Clinical trial NCT06108076: Acute and Chronic Effects of Oral Ketones in Subjects With HFrEF and Diabetes
Official title: Acute and Chronic Effects of Oral Ketones in Subjects With HFrEF and Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Type 2 Diabetes
Heart Failure, Reduced Ejection Fraction
Keywords: Ketone esters
Cardiopulmonary benefits
Left Ventricular function
Stroke volume
Cardiac output
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2023-10-30
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label, pilot trial
Primary purpose: TREATMENT

Brief summary: This study will provide insight into whether cardiac function changes with oral Ketone Esters (KE) administered to patients with Type 2 Diabetes Mellitus (T2DM) and Heart failure with reduced ejection fraction (HFrEF). Plasma ketones are avidly extracted by cardiac muscle and their uptake is not dependent upon insulin or influenced by insulin resistance.

Detailed description: After the screening visit, subject will take two separate doses of oral ketones during visit two. Subjects will have their first dose (400mg/kg) upon completion of the baseline Magnetic Resonance Imaging (MRI), and then a second dose (400mg/kg) approximately 1.5 hours after their consumption of the 1st dose. Approximately 1.5 hours after their second dose (3hr since first dose), the subject will undergo a second cardiac MRI. Baseline Blood samples of Beta-hydroxybutyrate (BOHB), acetoacetate (ACAC), Free Fatty Acids (FFA), insulin, c-peptide, glucagon, and an additional 10ml (for storage and later analysis) will be drawn prior to their first dose, then every 30 minutes after their first dose, until completion of the second MRI, then a final blood draw upon completion of the MRI for a total of 8 blood draws during visit 2. An IV catheter will be placed into one antecubital vein by a study nurse for all blood draws during visit 2.

The subject will then be asked to return to complete a third MRI approximately 24 hours after their second MRI. Blood samples for BOHB, acetoacetate (ACAC), insulin, c-peptide and glucagon, and an additional 10 ml will be drawn prior to their third MRI. An IV catheter will be placed into one antecubital vein by a study nurse for all blood draws during visit 3.

After completion of the third MRI, subjects will be dosed KE 400mg/kg once daily until the visit 4 MRI can be completed.

Blood samples for BOHB, acetoacetate (ACAC), insulin, c-peptide, glucagon, proBNP, and an additional 10 ml will be drawn prior to their fourth MRI. An IV catheter will be placed into one antecubital vein by a study nurse for all blood draws during visit 4. The 4th MRI, based on subject and scanner availability at approximately Day 7

Eligibility criteria: Inclusion Criteria:

* Subjects must be on a stable dose of guideline-directed medications for Heart Failure (HF).
* Patients will have an established diagnosis of HF before the screening visit, documented by an acceptable imaging modality in the last 6 months.
* Age = 18-80 y
* Body Mass Index (BMI) =23-38 kg/m2
* Glycated hemoglobin (HbA1c) = 6.0-10.0%
* Blood Pressure (BP) \< 145/85 mmHg
* Estimated Glomerular Filtration Rate (eGFR) \> 30 ml/min•1.73 m2
* For women of child-bearing age (WOCBA) willingness to use contraception, if applicable.

Exclusion Criteria:

* Patients treated with Sodium-Glucose Transport Protein (SGLT2i's) or medications that may impair heart function or acutely worsen glycemic control will be excluded.
* Pregnancy, lactation, or plans to become pregnant. A negative pregnancy test will be performed before each Magnetic resonance imaging (MRI) study to assess current status.
* Allergy/sensitivity to study drugs or their ingredients.
* Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
* Subjects with a history of cancer (except basal or squamous cell cancer that has been resolved/remission for 5 years)
* Cardiovascular event within the last 3 months
* Major organ or metabolic diseases, or physical limitations that will not allow the subject to complete the study.

Primary outcomes:
measure: Cardiac Efficiency after acute dose (Left-ventricular function)
timeFrame: 1.5 hours to 24 hours
measure: Cardiac Efficiency after chronic dosing (Left-ventricular function)
timeFrame: 1.5 hours to 7 days
Secondary outcomes:
measure: Six minute walk test
timeFrame: Baseline to 7 days
measure: Acetoacetate
timeFrame: Baseline to 7 days
measure: Glucose
timeFrame: Baseline to 7 days
measure: Free Fatty Acids (FFAs)
timeFrame: Baseline to 7 days
measure: Insulin/C-peptide
timeFrame: Baseline to 7 days
measure: Glucagon
timeFrame: Baseline to 7 days
measure: Beta-hydroxybutyrate
timeFrame: Baseline to 7 days
measure: Patient Reported Outcomes Measure Information System (PROMIS) - Physical Function
timeFrame: Baseline to 7 days
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: University of Texas Health Science Center San Antonio
name: Carolina Solis-Herrera, MD
role: PRINCIPAL_INVESTIGATOR
References: