Mandibular Advancement to Reduce Ventricular Load and Improve Quality-of-life in Heart Failure (MARVEL-HF)

Mandibular Advancement to Reduce Ventricular Load and Improve Quality of Life in Heart Failure - a Randomized Controlled Trial

Heart failure with reduced ejection fraction (HFrEF) is a serious condition that limits daily activities and often leads to hospital stays and early death. Many patients with HFrEF also have obstructive sleep apnea (OSA), a common but often undiagnosed condition where breathing repeatedly stops during sleep. This causes drops in oxygen, poor sleep, and stress on the heart, which can make heart failure worse.

The investigators are studying whether a device called a mandibular advancement device (MAD)-a mouthpiece worn during sleep that keeps the airway open-can help people with both HFrEF and moderate-to-severe OSA. This device is already approved to treat OSA and is often more comfortable and easier to use than a CPAP machine.

In our study, 328 patients in Singapore will be randomly assigned to use either the MAD or a sham device that looks the same but doesn't move the jaw. They will wear the device for 12 months. We will measure changes in a blood marker linked to heart failure severity, as well as exercise ability, blood pressure, sleep quality, and hospital visits.

The investigators hope this study will show that MAD is a simple and patient-friendly way to improve outcomes in people with heart failure.

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure; OSA - Obstructive Sleep Apnea
• Intervention / Treatment: Device: Mandibular advancement device; Device: Mandibular advancement device (Sham)

Detailed Description

Heart failure profoundly impacts health, quality-of-life, and survival. Patients with heart failure (HF) experience fatigue, breathlessness, and exercise intolerance. Recurrent hospitalizations due to disease exacerbations further burden patients and healthcare systems. Despite advances in therapies, long-term outcomes remain poor with only 50% survival at 5 years post-diagnosis. Based on the left ventricular ejection fraction, HF is classified into three categories: reduced, mildly reduced, and preserved ejection fraction. This proposal focuses specifically on HF with reduced ejection fraction, which carries the worst prognosis. The term "HF" in this proposal refers exclusively to this subtype.

A growing body of evidence highlights the critical role of non-traditional and modifiable risk factors in heart failure progression, with obstructive sleep apnea (OSA) emerging as a particularly important contributor. OSA is highly prevalent in patients with HF, with estimates ranging from 40% to 70%. However, it remains substantially underdiagnosed and undertreated. OSA is characterized by repeated collapse of the upper airway during sleep, resulting in intermittent hypoxia, hypercapnia, serial arousals, and surges in sympathetic activity and blood pressure. These stressors contribute to elevated cardiac afterload, myocardial oxygen demand, and neurohormonal activation-all of which exacerbate ventricular dysfunction and HF progression. The relationship between OSA and HF is bidirectional. OSA not only contributes to the worsening of HF, but HF itself can increase the likelihood of OSA due to pulmonary congestion and fluid redistribution during sleep. Among patients with established HF, the presence of OSA has been linked to worse outcomes, including more frequent hospitalizations and higher mortality.

Despite this compelling evidence, the therapeutic potential of treating OSA in HF remains underexplored. While small studies suggest that short-term (3-6 months) treatment with continuous positive airway pressure (CPAP) in HF may improve cardiac function, adherence is suboptimal, with many patients unable to tolerate nightly use of CPAP. Given the rising prevalence of obesity, OSA and HF, there is an urgent need for well-tolerated, effective alternatives to CPAP. The mandibular advancement device (MAD) is an oral appliance approved for the treatment of OSA. Compared with CPAP, more patients accept MAD and use it for long-term with better adherence. Our team previously demonstrated in a randomized trial that MAD was associated with better adherence and improved nighttime blood pressure control compared to CPAP. In a pilot study of HF patients, the investigators found that treatment of OSA with MAD led to a reduction in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP)-a robust prognostic biomarker for HF

• Study Type: Interventional
• Enrollment (Estimated): 328
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chi-Hang Ronald Lee, MBBS, MD; Phone Number: 2493 +6567722493; Email: mdclchr@nus.edu.sg

Study Locations

• Singapore
  • Kent Ridge
    • Singapore, Kent Ridge, Singapore, 119228
      • National University Hospital
      • Contact: Chi-Hang Ronald Lee, MD; Phone Number: 91263120; Email: mdclchr@nus.edu.sg
      • Principal Investigator: Juliana Colpani, BDS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age of at least 40 years old with the capacity to provide signed, written informed consent
• Ischemic or non-ischemic cardiomyopathy with a left ventricular ejection fraction of 20% to 40% in the previous 6 months
• Stable chronic HF with NYHA functional class I-III symptoms on maximally tolerated background therapy for at least 4 weeks
• NT-proBNP >600 pg/mL (for participants in sinus rhythm) or >900 pg/mL (for participants in atrial fibrillation) in the previous 6 months (same as leading HF trials)
• Agree to follow the study protocol
• Able and willing to undergo a hospital-based overnight polysomnography

Exclusion Criteria:

• Known OSA and already on regular treatment
• Moderate or severe valvular stenosis or regurgitation
• Severe hypoxemia on polysomnography ODI >60 or min SpO2 <60%
• Specific HF etiologies, including hypertrophic cardiomyopathy with left ventricular outflow tract obstruction; pericardial disease; infiltrative or inflammatory myocardial disease; valvular heart disease with severe aortic or primary mitral regurgitation, moderate or severe aortic stenosis, any mitral stenosis requiring surgical repair, or active endocarditis
• 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 (with mobility affecting MAD stability).
• Patients who are planning to have restorations, dental prostheses or implants done in the next 12 months
• Limited life expectancy (< one year)
• Cardiac or cerebrovascular events in the past 6 months, including myocardial infarction, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid revascularization, endovascular procedure, or surgical intervention for peripheral vascular disease
• Current or planned mechanical circulatory support or heart transplantation Current or planned (within the next 6 months) hemodialysis or peritoneal dialysis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mandibular advancement device; The mandibular advancement device (MAD) is an oral appliance approved for the treatment of OSA. Compared with CPAP, more patients accept MAD and use it for long-term with better adherence. Our team previously demonstrated in a randomized trial that MAD was associated with better adherence and improved nighttime blood pressure control compared to CPAP	Device: Mandibular advancement device; Mandibular advancement devices (MAD) and continuous positive airway pressure (CPAP) are non-surgical treatments for obstructive sleep apnea (OSA) that maintain upper airway patency during sleep. CPAP delivers pressurized air via a mask to splint the airway and is the gold-standard therapy, providing the greatest reduction in apnea-hypopnea index across all OSA severities. MADs are custom-made oral appliances that advance the mandible forward, enlarging the upper airway and reducing collapsibility, and are most effective in mild to moderate OSA. Both therapies improve snoring, daytime sleepiness, and sleep quality, but differ in efficacy and tolerability. CPAP is more physiologically effective, while MADs are often better tolerated, more portable, and associated with higher real-world adherence. As a result, MADs are an accepted alternative for patients who cannot tolerate CPAP, with overall effectiveness influenced by both efficacy and adherence.
Sham Comparator: Mandibular advancement device (sham control); The patients randomized to the sham MAD arm, the same MAD device as described above for the MAD arm will be used. Unlike an active MAD which advances the mandible to maintain airway patency, the sham-MAD is designed to resemble the real device while minimizing therapeutic effects. Its titration process ensures participant comfort while maintaining study blinding. The sham MAD is custom-fitted using standard dental impressions but is adjusted to allow only minimal mandibular protrusion (0-2 mm). During follow-up visits, minor, non-therapeutic adjustments are made to simulate an active titration process. These may involve small, inconsequential changes that do not significantly alter mandibular position.	Device: Mandibular advancement device (Sham); Arm Description: The patients randomized to the sham MAD arm, the same MAD device as described above for the MAD arm will be used. Unlike an active MAD which advances the mandible to maintain airway patency, the sham-MAD is designed to resemble the real device while minimizing therapeutic effects. Its titration process ensures participant comfort while maintaining study blinding. The sham MAD is custom-fitted using standard dental impressions but is adjusted to allow only minimal mandibular protrusion (0-2 mm). During follow-up visits, minor, non-therapeutic adjustments are made to simulate an active titration process. These may involve small, inconsequential changes that do not significantly alter mandibular position.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
N-terminal pro-B-type natriuretic peptide (NT-pro BNP)	NT-proBNP (Primary endpoint) is a circulating biomarker released from the cardiac ventricles in response to myocardial wall stress and volume overload. It is commonly used to assess the presence and severity of heart failure. NT-proBNP levels are measured in picograms per milliliter (pg/mL). Higher values indicate greater cardiac wall stress and worse heart failure severity.	Baseline and 6 months (primary outcome)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular ejection fraction (LVEF), expressed as percentage (%).	Transthoracic echocardiography determined parameters	Baseline and 6 months
Kansas City Cardiomyopathy Questionnaire (KCCQ).	Quality of life assessment tool for heart failure. The Overall Summary Score ranges from 0 to 100, with higher scores indicating better health status and quality of life.	Baseline, 6 months, and 12 months
Epworth Sleepiness Scale (ESS)	The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire used to evaluate daytime sleepiness. The total score ranges from 0 to 24, with higher scores indicating greater daytime sleepiness.	Baseline, 6 months, and 12 months
Sleep Apnea Quality of Life Index (SAQLI)	The Sleep Apnea Quality of Life Index (SAQLI) is a disease-specific questionnaire assessing the impact of obstructive sleep apnea on daily functioning, social interactions, emotional functioning, and symptoms. The total score ranges from 1 to 7, with higher scores indicating better quality of life.	Baseline, 6 months, and 12 months
EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L)	The EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) is a standardized instrument used to measure general health status across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The index score typically ranges from less than 0 (worse than death) to 1.0 (perfect health), with higher scores indicating better health status.	Baseline, 6 months, and 12 months
Montreal Cognitive Assessment (MoCA)	The Montreal Cognitive Assessment (MoCA) is a widely used screening tool for the assessment of global cognitive function, including domains such as attention, executive function, memory, language, visuospatial ability, abstraction, and orientation. The total score ranges from 0 to 30, with higher scores indicating better cognitive function. A score of 26 or above is considered normal cognitive function.	Baseline, 6 months, and 12 months
Adverse cardiovascular events	Adverse events. Although this trial is not powered to detect differences in hard clinical outcomes, we will collect them for exploratory analysis: hierarchical composite of death within 12 months after randomization and HF hospitalizations within 12 months after randomization.	6 months, 12 months, and 36 months
Ambulatory BP monitoring	Ambulatory BP will be performed over a 24-hour period at baseline and 12 months. Key parameters will include 24-hour mean systolic and diastolic BP, daytime and nighttime averages, and nocturnal BP dipping patterns.	Baseline and 6 months
Peak oxygen uptake (VO₂peak)	Peak oxygen uptake (VO₂peak) is measured (one third of the participants) during cardiopulmonary exercise testing and reflects the maximum capacity of the body to transport and utilize oxygen during exercise, representing overall cardiorespiratory fitness. VO₂peak is expressed in mL/kg/min. Higher values indicate better cardiorespiratory fitness and exercise capacity.	Baseline and 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Office BP	Office BP will be measured at baseline, 6 months and 12 months using a standardized protocol with an automated sphygmomanometer. Three consecutive readings will be taken after the participant has been seated quietly for at least 5 minutes, and the average of the last two readings will be recorded. Office BP remains a practical and widely used metric in routine clinical care.	Baseline, 6 months and 12 months
Subjective sleep duration	Subjective sleep duration will be assessed via patient self-report using standardized sleep questionnaires and sleep diaries, collected at baseline, 6 months and 12 months. Participants will be asked to estimate their average nightly sleep duration over the past month, as well as on weekdays and weekends separately.	Baseline, 6 months, and 12 months.

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Alexandra Hospital; Ng Teng Fong General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 1, 2031
• Study Completion (Estimated): April 1, 2031

Study Registration Dates

• First Submitted: February 23, 2026
• First Submitted That Met QC Criteria: March 4, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: quality of life; OSA; biomarker; clinical trial; heart failure
• Additional Relevant MeSH Terms: Nervous System Diseases; Cardiovascular Diseases; Heart Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Wake Disorders; Apnea; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Apnea Syndromes; Heart Failure; Sleep Apnea, Obstructive; Orthopedic Equipment; Surgical Equipment; Equipment and Supplies; Orthotic Devices; Occlusal Splints
• Other Study ID Numbers: ECOS Ref: 2025-1331

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Upon reasonable requests and obtained institution approval
• IPD Sharing Time Frame: 1 year after the trial completion
• IPD Sharing Access Criteria: Academics
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

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