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Nutritional Ketosis in Heart Failure (INNKA-HF)

Primary Purpose

Chronic Heart Failure

Status

Unknown status

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

beta hydroxybutyrate (BHB) ester

Placebo

About this trial

This is an interventional treatment trial for Chronic Heart Failure focused on measuring ketosis, beta-hydroxybutyrate, insulin, bioenergetics, exercise tolerance, metabolic, diabetes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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:
1. Current use of supplemental oxygen, aside from nocturnal O2 for the treatment of obstructive sleep apnea
2. The use of steroids/antibiotics within the past 6 months for an acute exacerbation of obstructive pulmonary disease
3. 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)
4. 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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Group A

Group B

Arm Description

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).

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

Outcomes

Primary Outcome Measures

BHB Concentration in blood

Beta-hydroxybutyrate concentration in blood

Minutes at maximum exertion [Exercise Capacity]

Minutes at maximum exertion

Left ventricular ejection fraction (%)

Left ventricular ejection fraction, measured by echocardiogram

Cardiac output (L/min)

Cardiac output, measured by echocardiogram

Left ventricular end diastolic diameter (LVEDD) (cm)

LVEDD, measured by echocardiogram

Insulin concentration

Insulin concentration in blood

Bicarbonate concentration

Bicarbonate concentration in blood

Secondary Outcome Measures

Full Information

NCT ID

NCT04370600

First Posted

March 10, 2020

Last Updated

April 28, 2020

Sponsor

Thomas Jefferson University

1. Study Identification

Unique Protocol Identification Number

NCT04370600

Brief Title

Nutritional Ketosis in Heart Failure

Acronym

INNKA-HF

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2020

Overall Recruitment Status

Unknown status

Study Start Date

June 2020 (Anticipated)

Primary Completion Date

June 2021 (Anticipated)

Study Completion Date

June 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Thomas Jefferson University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Heart Failure

Keywords

ketosis, beta-hydroxybutyrate, insulin, bioenergetics, exercise tolerance, metabolic, diabetes

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Model Description

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

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

16 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Active Comparator

Arm Description

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).

Arm Title

Group B

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

beta hydroxybutyrate (BHB) ester

Other Intervention Name(s)

Delta G

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Denatonium benzoate + HVMN ketone placebo flavor mix + Stevia

Primary Outcome Measure Information:

Title

BHB Concentration in blood

Description

Beta-hydroxybutyrate concentration in blood

Time Frame

1 Year

Title

Minutes at maximum exertion [Exercise Capacity]

Description

Minutes at maximum exertion

Time Frame

1 Year

Title

Left ventricular ejection fraction (%)

Description

Left ventricular ejection fraction, measured by echocardiogram

Time Frame

1 Year

Title

Cardiac output (L/min)

Description

Cardiac output, measured by echocardiogram

Time Frame

1 Year

Title

Left ventricular end diastolic diameter (LVEDD) (cm)

Description

LVEDD, measured by echocardiogram

Time Frame

1 Year

Title

Insulin concentration

Description

Insulin concentration in blood

Time Frame

1 Year

Title

Bicarbonate concentration

Description

Bicarbonate concentration in blood

Time Frame

1 Year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Michael W Foster, M.D.

Phone

6107160962

mfoster610@gmail.com

First Name & Middle Initial & Last Name or Official Title & Degree

Melissa McCarey

Phone

2155037417

melissa.mccarey@jefferson.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

J. Eduardo Rame, M.D.

Organizational Affiliation

Thomas Jefferson University

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Nutritional Ketosis in Heart Failure

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