Clinical trial NCT05420285: Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction
Official title: Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction: an Exploratory Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Heart Failure
Reduced Ejection Fraction
Keywords: heart failure
HFrEF
myocardial function
fibrosis
metabolism
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-06-15
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Gliflozins have demonstrated a beneficial effect in terms of incident heart failure and related events in patients with or without diabetes. The clinical trial ICARD is an exploratory study that aims to evaluate the cardiometabolic mechanistic effects on the myocardium of dapagliflozin in heart failure with reduced ejection fraction. Deep phenotyping of cardiac and vascular function will be performed using MRI. Myocardial tissue characterization will be based on MRI and FDG-PET for glucose metabolism assessment. Liver steatosis and fibrosis will simultaneously be assessed.

Detailed description: Open-label, non-controlled clinical trial (Jardé 1) to assess the cardiovascular and metabolic effects of once-daily dapagliflozin 10 mg during 6 months in patients with heart failure and reduced ejection fraction.

Eligibility of patients addressed to the Department of Cardiology (Prof R. Isnard, Pitié-Salpêtrière Hospital, Paris, France) will be investigated at V0: inclusion and exclusion criteria will be checked and informed consent will be signed.

Up to twenty one days after V0, patients will come to the VMRI visit (VMRI) for the cardiac and liver gadolinium-injected MRI and AGE Reader (VRMI) and to the baseline visit (V1). Pregnancy will be ruled out in women of childbearing potential with blood beta-HCG. A blood test (including metabolomics and lipidomics) and FDG-PET MRI including Glucose Tolerance Test (GTT) will be performed. Dapagliflozin 10 mg once daily during six months will be prescribed.

Fifteen to twenty-one days after treatment initiation, a safety visit (V2) will take place in order to verify the tolerance.

A pre-final visit (V3) will be organized after a total of 23 weeks (± 1 week) of treatment. Pregnancy will be ruled out in women of childbearing potential with blood beta-HCG. A blood test (including metabolomics and lipidomics), ECG, trans-thoracic echocardiography (TTE), cardiac and liver MRI and AGE Reader will be performed.

After 24 weeks of treatment (6-month treatment), patients will come to the end of study visit (V4), to undergo the final FDG-PET MRI including Glucose Tolerance Test (GTT).

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* NYHA functional class II-IV.
* Previous hospitalization for heart failure anytime or NT-proBNP \>125 pg/ml in the previous 12 months
* Left ventricular ejection fraction ≤ 50% measured at least 1 time in transthoracic echocardiography in the last 12 months
* Treated by optimal medical therapy (ACE-I or angiotensin receptor blocker or sacubitril-valsartan, and betablockers, and mineralocorticoid receptor antagonist and furosemide) unless such use was contraindicated or previously associated with side-effects leading to drug discontinuation. No change in drugs dosages in the last month.
* Able to give written informed consent
* If female of childbearing potential, have a negative serum pregnancy test
* Use of a validated method of birth control until the end of the study (men and women)
* Affiliation to a social security regime

Exclusion Criteria:

* Hypersensitivity to dapagliflozin or to any of the excipients
* Current treatment with gliflozine
* Cardiac rhythm disorder including atrial fibrillation \> 100 bpm
* Significant valvular heart disease including mitral or aortic regurgitation \> II/IV
* Hospitalisation for heart failure or unplanned visit for worsening heart failure in the last month
* Recent (last 3 months) or planned coronary revascularization
* Acute coronary syndrome, stroke, or transient ischemic attack in the last 3 months
* Body mass-index \> 40 kg/m2
* Uncontrolled type 2 diabetes (Hb1AC \> 9%) or type 1 diabetes
* Genetic diabetes (Maturity Onset Diabetes of the Young, MODY)
* Current treatment for cancer, cardiotoxic cancer treatment in the last year
* Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones in the last 6 weeks
* Active infectious diseases
* Hypovolemia or dehydration, severe hypokalaemia, or severe hyponatremia
* Contraindication to MRI or to contrast agents used
* Estimated glomerular filtration rate (eGFR) \< 30 ml per minute per 1.73 m2 of body-surface area (according to the Modification of Diet in Renal Disease criteria)
* Patient on AME (state medical aid)
* Pregnant or breast-feeding female
* Current participation in another interventional study or being in the exclusion period at the end of a previous study
* Patient protected by law (guardianship, tutelage measure, deprived of liberty)

Primary outcomes:
measure: To evaluate changes in left ventricular (LV) extracellular mass index (ECMi) measured by MRI, induced by once-daily dapagliflozin 10mg during 6 months in patients with heart failure and reduced ejection fraction
timeFrame: 6 months
Secondary outcomes:
measure: To evaluate myocardial morphology
timeFrame: 6 months
measure: To evaluate myocardial morphology
timeFrame: 6 months
measure: Left ventricular ejection fraction as a biomarker of myocardial function
timeFrame: 6 months
measure: Right ventricular ejection fraction as a biomarker of myocardial function
timeFrame: 6 months
measure: Left atrial ejection fraction as a biomarker of myocardial function
timeFrame: 6 months
measure: Peak global longitudinal strain as a biomarker of myocardial function
timeFrame: 6 months
measure: Peak radial strain as a biomarker of myocardial function
timeFrame: 6 months
measure: Peak circumferential strain as a biomarker of myocardial function
timeFrame: 6 months
measure: Peak circumferential strain as a biomarker of left atrial function
timeFrame: 6 months
measure: Peak circumferential strain as a biomarker of left atrial function
timeFrame: 6 months
measure: LV myocardial dense fibrosis (late gadolinium enhancement) as a biomarker of fibrosis
timeFrame: 6 months
measure: Intracellular mass index (ICMi) as a biomarker of fibrosis
timeFrame: 6 months
measure: Extracellular mass index (ECMi) as a biomarker of fibrosis
timeFrame: 6 months
measure: To evaluate adipose tissue
timeFrame: 6 months
measure: To evaluate myocardial steatosis
timeFrame: 6 months
measure: To evaluate glucose metabolism
timeFrame: 6 months
measure: Effects of dapagliflozin therapy on the proximal aorta
timeFrame: 6 months
measure: Effects of dapagliflozin therapy on the proximal aorta
timeFrame: 6 months
measure: Effects of dapagliflozin therapy on the proximal aorta
timeFrame: 6 months
measure: Effects of dapagliflozin therapy on the proximal aorta
timeFrame: 6 months
measure: Effects of dapagliflozin therapy on the proximal aorta
timeFrame: 6 months
measure: To evaluate the evolution of body composition in multimodality imaging
timeFrame: 6 months
measure: To evaluate the changes in fasting glucagon
timeFrame: 6 months
measure: To evaluate the changes in fasting β-hydroxybutyrate
timeFrame: 6 months
measure: To evaluate the changes in fasting glycerol
timeFrame: 6 months
measure: To evaluate the changes in free fatty acid (FFA)
timeFrame: 6 months
measure: To evaluate the changes in fasting glycemia
timeFrame: 6 months
measure: To evaluate the subcutaneous tissue Advanced end-Glycation Products (AGE)
timeFrame: 6 months
measure: Evaluation of pathophysiological changes at the molecular level (metabolite profiling)
timeFrame: 6 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Pitié-Salpêtrière Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Alban REDHEUIL, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: