Acute and Chronic Effects of Oral Ketones in Subjects With HFrEF and Diabetes

Study Overview
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Brief Summary
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This study will provide insight into whether cardiac function changes with oral Ketone Esters (KE) administered to patients with Type 2 Diabetes Mellitus (T2DM) and Heart failure with reduced ejection fraction (HFrEF). Plasma ketones are avidly extracted by cardiac muscle and their uptake is not dependent upon insulin or influenced by insulin resistance.

Detailed Description
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After the screening visit, subject will take two separate doses of oral ketones during visit two. Subjects will have their first dose (400mg/kg) upon completion of the baseline Magnetic Resonance Imaging (MRI), and then a second dose (400mg/kg) approximately 1.5 hours after their consumption of the 1st dose. Approximately 1.5 hours after their second dose (3hr since first dose), the subject will undergo a second cardiac MRI. Baseline Blood samples of Beta-hydroxybutyrate (BOHB), acetoacetate (ACAC), Free Fatty Acids (FFA), insulin, c-peptide, glucagon, and an additional 10ml (for storage and later analysis) will be drawn prior to their first dose, then every 30 minutes after their first dose, until completion of the second MRI, then a final blood draw upon completion of the MRI for a total of 8 blood draws during visit 2. An IV catheter will be placed into one antecubital vein by a study nurse for all blood draws during visit 2. The subject will then be asked to return to complete a third MRI approximately 24 hours after their second MRI. Blood samples for BOHB, acetoacetate (ACAC), insulin, c-peptide and glucagon, and an additional 10 ml will be drawn prior to their third MRI. An IV catheter will be placed into one antecubital vein by a study nurse for all blood draws during visit 3. After completion of the third MRI, subjects will be dosed KE 400mg/kg once daily until the visit 4 MRI can be completed. Blood samples for BOHB, acetoacetate (ACAC), insulin, c-peptide, glucagon, proBNP, and an additional 10 ml will be drawn prior to their fourth MRI. An IV catheter will be placed into one antecubital vein by a study nurse for all blood draws during visit 4. The 4th MRI, based on subject and scanner availability at approximately Day 7

Official Title
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Acute and Chronic Effects of Oral Ketones in Subjects With HFrEF and Diabetes

Conditions
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Type 2 Diabetes, Heart Failure, Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Ketone Monoester (KE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be on a stable dose of guideline-directed medications for Heart Failure (HF). Patients will have an established diagnosis of HF before the screening visit, documented by an acceptable imaging modality in the last 6 months. Age = 18-80 y Body Mass Index (BMI) =23-38 kg/m2 Glycated hemoglobin (HbA1c) = 6.0-10.0% Blood Pressure (BP) < 145/85 mmHg Estimated Glomerular Filtration Rate (eGFR) > 30 ml/min•1.73 m2 For women of child-bearing age (WOCBA) willingness to use contraception, if applicable. Exclusion Criteria: Patients treated with Sodium-Glucose Transport Protein (SGLT2i's) or medications that may impair heart function or acutely worsen glycemic control will be excluded. Pregnancy, lactation, or plans to become pregnant. A negative pregnancy test will be performed before each Magnetic resonance imaging (MRI) study to assess current status. Allergy/sensitivity to study drugs or their ingredients. Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Inability or unwillingness of individual or legal guardian/representative to give written informed consent. Subjects with a history of cancer (except basal or squamous cell cancer that has been resolved/remission for 5 years) Cardiovascular event within the last 3 months Major organ or metabolic diseases, or physical limitations that will not allow the subject to complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Interventional Model Description: Open label, pilot trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketone Ester administration<br>Monitored administration of oral Ketone monoester at 400mg/kg dosed twice on visit 2 (cardiac MRI day) Self administered oral β-hydroxybutyrate (BOHB) at 400mg/kg/day for a period of 6 days | Drug: Ketone Monoester (KE)<br>* Ketones are a nutritional supplement currently used by athletes for their performance enhancing effects - specifically their cardio-pulmonary benefits<br>* Other names: DeltaG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Efficiency after acute dose | Change in cardiac efficiency after acute dosing of KE, measured by change in Left-ventricular function | 1.5 hours to 24 hours | 
| Cardiac Efficiency after chronic dosing | Change in cardiac efficiency after chronic (7 day) dosing of KE, measured by change in Left-Ventricular function | 1.5 hours to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six minute walk test | Participants will be asked to walk as far as possible for 6 minutes, escorted by a member of the research team. Baseline to 7 day distance will be compared. | Baseline to 7 days | 
| Acetoacetate | Baseline to 7 day level will be compared. | Baseline to 7 days | 
| Glucose | Baseline to 7 day level will be compared. | Baseline to 7 days | 
| Free Fatty Acids (FFAs) | Baseline to 7 day level will be compared. | Baseline to 7 days | 
| Insulin/C-peptide | Baseline to 7 day level will be compared. | Baseline to 7 days | 
| Glucagon | Baseline to 7 day level will be compared. | Baseline to 7 days | 
| Beta-hydroxybutyrate | Baseline to 7 day level will be compared. | Baseline to 7 days | 
| Patient Reported Outcomes Measure Information System (PROMIS) - Physical Function | This tool is a well-developed and validated method to obtain self-reported parameters of health in adults, we will be using: PROMIS® Item Bank v2.0 - Physical Function - Short Form 20a Subjects will rank 20 questions from a scale of 1 - 5, with 5 being the highest physical function and 1 being the lowest. The score will be added up, and the Raw score will be converted to T-Score using the PROMIS Adult v2.0 Physical Function 20a Short Form Conversion Table. Baseline to 7 day T-Score will be compared, with a Higher T-Score indicating higher physical function. | Baseline to 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketone esters, Cardiopulmonary benefits, Left Ventricular function, Stroke volume, Cardiac output