Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction

Heart Failure Clinical Trial

— ICARD  

Official title:

Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction: an Exploratory Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05420285
• Other study ID #: APHP210166
• Secondary ID: 2021-000481-14
• Status: Recruiting
• Phase: Phase 2
• Start date: June 26, 2022
• Est. completion date: May 2024

Study information

• Verified date: February 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Alban REDHEUIL, MD PhD
• Phone: +33(0)1.42.16.55.45
• Email: alban.redheuil[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: May 2024
• Est. primary completion date: September 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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)

Related Conditions & MeSH terms

• Heart Failure
• Reduced Ejection Fraction

Intervention

Drug:
• Dapagliflozin
Dapagliflozin (Forxiga) is a very potent selective and reversible inhibitor of SGLT2.

Locations

Country	Name	City	State
France	Pitié-Salpêtrière Hospital	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	MRI measurement of changes in left ventricular extracellular mass index (ECMI) after a 6-month once-daily dapagliflozin 10 mg regimen	6 months
Secondary	To evaluate myocardial morphology	MRI measurement of change: Left and right ventricular volumes and Left atrial volumes	6 months
Secondary	To evaluate myocardial morphology	MRI measurement of change: LV mass	6 months
Secondary	Left ventricular ejection fraction as a biomarker of myocardial function	MRI measurement of change of left ventricular ejection fraction	6 months
Secondary	Right ventricular ejection fraction as a biomarker of myocardial function	MRI measurement of change of right ventricular ejection fraction	6 months
Secondary	Left atrial ejection fraction as a biomarker of myocardial function	MRI measurement of change of left atrial ejection fraction	6 months
Secondary	Peak global longitudinal strain as a biomarker of myocardial function	MRI measurement of change of peak global LV longitudinal strain	6 months
Secondary	Peak radial strain as a biomarker of myocardial function	MRI measurement of change of peak radial LV strain	6 months
Secondary	Peak circumferential strain as a biomarker of myocardial function	MRI measurement of change of peak circumferential LV strain	6 months
Secondary	Peak circumferential strain as a biomarker of left atrial function	MRI measurement of change of peak circumferential LA strain (reservoir)	6 months
Secondary	Peak circumferential strain as a biomarker of left atrial function	MRI measurement of change of peak circumferential LA strain (booster)	6 months
Secondary	LV myocardial dense fibrosis (late gadolinium enhancement) as a biomarker of fibrosis	MRI measurement of change of LV myocardial dense fibrosis (late gadolinium enhancement mass)	6 months
Secondary	Intracellular mass index (ICMi) as a biomarker of fibrosis	MRI measurement of change of intracellular mass index (ICMi)	6 months
Secondary	Extracellular mass index (ECMi) as a biomarker of fibrosis	MRI measurement of change of extracellular mass index (ECMi)	6 months
Secondary	To evaluate adipose tissue	MRI measurement of change: epicardial adipose tissue (EAT) and steatosis (triglyceride fraction)	6 months
Secondary	To evaluate myocardial steatosis	1H-MR spectromscopy measurement of modifications of relative myocardial triglyceride content.	6 months
Secondary	To evaluate glucose metabolism	18FDG-PET-MRI measurement of change with glucose uptake analysis	6 months
Secondary	Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of ascending aortic areas	6 months
Secondary	Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of descending aortic areas	6 months
Secondary	Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of ascending aortic distensibility	6 months
Secondary	Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of descending aortic distensibility	6 months
Secondary	Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of aortic arch pulse wave velocity (PWV)	6 months
Secondary	To evaluate the evolution of body composition in multimodality imaging	MRI measurement of change in abdominal subcutaneous and visceral fat using the ATQUA method on DIXON MRI images	6 months
Secondary	To evaluate the changes in fasting glucagon	Blood measurement change in glucagon	6 months
Secondary	To evaluate the changes in fasting ß-hydroxybutyrate	Blood measurement change in ß-hydroxybutyrate	6 months
Secondary	To evaluate the changes in fasting glycerol	Blood measurement change in glycerol	6 months
Secondary	To evaluate the changes in free fatty acid (FFA)	Blood measurement change in free fatty acid (FFA)	6 months
Secondary	To evaluate the changes in fasting glycemia	Blood measurement change in glycemia	6 months
Secondary	To evaluate the subcutaneous tissue Advanced end-Glycation Products (AGE)	Measurement of the value of AGE on AGE reader	6 months
Secondary	Evaluation of pathophysiological changes at the molecular level (metabolite profiling)	Blood measurement of targeted metabolites by LC-MS (Liquid chromatography coupled to mass spectrometry) and by GC-MS (Gas chromatography coupled to mass spectrometry)	6 months