Chronic Exogenous Ketosis in HFpEF

NCT06937320 | Enrolling By Invitation Phase 2 FDA Drug

• 1 other identifier: Pro00117625
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Heart Failure With Preserved Ejection Fraction (HFPEF); Heart Failure With Normal Ejection Fraction; Heart Failure, Diastolic

Keywords

heart failure; ketosis; exercise; chronic; ketones; metabolism; echocardiography; cardiopulmonary exercise test

Outcome Measures

Primary Outcomes (1)

• Maximal exercise capacity

  Peak VO2 assessed by cardiopulmonary exercise testing

  8 weeks

Secondary Outcomes (6)

• Respiratory exchange ratio

  8 weeks

• Vasodilatory reserve

  8 weeks

• Left atrial volume index

  8 weeks

• Resting E/e'

  8 weeks

• Heart failure-related health status

  8 weeks

Other Outcomes (6)

• Global longitudinal strain

  8 weeks

• Exercise E/e' ratio

  8 weeks

• Hemoglobin A1c

  8 weeks

Study Arms (2)

Exogenous ketone drink

EXPERIMENTAL

(R)-1,3-butanediol (commercially obtained as "KetoneIQ")

Dietary Supplement: Exogenous Ketone Drink

Placebo

PLACEBO COMPARATOR

ketone-free solution

Dietary Supplement: Placebo

Interventions

Exogenous Ketone Drink DIETARY_SUPPLEMENT

(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

Also known as: (R)-1,3-butanediol, KetoneIQ, ketone

Exogenous ketone drink

Placebo DIETARY_SUPPLEMENT

equi-volume placebo administered for 8 weeks

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age or older
• Stable medical therapy for at least 2 weeks
• New York Heart Association (NYHA) class symptoms II or III
• Left ventricular ejection fraction ≥ 50%
• 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.

You may not qualify if:

• Intentional ketogenic (high fat, low carbohydrate) diet in the last week
• Cirrhosis or alcohol use disorder (\>14 drinks/week).
• 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).
• 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.
• \> Moderate aortic stenosis, \>mild mitral stenosis, \> moderate aortic or mitral regurgitation on screening echocardiogram, or presence of a prosthetic valve in the mitral position.
• Type 1 diabetes mellitus
• Start of a GLP-1 RA within the past 6 months.
• Pregnant women.
• Angina due to epicardial coronary disease or known presence of clinically-significant, unrevascularized epicardial coronary disease, in the investigator's opinion.
• Prior reduced LVEF to \< 45% by echocardiography or cardiac MRI
• 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).
• Conditions that may render the patient unable to complete the study, in the opinion of the investigator.

Sponsors & Collaborators

• Duke University: lead

Study Sites (1)

Duke University

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Heart Failure, Diastolic; Heart Failure; Ketosis; Motor Activity; Bronchiolitis Obliterans Syndrome

Interventions

Ketones

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Behavior; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Organic Chemicals

Study Officials

• Senthil Selvaraj, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an 8-week randomized, crossover, double-blind, placebo-controlled trial to evaluate the effects of an exogenous ketone drink on peak VO2 in 20 patients with heart failure with preserved ejection fraction (HFpEF).

Study Record Dates

• First Submitted: April 15, 2025
• First Posted: April 22, 2025
• Study Start: July 28, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: September 17, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)