NCT07091136

Exploration of Manidipine to Reverse Aortic Valve Calcification

Exploration of Manidipine to Reverse Aortic Valve Calcification by Activating Valvular Osteoclasts in Patients With Severe Calcific Aortic Valvular Disease

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 100 (estimated)
• Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology · Academic / Other
• Sex: All
• Age: 60 Years – 85 Years
• Healthy volunteers: Not accepted

Summary

This is a prospective, randomized, comparative, clinical trial conducted by Wuhan Union Hospital that aims to evaluate the efficacy and safety of manidipine compared to placebo in patients with calcific aortic valve disease with mild aortic valve stenosis.

Detailed description

This multicentre, randomized, double-blind, placebo-controlled phase IIb study will enrol 100 adults aged 60 to 85 years with MDCT-confirmed mild-to-moderate aortic valve calcification (Agatston score 300-2 000 AU) and preserved left-ventricular ejection fraction to receive manidipine 10 mg, manidipine 20 mg, or matched placebo once daily for 12 months, followed by a 3-month safety observation, with the primary endpoint being the absolute and relative change in aortic valve calcium score at 12 months; secondary endpoints include echocardiographic valve area and transvalvular gradients, six-minute walk distance, peak oxygen uptake, and comprehensive safety outcomes; the trial is grounded in extensive mechanistic work showing that calcific heart valve disease affects more than 209 million people worldwide-over 25 million in China alone-and that osteoclast deficiency or dysfunction within valvular tissue is a pivotal driver of progressive calcium deposition, with persistent up-regulation of the NLRP3 inflammasome suppressing osteoclastogenesis and the key resorptive enzyme Cathepsin K; through high-content screening of 198 candidate NLRP3 inhibitors and confirmatory concentration-response assays, the investigators identified the fourth-generation dihydropyridine calcium-channel blocker manidipine as uniquely capable of simultaneously down-regulating NLRP3 and up-regulating Cathepsin K, thereby restoring osteoclastic capacity to dissolve pathological calcium deposits and dramatically reducing valvular calcification in murine models; extrapolating these findings to humans, the study seeks to establish manidipine as the first mechanism-based, orally available, cost-effective pharmacotherapy capable of halting or reversing calcific progression, potentially obviating or delaying the need for valve replacement surgery, mitigating the limitations of current mechanical and bioprosthetic options (lifelong anticoagulation, re-calcification, repeat procedures), and ultimately reducing morbidity, mortality, and healthcare expenditure associated with CHVD; rigorous imaging core-lab analysis, blinded adjudication of endpoints by an independent committee, and periodic oversight by a data-safety monitoring board will ensure robustness of findings, while predefined statistical plans employing ANCOVA for the primary endpoint (with baseline calcium score and centre as covariates), mixed-effects models for repeated-measures secondary variables, and survival analysis for clinical events will provide comprehensive efficacy and safety profiles; if the trial demonstrates a clinically meaningful slowing or reversal of calcification alongside an acceptable safety profile, manidipine could rapidly progress to phase III evaluation and, given its established antihypertensive indications and favourable pharmacokinetics, could be repurposed swiftly to address the global unmet need for a pharmacological solution to calcific heart valve disease.

Conditions

• Calcific Aortic Valve Disease

Interventions

Type	Name	Description
DRUG	manidipine	study will enrol 100 adults aged 60 to 85 years with MDCT-confirmed mild-to-moderate aortic valve calcification (Agatston score 300-2 000 AU) and preserved left-ventricular ejection fraction to receive manidipine 10 mg, manidipine 20 mg, or matched placebo once daily for 12 months, followed by a 3-month safety observation, with the primary endpoint being the absolute and relative change in aortic valve calcium score at 12 months; secondary endpoints include echocardiographic valve area and transvalvular gradients, six-minute walk distance, peak oxygen uptake, and comprehensive safety outcomes
DRUG	Placebo	study will enrol 100 adults aged 60 to 85 years with MDCT-confirmed mild-to-moderate aortic valve calcification (Agatston score 300-2 000 AU) and preserved left-ventricular ejection fraction to receive manidipine 10 mg, manidipine 20 mg, or matched placebo once daily for 12 months, followed by a 3-month safety observation, with the primary endpoint being the absolute and relative change in aortic valve calcium score at 12 months; secondary endpoints include echocardiographic valve area and transvalvular gradients, six-minute walk distance, peak oxygen uptake, and comprehensive safety outcomes

Timeline

• Start date: 2025-08-01
• Primary completion: 2026-08-01
• Completion: 2026-10-31
• First posted: 2025-07-29
• Last updated: 2025-07-29

Regulatory

• FDA-regulated drug study