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

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

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis; Left Ventricle Hypertrophied
• Intervention / Treatment: Drug: SGLT2 inhibitor; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 106
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Anders Lehmann Dahl Pedersen, MD; Phone Number: 0045 2785 2009; Email: anlepe@rm.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Contact: Anders Lehmann Dahl Pedersen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention group; 10 mg (oral) SGLT-2 inhibitor once daily	Drug: SGLT2 inhibitor; 10 mg orally once daily in addition to standard medical treatment.
Placebo Comparator: Control group; Placebo tablet encapsulated as the active treatment.	Drug: Placebo; Placebo tablets similar to active treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in the change in eGFR	Difference between active treatment and placebo at 12-months follow-up	baseline to 12-months
Difference in eGFR	Difference between active treatment and placebo at 12-months follow-up	12-months
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
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
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
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
All-cause mortality	Difference between active treatment and placebo.	Baseline to 12-months post-TAVR
Worsening HF with hospitalization or urgent outpatient clinical visit due to HF	Difference between active treatment and placebo.	12-months post-TAVR
Difference in the change in urinary albumin/creatinine ratio	Difference between active treatment and placebo.	Baseline to 12-months
Difference in ACR at 12-months follow-up	Difference between active treatment and placebo.	12-months follow-up
24-hour ambulatory blood pressure changes	Difference between active treatment and placebo in both systolic and diastolic blood pressure.	baseline to 12 months
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
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.
LVMi reduction of 10 % point (by CMRI)	Difference between active treatment and placebo.	baseline to 12-months.
LV GLS absolute increase of 2.0 % point (by TTE)	Difference between active treatment and placebo.	Baseline to 12-months follow-up
A decrease in serum Nt-proBNP of more than 25% follow-up	Difference between active treatment and placebo.	baseline to 12-months follow-up.
Relative increase of 10% in eGFR	Difference between active treatment and placebo.	Baseline to 12-months follow-up

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital
• Investigators: Principal Investigator: Steen Hvitfeldt Poulsen, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2022
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: January 18, 2022
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 15, 2022

Study Record Updates

• Last Update Posted (Actual): February 15, 2022
• Last Update Submitted That Met QC Criteria: February 11, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Cardiomegaly; Hypertrophy; Aortic Valve Stenosis; Constriction, Pathologic; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors
• Other Study ID Numbers: DAPAS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No