This is a Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial evaluating the safety and efficacy of once-weekly semaglutide 2.4 mg in adult patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) who meet current clinical criteria for semaglutide treatment. A total of 826 participants will be randomized 1:1 to receive semaglutide or placebo as an add-on to standard-of-care, starting 3 months before TAVR and continuing for 24 months post-procedure. The primary endpoint is time to first occurrence of a composite of cardiovascular (CV) death, non-fatal myocardial infarction, non-fatal stroke or transient ischemic accident (TIA), and hospitalization for heart failure (HF). The study is event-driven and powered to detect a 20% relative risk reduction in primary outcome events. This trial aims to address the unmet need for medical therapies that improve outcomes in patients with severe AS following TAVR, with potential for direct clinical implementation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
826
Semaglutide 2.4 mg subcutaneous once-weekly starting 3 months prior TAVR and continued 24 months post-TAVR. During the first 16 weeks, the dose of semaglutide or placebo will be gradually escalated from 0.25 mg once weekly until target dose as an add-on to standard-of-care. The treatment will continue until the 'end of treatment' visit followed by a 8 weeks follow-up period.
Matching placebo subcutaneous once-weekly.
CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for HF
From randomization to first occurrence of a composite endpoint consisting of: CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for HF.
Time frame: From randomization through 12 and 27 months
Incidence rate of each component of the primary outcome.
Time frame: From randomization at 12 months and 27 months
Change in high sensitivity C-Reactive Protein (hsCRP) (mg/L)
Time frame: From randomization at 12 and 27 months
A 5-component composite nephropathy endpoint consisting of: onset of persistent macroalbuminuria, persistent 50% reduction in eGFR compared with baseline (randomization), onset of persistent eGFR < 15 ml/min/1.73m2, initiation of chronic renal replacemen
Time frame: From randomization at 12 and 27 months
Change in Lipid Profile (mg/dL)
Time frame: From randomization at 12 and 27 months
Change in waist circumference
Time frame: From randomization at 12 and 27 months
Change in HbA1c (%, mmol /mol)
Time frame: From randomization at 12 and 27 months
Change in systolic blood pressure
Time frame: From randomization at 12 and 27 months
Changes in LV remodeling (echocardiographic assessment of LV size, mass, systolic and diastolic function)
Time frame: From randomization at 12 and 27 months
Change in loop diuretic medication
Time frame: From randomization at 12 and 27 months
Change in H2FPEF score
Change in H2FPEF score scale
Time frame: From randomization at 12 and 27 months
Change in NT-proBNP
Time frame: From randomization at 12 and 27 months
Change in KCCQ score
Change in the KCCQ score scale
Time frame: From randomization at 12 and 27 months.
Subject experiencing deterioration in NYHA functional class
Subject experiencing deterioration in NYHA functional class
Time frame: From randomization at 12 and 27 months
Change in body weight (%)
Change in body weight from randomization.
Time frame: From randomization at 12 and 27 months.
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