Clinical Trials Register

Summary
EudraCT Number:	2019-002046-20
Sponsor's Protocol Code Number:	FIBHGM-ECNC001-2019
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-21
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2019-002046-20

A.3

Full title of the trial

Effects of SGLT2 inhibition on the mechanisms of cardiac damage in the diabetic patient with HFpEF.-CARDIA-STIFF.

Efectos de la inhibición del cotransportador sodio-glucosa-2 sobre los mecanismos de la insuficiencia cardiaca con fracción de eyección preservada del paciente diabético”-CARDIA-STIFF

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Effects of dapagliflozin inhibition on the mechanisms of cardiac damage in the diabetic patient with HFpEF.-CARDIA-STIFF

Efectos de la dapagliflozina sobre los mecanismos de la insuficiencia cardiaca con fracción de eyección preservada del paciente diabético”-CARDIA-STIFF

A.3.2

Name or abbreviated title of the trial where available

CARDIA-STIFF

A.4.1

Sponsor's protocol code number

FIBHGM-ECNC001-2019

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Fundación para la Innovación en Biomedicina-FIBMED
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Instituto de Salud Carlos III
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Fundación para la Investigación Biomédica del Hospital Gregorio Marañón-FIBHGM
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Funndación para la Innovación en Biomedicina-FIBMED
B.5.2	Functional name of contact point	Clinical trial
B.5.3	Address:
B.5.3.1	Street Address	calle velazquez 25, 2A
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28001
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034917123580
B.5.6	E-mail	gerencia@fibmed.org

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Forxiga 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	ASTRAZENECA AB
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dapagliflozin propanediol monohydrate
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN
D.3.9.4	EV Substance Code	SUB31650
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Diabetes mellitus type 2 and Heart Failure with preserved Ejection Fraction.

pacientes con diabetes de tipo 2 e insuficiencia cardíaca con fracción de eyección preservada

E.1.1.1

Medical condition in easily understood language

Diabetic patients with Heart failure

Pacientes diabéticos con insuficiencia cardíaca

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main aim of this study is to identify the underlying mechanisms of iSGLT2, which are associated to better outcomes in HFpEF and DM2.

El objetivo general del proyecto es identificar los mecanismos biológicos y biomecánicos responsables del beneficio cardiovascular de los iSGLT2 en pacientes diabéticos con ICFEP.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Characterization of one cohort from CARDIA-STIFF:
1. To study the differences in the relative contribution of the intrinsic diastolic properties of the ventricular chamber and of the flow patterns on filling pressures of diabetic patients with HFpEF with and without DM2.
2. To study the structural and biomechanical alterations that characterize the ICFEP in patients with DM2 vs the non-DM2. Alterations in cardiomyocytes, interstitial and perivascular fibrosis and the degree of cross-linking of collagen, alterations in the microvasculature (blood and lymphatic) including rarefaction and endothelial dysfunction, as well as inflammation will be evaluated.
3. To compare the histological, molecular, biochemical and biomechanical characteristics of HFpEF of patients with and without DM2. Histological, molecular and biochemical variables obtained by cardiac biopsy and blood biomarkers will be compared, analyzing the different components of the myocardium: cardiomyocytes, extracellular matrix, intramyocardial microvasculature and inflammation. Likewise, the biomechanical properties obtained by dynamic pressure-volume catheterization (elastic recoil, relaxation, rigidity, systolic elastance) will be analyzed.
4. To compare the relative contribution of the intrinsic diastolic properties of the ventricular chamber (relaxation, stiffness and elastic recoil), and of the flow patterns on filling pressures of patients with HFpEF and with and without DM2.
5. Characterize the histological patterns of myocardial remodeling in endomyocardial biopsies of patients with HFpEF with and without DM and correlate them with non-invasive patterns of cardiac remodeling.

Cohorte de caracterización del CARDIA-STIFF:
1. Estudiar las diferencias en la contribución relativa de las propiedades diastólicas intrínsecas de la cámara ventricular y de los patrones de flujo sobre las presiones de llenado de los pacientes diabéticos con ICFEP con y sin DM2.
2. Estudiar las alteraciones estructurales y biomecánicas que caracterizan la ICFEP del paciente diabético frente al no diabético. Se evaluarán las alteraciones en los cardiomiocitos, la fibrosis intersticial y perivascular y el grado de entrecruzamiento del colágeno, las alteraciones en la microvasculatura (sanguínea y linfática) incluyendo rarefacción y disfunción endotelial, así como la inflamación.
3. Comparar las características histológicas, moleculares, bioquímicas y biomecánicas de la ICFEP de los pacientes con y sin DM2. Se compararán variables histológicas, moleculares y bioquímicas obtenidas mediante biopsia cardiaca y biomarcadores en sangre, analizando los distintos componentes del miocardio: cardiomiocitos, matriz extracelular, microvasculatura intramiocárdica e inflamación. Igualmente, se analizarán las propiedades biomecánicas obtenidas mediante cateterismo dinámico de presión-volumen (retroceso elástico, relajación, rigidez, elastancia sistólica).
4. Comparar la contribución relativa de las propiedades diastólicas intrínsecas de la cámara ventricular (relajación, rigidez y retroceso elástico), y de los patrones de flujo sobre las presiones de llenado de los pacientes con ICFEP y con y sin DM2.
5. Caracterizar los patrones histológicos del remodelado miocárdico en biopsias endomiocárdicas de los pacientes con ICFEP con y sin DM y correlacionarlos con patrones no invasivos de remodelado cardíaco.

E.3

Principal inclusion criteria

- Both female and male adults between the ages of 18 and 75.
• Diagnosis of DM2 based on the established criteria: HbA1c ≥ 6.5% (48 mmol / mol) and fasting plasma glucose ≥ 7.0 mmol / L (≥126 mg / dL) or 2-h after overload ≥ 11.1 mmol / L ( ≥ 200 mg / dL).
• LVEF ≥ 50%.
• Diagnosis of ICFEP according to clinical criteria, with a hospital admission in the previous 6 months with demonstration of diastolic dysfunction according to the echocardiographic criteria.
• Stable clinical situation (> 1 month after hospitalization due to IC decompensation).
• Clinical indication of cardiac catheterization.
• Signature of informed consent.

• Adultos de ambos sexos con edad comprendida entre los 18 y 75 años.
• Diagnóstico de DM2 en base a los criterios establecidos: HbA1c ≥ 6.5% (48 mmol/mol) y glucosa plasmática en ayunas ≥ 7.0 mmol/L (≥126 mg/dL) o 2-h tras sobrecarga ≥ 11.1 mmol/L (≥ 200 mg/dL).
• FEVI ≥ 50%.
• Diagnóstico de ICFEP conforme a criterios clínicos, con un ingreso hospitalario en los 6 meses previos con demostración de disfunción diastólica según los criterios ecocardiográficos.
• Situación clínica estable (> 1 mes tras hospitalización por descompensación por IC).
• Indicación clínica de cateterismo cardíaco.
• Firma del consentimiento informado.

E.4

Principal exclusion criteria

• Previous treatment with iSGLT2.
• Significant coronary disease.
• Aortic or mitral valve disease ≥ moderate (grades 3 or 4/4 for valve regurgitations)
• Contraindications for dapagliflozin treatment according to the data sheet (hereditary galactose intolerance, Lapp lactase insufficiency or glucose-galactose malabsorption, moderate-severe renal failure -CrCl <60 ml / min or eGFR <60 ml / min / 1 , 73 m2-, severe hepatic insufficiency).

• Tratamiento previo con iSGLT2.
• Enfermedad coronaria significativa.
• Valvulopatías aórtica o mitral ≥ moderada (grados 3 ó 4 / 4 para las regurgitaciones valvulares)
• Contraindicaciones para el tratamiento con dapagliflozina según ficha técnica (intolerancia hereditaria a la galactosa, insuficiencia de lactasa de Lapp o malabsorción de glucosa y galactosa; insuficiencia renal moderada-grave -CrCl < 60 ml/min o TFGe < 60 ml/min/1,73 m2-; insuficiencia hepática grave).

E.5 End points

E.5.1

Primary end point(s)

1. Functional Main Objective: To compare the impact of iSGLT2 (dapagliflozin 10 mg / day) on LV diastolic properties in patients with HFpEF-DM2 in terms of the change in the LV stiffness constant (S +) at the peak of effort between the two treatment groups (baseline vs. 12 months).
2. Main Structural Objective: Comparison between the two treatment groups of change (baseline vs. 12 months) in levels of plasma deposit and cross-linking biomarkers of type I collagen.

1. Objetivo Principal Funcional: Comparar el impacto de los iSGLT2 (dapagliflozina 10 mg/día) sobre las propiedades diastólicas del VI en pacientes con ICFEP-DM2 en términos del cambio en la constante de rigidez del VI (S+) en el pico del esfuerzo entre los dos grupos de tratamiento (basal vs. 12 meses).
2. Objetivo Principal Estructural: Comparación entre los dos grupos de tratamiento del cambio (basal vs. 12 meses) en los niveles de biomarcadores plasmáticos de depósito y entrecruzamiento de colágeno tipo I.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline vs 12 months

Basal vs 12 meses

E.5.2

Secondary end point(s)

1. To evaluate the impact of iSGLT2 on the diastolic and systolic properties of LV between the group treated with iSGLT2 and placebo in patients with HFpEF DM2.
2. To evaluate the impact of iSGLT2 on myocardial remodeling between the group treated with iSGLT2 and placebo in patients with HFpEF DM2.
3. To quantify the relative contribution of the intrinsic diastolic properties of the LV and the flow patterns on filling pressures of patients with HFpEF and DM2 and their modulation under treatment with iSGLT2.
4. Identify the baseline phenotypic characteristics associated with greater benefit of iSGLT2 in patients with HFpEF.
5. To correlate myocardial remodeling patterns with the intrinsic diastolic properties of chamber VI with systolic function in patients with HFpEF.
6. Establish a pattern based on plasmatic and image biomarkers to identify, select and monitor the candidates to be treated with iSGLT2.
7. To compare the histological, molecular, biochemical and biomechanical features of the HFpEF patients with and without DM2. Histological, molecular and biochemical variables obtained by cardiac biopsy and blood biomarkers will be compared, analyzing the different components of the myocardium: cardiomyocytes, extracellular matrix, intramyocardial microvasculature and inflammation. Likewise, the biomechanical properties obtained by dynamic pressure-volume catheterization (elastic recoil, relaxation, rigidity, systolic elastance) will be analyzed. The associations of histological patterns with blood biochemical markers will be studied to validate their usefulness as noninvasive biomarkers of myocardial remodeling in patients with DM2 and HFpEF.
8. To compare the relative contribution of the intrinsic diastolic properties of the ventricular chamber (relaxation, stiffness and elastic recoil), and of the flow patterns on filling pressures of patients with HFpEF and with and without DM2.
9. Characterize the histological patterns of myocardial remodeling in endomyocardial biopsies of patients with HFpEF with and without DM and correlate them with non-invasive patterns of cardiac remodeling.

1. Evaluar el impacto de los iSGLT2 sobre las propiedades diastólicas y sistólicas del VI entre el grupo tratado con iSGLT2 y el placebo en pacientes con ICFEP DM2.
2. Evaluar el impacto de los iSGLT2 sobre el remodelado miocárdico entre el grupo tratado con iSGLT2 y el placebo en pacientes con ICFEP DM2.
3. Cuantificar la contribución relativa de las propiedades diastólicas intrínsecas del VI y de los patrones de flujo sobre las presiones de llenado de los pacientes con ICFEP y DM2 y su modulación bajo el tratamiento con iSGLT2.
4. Identificar las características fenotípicas basales asociadas a mayor beneficio de los iSGLT2 en pacientes con ICFEP.
5. Correlacionar los patrones de remodelado miocárdico con las propiedades diastólicas intrínsecas de la cámara VI con la función sistólica en pacientes con ICFEP.
6. Establecer un patrón basado en biomarcadores plasmáticos y de imagen para identificar, seleccionar y monitorizar los candidatos a ser tratados con iSGLT2.
7. Comparar las características histológicas, moleculares, bioquímicas y biomecánicas de la ICFEP de los pacientes con y sin DM2. Se compararán variables histológicas, moleculares y bioquímicas obtenidas mediante biopsia cardiaca y biomarcadores en sangre, analizando los distintos componentes del miocardio: cardiomiocitos, matriz extracelular, microvasculatura intramiocárdica e inflamación. Igualmente, se analizarán las propiedades biomecánicas obtenidas mediante cateterismo dinámico de presión-volumen (retroceso elástico, relajación, rigidez, elastancia sistólica). Se estudiarán las asociaciones de los patrones histológicos con los marcadores bioquímicos sanguíneos para validar su utilidad como biomarcadores no invasivos del remodelado miocárdico en los pacientes con DM2 e ICFEP.
8. Comparar la contribución relativa de las propiedades diastólicas intrínsecas de la cámara ventricular (relajación, rigidez y retroceso elástico), y de los patrones de flujo sobre las presiones de llenado de los pacientes con ICFEP y con y sin DM2.
9. Caracterizar los patrones histológicos del remodelado miocárdico en biopsias endomiocárdicas de los pacientes con ICFEP con y sin DM y correlacionarlos con patrones no invasivos de remodelado cardíaco.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline vs 12 months

Basal vs 12 meses

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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 trial is reached when all the patients completed the follow-up period and any.
The study will cease only in response to the request of the Independent Committee for Safety and Monitoring of Drug Efficacy (DSMEB). In the event of the occurrence of any Severe Adverse Event or SAE, the patient involved will be terminated, after notifying the CRO, the promoter and the IDSEMB.

El estudio se considera finalizado cuando todos los pacientes completen el tratamiento y el periodo de seguimiento.
El estudio se cesará únicamente como respuesta a la solicitud del Comité Independiente de Seguridad y Monitorización de la Eficacia de Medicamentos (DSMEB). En caso de aparición de algún Evento Adverso Severo o SAE, se procederá al cese de tratamiento del paciente involucrado, previa comunicación a la CRO, al promotor y al IDSEMB.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

none

Ninguno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-07-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-24

P. End of Trial
P.	End of Trial Status	Ongoing

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