Clinical trial NCT06937320: Chronic Exogenous Ketosis in HFpEF
Official title: Chronic Effects of Exogenous Ketone Administration in Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
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
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2025-04-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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).
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Maximal exercise capacity
timeFrame: 8 weeks
Secondary outcomes:
measure: Respiratory exchange ratio
timeFrame: 8 weeks
measure: Vasodilatory reserve
timeFrame: 8 weeks
measure: Left atrial volume index
timeFrame: 8 weeks
measure: Resting E/e'
timeFrame: 8 weeks
measure: Heart failure-related health status
timeFrame: 8 weeks
measure: NT-proBNP
timeFrame: 8 weeks
Other outcomes:
measure: Global longitudinal strain
timeFrame: 8 weeks
measure: Exercise E/e' ratio
timeFrame: 8 weeks
measure: Hemoglobin A1c
timeFrame: 8 weeks
measure: Fat free mass
timeFrame: 8 weeks
measure: Pulse wave velocity
timeFrame: 8 weeks
measure: Ventilatory efficiency
timeFrame: 8 weeks
Locations:
city: Durham
country: United States
facility: Duke University
state: North Carolina
Study officials:
affiliation: Duke University
name: Senthil Selvaraj, MD
role: PRINCIPAL_INVESTIGATOR
References: