INNKA-HF: Nutritional Ketosis in Heart Failure

Sponsor

Thomas Jefferson University (Other)

Overall Status

Unknown status

CT.gov ID

NCT04370600

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Chronic, ambulatory heart failure patients will be given ketone ester dietary supplementation to determine therapeutic efficacy, metabolic adaptation, pharmacokinetics, associated cognitive changes, and safety within this patient cohort in order to establish preliminary data to later conduct a multi-center randomized clinical trial.

Condition or Disease	Intervention/Treatment	Phase
Chronic Heart Failure	Drug: beta hydroxybutyrate (BHB) ester Drug: Placebo	Phase 1

Detailed Description

We previously demonstrated a metabolic signature of increased ketone utilization-increased peripheral blood concentration of beta-hydroxybutyrate (BHB) and decreased myocardial concentration of BHB-and markedly decreased acylcarnitine levels in the failing human myocardium procured from lean, non-diabetic patients with advanced heart failure at the time of cardiac transplantation. In this working model of the metabolic adaptations in human heart failure where the mobilization of lipids and ketones are required for an energetically deficient, failing heart it is likely that the development of insulin resistance may be adaptive since increased insulin or insulin signaling would put a brake on the hydrolysis of lipids and hepatic ketogenesis. In parallel with the recent discovery that the failing human heart is reliant on ketones, investigators at Oxford and the NIH have identified a nutritional ketone supplement that reliably increases the serum concentration of BHB in humans.

We hypothesize that the induction of ketosis by exogenous administration of the nutritional ketone monoester will improve myocardial function in heart failure by increasing the energetic substrate available to the myocardium, in essence supporting the energetic deficit of the failing human heart which we have demonstrated to be reliant on ketone bodies for fuel given the limited myocardial oxidation of glucose.

This is a prospective, double-blinded, sequence control crossover trial enrolling NYHA Class II-III ambulatory heart failure patients to receive either ketone mono-ester drink versus placebo for two weeks. Following 2 weeks of therapy, echocardiogram and peak exercise test will be performed. There will be a 1-week "washout" period between phases. Subjects will serve as their own controls for this crossover study, as each will have both baseline testing and testing in the setting of mild nutritional ketosis.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Biological drug + placebo (Group A) or placebo + biological drug (Group B)Biological drug + placebo (Group A) or placebo + biological drug (Group B)

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase 1, Crossover, Pharmacokinetic Study of Nutritional Ketosis on Exercise Capacity, Metabolic Adaptations, and Myocardial Function in Chronic Ambulatory Heart Failure

Anticipated Study Start Date :

Jun 1, 2020

Anticipated Primary Completion Date :

Jun 1, 2021

Anticipated Study Completion Date :

Jun 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group A These patients will receive ketone supplementation between visits 1 and 2 and will receive placebo drink between visits 2 and 3 (after the washout period).	Drug: beta hydroxybutyrate (BHB) ester Ketone supplementation given 3x/day (60mL per dose, or 22g BHB) Other Names: Delta G Drug: Placebo Denatonium benzoate + HVMN ketone placebo flavor mix + Stevia
Active Comparator: Group B These patients will receive ketone supplementation between visits 2 and 3 (after the washout period) and will receive placebo drink between visits 1 and 2	Drug: beta hydroxybutyrate (BHB) ester Ketone supplementation given 3x/day (60mL per dose, or 22g BHB) Other Names: Delta G Drug: Placebo Denatonium benzoate + HVMN ketone placebo flavor mix + Stevia

Arm

Intervention/Treatment

Active Comparator: Group A

These patients will receive ketone supplementation between visits 1 and 2 and will receive placebo drink between visits 2 and 3 (after the washout period).

Drug: beta hydroxybutyrate (BHB) ester

Ketone supplementation given 3x/day (60mL per dose, or 22g BHB)

Other Names:

Delta G

Drug: Placebo

Denatonium benzoate + HVMN ketone placebo flavor mix + Stevia

Active Comparator: Group B

These patients will receive ketone supplementation between visits 2 and 3 (after the washout period) and will receive placebo drink between visits 1 and 2

Drug: beta hydroxybutyrate (BHB) ester

Ketone supplementation given 3x/day (60mL per dose, or 22g BHB)

Other Names:

Delta G

Drug: Placebo

Denatonium benzoate + HVMN ketone placebo flavor mix + Stevia

Outcome Measures

Primary Outcome Measures

BHB Concentration in blood [1 Year]
Beta-hydroxybutyrate concentration in blood
Minutes at maximum exertion [Exercise Capacity] [1 Year]
Minutes at maximum exertion
Left ventricular ejection fraction (%) [1 Year]
Left ventricular ejection fraction, measured by echocardiogram
Cardiac output (L/min) [1 Year]
Cardiac output, measured by echocardiogram
Left ventricular end diastolic diameter (LVEDD) (cm) [1 Year]
LVEDD, measured by echocardiogram
Insulin concentration [1 Year]
Insulin concentration in blood
Bicarbonate concentration [1 Year]
Bicarbonate concentration in blood

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Equal to or greater than 18 years of age
Diagnosis of heart failure and be classified as NYHA Class II or III either pre-enrollment or at the time of enrollment
Stable medical therapy for at least 1 month prior to enrollment
Taking appropriate daily cardiac medications as determined by the principal investigator, who is a heart failure specialist

Exclusion Criteria:

Atrial fibrillation
Inability to exercise on a supine bicycle.
Moderate or greater valvular disease.
Hemoglobin <10 g/dL.
Daily insulin use
Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
Pericardial disease.
Current angina due to clinically significant obstructive epicardial coronary disease
Acute coronary syndrome or coronary intervention within the past 2 months.
Primary pulmonary arteriopathy.
Known clinically significant lung disease defined as:
Current use of supplemental oxygen, aside from nocturnal O2 for the treatment of obstructive sleep apnea
The use of steroids/antibiotics within the past 6 months for an acute exacerbation of obstructive pulmonary disease
Most proximal pulmonary function test indicating severe obstructive disease, defined as an FEV1<50% predicted in the context of an FEV1/FVC ratio of <0.70 ("Stage III COPD according to GOLD Criteria). (note: only to be used if the subject had PFTs prior to screening)
Most proximal 6-minute walk test during which the subject experienced arterial desaturation (<94%) without a subsequent normal study.
Ischemia on stress testing without subsequent revascularization or left heart catheterization showing non-obstructive epicardial coronary disease.
Significant liver disease impacting synthetic function or volume control.
Uncontrolled hypertension: BP >180/110 at baseline.
eGFR <30 mL/min/m2 or Cr >2.5.
Alcohol dependence
Chronic narcotic use that cannot be interrupted
Pregnant or lactating females