Exploration of Manidipine to Reverse Aortic Valve Calcification

NCT ID: NCT07091136

Last Updated: 2025-07-29

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-08-01
• Study Completion Date: 2026-10-31

Brief 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

manidipine 10 mg

Participants are giving manidipine 10 mg once daily for 12 months, followed by a 3-month safety observation.

Group Type: EXPERIMENTAL

manidipine

Intervention Type: DRUG

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

placebo

Participants are giving placebo once daily for 12 months, followed by a 3-month safety observation.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

manidipine 20 mg

Participants are giving manidipine 20 mg once daily for 12 months, followed by a 3-month safety observation.

Group Type: EXPERIMENTAL

manidipine

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female adult ≥ 60 years of age at the time of rescruiting.
• Subject has calcific aortic valve disease with mild to moderate aortic valve stenosis as defined by Doppler echocardiography results: Aortic Valve mean pressure gradient between 10-30 mmHg and Aortic Valve Area ≥ 1.2 and ≤ 2.0 cm2 on TTE within 2 weeks prior to randomization and Cardiac Compute Tomography (CT) test results: aortic valve calcium score (Agatston score) ≥ 200 AU at baseline cardiac CT within 1 month prior to randomization
• Subject provides written informed consent prior to initiation of any study procedures.
• Subject understands and agrees to comply with planned study procedures.

Exclusion Criteria

• Subject has concomitant moderate or severe mitral or tricuspid valve disease.
• Subject has left ventricular ejection fraction < 50%.
• Subject previous history of aortic valve surgery, pancreatitis, malignant tumor, drug or alcohol abuse.
• Subjects whose alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times the upper limit of normal range.
• Subjects who cannot undergo Cardiac CT.
• Pregnant or lactating women.
• Consideration by the investigator, for safety reasons, that the subject is an unsuitable candidate to receive study treatment.

• Minimum Eligible Age: 60 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Fei Li

Role: CONTACT

lifei_union@hust.edu.cn

+8615972969897

Other Identifiers

Wuhan Union Hospital

Identifier Type: -

Identifier Source: org_study_id