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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
250
1,3-butanediol (Ketone-IQ®) 118 mL (33 g) servings trice daily
Taste-matched placebo (isovolumic, isoviscous water with stevia) 118 mL servings trice daily
Department of Cardiology, Aalborg University Hospital
Aalborg, Denmark
NOT_YET_RECRUITINGDepartment of Cardiology, Aarhus University Hospital
Aarhus N, Denmark
RECRUITINGDepartment of Cardiology, Herlev-Gentofte Hospital
Change in clinical benefit during 1,3-butanediol treatment versus placebo
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.
Time frame: From baseline (day 0) to end of treatment (day 30)
Time to all-cause death
Time frame: From baseline (day 0) to end of treatment (day 30)
Time to first heart failure event
Time frame: From baseline (day 0) to end of treatment (day 30)
Change in six-minute walking distance
Time frame: From baseline (day 0) to end of treatment (day 30)
Change in daily activity level
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.
Time frame: From discharge, day 30, and end of treatment (day 30)
Change in NT-proBNP
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
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Copenhagen, Denmark
Department of Cardiology, Rigshospitalet
Copenhagen, Denmark
NOT_YET_RECRUITINGDepartment of Cardiology, Gødstrup Hospital, Herning, Denmark
Herning, Denmark
RECRUITINGDepartment of Cardiology, Copenhagen University Hospital - Amager and Hvidovre Hospital
Hvidovre, Denmark
RECRUITINGDepartment of Cardiology, Odense University Hospital
Odense, Denmark
NOT_YET_RECRUITINGDepartment of Cardiology, Viborg Hospital
Viborg, Denmark
RECRUITINGChange in KCCQ-12 total summary score
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Change in VAS dyspnea score
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Change in physical exertion score during six- minute walk test
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Change in systolic blood pressure
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Change in body weight
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Diuretic response
Diuretic response will be defined as Δ weight kg/\[(total intravenous dose)/40mg\] + \[(total oral dose)/80mg)\] furosemide or equivalent loop diuretic dose
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Cumulative dose of loop diuretic medication
Time frame: From baseline (day 0) to discharge and end of treatment (day 30)
Need for inotropes
Time frame: From baseline (day 0) to end of treatment (day 30)
Transfer to the intensive care unit
Time frame: From baseline (day 0) to end of treatment (day 30)
Need for dialysis
Time frame: From baseline (day 0) to end of treatment (day 30)