Effects of a Single Oral Dose of KETone Ester ON Exercise Performance in Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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In a randomized, double-blind, placebo-controlled cross-over design, subjects will either receive a supplemental drink containing a commercially available ketone ester (DeltaG®, 500 mg/kg body weight), or a taste matched, isovolumic placebodrink and will then perform the 31phosphorus Magnetic Resonance Spectroscopy (31P MRS) exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time receiving the other treatment.

Detailed Description
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The goal of this study is to investigate if oral ketone supplementation stimulates mitochondrial ATP production and improves exercise performance in patients with chronic HF. In a randomized, double-blind, placebo-controlled cross-over design, subjects will either receive a supplemental drink containing a commercially available ketone ester (DeltaG®, 500 mg/kg body weight), or a taste matched, isovolumic placebodrink and will then perform the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time receiving the other treatment. Endpoints include rate and magnitude of change in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations from baseline to maximum exercise, rate and magnitude of change in PCr and Pi concentrations during recovery, rates and magnitude of change in intramuscular pH during exercise and recovery, maximal exercise performance and change in concentrations of beta-hydroxybutyrate and other metabolites before consumption of the supplemental drink, after consumption of the supplemental drink and after exercise.

Official Title
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Effects of a Single Oral Dose of KETone Ester ON Exercise Performance in Patients With Chronic Heart Failure

Conditions
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Heart Failure With Reduced Ejection Fraction, Heart Failure

Intervention / Treatment
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* Dietary Supplement: Ketone ester drink (DeltaG®, 500 mg/kg body weight)
* Dietary Supplement: Taste-matched, isovolumic placebo drink


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic Heart Failure NYHA II - III LVEF ≤40% Stable for the last 1 month prior to the study Exclusion Criteria: Age <18 years; Unable or unwilling to undergo exercise MRI (physical disabilities, claustrophobia); Unable to complete the exercise protocol during the screening visit according to the professional opinion of the investigators; Comorbidities which can influence study results such as muscular dystrophies, peripheral artery disease, diabetes mellitus, severe anaemia (defined as Hb ≤6 mmol/L); Pregnant/trying to get pregnant/breastfeeding during the period from the first exercise test until 4 weeks after the last exercise test); Absolute contra-indications to undergo MRI according to the current UMCG protocols and guidelines (e.g. non-conditional medical device, recent device implantation, incompatible ferromagnetic objects in the body). BMI < 16 kg/m2; BMI > 35 kg/m2 Unable to understand study procedures; Unable or unwilling to provide informed consent.

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: Crossover Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled cross-over design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Ketone - Placebo treatment<br>Patients will first receive a supplemental drink containing a ketone ester before performing the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time after receiving the placebo treatment. | Dietary Supplement: Ketone ester drink (DeltaG®, 500 mg/kg body weight)<br>* In a double blind fashion, subjects will receive a ketone ester drink ór a taste-matched, isovolumic placebo drink and will then perform the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time receiving the other treatment.<br>Dietary Supplement: Taste-matched, isovolumic placebo drink<br>* In a double blind fashion, subjects will receive a ketone ester drink ór a taste-matched, isovolumic placebo drink and will then perform the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time receiving the other treatment.<br>|
| Other: Placebo - Ketone treatment<br>Patients will first receive a placebodrink before performing the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time after receiving the supplemental drink containing a ketone ester. | Dietary Supplement: Ketone ester drink (DeltaG®, 500 mg/kg body weight)<br>* In a double blind fashion, subjects will receive a ketone ester drink ór a taste-matched, isovolumic placebo drink and will then perform the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time receiving the other treatment.<br>Dietary Supplement: Taste-matched, isovolumic placebo drink<br>* In a double blind fashion, subjects will receive a ketone ester drink ór a taste-matched, isovolumic placebo drink and will then perform the 31P MRS exercise protocol. After 1-2 weeks, subjects will cross-over and repeat the 31P MRS exercise protocol, this time receiving the other treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations from baseline to maximum exercise | Rate and magnitude of change in PCr and Pi concentrations from baseline to maximum exercise. | During study-visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate and magnitude of change in PCr and Pi concentrations during recovery | Rate and magnitude of change in PCr and Pi concentrations during recovery of change in PCr and Pi is expressed as change in Pi/PCr (ΔPi/PCr) | During study visit | 
| Intramuscular pH | Rates and magnitude of change in intramuscular pH during exercise and recovery | During study visit | 
| Maximal exercise performance | Maximal exercise performance | During study visit | 
| Change in concentrations of beta-hydroxybutyrate and other metabolites before consumption of the supplemental drink, after consumption of the supplemental drink and after exercise | Change in concentrations of beta-hydroxybutyrate and other metabolites before consumption of the supplemental drink, after consumption of the supplemental drink and after exercise | During study visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Ketone Body, HFrEF, Skeletal Muscle Metabolism, Mitochondrial Ketone Oxidation, 31P MRS, Pi/Pcr