Rationale and design of the randomised controlled trial: A Multi-Ethnic, multi-centre raNdomised, controlled trial of a low-energy Diet for improving functional status in Heart failure with Preserved ejection fraction (AMEND-Preserved)

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is characterised by severe exercise intolerance, particularly in those living with obesity. Low-energy meal-replacement plans (MRPs) have shown significant weight loss and potential cardiac remodelling benefits. This pragmatic randomised trial aims to evaluate the efficacy of MRP-directed weight loss on exercise intolerance, symptoms, quality of life, and cardiovascular remodelling in a multi-ethnic cohort with obesity and HFpEF.

Methods:
Prospective multi-centre, open-label, blinded endpoint randomised controlled trial comparing low-energy MRP with guideline-driven care plus health coaching. Participants (n=110, age ≥18 years) with HFpEF and clinical stability for at least 3 months will be randomised to receive either MRP (810 kcal/day) or guideline-driven care for 12 weeks. Randomisation is stratified by sex, ethnicity, and baseline Sodium Glucose Cotransporter-2 inhibitor (SGLT2i) use, using the 'blockrand' package in R and electronic database RedCap with allocation concealment. Key exclusion criteria include severe valvular, lung or renal disease, infiltrative cardiomyopathies, symptomatic biliary disease, or history of an eating disorder.

Assessments:
Participants will undergo glycometabolic profiling, echocardiography, magnetic resonance imaging (MRI) for cardiovascular structure and function, body composition analysis (including visceral and subcutaneous adiposity quantification), and 6-minute walk test (6MWT), at baseline and 12 weeks. An optional 24-week assessment will include non-contrast CMR, 6MWT, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Optional sub-studies include a qualitative study assessing participants' experiences and barriers to adopting MRP, and skeletal muscle imaging and cardiac energetics using 31Phosphorus magnetic resonance spectroscopy.

Statistical Analysis:
Complete case analysis will be conducted with adjustment for baseline randomisation factors including sex, ethnicity, and baseline SGLT2i use. The primary outcome is the change in distance walked during the 6MWT. The primary imaging endpoint is the change in left atrial volume indexed to height on cardiac magnetic resonance imaging. Key secondary endpoints include symptoms and quality of life measured by the KCCQ score.