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

Primary Purpose

Heart Failure, Reduced Ejection Fraction

Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Dapagliflozin
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring heart failure, HFrEF, myocardial function, fibrosis, metabolism

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept 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)

Sites / Locations

  • Pitié-Salpêtrière HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dapagliflozin

Arm Description

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

Outcomes

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

Full Information

First Posted
May 12, 2022
Last Updated
December 7, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT05420285
Brief Title
Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction
Acronym
ICARD
Official Title
Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction: an Exploratory Study
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 26, 2022 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
May 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. 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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Reduced Ejection Fraction
Keywords
heart failure, HFrEF, myocardial function, fibrosis, metabolism

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dapagliflozin
Arm Type
Experimental
Arm Description
Dapagliflozin is taken orally, once daily at the dosage of 10 mg during 6 months.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Other Intervention Name(s)
Forxiga
Intervention Description
Dapagliflozin (Forxiga) is a very potent selective and reversible inhibitor of SGLT2.
Primary Outcome Measure Information:
Title
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
Description
MRI measurement of changes in left ventricular extracellular mass index (ECMI) after a 6-month once-daily dapagliflozin 10 mg regimen
Time Frame
6 months
Secondary Outcome Measure Information:
Title
To evaluate myocardial morphology
Description
MRI measurement of change: Left and right ventricular volumes and Left atrial volumes
Time Frame
6 months
Title
To evaluate myocardial morphology
Description
MRI measurement of change: LV mass
Time Frame
6 months
Title
Left ventricular ejection fraction as a biomarker of myocardial function
Description
MRI measurement of change of left ventricular ejection fraction
Time Frame
6 months
Title
Right ventricular ejection fraction as a biomarker of myocardial function
Description
MRI measurement of change of right ventricular ejection fraction
Time Frame
6 months
Title
Left atrial ejection fraction as a biomarker of myocardial function
Description
MRI measurement of change of left atrial ejection fraction
Time Frame
6 months
Title
Peak global longitudinal strain as a biomarker of myocardial function
Description
MRI measurement of change of peak global LV longitudinal strain
Time Frame
6 months
Title
Peak radial strain as a biomarker of myocardial function
Description
MRI measurement of change of peak radial LV strain
Time Frame
6 months
Title
Peak circumferential strain as a biomarker of myocardial function
Description
MRI measurement of change of peak circumferential LV strain
Time Frame
6 months
Title
Peak circumferential strain as a biomarker of left atrial function
Description
MRI measurement of change of peak circumferential LA strain (reservoir)
Time Frame
6 months
Title
Peak circumferential strain as a biomarker of left atrial function
Description
MRI measurement of change of peak circumferential LA strain (booster)
Time Frame
6 months
Title
LV myocardial dense fibrosis (late gadolinium enhancement) as a biomarker of fibrosis
Description
MRI measurement of change of LV myocardial dense fibrosis (late gadolinium enhancement mass)
Time Frame
6 months
Title
Intracellular mass index (ICMi) as a biomarker of fibrosis
Description
MRI measurement of change of intracellular mass index (ICMi)
Time Frame
6 months
Title
Extracellular mass index (ECMi) as a biomarker of fibrosis
Description
MRI measurement of change of extracellular mass index (ECMi)
Time Frame
6 months
Title
To evaluate adipose tissue
Description
MRI measurement of change: epicardial adipose tissue (EAT) and steatosis (triglyceride fraction)
Time Frame
6 months
Title
To evaluate myocardial steatosis
Description
1H-MR spectromscopy measurement of modifications of relative myocardial triglyceride content.
Time Frame
6 months
Title
To evaluate glucose metabolism
Description
18FDG-PET-MRI measurement of change with glucose uptake analysis
Time Frame
6 months
Title
Effects of dapagliflozin therapy on the proximal aorta
Description
High resolution cine aortic MRI measurement of ascending aortic areas
Time Frame
6 months
Title
Effects of dapagliflozin therapy on the proximal aorta
Description
High resolution cine aortic MRI measurement of descending aortic areas
Time Frame
6 months
Title
Effects of dapagliflozin therapy on the proximal aorta
Description
High resolution cine aortic MRI measurement of ascending aortic distensibility
Time Frame
6 months
Title
Effects of dapagliflozin therapy on the proximal aorta
Description
High resolution cine aortic MRI measurement of descending aortic distensibility
Time Frame
6 months
Title
Effects of dapagliflozin therapy on the proximal aorta
Description
High resolution cine aortic MRI measurement of aortic arch pulse wave velocity (PWV)
Time Frame
6 months
Title
To evaluate the evolution of body composition in multimodality imaging
Description
MRI measurement of change in abdominal subcutaneous and visceral fat using the ATQUA method on DIXON MRI images
Time Frame
6 months
Title
To evaluate the changes in fasting glucagon
Description
Blood measurement change in glucagon
Time Frame
6 months
Title
To evaluate the changes in fasting β-hydroxybutyrate
Description
Blood measurement change in β-hydroxybutyrate
Time Frame
6 months
Title
To evaluate the changes in fasting glycerol
Description
Blood measurement change in glycerol
Time Frame
6 months
Title
To evaluate the changes in free fatty acid (FFA)
Description
Blood measurement change in free fatty acid (FFA)
Time Frame
6 months
Title
To evaluate the changes in fasting glycemia
Description
Blood measurement change in glycemia
Time Frame
6 months
Title
To evaluate the subcutaneous tissue Advanced end-Glycation Products (AGE)
Description
Measurement of the value of AGE on AGE reader
Time Frame
6 months
Title
Evaluation of pathophysiological changes at the molecular level (metabolite profiling)
Description
Blood measurement of targeted metabolites by LC-MS (Liquid chromatography coupled to mass spectrometry) and by GC-MS (Gas chromatography coupled to mass spectrometry)
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alban REDHEUIL, MD PhD
Phone
+33(0)1.42.16.55.45
Email
alban.redheuil@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Fabrizio ANDREELLI, MD PhD
Phone
33(0)1.42.17.80.59
Email
fabrizio.andreelli@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alban REDHEUIL, MD PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Pitié-Salpêtrière Hospital
City
Paris
ZIP/Postal Code
75013
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alban REDHEUIL, MD PhD
Phone
+33(0)1.42.16.55.45
Email
alban.redheuil@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

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

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