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    Summary
    EudraCT Number:2021-000481-14
    Sponsor's Protocol Code Number:APHP210166
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-10-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2021-000481-14
    A.3Full title of the trial
    Cardiometabolic effects of dapagliflozin in heart failure with reduced ejection fraction: an exploratory study.
    Les effets cardiométaboliques de la dapagliflozine dans l’insuffisance cardiaque à fraction d’éjection réduite.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Imaging Cardiometabolism in heart failure patients receiving Dapagliflozin
    Imagerie du cardiométabolisme chez les patients insuffisants cardiaques recevant de la dapagliflozine
    A.3.2Name or abbreviated title of the trial where available
    ICARD
    A.4.1Sponsor's protocol code numberAPHP210166
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAssistance Publique – Hôpitaux de Paris (AP-HP)
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstrazeneca
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAssistance Publique – Hôpitaux de Paris (AP-HP)
    B.5.2Functional name of contact pointclinical trial informations
    B.5.3 Address:
    B.5.3.1Street Address1, avenue Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+330142161685
    B.5.5Fax number+330142162440
    B.5.6E-mailtouria.el-aamri@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Forxiga (Dapagliflozin)
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart failure with reduced ejection fraction
    Insuffisance cardiaque avec fraction d'éjection réduite
    E.1.1.1Medical condition in easily understood language
    Heart failure
    Insuffisance cardiaque
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate changes in left ventricular (LV) extracellular mass index (ECMi) measured by MRI, induced by once-daily dapagliflozin 10 mg during 6 months in patients with heart failure and reduced ejection fraction.
    Evaluer par IRM les changements de l'indice de masse extracellulaire (iMEC) du ventriculaire gauche (VG) induits par la dapagliflozine 10 mg une fois par jour pendant 6 mois chez des patients atteints d'insuffisance cardiaque à fraction d'éjection réduite.
    E.2.2Secondary objectives of the trial
    Describe the magnitude and relationships between changes in multiorgan (heart, liver, abdominal adipose) tissue characteristics (dense & interstitial fibrosis and fat) during dapagliflozin administration.
    Décrire l'ampleur et les relations entre les modifications des caractéristiques des tissus (fibrose dense et interstitielle et graisse) multi-organes (cœur, foie, tissu adipeux abdominal) au cours de l'administration de la dapagliflozine.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 and agree to use a validated method of birth control
    -Affiliation to a social security regime
    - Age ≥ 18 ans
    - NYHA classe II-III.
    - NT-proBNP > 600 pg/ml (> 400 pg/ml si hospitalisation pour insuffisance cardiaque dans les 12 derniers mois)
    - Fraction d'éjection ventriculaire gauche ≤ 40% mesurée en échocardiographie transthoracique dans les 6 derniers mois
    - Traitement médical optimal (IEC ou inhibiteur des récepteurs de l'angiotensine ou sacubitril-valsartan, bêtabloquants, antagoniste des récepteurs minéralocorticoïdes et furosémide) sauf si cette utilisation était contre-indiquée ou précédemment associée à des effets secondaires conduisant à l'arrêt du médicament. Aucun changement dans les dosages des médicaments au cours du dernier mois.
    - Débit de filtration glomérulaire (eGFR) estimé ≥ 30 ml par minute pour 1,73 m2 de surface corporelle (selon les critères MDRD).
    - Capacité de donner un consentement éclairé écrit
    - Si femme en âge de procréer, test de grossesse sérique négatif et méthode de contraception efficace
    -Affiliation à un régime de sécurité sociale
    E.4Principal exclusion criteria
    -Hypersensitivity to dapagliflozin or to any of the excipients
    -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
    -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
    -Hypersensibilité à la dapagliflozine ou à l'un des excipients
    -Trouble du rythme cardiaque y compris fibrillation auriculaire > 60 bpm
    - Cardiopathie valvulaire importante > II/IV
    -Hospitalisation pour insuffisance cardiaque ou visite imprévue pour aggravation de l'insuffisance cardiaque au cours des 3 derniers mois
    -Revascularisation coronaire récente (6 derniers mois) ou planifiée
    -Resynchronisation cardiaque au cours des 6 derniers mois
    -Syndrome coronarien aigu, accident vasculaire cérébral ou accident ischémique transitoire au cours des 2 derniers mois
    -Indice de masse corporelle > 40 kg/m2
    -Diabète de type 2 non contrôlé (Hb1AC > 9 %) ou diabète de type 1
    -Diabète génétique (Maturity Onset Diabetes of the Young, MODY)
    -Antécédents médicaux de cancer (autre que le carcinome basocellulaire) et/ou traitement pour un cancer au cours des 5 dernières années
    -Traitement avec des stéroïdes systémiques au moment du consentement éclairé ou changement de dosage des hormones thyroïdiennes au cours des 6 dernières semaines
    -Maladies infectieuses actives
    -Hypovolémie ou déshydratation, hypokaliémie sévère ou hyponatrémie sévère
    -Contre-indication à l'IRM ou aux produits de contraste utilisés
    -Patient sous AME (aide médicale de l'Etat)
    -Femme enceinte ou allaitante
    -Participation actuelle à une autre étude interventionnelle ou être en période d'exclusion à la fin d'une étude précédente
    E.5 End points
    E.5.1Primary end point(s)
    MRI measurement of changes in left ventricular extracellular mass index (ECMI) after a 6-month once-daily dapagliflozin 10 mg regimen
    Mesure par IRM des modifications de l'indice de masse extracellulaire du ventricule gauche après un apport de 10 mg de dapagliflozine une fois par jour pendant 6 mois.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 6 months of treatment with dapagliflozin (10mg once daily) - visit V4.
    Après 6 mois de traitement par la dapagliflozine (10 mg une fois par jour) - visite V4.
    E.5.2Secondary end point(s)
    Myocardial endpoints:
    ● Morphology and Function: Left and right ventricular volumes and LV mass; Left atrial volumes; Left and right ventricular and atrial ejection fraction; Peak global longitudinal, radial and circumferential LV and left atrial (LA) strain.
    ● MRI Tissue analysis and metabolism: LV myocardial water content, dense and interstitial fibrosis (late gadolinium enhancement and T1 mapping indices: native T1, extra cellular volume (ECV), intracellular mass index (ICMi)), epicardial adipose tissue (EAT) and steatosis (triglyceride fraction)
    ● to elucidate how changes in myocardial extracellular content and improvements in cardiac contractility may be related to a metabolic switch in the heart, we will study how dapagliflozin treatment modifies relative myocardial water/fat content using H1-MR spectroscopy.
    ● glucose metabolism with glucose uptake analysis using 18FDG-PET-MRI.
    Vascular endpoints:
    The effects of dapagliflozin therapy on the proximal aorta will be studied using high resolution aortic MRI combined with central pressures measured non-invasively. The studied vascular parameters will be:
    ● ascending and descending aortic areas
    ● ascending and descending aortic distensibility
    ● aortic arch PWV.

    Metabolic endpoints
    ● Evolution of body composition in multimodality imaging: abdominal subcutaneous and visceral fat in MRI using the ATQUA method (ICAN) and liver steatosis (Dixon MRI and H1-MRS).
    ● Changes in fasting glucagon, β−hydroxybutyrate, glycerol, free fatty acid (FFA) and glucose metabolism.
    ● Subcutaneous tissue advanced end-glycation products quantifications using AGE reader. Study of the associations between the various imaging parameters and the non invasive measurement of glycated proteins in the subcutaneous tissue will be performed.

    Metabolomic study
    ● targeted metabolomics in blood.
    Paramètres myocardiques :
    ● Morphologie et fonction : volumes ventriculaires gauche et droit et masse VG ; volumes auriculaires gauches ; fraction d'éjection ventriculaire gauche et droite et auriculaire ; déformation globale maximale longitudinale, radiale et circonférentielle du VG et de l'oreillette gauche (OG).
    ● Analyse tissulaire et métabolisme par IRM : teneur en eau myocardique du VG, fibrose dense et interstitielle (rehaussement tardif du gadolinium et indices de cartographie T1 : T1 natif, T1 post contraste, volume extracellulaire (VEC), indice de masse intracellulaire (iMIC)) ; tissu adipeux épicardique (TAE) et stéatose (fraction des triglycérides)
    ● pour élucider comment les modifications du contenu extracellulaire du myocarde et les améliorations de la contractilité cardiaque peuvent être liées à un changement métabolique dans le cœur, nous étudierons comment le traitement par la dapagliflozine modifie la teneur relative en eau/graisse du myocarde en utilisant la spectroscopie H1-MR.
    ● analyse du métabolisme du glucose avec analyse de la captation du glucose par 18FDG-TEP-IRM
    Paramètres vasculaires :
    Les effets du traitement par la dapagliflozine sur l'aorte proximale seront étudiés grâce à une IRM aortique à haute résolution combinée à des pressions centrales mesurées de manière non invasive. Les paramètres vasculaires étudiés seront :
    ● aires aortiques ascendantes et descendantes
    ● distensibilité aortique ascendante et descendante
    ● VOP dans la crosse aortique

    Paramètres métaboliques :
    ● Evolution de la composition corporelle en imagerie multimodale : graisse abdominale sous-cutanée et viscérale en IRM selon la méthode ATQUA (ICAN) et stéatose hépatique (IRM Dixon et H1-MRS).
    ● Modifications du métabolisme à jeun (glucagon, β−hydroxybutyrate, glycérol, acides gras libres (AGL) et glucose).
    ● Quantifications des produits de glycation avancée du tissu sous-cutané à l'aide de l’AGE reader. Etude des associations entre les différents paramètres d'imagerie et la mesure non invasive des protéines glyquées dans le tissu sous-cutané sera réalisée.
    Étude métabolomique
    ● métabolomique ciblée dans le sang.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6 months of treatment
    Après 6 mois de traitement
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is the last visit of the last subject.
    La fin de la recherche est la dernière visite du dernier patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months24
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Normal treatment of that condition
    Traitement standard pour cette pathologie
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-20
    P. End of Trial
    P.End of Trial StatusCompleted
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