Effects of sodium-glucose cotransporter 2 inhibition on the mechanisms of heart failure with preserved ejection fraction

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundación para la Innovación en Biomedicina, Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Decision date (initial)

2025-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2025-520969-51-00

EudraCT number

2019-002046-20

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Diagnosis, Efficacy

To identify the underlying the biological and biomechanical mechanisms responsible for the cardiovascular benefit demonstrated by iSGLT2 in patients with ICFEP.

Secondary objectives 9

1. To evaluate the effect of iSGLT2 treatment on LV systolic (maximum elastance) and diastolic properties (relaxation, stiffness and elastic recoil) in patients with HFpEF
2. To quantify the relative contribution of intrinsic diastolic properties of the ventricular chamber (relaxation, stiffness and elastic recoil), and of flow patterns on filling pressures in diabetic patients with HFpEF and their modulation under SGLT2 treatment.
3. Investigate whether geometric remodeling is associated with modifications in intraventricular flow and whether these changes contribute to alterations in diastolic function, filling pressures, and functional limitation in patients with HFpEF
4. Study the structural and biomechanical alterations that characterize HFpEF. This will include evaluating changes in cardiomyocytes, interstitial and perivascular fibrosis, the degree of collagen cross-linking, microvascular (blood and lymphatic) abnormalities including rarefaction and endothelial dysfunction, as well as inflammation
5. Study the effect of dapagliflozin on the histological, cellular, and molecular patterns of myocardial remodeling in endomyocardial biopsies from patients with HFpEF
6. To Investigate the effect of dapagliflozin on molecules involved in cardiomyocyte stiffness (titin) and extracellular matrix remodeling (lysyl oxidases and hydroxylases, miR-19b, WISPER, and AGEs)
7. Quantify the panel of circulating biochemical markers of myocardial remodeling in patients with HFpEF, reflecting alterations in different myocardial components: cardiomyocyte damage, fibrosis and ECM remodeling, microvascular abnormalities, and inflammation
8. To correlate histological and biochemical findings with cardiac biomechanics and functional parameters to achieve an in-depth phenotyping of patients and to better understand the mechanism of action of dapagliflozin
9. Evaluate the impact of dapagliflozin treatment on circulating biomarkers of myocardial remodeling

Conditions and MedDRA coding

Heart failure with preserved ejection fraction

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Adults of both genders ≥ 18 years
2. LVEF ≥ 50%
3. Diagnosis of HFpEF according to clinical criteria, with a history of hospitalization or the need for intravenous diuretic treatment in the previous 6 months, along with evidence of diastolic dysfunction based on echocardiographic criteria
4. Patients with or without Type II Diabetes Mellitus
5. Clinically stable condition (> 1 month after hospitalization for HF decompensation or since the last dose of intravenous diuretic treatment)
6. Clinical indication for cardiac catheterization
7. Clinical indication to receive de novo treatment with SGLT2 inhibitors
8. Signed informed consent

Exclusion criteria 9

1. Participation in another clinical trial within 30 days prior to the start of the current study
2. Pregnant or breastfeeding women
3. Prior or current treatment with SGLT2 inhibitors
4. Significant coronary artery disease
5. Aortic or mitral valvular disease ≥ moderate
6. Contraindications for dapagliflozin treatment according to the product label (hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption; moderate-to-severe renal insufficiency - CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m² -; severe hepatic insufficiency).
7. Stroke within 12 months prior to inclusion
8. Respiratory impairment or the need for home oxygen therapy
9. Life expectancy of less than 2 years due to any cause

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Systolic properties derived from PV curve analysis: Maximum elastance
2. Diastolic properties derived from PV curve analysis: Relaxation, stiffness, equilibrium volume, elastic recoil

Secondary endpoints 9

1. Reverse geometric remodeling variables of the LV: Ventricular volumes and mass measured by cardiac magnetic resonance imaging (MRI)
2. Intraventricular flow patterns based on Doppler echocardiography and phase-contrast MRI: Vorticity parameters and blood transport into the LV; energy exchange between the myocardium and blood
3. Cardiomyocyte alterations: grade of hypertrophy assessed by morphometry and expression of pro-hypertrophic genes (atrial natriuretic peptide, sarcomeric proteins using real-time RT-PCR and western blot)
4. Interstitial and perivascular fibrosis
5. Degree of collagen crosslinking
6. Microvascular alterations
7. Cardiomyocyte stiffness: Titin
8. Extracellular matrix: Lysyl-oxidases and hydroxylases, miR-19b, WISPER, and AGEs
9. Cardiomyocytes: NT-proBNP, high-sensitivity troponin T (TnT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundación para la Innovación en Biomedicina

Sponsor organisation

Fundación para la Innovación en Biomedicina

Address

C/ Alcalde Sainz de Baranda 39, 5º B

City

Madrid

Postcode

28009

Country

Spain

Scientific contact point

Organisation

Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon

Contact name

Dr. Javier Bermejo

Public contact point

Organisation

Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon

Contact name

Dr. Javier Bermejo

Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon

Sponsor organisation

Fundacion Para La Investigacion Biomedica Del Hospital Gregorio Maranon

Address

Calle Del Doctor Esquerdo 46

City

Madrid

Postcode

28007

Country

Spain

Sponsor responsibilities

Article 77 compliance

Fundación para la Innovación en Biomedicina

Contact point sponsor

Fundación para la Innovación en Biomedicina

Article 77 implementation

Fundación para la Innovación en Biomedicina

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications