Chronic Exogenous Ketosis in HFpEF

Chronic Effects of Exogenous Ketone Administration in Heart Failure With Preserved Ejection Fraction

The goal of this clinical research study is to test what effects a ketone drink will have in people with heart failure with preserved ejection fraction (HFpEF), including on exercise and heart function. Patients with HFpEF often have difficulty exercising, and our goal is to understand whether a ketone drink changes much patients can exercise. The study has three visits, including a baseline visit to assess for study eligibility, and two visits (one after 8 weeks of a ketone drink or a placebo drink, and another one after 8 weeks of whichever drink the participant did not receive the first time).

Study Overview

• Status: Enrolling by invitation
• Conditions: Heart Failure, Diastolic; Heart Failure With Normal Ejection Fraction; Heart Failure With Preserved Ejection Fraction (HFPEF)
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Exogenous Ketone Drink

• Study Type: Interventional
• Enrollment (Estimated): 20
• 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. 18 years of age or older
2. Stable medical therapy for at least 2 weeks
3. New York Heart Association (NYHA) class symptoms II or III
4. Left ventricular ejection fraction ≥ 50%

5. Evidence for elevated filling pressures as follows (at least one of the following between a-d):

   a. Mitral early (E)/mitral septal tissue annular (e') velocity ratio > 8 on echocardiography in addition to one of the following:

   i. Enlarged left atrium (LA>4.0 cm width or LA volume index >34 mL/m2)

ii. Chronic loop diuretic use for control of symptoms

iii. Elevated natriuretic peptides within the past year (NT-proBNP>125 pg/ml or BNP>35 pg/ml)

b. Mitral E/e' ratio > 14 at rest or with exercise on echocardiography

c. Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure >16 mm Hg or pulmonary capillary wedge pressure > 14 mmHg; or PCWP or LVEDP ≥ 25 mmHg with exercise)

d. Prior episode of acute heart failure requiring IV diuretics with evidence of volume overload on exam or radiology, or evidence of elevated natriuretic peptides.

Exclusion Criteria:

1. Intentional ketogenic (high fat, low carbohydrate) diet in the last week
2. Cirrhosis or alcohol use disorder (>14 drinks/week).
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/inflammatory 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, defined as severe obstructive lung disease (Gold stage 3), a requirement for supplemental oxygen, or chronic obstructive pulmonary disease with an exacerbation requiring steroids or antibiotics within the last 2 months.
5. > Moderate aortic stenosis, >mild mitral stenosis, > moderate aortic or mitral regurgitation on screening echocardiogram, or presence of a prosthetic valve in the mitral position.
6. Type 1 diabetes mellitus
7. Start of a GLP-1 RA within the past 6 months.
8. Pregnant women.
9. Angina due to epicardial coronary disease or known presence of clinically-significant, unrevascularized epicardial coronary disease, in the investigator's opinion.
10. Prior reduced LVEF to < 45% by echocardiography or cardiac MRI
11. Participation in another clinical study with an investigational product in the previous 4 weeks prior to enrollment (or longer if deemed necessary by the investigator).
12. Conditions that may render the patient unable to complete the study, in the opinion of the investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exogenous ketone drink; (R)-1,3-butanediol (commercially obtained as "KetoneIQ")	Dietary supplement: Exogenous Ketone Drink; (R)-1,3-butanediol (BD, commercially available as "KetoneIQ") initially dosed 300 mg/kg BID (target dose 400 mg/kg grams BID if tolerated) for 8 weeks; Other Names: (R)-1,3-butanediol; KetoneIQ; ketone
Placebo Comparator: Placebo; ketone-free solution	Dietary supplement: Placebo; equi-volume placebo administered for 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal exercise capacity	Peak VO2 assessed by cardiopulmonary exercise testing	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left atrial volume index	Left atrial volume index measured by echocardiogram	8 weeks
Resting E/e'	Resting E/e' on echocardiogram	8 weeks
NT-proBNP	N-terminal pro-B-type natriuretic peptide levels measured in peripheral blood.	8 weeks
Heart failure-related health status	Heart failure-related health status using Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS). Score range is from 0 to 100, with higher scores indicating better health status and lower scores indicating poorer health status.	8 weeks
Respiratory exchange ratio	Respiratory exchange ratio (RER) during cardiopulmonary exercise testing at 25 watts	8 weeks
Vasodilatory reserve	Percent change in total peripheral resistance from rest to peak exercise	8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse wave velocity	Pulse wave velocity measured during arterial tonometry	8 weeks
Global longitudinal strain	Global longitudinal strain measured by echocardiogram	8 weeks
Exercise E/e' ratio	Measured during exercise as the ratio of early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e')	8 weeks
Hemoglobin A1c	Hemoglobin A1c level measured in peripheral blood	8 weeks
Fat free mass	Fat free mass measured by body composition scan (DXA)	8 weeks
Ventilatory efficiency	VE/VCO2 slope during cardiopulmonary exercise testing	8 weeks

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Senthil Selvaraj, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 15, 2025
• First Submitted That Met QC Criteria: April 15, 2025
• First Posted (Actual): April 22, 2025

Study Record Updates

• Last Update Posted (Estimated): September 17, 2025
• Last Update Submitted That Met QC Criteria: September 16, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: exercise; echocardiography; heart failure; chronic; metabolism; ketones; cardiopulmonary exercise test; ketosis
• Additional Relevant MeSH Terms: Organizing Pneumonia; Cardiovascular Diseases; Heart Diseases; Metabolic Diseases; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Acid-Base Imbalance; Acidosis; Graft vs Host Disease; Behavior; Nutritional and Metabolic Diseases; Bronchiolitis Obliterans Syndrome; Heart Failure; Ketosis; Heart Failure, Diastolic; Motor Activity; Organic Chemicals; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs; Ketones
• Other Study ID Numbers: Pro00117625

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