Phase 2b/3 Randomized Double‑Blind Placebo‑Controlled Trial of Ataciguat to Slow Progression and Improve Peak VO2 in Moderate Calcific Aortic Valve Stenosis

In participants with moderate calcific aortic valve stenosis, the primary objectives are to (1) assess whether oral ataciguat 200 mg daily reduces the rate of decline in aortic valve area, an indicator of disease progression, and (2) evaluate the drug’s impact on functional capacity as measured by peak VO2, reflecting exercise tolerance and cardiac performance. Secondary objectives include (1) determining the effect of ataciguat on the rate of aortic valve calcium deposition, and (2) assessing whether treatment postpones clinically relevant events such as the decision to proceed with TAVR/SAVR, all‑cause mortality, or progression to an aortic valve area < 1.0 cm².

The study population comprised 780 adult men and women aged 50 years and older who met the criteria for Moderate Calcific Aortic Valve Stenosis. Eligible individuals demonstrated an aortic valve area between 1.0 and 1.5 cm², an aortic valve calcification score within the protocol‑specified range, and a left ventricular ejection fraction of at least 45 % as assessed by a central imaging laboratory. Both sexes were represented, and participants were required to be in generally stable health, with any beta‑blocker therapy maintained at a constant dose for at least 90 days prior to screening. Selection was based on fulfillment of the principal inclusion criteria and the absence of protocol‑defined exclusion factors; additional eligibility requirements were applied as detailed in the study protocol. Lifestyle factors such as diet, physical activity, or smoking status were not specified as selection criteria.

The study is a Phase 2b/3 randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of 200 mg oral ataciguat capsules versus matching placebo in adults with moderate calcific aortic valve stenosis. After an initial screening visit to confirm eligibility, participants are assigned in a 1:1 ratio to either the investigational product or placebo and receive the first dose at the baseline visit (Week 0). Subsequent study visits occur at Weeks 12, 24, 36, and 48 to assess safety, adherence, and efficacy endpoints, including the primary measurements of AVA change by echocardiography and change in peak VO2 by cardiopulmonary exercise testing from baseline to Week 48. The end‑of‑study visit at Week 48 completes the 48‑week participant involvement. Early termination may occur if a participant withdraws consent, experiences a serious adverse event, requires aortic valve intervention (TAVR/SAVR), or violates key protocol criteria. All visits and assessments are conducted in accordance with the protocol schedule.

The investigational product, Ataciguat, is supplied as an oral capsule containing 200 mg of the active substance. The medication is administered by mouth in accordance with the study dosing schedule; each dose consists of a single 200 mg capsule.

The comparator is a matching placebo designed to be indistinguishable from the active capsule. The placebo contains no active pharmaceutical ingredient and is provided in the same capsule form for blinding purposes.

Both study medications are dispensed at scheduled study visits. Dosing compliance is monitored through pill counts and documentation in a study diary. Administration times are recorded in the trial database to ensure adherence to the prescribed regimen.

Efficacy will be evaluated primarily by the percent change in AVA as measured by transthoracic echocardiogram from baseline to Week 48, and by the change in peak VO₂ assessed with cardiopulmonary exercise testing (CPET) over the same period. Secondary efficacy assessments include the change in aortic valve calcium (AVC) score obtained from non‑contrast computed tomography from baseline to Week 48, the time to a clinical decision for transcatheter or surgical aortic valve replacement (TAVR/SAVR) or all‑cause death, and the proportion of participants whose aortic stenosis progresses to an AVA < 1.0 cm² at Week 48.

All imaging and functional assessments will be performed at screening (baseline) and at the Week 48 visit. Echocardiograms will be analyzed centrally for AVA measurements. CPET will be conducted using standardized protocols to determine peak VO₂. Non‑contrast CT scans will be evaluated for AVC scoring by a blinded core laboratory. Time‑to‑event outcomes will be captured continuously throughout the study period and analyzed using appropriate survival methods.