Acute Effects of Exogenous Ketone Ester Administration in Heart Failure

The purpose of this study is to test whether a ketone ester drink will improve exercise in people with heart failure (HF) compared to a placebo. In HF, 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.

There is some evidence that in addition to problems with the heart, patients with HF also have problems with their arteries and muscles that affect their ability to exercise. Ketones have been shown to improve exercise capacity in healthy volunteers, which may be related to effects on the heart function or on muscles. An infusion of ketones through an intravenous (IV) line has also been shown to significantly improve heart function, but whether a drink can produce similar improvements in HF patients is not known. 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: Completed
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Dietary supplement: Ketone ester; Dietary supplement: placebo drink

Detailed Description

This is a randomized, crossover trial of ketone ester versus placebo in 20 patients with heart failure with preserved ejection fraction. Participants come for a baseline assessment. If they meet eligibility criteria, they are randomized to receive ketone ester first or placebo first. After approximately a week washout period, participants return for the last visit to receive the product they did not receive at the previous visit.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Left ventricular ejection fraction ≥ 50%

2. 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 in addition to one of the following: i. Large 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 c. Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure >16 mm Hg or pulmonary capillary wedge pressure > 15 mmHg; or PCWP/LVEDP ≥ 25 mmHg with exercise) d. Prior episode of acute heart failure requiring IV diuretics with evidence of volume overload on exam/radiology or elevated natriuretic peptides.

Exclusion Criteria

1. Intentional ketogenic (high fat, low carbohydrate) diet in the last week or use of ketogenic medications (SGLT2 inhibitors)
2. Significant liver disease (liver function tests > 3x upper limit of normal, cirrhosis) or alcohol abuse 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<30 mL/min/1.73 m2, and hemoglobin < 9 mg/dL).
4. Clinically significant lung disease. This would be defined by 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
6. Type 1 diabetes mellitus
7. Pregnant women. Due to unknown affects of nutritional ketosis in pregnant women, pregnancy will be an exclusion. Accordingly, women of childbearing age with a menstrual cycle within the past year will be asked to submit a urine specimen for pregnancy testing.
8. Angina due to epicardial coronary disease or known presence of clinically-significant, unrevascularized epicardial coronary disease, in the investigator's opinion.
9. Prior reduced LVEF to < 45%

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; A nutraceutical ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate which provides systemic ketosis
Placebo Comparator: Placebo; KE-free solution	Dietary supplement: placebo drink; KE free placebo drink

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Exercise Capacity (Peak VO2) Assessed by Cardiopulmonary Exercise Testing	Peak VO2	Assessed 60 minutes after the intervention.
Submaximal Exercise Capacity (Exercise Time at 75% of Peak Workload) Assessed by Cardiopulmonary Exercise Testing.	Exercise time at 75% of peak workload	Assessed 30 minutes after the intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Systemic Vascular Resistance With Exercise	Percent change in systemic vascular resistance with exercise	Assessed 60 minutes after the intervention.
Substrate Utilization (Reflected by the Respiratory Exchange Ratio) Assessed by Cardiopulmonary Exercise Testing.		Assessed 60 minutes after the intervention.
VO2 Efficiency (Total Work Performed Over Oxygen Consumed) During Submaximal Cardiopulmonary Exercise Testing.		Assessed 60 minutes after the intervention.
Presence of Exercise-induced Arrhythmias (Significant Atrial or Ventricular Arrhythmias)		Assessed throughout the study visit date after the intervention is given (until leaving the research study center that day).

Other Outcome Measures

Outcome Measure	Time Frame
Heart rate variability at rest	Assessed 20 minutes after the intervention.
Left ventricular global longitudinal strain (%) assessed by echocardiography strain analysis at rest.	Assessed 30 minutes after the intervention.
Exercise-induced extravascular lung water (B-lines) assessed during lung ultrasound with exercise.	Assessed 60 minutes after the intervention.
VO2 kinetics (Tau) during submaximal cardiopulmonary exercise testing	Assessed 30 minutes after the intervention.
Tissue Doppler velocity measured during rest echocardiography.	Assessed 30 minutes after the intervention.
E/e' ratio measured during stress echocardiography.	Assessed 60 minutes after the intervention.

Collaborators and Investigators

• Sponsor: University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2020
• Primary Completion (Actual): October 4, 2023
• Study Completion (Actual): October 16, 2023

Study Registration Dates

• First Submitted: October 23, 2020
• First Submitted That Met QC Criteria: November 11, 2020
• First Posted (Actual): November 18, 2020

Study Record Updates

• Last Update Posted (Estimated): November 27, 2024
• Last Update Submitted That Met QC Criteria: November 6, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure
• Other Study ID Numbers: 833870

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