E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with aortic stenosis undergoing trans catheter aortic valve replacement. |
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E.1.1.1 | Medical condition in easily understood language |
Aortic stenosis is a narrowing of the aortic valve opening |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058186 |
E.1.2 | Term | Aortic valve stenosis and insufficiency |
E.1.2 | System Organ Class | 100000004849 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The overall purpose of this study is to improve treatment of AS patients treated with TAVR. The study evaluates the effect of Dapagliflozin on mitochondrial function, myocardial fibrosis, LVH, systolic function, renal function, incidence of worsening HF and mortality. This will test the potential beneficial effects of Dapagliflozin on myocyte function, interstitial fibrosis, LVH, systolic dysfunction, renal dysfunction, incidence of worsening HF and mortality in AS patients treated with TAVR. |
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E.2.2 | Secondary objectives of the trial |
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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 |
Right heart catherization and endomyocardial biopsies in 40 of the included patients. The objective is to investigate the mitochondrial function in myocytes and assess fibrosis using a electron microscope |
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E.3 | Principal inclusion criteria |
1. Signed informed consent 2. Scheduled TAVR for significant symptomatic AS according to current guidelines 3. Age > 18 years and < 85 years. 4.* - LVEF >/= 40% and </= 50 % or LVEF > 50% with LV GLS </= 15% by TTE - LV septum or posterior wall thickness >/= 12mm by echo or LV mass index >108/131 g/m2 for females/males (mild LVH) - LVEF > 50 % and Nt-proBNP > 600/900 ng/l (sinus rhythm/atrial fibrillation) 5. eGFR > 30 mL/min/1.73 m2
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E.4 | Principal exclusion criteria |
1. Medically treated type 1 or type 2 diabetes mellitus 2. Ongoing treatment with an SGLT2-inhibitor or intolerance to SGLT2-inhibitors 3. Life expectancy < 12 months 4. Symptomatic hypotension or persistent SBP < 100 mmHg 5. Contraindications to CMRI 6. HF due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis or hypertrophic obstructive cardiomyopathy 7. Additional other untreated severe valvular disease 8. Liver failure 9. Women who are pregnant or plan to be within the study period.** 10. Allergy to any substance in the project medicine, both placebo and active medicine. 11. Previous renal transplantation. 12. Chronic dialysis treatment.
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E.5 End points |
E.5.1 | Primary end point(s) |
A composite endpoint of changes in LV mass, systolic function, eGFR, and serum Nt-proBNP - all parameters related to HF and adverse outcome in the AS setting is planned. Changes from baseline to 12 months of follow-up in at least 2 out of 4 well-known parameters of performance in AS is required to reach the primary endpoint. The level of change, in percentage points (%P), is considered clinically significant based on existing litterature: • LVMi reduction of 10 % point (by CMRI) • LV GLS absolute increase of 2.0 % point (by TTE) • A decrease in serum Nt-proBNP of more than 25% • Relative increase of 10% in eGFR
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timepoint of evaluation is 12-months after transcatheter aortic valve replacement (TAVR). The values assessed at 12-months follow-up will be compared to the baseline measures (1-month before TAVR) to evaluate whether the patients meet the primary endpoint. |
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E.5.2 | Secondary end point(s) |
1. Difference in the change in eGFR from baseline to 12-months 2. Difference in eGFR at 12-months. 3. The number of patients with a relative difference of 10 % of myocardial interstitial fibrosis evaluated by the biomarker extracellular volume (ECV) by late enhancement gadolinium by CMR 4. The number of patients with a >10% decrease in cardiac fibrosis when assessed by histology and quantified by stereology (sub study) 5. The number of patients with an increase in the respiratory control ratio (RCR) by ≥10% measured by High Resolution Respirometry (HRR) (sub study) 6. Composite endpoint of worsening HF with hospitalization or urgent outpatient clinical visit due to HF, cardiovascular- and all-cause mortality 7. All-cause mortality 8. Worsening HF with hospitalization or urgent outpatient clinical visit due to HF 9. Difference in the change in urinary albumin/creatinine ratio (ACR) from baseline to 12-months. 10. Difference in ACR at 12-months. 11. 24-hour ambulatory blood pressure changes from baseline to 12 months. 12. Change from baseline to 12-months follow-up in the KCCQ Total Symptom Score 13. Change from baseline to 12-months follow-up in NYHA-class 14. LVMi reduction of 10 % point (by CMRI) from baseline to 12-months follow-up 15. LV GLS absolute increase of 2.0 % point (by TTE) from baseline to 12-months follow-up 16. A decrease in serum Nt-proBNP of more than 25% from baseline to 12-months follow-up 17. Relative increase of 10% in eGFR measured at baseline and 12-months
Explorative endpoints. 1. Urinary excretion of fibrosis markers. 2. P-Pro Collagen III 3. P-PICP 4. P-Copeptin 5. Weight & body composition by Impedance measurement
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 12-months follow-up after transcatheter aortic valve replacement. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |