Ketones in Heart Failure With Reduced Ejection Fraction (HFrEF)

Acute Effects of Ketones in Heart Failure With Reduced Ejection Fraction

The purpose of this study is to understand the effects of a ketone drink on exercise capacity and other cardiovascular parameters in patients with heart failure. In heart failure, patients are limited in their ability to do all the things they want to do, and exercise as much as they would like, due to becoming tired and short of breath early. There may be several reasons why these symptoms occur. This study is assessing whether the ketone drink can improve these symptoms. This drink has been given status by Food and Drug Administration as "generally regarded as safe".

The use of DeltaG in this study is experimental. DeltaG has not been approved by the Food and Drug Administration (FDA) for the use being evaluated in this study.

Study Overview

• Status: Enrolling by invitation
• Conditions: Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Dietary supplement: ketone ester; Dietary supplement: placebo

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Stable cardiovascular medical therapy for 2 weeks
2. Participants will be required to have heart failure with reduced ejection fraction (left ventricular EF </= 45%) and New York Heart Association (NYHA) class II or III symptoms. In cases of ambiguity of functional status, reduced peak VO2 (<85% predicted VO2) at the baseline visit can be used to confirm reduced exercise tolerance.

Exclusion Criteria:

1. Intentional ketogenic diet in the last week
2. Cirrhosis or significant alcohol consumption
3. Contraindications to stress testing, conditions that limit exercise, and other clinically-significant causes of exertional limitation (claudication with peripheral artery disease, atrial fibrillation and heart rate >110 at rest, systolic blood pressure>180 mmHg or diastolic blood pressure>110 mmHg, infiltrative/hypertrophic cardiomyopathy, clinically significant pericardial disease, joint or neuromuscular disease that precludes exercise, acute coronary syndrome within the last 2 months, estimated glomerular filtration rate<20 mL/min/1.73 m2, and hemoglobin < 9 mg/dL).
4. Clinically significant lung disease: supplemental oxygen (aside from obstructive sleep apnea), chronic obstructive pulmonary disease requiring home oxygen or exacerbation within the last 2 months requiring steroids or antibiotics, severe obstructive lung disease (Gold stage 3).
5. >/= Moderate aortic stenosis, >mild mitral stenosis, > moderate aortic or mitral regurgitation
6. Type 1 diabetes mellitus
7. Implant of cardiac resynchronization therapy, cardiac contractility modulation, or barostim device within the previous 3 months.
8. Systolic blood pressure <90 mmHg
9. Pregnant women
10. Angina due to epicardial coronary disease or known presence of clinically-significant, unrevascularized epicardial coronary disease, in the investigator's opinion.
11. History of heart transplant, left ventricular assist device, or use of inotropic medication.
12. Participation in another clinical study with an investigational product in the previous 4 weeks prior to enrollment.
13. Conditions that may render the patient unable to complete the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ketone ester; (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone ester	Dietary supplement: ketone ester; 500 mg/kg of ketone ester administered approximately 1 hour prior to the maximal exercise testing and 250 mg/kg administered approximately 30 minutes prior to submaximal exercise testing; Other Names: ketone drink; KE drink; KE therapy; DeltaG therapy; ketone therapy
Placebo Comparator: placebo; KE-free solution	Dietary supplement: placebo; ketone-free placebo administered approximately 1 hour prior to the maximal exercise testing and ketone-free placebo administered approximately 30 minutes prior to submaximal exercise testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal exercise capacity	Peak VO2 assessed by cardiopulmonary exercise testing	60 minutes after the intervention
Submaximal exercise capacity	Exercise time at 75% of peak workload assessed by cardiopulmonary exercise testing	30 minutes after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular systolic function	Left ventricular ejection fraction measured during resting echocardiography.	Assessed 30 minutes after the intervention
Left ventricular filling pressures	E/e' ratio measured during stress echocardiography	Assessed 60 minutes after the intervention
Substrate utilization	Substrate utilization (reflected by the respiratory exchange ratio) assessed by cardiopulmonary exercise testing.	60 minutes after the intervention
Vasodilation at rest	Total peripheral resistance measured at rest (calculated using cardiac output from echocardiography and brachial blood pressure)	60 minutes after the intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial stiffness	Central augmentation index measured during arterial tonometry	Assessed 50 minutes after the intervention
Anaerobic threshold	Anaerobic threshold measured during cardiopulmonary exercise testing	Assessed 60 minutes after the intervention
Right ventricular function	Right ventricular function (tricuspid annular planar systolic excursion) assessed by echocardiography at rest	Assessed 30 minutes after the intervention
Cardiac output	Cardiac output measured during stress echocardiography	Assessed 60 minutes after the intervention
Pulse wave velocity	Pulse wave velocity measured by arterial tonometry	Assessed 50 minutes after the intervention
VO2 efficiency	VO2 efficiency (total work performed over oxygen consumed) during submaximal cardiopulmonary exercise testing	Assessed 30 minutes after the intervention
Vasodilation during exercise	Total peripheral resistance measured during cardiopulmonary exercise testing	60 minutes after the intervention
Pulmonary artery pressure	Pulmonary artery systolic pressure assessed through echocardiography during cardiopulmonary exercise testing	Assessed 60 minutes after the intervention
Ventilatory efficiency	Ratio of minute ventilation to carbon dioxide production measured during cardiopulmonary exercise testing	Assessed 60 minutes after the intervention

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); American Heart Association
• Investigators: Principal Investigator: Senthil Selvaraj, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: December 14, 2023
• First Submitted That Met QC Criteria: December 26, 2023
• First Posted (Actual): January 8, 2024

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: exercise; heart failure; metabolism; ketones; ketosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Metabolic Diseases; Acid-Base Imbalance; Acidosis; Behavior; Nutritional and Metabolic Diseases; Heart Failure; Ketosis; Motor Activity; formic acid 4-(3-oxobutyl)phenyl ester
• Other Study ID Numbers: Pro00111539; 1K23HL161348-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes