ICARD: Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05420285

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure Reduced Ejection Fraction	Drug: Dapagliflozin	Phase 2

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) or the Department of Diabetology and Metabolism (Prof F. Andreelli, 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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

May 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin Dapagliflozin is taken orally, once daily at the dosage of 10 mg during 6 months.	Drug: Dapagliflozin Dapagliflozin (Forxiga) is a very potent selective and reversible inhibitor of SGLT2. Other Names: Forxiga

Arm

Intervention/Treatment

Experimental: Dapagliflozin

Dapagliflozin is taken orally, once daily at the dosage of 10 mg during 6 months.

Drug: Dapagliflozin

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

Other Names:

Forxiga

Outcome Measures

Primary Outcome Measures

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 [6 months]
MRI measurement of changes in left ventricular extracellular mass index (ECMI) after a 6-month once-daily dapagliflozin 10 mg regimen

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years
NYHA functional class II-III.
NT-proBNP > 600 pg/ml (> 400 pg/ml if hospitalized for heart failure in the previous 12 months)
Left ventricular ejection fraction ≤ 40% measured in transthoracic echocardiography in the 6 last 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.
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).
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 > 60 bpm
Significant valvular heart disease > II/IV
Hospitalisation for heart failure or unplanned visit for worsening heart failure in the last 3 months
Recent (last 6 months) or planned coronary revascularization
Cardiac resynchronization in the last 6 months
Acute coronary syndrome, stroke, or transient ischemic attack in the last 2 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)
Medical history of cancer (other than basal cell carcinoma) and/or treatment for cancer in the last 5 years
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
Left ventricular ejection fraction ≥ 55% measured in the routine transthoracic echocardiography
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)