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Effects of Ketones and Niacin in Heart Failure Patients (KETO-COX)

Primary Purpose

Heart Failure, Systolic, Ketonemia

Status
Completed
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Placebo NaCl
Niacin
Na-3-OHB
Sponsored by
University of Aarhus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure, Systolic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Chronic heart failure, Age ≥ 18 years old, LVEF ≤40%, New York Heart Association (NYHA) classification 2-3, Negative urine-HCG for women of childbearing potential, Ability to understand the written patient information and to give informed consent.

Exclusion Criteria:

  • Symptomatic cardiac valve disease, Signs or history of major myocardial infarction (STEMI) within 1 month, Insulin treatment, Other disease or treatment making subject unsuitable for study participation as judged by the investigator.

Significant liver disease (defined by serum levels of alanine aminotransferase (ALAT) above 3 x upper limit of normal).

Sites / Locations

  • Aarhus University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Niacin

Na-3-OHB

Arm Description

12 patients with Heart failure with reduced ejection fraction (HFrEF) investigated with echocardiography and right heart catheterization.

12 patients with Heart failure with reduced ejection fraction (HFrEF) investigated with echocardiography and right heart catheterization. All patients will receive Aspirin before intervention and randomization.

Outcomes

Primary Outcome Measures

Cardiac Output
L/min

Secondary Outcome Measures

Mixed venous saturation
SvO2
Pulmonary wedge pressure
PWR
Left ventricular ejection fraction
EF
Circulating prostaglandin levels
prostaglandins

Full Information

First Posted
January 8, 2021
Last Updated
December 2, 2021
Sponsor
University of Aarhus
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1. Study Identification

Unique Protocol Identification Number
NCT04703361
Brief Title
Effects of Ketones and Niacin in Heart Failure Patients
Acronym
KETO-COX
Official Title
Effects of Ketones and Niacin in Heart Failure Patients
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
February 15, 2021 (Actual)
Primary Completion Date
September 3, 2021 (Actual)
Study Completion Date
September 3, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Ketones, 3-hydroxybutyrate (3-OHB), have shown to have beneficial hemodynamics effect in patients with hearth failure with reduced ejection fraction. The mechanisms behind these marked hemodynamic effects are currently unknown, but could involve prostaglandin-release. 3-OHB is the endogenous ligand for the G protein-coupled receptor hydroxy-carboxylic acid 2 (HCA2) receptor. This receptor has proven downstream effects on cAMP and systemic effects via release of prostaglandins. In this present study we will investigate the cardiovascular effects of HCA2-receptor stimulation in heart failure patients.
Detailed Description
Heart Failure (HF) is a major public health issue because the disease affects 1-2% of the Western population and the lifetime risk of HF is 20%. HF is responsible for 1-2% of all healthcare expenditures and 5% of all hospital admissions. The cornerstone in the medical treatment of chronic HF is a combination of ACE-inhibitors/ATII-receptor antagonists, beta-blockers and mineralocorticoid receptor antagonists. Despite major improvements in the management and care of patients with HF, the 1-year mortality in patients with HF is 13 % 4 and >50% of HF-patients are admitted within a 2.5 year period 5. Furthermore, patients with HF have markedly decreased physical capacity and quality of life. Thus, there is a need for new treatment modalities in this group of patients. Ketone bodies are produced in the liver and are crucial for energy generation during fasting in the heart and brain during, exercise and severe illnesses. However, ketosis can be safely obtained using dietary supplements and can increase exercise capacity in athletes. The most important ketone bodies are 3-hydroxybutyrate (3-OHB) and acetoacetate. Recently, it was demonstrated that patients with severe HF have increased myocardial utilization of the ketone body 3-OHB. It has been hypothesized that ketone bodies may act as a "superfuel" for the failing heart. In support of this, the glucose-lowering SGLT-2 inhibitor empagliflozin reduces the risk of hospitalizations and cardiovascular death in diabetic patients with HF and also increases circulating levels of 3-OHB. By Positron Emission Tomography (PET) we have shown that ketone body infusion reduces myocardial glucose uptake and increases myocardial blood flow in healthy subjects. Data from another study conducted by our group show a 40% increase in cardiac output during infusion of 3-OHB. The mechanisms behind these marked hemodynamic effects are currently unknown, but could involve prostaglandin-release. 3-OHB is the endogenous ligand for the G protein-coupled receptor hydroxy-carboxylic acid 2 (HCA2) receptor. This receptor has proven downstream effects on cAMP and systemic effects via release of prostaglandins. 3-OHB have affinity to the HCA2 receptor and possibly a downstream effect resulting in the release of prostaglandins. The prostaglandin synthesis is dependent of cyclooxygenase (COX) enzyme, which can be inhibited by aspirin (ASA). Niacin, vitamin B3, has been used as a treatment for dyslipidemia. Niacin is also a ligand for HCA2 receptor and the downstream release of prostaglandin cause side effects such as cutaneous flushing. In this study we will investigate the cardiovascular effects of HCA2-receptor stimulation in heart failure patients. This will be done by comparing infusion of 3-OHB (preceded with ASA) and niacin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Systolic, Ketonemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Niacin
Arm Type
Experimental
Arm Description
12 patients with Heart failure with reduced ejection fraction (HFrEF) investigated with echocardiography and right heart catheterization.
Arm Title
Na-3-OHB
Arm Type
Experimental
Arm Description
12 patients with Heart failure with reduced ejection fraction (HFrEF) investigated with echocardiography and right heart catheterization. All patients will receive Aspirin before intervention and randomization.
Intervention Type
Biological
Intervention Name(s)
Placebo NaCl
Intervention Description
Placebo
Intervention Type
Biological
Intervention Name(s)
Niacin
Intervention Description
B3 vitamin, Niacin
Intervention Type
Biological
Intervention Name(s)
Na-3-OHB
Intervention Description
Na-3-OHB
Primary Outcome Measure Information:
Title
Cardiac Output
Description
L/min
Time Frame
3 hours
Secondary Outcome Measure Information:
Title
Mixed venous saturation
Description
SvO2
Time Frame
3 hours
Title
Pulmonary wedge pressure
Description
PWR
Time Frame
3 hours
Title
Left ventricular ejection fraction
Description
EF
Time Frame
3 hours
Title
Circulating prostaglandin levels
Description
prostaglandins
Time Frame
3 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chronic heart failure, Age ≥ 18 years old, LVEF ≤40%, New York Heart Association (NYHA) classification 2-3, Negative urine-HCG for women of childbearing potential, Ability to understand the written patient information and to give informed consent. Exclusion Criteria: Symptomatic cardiac valve disease, Signs or history of major myocardial infarction (STEMI) within 1 month, Insulin treatment, Other disease or treatment making subject unsuitable for study participation as judged by the investigator. Significant liver disease (defined by serum levels of alanine aminotransferase (ALAT) above 3 x upper limit of normal).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nigopan Gopalasingam, MD
Organizational Affiliation
University of Aarhus
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Henrik Wiggers, MD, PhD, DMSc
Organizational Affiliation
Aarhus University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aarhus University Hospital
City
Aarhus
ZIP/Postal Code
8200
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
No

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Effects of Ketones and Niacin in Heart Failure Patients

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