Exogenous Ketones for Acutely Decompensated HEart Failure

Phase 3

• Conditions: Hemodynamic Instability; Low Cardiac Output Syndrome; Acute Heart Failure; Ketosis
• Interventions: Other: Placebo; Dietary Supplement: 25g Ketone monoester without added salts

• Registration Number: NCT04698005
• Lead Sponsor: Institute for Clinical and Experimental Medicine

Brief Summary

This study will evaluate whether supplementation of exogenous ketones in patients with severe left ventricular dysfunction and acutely decompensated heart failure requiring inotropic therapy would improve the patient's hemodynamics and symptoms.

Detailed Description

The study will include patients with acutely decompensated chronic heart failure requiring inotropic therapy for the syndrome of low cardiac output. While being on the inotropic therapy, the patients will be randomized to oral supplementation of exogenous ketones vs. placebo, which will be repeatedly administered over 9 hours. The patients will undergo continuous invasive hemodynamic monitoring by pulmonary artery catheter, repeated laboratory assessment, and repeated assessment of the severity of symptoms for 24 hours.

Exogenous ketones will be administered orally using monoester 3-OHB concentrate without added salts (25g 3-OHB in 65ml H.V.M.N Ketone Ester, H.V.M.N, USA or equivalent). The drink will be administered over 10 mins every 3 hours, 3 times in a row (hour 0, 3, 6).

All patients with K\<3.7 mmol/l will receive a continuous infusion of 7.5% potassium until reach target K levels of 4.0-4.9 mmol /l. Glycemia will be controlled as needed by insulin and dextrose to maintain glucose concentration of 4 - 12 mmol/l

All patients will receive standard treatment of acute heart failure, including intravenous diuretics and inotropic therapy. The recommended inotropic therapy will include milrinone 0.5 ug/kg/min, levosimendan 0.1 ug/kg/min up to 25mg without initial bolus, or dobutamine 0.5 ug/kg/min in patients without chronic therapy with beta-blockers.

The severity of symptoms will be self-reported by the patient using 1-10 visual analog scale.

Workflow:

* Hemodynamic assessment, assessment of ketones concentration: 1-3h before randomization, 0-9h hourly, 16-24h (next morning)

* Biochemical assessment (renal function, liver enzymes, BNP, hs-TnT) 0h, 9h, 16-24h

* Assessment of symptoms and Scv02: 0h, 1h, 3h, 9h, 16-24h

Statistical methods:

Each study arm will include 12 patients. The study size was estimated to have power of (1 - beta) of 0.8 and alpha of 5% for between-group comparison of changes in cardiac index and stroke volume index by ANOVA and for comparison of the changes in cardiac index and stroke volume index by paired t-tests.

Study Timeline

• Study Start: 2020-12-02
• Study First Submitted: 2020-12-02
• Status Verified: 2021-01
• Study First Submitted QC: 2021-01-05
• Last Update Submitted: 2021-01-05
• Study First Posted: 2021-01-06
• Last Update Posted: 2021-01-06
• Primary Completion: 2021-12-31
• Study Completion: 2021-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

• Chronic heart failure due ischemic or nonischemic cardiomyopathy
• Acute decompensation of heart failure with the need of inotropes
• Achievement of relative stabilization on inotropes (INTERMACS class >2)
• Left ventricular ejection fraction <= 35%
• Age >18 years

Exclusion Criteria

• Deteriorating cardiogenic shock with likely need of mechanical circulatory support in the subsequent 48 hours
• Chronic kidney disease grade 4 or 5
• Diabetic ketoacidosis (3-OHB >2mmol/l at baseline)
• Hemodynamic severe arrhythmias
• Acute heart failure due to transient triggers (acute coronary syndrome, atrial fibrillation, infection etc..)
• Contraindications to invasive hemodynamic monitoring

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control group	Placebo	The patients will receive a placebo drink (drinking water) of equivalent volume (3x 65ml)
Supplementation of exogenous ketones	25g Ketone monoester without added salts	Exogeneous ketones will be administered orally using monoester 3-OHB concentrate without added salts (25g 3-OHB in 65ml H.V.M.N Ketone Ester, H.V.M.N, USA or equivalent). The drink will be administered over 10 mins every 3 hours, 3 times in a row.

Primary Outcome Measures

Name	Time	Method
Maximum change of stroke volume index	Maximum value of stroke volume index measured between hour 1 - 3 of the study protocol at 15-minute intervals	Maximum change of stroke volume index (ml/m2) between baseline and hour 1 - 3
Maximum change of cardiac index	Maximum value of cardiac index measured between hour 1 - 3 of the study protocol at 15-minute intervals	Maximum change of cardiac index (L/m2) between baseline and hour 1 - 3
Change of mean cardiac index	Mean value of cardiac index measured every 15 minutes during 9 hours of the study protocol	Difference between baseline cardiac index (L/m2) and mean cardiac index during the study protocol
Change of mean stroke volume index	Mean value of stroke volume index measured every 15 minutes during 9 hours of the study protocol	Difference between baseline stroke volume index and mean stroke volume index (ml/m2) during the study protocol

Secondary Outcome Measures

Name	Time	Method
Change in patient/symptoms	Symptoms scored at hours 0, 1, 10, 24 and expressed as an area under the curve	Change in patient-referred symptoms by visual-analog scale (1=unbearable dyspnea, 10=no symptoms)

Trial Locations

Locations (1)

Institute for Clinical and Experimental Medicine (IKEM); 🇨🇿 Prague, Czechia