Heart Failure With Preserved Ejection FractionPhase 2NCT04633460
Acute Effects of Exogenous Ketone Ester Administration in Heart Failure
A Phase 2 study testing Ketone ester in people with Heart Failure With Preserved Ejection Fraction, run by University of Pennsylvania at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 85 years
- Conditions the study is for
- Heart Failure With Preserved Ejection Fraction
- What is being tested?
- Ketone ester
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 26 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Oct 2020to 16 Oct 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Left ventricular ejection fraction ≥ 50%
- Evidence for elevated filling pressures as follows (at least one of the following between a-d):
- 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.
Who cannot join
- Intentional ketogenic (high fat, low carbohydrate) diet in the last week or use of ketogenic medications (SGLT2 inhibitors)
- Significant liver disease (liver function tests > 3x upper limit of normal, cirrhosis) or alcohol abuse 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<30 mL/min/1.73 m2, and hemoglobin < 9 mg/dL).
- 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.
- >= Moderate aortic stenosis, >mild mitral stenosis, >= moderate aortic or mitral regurgitation on screening echocardiogram
- Type 1 diabetes mellitus
Show all 9Show fewer
- 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.
- 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%
Trial locations and contacts
1 site in 1 country.
United States1 site
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania, 19104
About this study
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.
Read the 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.
- Being tested
- Ketone ester, placebo drink
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketone esterDietary supplement
A nutraceutical ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate which provides systemic ketosis
placebo drinkDietary supplement
KE free placebo drink
| Study group | Role | What they receive |
|---|---|---|
| Ketone ester | Experimental | (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone ester Receives: Dietary Supplement: Ketone ester |
| Placebo | Placebo comparator | KE-free solution Receives: Dietary Supplement: placebo drink |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximal Exercise Capacity (Peak VO2) Assessed by Cardiopulmonary Exercise Testing
Peak VO2
Measured: 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
Measured: Assessed 30 minutes after the intervention.
Secondary outcomes (4)
Percent Change in Systemic Vascular Resistance With Exercise
Percent change in systemic vascular resistance with exercise
Measured: Assessed 60 minutes after the intervention.
Substrate Utilization (Reflected by the Respiratory Exchange Ratio) Assessed by Cardiopulmonary Exercise Testing.
Measured: Assessed 60 minutes after the intervention.
VO2 Efficiency (Total Work Performed Over Oxygen Consumed) During Submaximal Cardiopulmonary Exercise Testing.
Measured: Assessed 60 minutes after the intervention.
Presence of Exercise-induced Arrhythmias (Significant Atrial or Ventricular Arrhythmias)
Measured: Assessed throughout the study visit date after the intervention is given (until leaving the research study center that day).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2020
- Study start6 Oct 2020
- Primary completion4 Oct 2023
- Study completion16 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart Failure With Preserved Ejection FractionStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Overview: The overall study design will be a randomized, double-blind crossover comparison of ketone ester (KE) therapy vs. KE-free vehicle in 20 patients with established HF with preserved ejection fraction (HFpEF). The main outcomes will be measures of exercise performance (peak and submaximal exercise).
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kenneth B Margulies, University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04633460
- Sponsor's protocol ID
- 833870
- Status last verified
- Nov 2024
- First submitted
- 23 Oct 2020
- Last updated
- 27 Nov 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Selvaraj S, Karaj A, Chirinos JA, Denney N, Grosso G, Fernando M, Chambers K, Demastus C, Reddy R, Langham M, Kumar D, Maynard H, Pourmussa B, Prenner SB, Cohen JB, Ischiropoulos H, Rickels MR, Poole DC, Church DD, Wolfe RR, Kelly DP, Putt M, Margulies KB, Zamani P. Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2025 Dec;13(12):102435. doi: 10.1016/j.jchf.2025.03.002. Epub 2025 Mar 29.
PubMed 40243975
Study at a glance
From the registry record, last updated by the sponsor on 27 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Acute Effects of Exogenous Ketone Ester Administration in Heart Failure
- ClinicalTrials.gov ID
- NCT04633460
- Acronym / sponsor ID
- 833870
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Study start
- 6 Oct 2020 (actual)
- Primary completion
- 4 Oct 2023 (actual)
- Study completion
- 16 Oct 2023 (actual)
- First posted
- 18 Nov 2020 (actual)
- Results
- Posted 27 Nov 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Overview: The overall study design will be a randomized, double-blind crossover comparison of ketone ester (KE) therapy vs. KE-free vehicle in 20 patients with established HF with preserved ejection fraction (HFpEF). The main outcomes will be measures of exercise performance (peak and submaximal exercise).
| Arm | Type | Receives |
|---|---|---|
| Ketone ester | Experimental | Dietary Supplement: Ketone ester(R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone ester |
| Placebo | Placebo comparator | Dietary Supplement: placebo drinkKE-free solution |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Left ventricular ejection fraction ≥ 50%
- Evidence for elevated filling pressures as follows (at least one of the following between a-d):
Key exclusion criteria (9 listed)
- Intentional ketogenic (high fat, low carbohydrate) diet in the last week or use of ketogenic medications (SGLT2 inhibitors)
- Significant liver disease (liver function tests > 3x upper limit of normal, cirrhosis) or alcohol abuse 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<30 mL/min/1.73 m2, and hemoglobin < 9 mg/dL).
- 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.
- >= Moderate aortic stenosis, >mild mitral stenosis, >= moderate aortic or mitral regurgitation on screening echocardiogram
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketone esterA nutraceutical ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate which provides systemic ketosis | Dietary supplement | Ketone ester |
| placebo drinkKE free placebo drink | Dietary supplement | Placebo |
Primary outcome
Maximal Exercise Capacity (Peak VO2) Assessed by Cardiopulmonary Exercise Testing
Time frame: Assessed 60 minutes after the intervention.
Peak VO2
Submaximal Exercise Capacity (Exercise Time at 75% of Peak Workload) Assessed by Cardiopulmonary Exercise Testing.
Time frame: Assessed 30 minutes after the intervention.
Exercise time at 75% of peak workload
4 secondary outcomes
Percent Change in Systemic Vascular Resistance With Exercise
Time frame: Assessed 60 minutes after the intervention.
Substrate Utilization (Reflected by the Respiratory Exchange Ratio) Assessed by Cardiopulmonary Exercise Testing.
Time frame: Assessed 60 minutes after the intervention.
VO2 Efficiency (Total Work Performed Over Oxygen Consumed) During Submaximal Cardiopulmonary Exercise Testing.
Time frame: Assessed 60 minutes after the intervention.
Presence of Exercise-induced Arrhythmias (Significant Atrial or Ventricular Arrhythmias)
Time frame: Assessed throughout the study visit date after the intervention is given (until leaving the research study center that day).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Nov 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40243975Selvaraj S, Karaj A, Chirinos JA, Denney N, Grosso G, Fernando M, Chambers K, Demastus C, Reddy R, Langham M, Kumar D, Maynard H, Pourmussa B, Prenner SB, Cohen JB, Ischiropoulos H, Rickels MR, Poole DC, Church DD, Wolfe RR, Kelly DP, Putt M, Margulies KB, Zamani P. Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2025 Dec;13(12):102435. doi: 10.1016/j.jchf.2025.03.002. Epub 2025 Mar 29.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ketone ester in people with Heart Failure With Preserved Ejection Fraction, run by University of Pennsylvania at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Nov 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximal Exercise Capacity (Peak VO2) Assessed by Cardiopulmonary Exercise Testing (time frame: Assessed 60 minutes after the intervention.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04633460, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Nov 2024.