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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Reduced Ejection Fraction
• Intervention / Treatment: Drug: Dapagliflozin

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).

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alban REDHEUIL, MD PhD; Phone Number: +33(0)1.42.16.55.45; Email: alban.redheuil@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • Pitié-Salpêtrière Hospital
    • Contact: Alban REDHEUIL, MD PhD; Phone Number: +33(0)1.42.16.55.45; Email: alban.redheuil@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate myocardial morphology	MRI measurement of change: Left and right ventricular volumes and Left atrial volumes	6 months
To evaluate myocardial morphology	MRI measurement of change: LV mass	6 months
Left ventricular ejection fraction as a biomarker of myocardial function	MRI measurement of change of left ventricular ejection fraction	6 months
Right ventricular ejection fraction as a biomarker of myocardial function	MRI measurement of change of right ventricular ejection fraction	6 months
Left atrial ejection fraction as a biomarker of myocardial function	MRI measurement of change of left atrial ejection fraction	6 months
Peak global longitudinal strain as a biomarker of myocardial function	MRI measurement of change of peak global LV longitudinal strain	6 months
Peak radial strain as a biomarker of myocardial function	MRI measurement of change of peak radial LV strain	6 months
Peak circumferential strain as a biomarker of myocardial function	MRI measurement of change of peak circumferential LV strain	6 months
Peak circumferential strain as a biomarker of left atrial function	MRI measurement of change of peak circumferential LA strain (reservoir)	6 months
Peak circumferential strain as a biomarker of left atrial function	MRI measurement of change of peak circumferential LA strain (booster)	6 months
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
Intracellular mass index (ICMi) as a biomarker of fibrosis	MRI measurement of change of intracellular mass index (ICMi)	6 months
Extracellular mass index (ECMi) as a biomarker of fibrosis	MRI measurement of change of extracellular mass index (ECMi)	6 months
To evaluate adipose tissue	MRI measurement of change: epicardial adipose tissue (EAT) and steatosis (triglyceride fraction)	6 months
To evaluate myocardial steatosis	1H-MR spectromscopy measurement of modifications of relative myocardial triglyceride content.	6 months
To evaluate glucose metabolism	18FDG-PET-MRI measurement of change with glucose uptake analysis	6 months
Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of ascending aortic areas	6 months
Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of descending aortic areas	6 months
Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of ascending aortic distensibility	6 months
Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of descending aortic distensibility	6 months
Effects of dapagliflozin therapy on the proximal aorta	High resolution cine aortic MRI measurement of aortic arch pulse wave velocity (PWV)	6 months
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
To evaluate the changes in fasting glucagon	Blood measurement change in glucagon	6 months
To evaluate the changes in fasting β-hydroxybutyrate	Blood measurement change in β-hydroxybutyrate	6 months
To evaluate the changes in fasting glycerol	Blood measurement change in glycerol	6 months
To evaluate the changes in free fatty acid (FFA)	Blood measurement change in free fatty acid (FFA)	6 months
To evaluate the changes in fasting glycemia	Blood measurement change in glycemia	6 months
To evaluate the subcutaneous tissue Advanced end-Glycation Products (AGE)	Measurement of the value of AGE on AGE reader	6 months
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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Alban REDHEUIL, MD PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2022
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): May 1, 2024

Study Registration Dates

• First Submitted: May 12, 2022
• First Submitted That Met QC Criteria: June 14, 2022
• First Posted (Actual): June 15, 2022

Study Record Updates

• Last Update Posted (Estimate): December 9, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: heart failure; metabolism; fibrosis; HFrEF; myocardial function
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: APHP210166; 2021-000481-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Data are available upon reasonable request. The procedures carried out with the French data privacy authority (CNIL, Commission Nationale de l'Informatique et des Libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No