Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention

Aortic Stenosis Clinical Trial

— DAPAS  

Official title:

Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05241431
• Other study ID #: DAPAS
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 12, 2022
• Est. completion date: April 1, 2024

Study information

• Verified date: January 2022
• Source: University of Aarhus
• Contact: Anders Lehmann Dahl Pedersen, MD
• Phone: 0045 2785 2009
• Email: anlepe[@]rm.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Randomized, double-blinded, placebo-controlled study in AS patients with subclinical or clinical heart failure undergoing treatment with TAVR.

Description:

This is a randomized, double-blinded, placebo-controlled study in AS patients with subclinical or clinical heart failure undergoing treatment with TAVR. It evaluates the effect of Dapagliflozin versus placebo, given once daily in addition to background standard medical therapy. Patients who are scheduled for TAVR at Aarhus University Hospital (AUH) will be informed about the project and invited to participate if they fulfill the inclusion criteria prior to the TAVR procedure.

Patients will be randomized 1:1 in blocks of 6 patients to either Dapagliflozin 10 mg daily or placebo within 1 months prior to the scheduled TAVR therapy.

The total treatment period is 13 months with 6 scheduled outpatient clinic visits at baseline (before TAVR) and at 1, 3, 6, 9, 12 months after TAVR.

Cardiac magnetic resonance imaging (CMRI) is performed at baseline and 12 months follow-up. Echocardiography is performed at baseline, 1- and 12 months. 24-hour ambulatory blood pressure is measured at baseline and 12-months post-TAVR. Clinical status, HF questionnaire and blood samples will be performed at each visit. Drug accountability and adherence to the protocol is evaluated at each visit.

A sub study in 40 of the included patients (20 treated with Dapagliflozin and 20 placebo) is planned. This will include additional endomyocardial biopsies taken at baseline and 12-months follow-up for high resolution respirometry (mitochondrial function) and electron microscopy (mitochondrial structure and interstitial fibrosis) supplemented by right heart catherization (RHC) for hemodynamic assessment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 106
• Est. completion date: April 1, 2024
• Est. primary completion date: March 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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 at least one of the following:

• LV GLS = 15% by TTE

• LV septum or posterior wall thickness = 12mm by TTE 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

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.

Related Conditions & MeSH terms

• Aortic Stenosis
• Aortic Valve Stenosis
• Constriction, Pathologic
• Hypertrophy, Left Ventricular

Intervention

Drug:
• SGLT2 inhibitor
10 mg orally once daily in addition to standard medical treatment.
• Placebo
Placebo tablets similar to active treatment.

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus

Sponsors (2)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite endpoint of changes in LV mass, systolic function, eGFR, and serum Nt-proBNP	Changes from baseline to 12 months of follow-up in at least 2 out of 4 well-known parameters is required to reach the primary endpoint: LVMi (grams) reduction of 10 % point (by CMRI); LV GLS (percent) absolute increase of 2.0 % point (by TTE); A decrease in serum Nt-proBNP (ng/L) of more than 25%; Relative increase of 10% in eGFR (ml/min/1.73m^2) If 2 or more of the 4 outcome measures are reached at 12-months follow-up, the patient has fulfilled the primary end-point.	Baseline assesment to 12-months follow-up post-TAVR
Secondary	Difference in the change in eGFR	Difference between active treatment and placebo at 12-months follow-up	baseline to 12-months
Secondary	Difference in eGFR	Difference between active treatment and placebo at 12-months follow-up	12-months
Secondary	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	Difference between active treatment and placebo.	Baseline to 12-months
Secondary	The number of patients with a >10% decrease in cardiac fibrosis when assessed by histology and quantified by stereology (sub study)	Difference between active treatment and placebo.	Baseline to 12-months
Secondary	The number of patients with an increase in the respiratory control ratio (RCR) by =10% measured by High Resolution Respirometry (HRR) (sub study)	Difference between active treatment and placebo.	Baseline to 12-months
Secondary	Composite endpoint of worsening HF with hospitalization or urgent outpatient clinical visit due to HF, and all-cause mortality.	Difference between active treatment and placebo in the incidence rate of hospitalization due to worsening heart failure or urgent clinical visit due to heart failure and all-cause mortality (using dates of the events to assess the incidence rates in the two groups: active treatment and placebo.	12-months post-TAVR
Secondary	All-cause mortality	Difference between active treatment and placebo.	Baseline to 12-months post-TAVR
Secondary	Worsening HF with hospitalization or urgent outpatient clinical visit due to HF	Difference between active treatment and placebo.	12-months post-TAVR
Secondary	Difference in the change in urinary albumin/creatinine ratio	Difference between active treatment and placebo.	Baseline to 12-months
Secondary	Difference in ACR at 12-months follow-up	Difference between active treatment and placebo.	12-months follow-up
Secondary	24-hour ambulatory blood pressure changes	Difference between active treatment and placebo in both systolic and diastolic blood pressure.	baseline to 12 months
Secondary	Change from baseline to 12-months follow-up in the Kansas City Cardiomyopathy questionnaire	Change from baseline in KCCQ will be reported. The KCCQ is a 23-item, self-administered questionnaire with score range of 0 to 100, and higher scores indicating better health. Difference in score for active treatment vs. placebo.	Baseline to 12-months
Secondary	Change from baseline to 12-months follow-up in New York Heart Association-class (NYHA)	The NYHA functional classification categorizes the extent of heart failure by placing subjects in one of four (I, II, III, IV) categories based on how much they are limited during physical activity and symptoms of shortness of breath and/or angina. Shift in NYHA-class between active treatment group and placebo.	baseline to 12-months.
Secondary	LVMi reduction of 10 % point (by CMRI)	Difference between active treatment and placebo.	baseline to 12-months.
Secondary	LV GLS absolute increase of 2.0 % point (by TTE)	Difference between active treatment and placebo.	Baseline to 12-months follow-up
Secondary	A decrease in serum Nt-proBNP of more than 25% follow-up	Difference between active treatment and placebo.	baseline to 12-months follow-up.
Secondary	Relative increase of 10% in eGFR	Difference between active treatment and placebo.	Baseline to 12-months follow-up