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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
Sponsored by
Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

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:

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

Exclusion Criteria:

  1. Atrial fibrillation
  2. Inability to exercise on a supine bicycle.
  3. Moderate or greater valvular disease.
  4. Hemoglobin <10 g/dL.
  5. Daily insulin use
  6. Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
  7. Pericardial disease.
  8. Current angina due to clinically significant obstructive epicardial coronary disease
  9. Acute coronary syndrome or coronary intervention within the past 2 months.
  10. Primary pulmonary arteriopathy.
  11. 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.
  12. Ischemia on stress testing without subsequent revascularization or left heart catheterization showing non-obstructive epicardial coronary disease.
  13. Significant liver disease impacting synthetic function or volume control.
  14. Uncontrolled hypertension: BP >180/110 at baseline.
  15. eGFR <30 mL/min/m2 or Cr >2.5.
  16. Alcohol dependence
  17. Chronic narcotic use that cannot be interrupted
  18. Pregnant or lactating females

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    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

    First Posted
    March 10, 2020
    Last Updated
    April 28, 2020
    Sponsor
    Thomas Jefferson University
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    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
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    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
    No
    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
    Email
    mfoster610@gmail.com
    First Name & Middle Initial & Last Name or Official Title & Degree
    Melissa McCarey
    Phone
    2155037417
    Email
    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
    No

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