 months
Sleep Apnea Quality of Life Index (SAQLI)	Difference in change in SAQLI score between the MAD and CPAP groups	6 months and 12 months
Functional Outcome of Sleep Questionnaire (FOSQ)	Difference in change in SAQLI score between the MAD and CPAP groups	6 months and 12 months
36-Item Short Form Health Survey (SF-36)	Difference in change in SF-36 score between the MAD and CPAP groups	6 months and 12 months
EuroQol 5Q (EQ5D)	Difference in change in EQ5D score between the MAD and CPAP groups	6 months and 12 months
Daytime systolic BP	Difference in change in daytime systolic BP between the patients in the MAD and CPAP	6 months and 12 months
Nighttime systolic BP	Difference in change in nighttime systolic BP between the patients in the MAD and CPAP	6 months and 12 months
Percentage of patient with 24-hour systolic BP<130 mmHg	Difference in percentage of patients with 24-hour systolic BP<130 mmHg in the MAD and CPAP groups	6 months and 12 months
Percentage of patient with 24-hour systolic BP<120 mmHg	Difference in percentage of patients with 24-hour systolic BP<120 mmHg in the MAD and CPAP groups	6 months and 12 months
NT-proBNP	Change in the plasma level of NT-proBNP from baseline to 6-month follow-up	6 months and 12 months
High sensitivity troponin	Change in the plasma level of high sensitivity troponin from baseline to 6-month follow-up	6 months and 12 months
High sensitive C-reactive protein	Change in the plasma level of high sensitive C-reactive protein from baseline to 6-month follow-up	6 months and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup analysis	Prespecified subgroups include - Age, Gender, BMI, wrist circumference, AHI, ODI, ESS, DM, IHD, number of HT medicine, Device adherence	6 months and 12 months

Collaborators and Investigators

• Sponsor: National University of Singapore
• Collaborators: National University Hospital, Singapore; National Heart Centre Singapore; Ng Teng Fong General Hospital
• Investigators: Principal Investigator: Chi-Hang Lee, MD, National University of Singapore

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2019
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): February 15, 2024

Study Registration Dates

• First Submitted: October 7, 2019
• First Submitted That Met QC Criteria: October 7, 2019
• First Posted (Actual): October 9, 2019

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 18, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: sleep; blood pressure; trial; remodeling
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Hypertension; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Essential Hypertension
• Other Study ID Numbers: Senior CSA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The individual participant data generated by the CRESCENT trial will be made available as soon as possible upon reasonable request, wherever legally and ethically possible.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No