A Randomised, Controlled Trial of a Low-energy Diet for Improving Functional Status in Heart Failure With PRESERVED Ejection Fraction Preserved Ejection Fraction

Study Overview
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Brief Summary
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Heart failure with preserved ejection fraction (HFpEF) is a common and serious complication of obesity and type 2 diabetes (T2D). HFpEF occurs when the heart muscle unable to relax efficiently to pump the blood around the body. This leads to fluid build-up, breathlessness and inability to tolerate physical exertion. People who develop HFpEF do less well because treatment options are limited. Pilot data in patients with obesity and diabetes and a small number of patients with HFpEF have shown improvements in exercise capacity and reversal of changes in the heart and blood vessels. This study will assess if this is achievable in a multi-ethnic cohort of patients with established HFpEF. A total of 102 adults will be invited and allocate by chance into two groups: either a 12-week diet or health advice on how to lose weight. The study will determine if weight loss over 12 weeks can improve heart function, symptoms and ability to exercise. Additionally, participants' views on changing their diet and how this has impacted their symptoms will be sought during the study in an optional interview. This will help guide treatments planning in the future to get maximum benefits, and to individualize support to patients from different cultural backgrounds.

Detailed Description
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Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogenous syndrome, typified by severe exercise intolerance and with limited treatment options. Weight loss achieved through a low energy meal-replacement plan (MRP) has been shown to lead to reversal of cardiovascular remodelling in ethnically diverse asymptomatic adults with pre-HFpEF and HFpEF. This trial will translate this experience with the pragmatic low energy MRP into a symptomatic, multi-ethnic cohort of obese HFpEF, across three sites (Leicester, Manchester and Oxford) to assess its efficacy in improving exercise intolerance, symptoms, quality of life, cardiovascular remodelling, and skeletal myopathy.

Official Title
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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)

Conditions
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Heart Failure With Preserved Ejection Fraction, Heart Failure, Diastolic, Diabetes Mellitus, Type 2, Diabetes Mellitus Type 2 in Obese, Obesity Adult Onset

Intervention / Treatment
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* Drug: Low calorie meal replacement plan
* Diagnostic Test: Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy
* Diagnostic Test: Transthoracic echocardiography
* Diagnostic Test: Blood test
* Diagnostic Test: Electrocardiogram
* Diagnostic Test: Accelerometery
* Diagnostic Test: 6 minute walk test (6MWT)
* Diagnostic Test: Skeletal muscle strength using handgrip strength and quadriceps (Cybex dynamometer)
* Other: Assessment of quality of life and heart failure symptoms
* Other: Assessment of sarcopenia
* Other: Assessment of frailty
* Other: Qualitative interview
* Diagnostic Test: Skeletal muscle magnetic resonance spectroscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established clinical diagnosis of heart failure with preserved ejection fraction HFpEF (EF>45%) made by a cardiologist or a primary care physician with heart failure expertise, or a heart failure nurse Clinically stable for ≥ 3 months (no admissions to hospital) Obesity (BMI ≥30kg/m2 if white European or ≥27kg/m2 if Asian, Middle Eastern or Black ethnicity) Age ≥18 Exclusion Criteria: Inability to walk/undertake 6-minute walk test Inability to follow a low-energy MRP HFpEF due to infiltrative cardiomyopathy (cardiac amyloidosis or sarcoidosis), genetic hypertrophic cardiomyopathy, restrictive cardiomyopathy/pericardial disease or congenital heart disease95 Known heritable, idiopathic or drug-induced pulmonary arterial hypertension Severe chronic obstructive pulmonary disease (FEV1< 1.0L) Severe primary valvular heart disease Anaemia (Hb<100g/L) Severe renal disease (eGFR < 30 ml/min/1.73 m2) Weight loss > 5kg in preceding 3 months. Known gallstones/previous biliary colic

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-centre, prospective, open-label blinded end-point randomized controlled trial of low-energy Meal Replacement Plan (MRP) versus guideline-driven care with attention control, and a nested qualitative sub-study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low calorie meal replacement plan (MRP) arm<br>The MRP comprises of 3-4 meals a day (850kcal/day) supplied by Counterweight. Participants will be supported by professional research dieticians, and a study clinician. Participant health and medications will be monitored throughout the study. | Drug: Low calorie meal replacement plan<br>* Meal replacement diet containing  850 kcal/day (40% protein, 50% carbohydrate, 10% fat) supplied by Counterweight® (www.counterweight.org).The meal replacement plan will comprise of 3-4 meal packs/day (to equate to 850 kcal) with sweet and savoury options, and an allowance of 100ml semi-skimmed milk or a non-dairy alternative.<br>* Other names: Diet;Diagnostic Test: Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy<br>* CMR scanning performed on a 3T MRI scanner. Standardised protocol incorporating cine functional assessment to determine LV mass, systolic function and left atrial volumes; global systolic strain and diastolic strain rates will be assessed by tagging and with tissue tracking analysis from cine images, adenosine rest and stress myocardial perfusion to assess reserve index and qualitative perfusion defects as previously described, aortic distensibility and pulse wave velocity to measure aortic stiffness, delayed contrast enhancement for assessment of LV fibrosis and evidence of previous myocardial infarction. Myocardial and liver triglyceride content will be assessed using the modified Hepafat® sequence or 1H MR spectroscopy at the inter ventricular septum. DIXON technique for the quantification of visceral adiposity and subcutaneous adipose tissue. Cardiac 31P magnetic resonance spectroscopy imaging to assess cardiac muscle energetics according to a standardised operating procedure<br>* Other names: CMR;Diagnostic Test: Transthoracic echocardiography<br>* Comprehensive transthoracic echocardiography, including: tissue Doppler indices of diastolic filling and speckle tracking for systolic and diastolic strain/strain rate, exclusion of valvular abnormalities, assessment of LV size and function<br>Diagnostic Test: Blood test<br>* Collection of blood samples from each participant to characterise the participant's health status and fibroinflammatory markers.<br>Diagnostic Test: Electrocardiogram<br>* An ECG will be obtained to assess for baseline rhythm.<br>* Other names: ECG;Diagnostic Test: Accelerometery<br>* Accelerometer (GeneActiv) measured daily activity levels continuously for 7 consecutive days.<br>Diagnostic Test: 6 minute walk test (6MWT)<br>* Supervised 6MWT will be performed with symptom assessment using dyspnoea scale (Borg's).<br>Diagnostic Test: Skeletal muscle strength using handgrip strength and quadriceps (Cybex dynamometer)<br>* Skeletal muscle strength will be measured using a cybex dynamometer.<br>Other: Assessment of quality of life and heart failure symptoms<br>* Quality of life and HF symptoms will be assessed using the Minnesota Living with Heart Failure (MLWHF) questionnaire, which is used as a standardised measure of self-reported health status, and HF symptoms and is considered to have a good discriminatory power and validity<br>Other: Assessment of sarcopenia<br>* Participants will be assessed for presence of sarcopenia using the Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls (SARC-F) questionnaire. It is a robust tool for diagnosis of sarcopenia and prediction poor physical function, with excellent specificity in multimorbid individuals.<br>Other: Assessment of frailty<br>* Frailty will be assessed using the Edmonton Frail Scale (EFS). The EFS is a multidimensional frailty assessment which assesses multiple domains of frailty including functional independence, social support, cognition, medication use, and mood.<br>Other: Qualitative interview<br>* Participants in the MRP and control groups will be invited to attend a focused semi-structured, 1-2-1 interview aimed to elicit barriers and enablers to the MRP and describe their perspective on the relationship between healthy eating and health interview during the 12-week visit. Participants who complete or drop out will be eligible. Inclusion of participants in the control arm will allow us to compare the experiences of MRP versus health coaching and detect any specific issues people face when trying to introduce lifestyle changes themselves.<br>Diagnostic Test: Skeletal muscle magnetic resonance spectroscopy<br>* Assessment of skeletal muscle volume (quadriceps and calf muscle) using MRI, and 31P-magnetic resonance spectroscopy (31P-MRS) of the skeletal muscle using fysiometer and during isometric exercise at rest and after 5 minutes of exercise to assess changes in muscle energetics at rest and on exercise.<br>|
| Active Comparator: Guideline driven care with attention control arm<br>Dietary advice to participants will be given in line with NICE guidelines for cardiovascular risk modification. Heart failure specific advice on exercise will be given in line with guidelines. Health advice will be reinforced at regular 4-weekly phone calls. | Diagnostic Test: Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy<br>* CMR scanning performed on a 3T MRI scanner. Standardised protocol incorporating cine functional assessment to determine LV mass, systolic function and left atrial volumes; global systolic strain and diastolic strain rates will be assessed by tagging and with tissue tracking analysis from cine images, adenosine rest and stress myocardial perfusion to assess reserve index and qualitative perfusion defects as previously described, aortic distensibility and pulse wave velocity to measure aortic stiffness, delayed contrast enhancement for assessment of LV fibrosis and evidence of previous myocardial infarction. Myocardial and liver triglyceride content will be assessed using the modified Hepafat® sequence or 1H MR spectroscopy at the inter ventricular septum. DIXON technique for the quantification of visceral adiposity and subcutaneous adipose tissue. Cardiac 31P magnetic resonance spectroscopy imaging to assess cardiac muscle energetics according to a standardised operating procedure<br>* Other names: CMR;Diagnostic Test: Transthoracic echocardiography<br>* Comprehensive transthoracic echocardiography, including: tissue Doppler indices of diastolic filling and speckle tracking for systolic and diastolic strain/strain rate, exclusion of valvular abnormalities, assessment of LV size and function<br>Diagnostic Test: Blood test<br>* Collection of blood samples from each participant to characterise the participant's health status and fibroinflammatory markers.<br>Diagnostic Test: Electrocardiogram<br>* An ECG will be obtained to assess for baseline rhythm.<br>* Other names: ECG;Diagnostic Test: Accelerometery<br>* Accelerometer (GeneActiv) measured daily activity levels continuously for 7 consecutive days.<br>Diagnostic Test: 6 minute walk test (6MWT)<br>* Supervised 6MWT will be performed with symptom assessment using dyspnoea scale (Borg's).<br>Diagnostic Test: Skeletal muscle strength using handgrip strength and quadriceps (Cybex dynamometer)<br>* Skeletal muscle strength will be measured using a cybex dynamometer.<br>Other: Assessment of quality of life and heart failure symptoms<br>* Quality of life and HF symptoms will be assessed using the Minnesota Living with Heart Failure (MLWHF) questionnaire, which is used as a standardised measure of self-reported health status, and HF symptoms and is considered to have a good discriminatory power and validity<br>Other: Assessment of sarcopenia<br>* Participants will be assessed for presence of sarcopenia using the Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls (SARC-F) questionnaire. It is a robust tool for diagnosis of sarcopenia and prediction poor physical function, with excellent specificity in multimorbid individuals.<br>Other: Assessment of frailty<br>* Frailty will be assessed using the Edmonton Frail Scale (EFS). The EFS is a multidimensional frailty assessment which assesses multiple domains of frailty including functional independence, social support, cognition, medication use, and mood.<br>Other: Qualitative interview<br>* Participants in the MRP and control groups will be invited to attend a focused semi-structured, 1-2-1 interview aimed to elicit barriers and enablers to the MRP and describe their perspective on the relationship between healthy eating and health interview during the 12-week visit. Participants who complete or drop out will be eligible. Inclusion of participants in the control arm will allow us to compare the experiences of MRP versus health coaching and detect any specific issues people face when trying to introduce lifestyle changes themselves.<br>Diagnostic Test: Skeletal muscle magnetic resonance spectroscopy<br>* Assessment of skeletal muscle volume (quadriceps and calf muscle) using MRI, and 31P-magnetic resonance spectroscopy (31P-MRS) of the skeletal muscle using fysiometer and during isometric exercise at rest and after 5 minutes of exercise to assess changes in muscle energetics at rest and on exercise.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the distance walked during 6 minute walk test (6MWT) | The primary outcome measure is a change in the distance walked on 6MWT measured in meters | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beneficial reverse cardiovascular remodelling | CMR-derived measures of cardiovascular remodelling defined as left ventricular mass/volume ratio | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Change in physical activity levels | Improvement in physical activity will be determined by change in daily activity as determined accelerometery | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Change in lower limb muscle power | Change in muscle power will be determined by quadriceps strength measured using Cybex dynanometer | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Change in upper limb muscle power | Change in muscle power will be determined by handgrip strength using fysiometer | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Improvement in exercise tolerance | This will be assessed by a)change in Borg dyspnoea scale during 6MWT | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Improvement in symptoms of heart failure | This will be assessed by a change in the Minessota Living with Heart failure score | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Change in frailty | This will be assessed by a change in the Edmonton frailty questionnaire score | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Change in sarcopenia | This will be assessed by a change in the SARC-F questionnaire score | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | 
| Exploratory outcome: Improving skeletal and cardiac energetics | 31P magnetic resonance spectroscopy: Cardiac PCr/ATP | Baseline and 12 weeks | 
| Exploratory outcome: change in fibroinflammatory biomarker panel | Exploratory analysis of the O-link fibroinflammatory biomarker panel to identify potential pathways involved in the development, progression or outcomes of HFpEF. | This will be evaluated at baseline and at 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure with preserved ejection fraction, Diastolic heart failure, Type 2 diabetes mellitus, Obesity, Meal replacement plan, Cardiac magnetic resonance imaging, Exercise intolerance, Diabetes remission