Clinical trial NCT06078683: Effects of Ketone Ester Consumption on Exercise Tolerance and Cardiac Function
Official title: Effects of Acute and Chronic Ketone Ester Consumption on Exercise Tolerance and Cardiac Function in Subjects With the Metabolic Phenotype of Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Heart Failure With Preserved Ejection Fraction
Type 2 Diabetes
Metabolic Syndrome
Lead sponsor: Ohio State University
Sponsor class: OTHER
First posted: 2023-10-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, double-blinded, placebo-controlled, crossover study
Primary purpose: BASIC_SCIENCE

Brief summary: This study is being done to evaluate how a ketone ester (KE) beverage affects heart function and health in people with heart failure compared to a placebo beverage (a beverage made with standard food ingredients that do not contain ketone esters).

Detailed description: This study is a single center, randomized controlled study of up to 30 subjects with metabolic heart failure with preserved ejection fraction (HFpEF) phenotype. The study is designed to compare the effects of KE versus an energy and volume matched placebo on maximal exercise performance measured by CPET. Eligible subjects will have a known diagnosis of HF or type 2 diabetes or metabolic syndrome or obesity and will be selected from a larger population being followed in the Heart Failure Clinic at the Ohio State University Wexner Medical Center. Enrolled subjects will be stratified by sex to ensure equal proportions of men and women in each group (KE and placebo) and then randomly assigned (1:1) to a group, before washing out and crossing over to the other group (KE or Placebo). Subjects will follow the intervention of twice daily consumption of the KE or placebo for a period of 6 weeks, followed by a 4 week washout. All subjects will then crossover to the other group (KE or placebo) for another 6 weeks of intervention. Primary data will be collected at baseline and at the end of the 6-week intervention for both groups. In addition, subjects will undergo daily monitoring of blood markers, blood pressure, heart rate, and overall health. All subjects will continue standard HF and diabetes therapies with adjustment in medications as needed.

Cardiopulmonary exercise testing (CPET) also known as Maximal oxygen consumption testing (VO2) will be used to assess exercise performance, and Cardiac Magnetic Resonance Imaging (CMR) to evaluate cardiac function, myocardial blood flow, and cardiac and vascular function. CMR will provide insightful data on the magnitude, timeline, and functional impact of nutritional ketosis on cardiovascular function in patients diagnosed with HFpEF.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria:

1. Age ≥ 18 years old and ≤ 80 years old
2. NYHA class I - III for at least 3 months
3. Ejection fraction ≥ 50% by biplane 2D echo, 3D echo, or CMR.
4. Echo findings of abnormal of indeterminant diastolic function or Right right heart catheterization (RHC) data: At rest: mean pulmonary capillary wedge pressure (PCWP) \> 15 mmHg. pulmonary vascular resistance (PVR) \< 3 Wood Units
5. Stable medical therapy for at least 3 months as determined by the treating physician (no new cardiac or diabetic medications within 3 months of enrollment, or during enrollment) and dosage should be stable for 1 month prior to enrollment). Dose down titration and discontinuation is allowed during the study
6. Dose of oral diuretics changes allowed, but must be stable for 1 week prior to randomization
7. Body Mass Index (BMI) ≥ 25 and ≤ 50 or Type II Diabetes Mellitus or prediabetes as defined by fasting glucose of 100 - 125 mg/dL or glycated hemoglobin (A1C) 5.7-6.4%, or metabolic syndrome

   a. To meet definition of metabolic syndrome (NCEP ATPIII), 3 of the following criteria must be met: i. Abdominal obesity, defined as a waist circumference ≥102 cm (40 in) in men and ≥88 cm (35 in) in females ii. Serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides iii. Serum high-density lipoprotein (HDL) cholesterol \<40 mg/dL (1 mmol/L) in males and \<50 mg/dL (1.3 mmol/L) in females or drug treatment for low HDL cholesterol iv. Blood pressure ≥130/85 mmHg or drug treatment for elevated blood pressure v. Fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose
8. Ability to participate in exercise treadmill testing
9. Ability to sign written consent

Exclusion Criteria:

1. Women who are pregnant, current breast-feeding, or have intention to become pregnant while in the trial
2. Known allergy or sensitivity to Gadolinium based contrast agents
3. Implanted pacemaker, cardioverter defibrillator, cardiac resynchronization therapy, left ventricular assist device
4. Other metallic implants/aneurysm clips that are contraindicated in MRI
5. Claustrophobia
6. History of severe kidney disease with estimated glomerular filtration rate (eGFR) \<30 ml/kg/1.73m2
7. Type I diabetes
8. History of diabetic ketoacidosis
9. Prescription use of sodium-glucose cotransporter-2 inhibitors (SGLT2i)
10. Prior diagnosis of oxygen dependent pulmonary disease
11. Body Mass Index (BMI) \< 25
12. Recent acute myocardial infarction or acute coronary syndrome (30 days)
13. Recent (within 30 days) or planned (within 30 days) cardiac revascularization.
14. History of un-revascularized left main coronary artery disease, severe un- revascularized triple vessel disease, coronary artery bypass graft surgery \< 30 days.
15. Left ventricular ejection fraction \< 50%
16. Uncontrolled systemic systolic/diastolic blood pressure (SBP/DBP) hypertension (SBP \>180 or DBP \>110 mmHg)
17. Severe stenotic or regurgitant valvular heart disease, expected to lead to surgery during the trial period.
18. Persistent atrial fibrillation.
19. History of uncontrolled or untreated ventricular arrhythmias
20. Cardiovascular diseases or treatments that increase the unpredictability of the subject's clinical course, independent of heart failure
21. Heart transplant or listing for heart transplant.
22. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or known pericardial constriction
23. Acute decompensated heart failure requiring intravenous diuretics, vasodilators, inotropic agents or mechanical support within 1 week of screening and during the screening period prior to randomization
24. Hemoglobin of \<9 g/dL at screening
25. Major surgery (major according to the investigator's assessment) performed within 90 days prior to screening, or major scheduled elective surgery (e.g. hip replacement) within 90 days after screening
26. Acute or chronic liver disease, defined by serum levels of transaminases or alkaline phosphatase more than three times the upper limit of normal at screening
27. Gastrointestinal surgery or gastrointestinal disorder that might interfere with supplement consumption. Prior bariatric surgery allowed if weight-stable for past 3 months.
28. Any documented active or suspected malignancy or history of malignancy within 2 years prior to screening, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or low-risk prostate cancer (subjects with pre-treatment prostate-specific antigen levels of \<10 ng/mL, and biopsy Gleason scores of ≤6 and clinical stage T1c or T2a)
29. Presence of any disease other than heart failure that results in a life expectancy of \<1 year (in the opinion of the investigator)
30. History or recurrent severe hypokalemia, potassium \< 3.0 mg/dL.
31. Current enrolment in another investigational device or drug study or completion within \<30 days of a trial of another investigational device or drug study.
32. Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, will make the subject unlikely to fulfil the trial requirements or complete the trial
33. Any other clinical condition that might jeopardize subject safety during participation in this trial or prevent the subject from adhering to the trial Protocol.
34. Unable or unwilling to follow guidelines of assigned supplement group.
35. Allergy to test article ingredients, or lactose intolerance
36. The subject cannot currently be on a low-carb diet plan. 30-day washout would be required.
37. Patient must have stable weight over the past 3 months (± 5% total body weight). If no weight was recorded in the past 3 months, will have 1 month lead in time for wash out.
38. Refusal to consent

Primary outcomes:
measure: Changes in maximal exercise performance
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
Secondary outcomes:
measure: Change in CMR measures of cardiac function
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: Change in New York Heart Association (NYHA) class
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: Change in Quality of Life Questionnaire
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: Metabolic Panel
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: Lipid Panel
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: B-natriuretic peptide (BNP)
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: Change in Cardiac function after acute ingestion of KE or placebo
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
Other outcomes:
measure: Change in fat storage
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
measure: Change in stiffness
timeFrame: Baseline, 6 weeks, 10 weeks, 16 weeks
Locations:
city: Columbus
country: United States
facility: The Ross Heart Hospital
state: Ohio
Study officials:
affiliation: Ohio State University
name: Yuchi Han, MD, MMSc
role: PRINCIPAL_INVESTIGATOR
References: