Exogenous KETOne Supplements in Patients Hospitalized for Acute Heart Failure

Phase 2

Recruiting

• Conditions: Acute Heart Failure (AHF)

• Registration Number: NCT06653725
• Lead Sponsor: Aarhus University Hospital

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled trial to investigate the clinical efficacy of treatment with exogenous dietary ketone supplement containing 1,3-butanediol in patients hospitalized with acute heart failure (AHF), potentially leading to better clinical outcomes.

Detailed Description

Acute heart failure (AHF) is life-threatening with a 30-day mortality rate between 10% and 50%, especially in patients with cardiogenic shock. Current medical treatments have not shown a survival benefit in randomized trials, highlighting the need for new therapies. Ketone bodies, particularly 3-hydroxybutyrate (3-OHB), are vital for energy in the heart and brain during stress. Elevated 3-OHB levels from exogenous sources, such as ketone esters or 1,3-butanediol, enhance organ perfusion and improve cardiac function. In chronic heart failure (HF), 3-OHB infusion increases cardiac output and left ventricular ejection fraction (LVEF) without excess oxygen consumption, supporting its role as an efficient energy source. Short-term ketone ester treatment has been shown to improve hemodynamics, reduce NT-proBNP, and enhance physical performance in heart failure with reduced ejection fraction (HFrEF) patients. In AHF patients, ketone ester improved cardiac output, LVEF, and filling pressures. Emerging evidence suggests that 1,3-butanediol supplements may sustain ketosis longer, offering potential for practical dosing in the acute phase of heart failure.

This proposal aims to study the clinical efficacy of treatment with exogenous dietary ketone supplement containing 1,3-butanediol in patients hospitalized with AHF.

The primary hypothesis is that in patients hospitalized with AHF, a 30-day treatment with 1,3- butanediol has beneficial clinical effects as compared with placebo. Clinical benefit is defined as a hierarchical composite of death, heart failure (HF) events, change from baseline in the 6-minute walk test (6MWT), and change from baseline in NT-proBNP at 30 days, as assessed using win ratio statistics.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-10-21
• Study First Submitted QC: 2024-10-21
• Study First Posted: 2024-10-22
• Last Update Submitted: 2025-03-19
• Study Start: 2025-03-20
• Last Update Posted: 2025-03-24
• Primary Completion: 2027-11-01
• Study Completion: 2028-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 250

Inclusion Criteria

Not provided

Exclusion Criteria

1. Current hospitalization for AHF triggered by significant arrhythmia (atrial fibrillation/flutter with sustained ventricular response >110 beats per minute, clinically significant bradycardia, or sustained ventricular tachycardia)
2. Cardiogenic shock in INTERMACS level 1 or 2 (i.e. unstable hemodynamics despite inotropic/vasopressor therapy)
3. Likelihood or current use of mechanical circulatory support
4. Recent cardiac surgery within 3 days
5. Ongoing severe infection or sepsis, severe anemia, acute exacerbation of chronic obstructive pulmonary disease, pulmonary embolism, or cerebrovascular accident
6. Significant primary valvular disease (hemodynamically severe uncorrected primary cardiac valvular disease)
7. Planned implantation of a cardiac resynchronization therapy device
8. eGFR <15 mL/min/1.73 m2 during current hospitalization (unless ongoing continuous renal replacement therapy) or recurring dialysis
9. Known obstructive hypertrophic cardiomyopathy, congenital heart disease, acute mechanical cause of acute heart failure (e.g., papillary muscular rupture), acute myocarditis, or constrictive pericarditis according to the treating physician
10. Type 1 diabetes
11. Advanced liver disease (Child-Pugh class C)
12. Dementia or other cognitive disorder making the patient unable to give informed consent
13. Pregnancy or breastfeeding
14. Inability to intake oral substances or severe dysphagia
15. Significant gastrointestinal disease (i.e. severe inflammatory bowel disease or gastric ulcer)
16. Adherent to a ketogenic diet within 30 days of enrollment
17. Awaiting cardiac transplantation
18. Very severe lung disease and/or treatment with continuous home oxygen therapy
19. Major comorbidity, medical condition, or health issue that, according to the investigator's judgment, would hinder the participant's capacity to engage in or successfully finish the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in clinical benefit during 1,3-butanediol treatment versus placebo	From baseline (day 0) to end of treatment (day 30)	Clinical benefit is defined through a hierarchical composite endpoint, using a win ratio, from day 0 to 30 in all-cause death and time to death, number of and time to heart failure events, ≥30 meters increase in the change from baseline to follow-up at 30 days in the 6MWT, (iv) \>30% decrease in the change from baseline to follow-up at 30 days in NT-proBNP, and (v) % decrease in NT-proBNP (continuous variable).; The primary endpoint will be evaluated using a win ratio, in an intention-to-treat approach, with participants analyzed within the treatment groups to which they were originally randomized. The win ratio method involves a pairwise hierarchical comparison of each participant against all others and is determined by dividing the total number of wins achieved by participants in the 1,3-butanediol group by the total number of losses.

Secondary Outcome Measures

Name	Time	Method
Time to all-cause death	From baseline (day 0) to end of treatment (day 30)
Time to first heart failure event	From baseline (day 0) to end of treatment (day 30)
Change in six-minute walking distance	From baseline (day 0) to end of treatment (day 30)
Change in daily activity level	From discharge, day 30, and end of treatment (day 30)	When discharged, a wearable triaxial accelerometer will be placed around the wrist of the patient. The accelerometer will measure daily physical activity (milligravitational units) between discharge and 30-day follow-up.
Change in NT-proBNP	From baseline (day 0) to discharge and end of treatment (day 30)
Change in KCCQ-12 total summary score	From baseline (day 0) to discharge and end of treatment (day 30)
Change in VAS dyspnea score	From baseline (day 0) to discharge and end of treatment (day 30)
Change in physical exertion score during six- minute walk test	From baseline (day 0) to discharge and end of treatment (day 30)
Change in systolic blood pressure	From baseline (day 0) to discharge and end of treatment (day 30)
Change in body weight	From baseline (day 0) to discharge and end of treatment (day 30)
Diuretic response	From baseline (day 0) to discharge and end of treatment (day 30)	Diuretic response will be defined as Δ weight kg/\[(total intravenous dose)/40mg\] + \[(total oral dose)/80mg)\] furosemide or equivalent loop diuretic dose
Cumulative dose of loop diuretic medication	From baseline (day 0) to discharge and end of treatment (day 30)
Need for inotropes	From baseline (day 0) to end of treatment (day 30)
Transfer to the intensive care unit	From baseline (day 0) to end of treatment (day 30)
Need for dialysis	From baseline (day 0) to end of treatment (day 30)

Trial Locations

Locations (8)

Department of Cardiology, Aalborg University Hospital; 🇩🇰 Aalborg, Denmark

Department of Cardiology, Aarhus University Hospital; 🇩🇰 Aarhus N, Denmark

Department of Cardiology, Herlev-Gentofte Hospital; 🇩🇰 Copenhagen, Denmark

Department of Cardiology, Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Department of Cardiology, Gødstrup Hospital, Herning, Denmark; 🇩🇰 Herning, Denmark

Department of Cardiology, Copenhagen University Hospital - Amager and Hvidovre Hospital; 🇩🇰 Hvidovre, Denmark

Department of Cardiology, Odense University Hospital; 🇩🇰 Odense, Denmark

Department of Cardiology, Viborg Hospital; 🇩🇰 Viborg, Denmark