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

Diabetes Mellitus, Type 2 Clinical Trial

— AMEND  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05887271
• Other study ID #: 0861
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 29, 2023
• Est. completion date: January 1, 2026

Study information

• Verified date: May 2023
• Source: University of Leicester
• Contact: Joanna M Bilak, BMBS
• Phone: +44 (0)116 258 3038
• Email: jmb99[@]leicester.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 102
• Est. completion date: January 1, 2026
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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

2. Clinically stable for = 3 months (no admissions to hospital)

3. Obesity (BMI =30kg/m2 if white European or =27kg/m2 if Asian, Middle Eastern or Black ethnicity)

4. Age =18

Exclusion Criteria:

1. Inability to walk/undertake 6-minute walk test

2. Inability to follow a low-energy MRP

3. HFpEF due to infiltrative cardiomyopathy (cardiac amyloidosis or sarcoidosis), genetic hypertrophic cardiomyopathy, restrictive cardiomyopathy/pericardial disease or congenital heart disease95

4. Known heritable, idiopathic or drug-induced pulmonary arterial hypertension

5. Severe chronic obstructive pulmonary disease (FEV1< 1.0L)

6. Severe primary valvular heart disease

7. Anaemia (Hb<100g/L)

8. Severe renal disease (eGFR < 30 ml/min/1.73 m2)

9. Weight loss > 5kg in preceding 3 months.

10. Known gallstones/previous biliary colic

Related Conditions & MeSH terms

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

Intervention

Drug:
• Low calorie meal replacement plan
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.

Diagnostic Test:
• Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy
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
• Transthoracic echocardiography
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
• Blood test
Collection of blood samples from each participant to characterise the participant's health status and fibroinflammatory markers.
• Electrocardiogram
An ECG will be obtained to assess for baseline rhythm.
• Accelerometery
Accelerometer (GeneActiv) measured daily activity levels continuously for 7 consecutive days.
• 6 minute walk test (6MWT)
Supervised 6MWT will be performed with symptom assessment using dyspnoea scale (Borg's).
• Skeletal muscle strength using handgrip strength and quadriceps (Cybex dynamometer)
Skeletal muscle strength will be measured using a cybex dynamometer.

Other:
• Assessment of quality of life and heart failure symptoms
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
• Assessment of sarcopenia
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.
• Assessment of frailty
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.
• Qualitative interview
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.

Diagnostic Test:
• Skeletal muscle magnetic resonance spectroscopy
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.

Locations

Country	Name	City	State
United Kingdom	University of Leicester, Glenfield Hospital, Groby Road	Leicester	Leicestershire
United Kingdom	University of Manchester, Wythenshawe Hospital, Southmoor Road	Manchester
United Kingdom	University of Oxford, John Radcliffe Hospital, Headley Way	Oxford

Sponsors (3)

Lead Sponsor	Collaborator
University of Leicester	University of Manchester, University of Oxford

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Exploratory outcome: Improving skeletal and cardiac energetics	31P magnetic resonance spectroscopy: Cardiac PCr/ATP	Baseline and 12 weeks
Secondary	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