Vericiguat for the Inhibition of Calcific Aortic Valve Stenosis Progression: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (VERIFICATION Study)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 238
- 主要终点
- Hierarchical Composite Endpoint including Time to all-cause death, Time to aortic valve-related clinical events and Change in aortic valve calcification (AVC) score from baseline at 24 months (log-transformed).
研究概览
简要总结
Calcific aortic valve stenosis (CAVS) is a condition in which the aortic valve progressively narrows and stiffens due to calcium deposition, eventually impairing blood flow from the heart to the body. No drug therapy has been proven to slow CAVS progression. Individuals with mild-to-moderate CAVS are managed with periodic monitoring until the stenosis becomes severe, at which point surgical or transcatheter valve replacement is the only treatment option. The goal of this clinical trial is to determine whether vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, can slow the progression of mild-to-moderate CAVS.
The primary questions this study aims to answer are:
Does vericiguat slow the progression of aortic valve calcium accumulation, as measured by the change in aortic valve calcium score from baseline to 24 months, compared to placebo?
The study will compare vericiguat against a placebo (an inactive pill that is identical in appearance but contains no active drug). Both participants and the research team will not know which treatment each participant is receiving throughout the study.
Participants will:
Take vericiguat or placebo orally once daily for 24 months; Begin treatment at 2.5 mg/day and undergo a stepwise dose increase every two weeks to a target dose of 10 mg/day, provided the drug is tolerated; Attend approximately 8 scheduled study visits over two years, during which they will undergo cardiac imaging examinations (transthoracic echocardiography and non-contrast cardiac CT), blood sample collection, physical assessment, and completion of standardized questionnaires on quality of life and heart failure symptoms; Undergo cardiac magnetic resonance imaging (MRI) at the beginning and end of the study, if there are no contraindications.
Approximately 238 participants will be enrolled across roughly 19 hospitals in China.
详细描述
BACKGROUND AND UNMET NEED Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease worldwide and a leading cause of heart failure, valve replacement, and cardiovascular death in older adults. In Western populations, the prevalence of CAVS reaches 1-2% among individuals aged ≥65 years and approximately 12% in those aged ≥75 years. In China, prevalence is rising sharply as the population ages. Once the aortic valve peak velocity exceeds 2.5 m/s, the disease typically progresses to severe stenosis within a decade. Among patients with symptomatic severe aortic stenosis who do not undergo intervention, two-year mortality approaches 50%.
Aortic valve replacement-either surgical (SAVR) or transcatheter (TAVI)-is currently the only effective treatment for severe CAVS. However, valve replacement carries substantial procedural risks (stroke, conduction block, paravalvular leak, bleeding, infection) and imposes a heavy economic burden. There is therefore an urgent clinical need for a pharmacological intervention that can slow CAVS progression at the mild-to-moderate stage and thereby reduce the proportion of patients who progress to severe stenosis requiring valve replacement.
Over the past two decades, numerous randomized controlled trials have tested pharmacological strategies for slowing CAVS progression, including intensive statin therapy (SALTIRE, TASS, ASTRONOMER), anti-osteoporotic agents (SALTIRE-2: denosumab and alendronate), vitamin K2 plus vitamin D supplementation, and DPP-4 inhibitors (evogliptin). All have yielded negative results. Recent evidence has reframed CAVS as an active fibro-calcific disease driven by valvular interstitial cell (VIC) osteogenic differentiation, endothelial dysfunction, and inflammatory signaling, rather than a passive degenerative process. The consistent failure of prior trials highlights the need for mechanistically novel therapeutic targets.
RATIONALE FOR TARGETING THE NO-sGC-cGMP PATHWAY Cyclic guanosine monophosphate (cGMP) is a critical second messenger in cardiovascular homeostasis, synthesized from GTP by guanylate cyclases. Soluble guanylate cyclase (sGC)-the principal receptor for nitric oxide (NO)-is widely expressed in valvular endothelial cells and VICs. cGMP activates protein kinase G (PKG), which exerts multiple protective effects including suppression of VIC osteogenic differentiation, preservation of mitochondrial function, and attenuation of oxidative stress.
In calcified aortic valve tissue, the NO-sGC-cGMP signaling axis is markedly impaired despite compensatory upregulation of sGC subunits. The key mechanism involves localized oxidative stress that converts sGC from its active (reduced, heme-containing) form to an oxidized or heme-free form that is insensitive to endogenous NO, thereby limiting cGMP production. Our group has further demonstrated that serum cGMP concentrations are significantly reduced in patients with CAVS and correlate inversely with CT-derived aortic valve calcium (AVC) scores and echocardiographic mean pressure gradients, supporting cGMP-PKG pathway downregulation as a hallmark of CAVS progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 35 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The participant agrees to enter this clinical trial and consents to long-term follow-up;
- •35 ≤ age < 80 years;
- •Echocardiographically confirmed mild-to-moderate (peak aortic jet velocity ≥ 2.5 m/s and < 4.0 m/s, aortic valve area > 1.0 cm², and mean aortic valve pressure gradient < 40 mmHg) non-rheumatic aortic valve stenosis;
- •Baseline aortic valve calcium score (Agatston score) ≥ 200 AU as measured by cardiac CT;
- •Male participants, or female participants who are not of childbearing potential, or female participants who commit to avoiding pregnancy through 4 weeks after the end of the trial.
排除标准
- •Severe aortic stenosis (AS peak velocity ≥ 4.0 m/s, or mean transvalvular aortic pressure gradient ≥ 40 mmHg, or aortic valve area ≤ 1.0 cm², or indexed effective aortic valve area < 0.6 cm²/m²), or very mild stenosis (AS peak velocity < 2.5 m/s), or a planned aortic valvuloplasty/replacement procedure;
- •Concomitant severe mitral or tricuspid valve disease (moderate or greater mitral or tricuspid regurgitation, or prior mitral or tricuspid valve repair/valvuloplasty/replacement);
- •Concomitant moderate or greater aortic regurgitation;
- •Use, within 1 month prior to the screening visit, of medications affecting the NO-sGC-cGMP pathway (e.g., sildenafil, nitrates, etc.), or known hypersensitivity to vericiguat or its components;
- •Left ventricular ejection fraction (LVEF) < 50%, or NYHA class III-IV (see Appendix 4 for NYHA classification criteria);
- •Presence of a malignancy (except those with an expected cure) or other serious non-cardiac disease with a life expectancy of less than 3 years;
- •Rheumatic valvular heart disease;
- •Systolic blood pressure (SBP) < 120 mmHg, or a history of symptomatic hypotension, or a history of hemodynamic instability or hypovolemia within the 4 weeks prior to screening;
- •Presence of hypertrophic obstructive cardiomyopathy (outflow tract obstruction defined as a peak left ventricular outflow tract pressure gradient ≥ 30 mmHg at rest or after provocative testing);
- •Infective endocarditis or complex congenital heart disease;
- •Estimated glomerular filtration rate < 15 mL/min/1.73 m², or on dialysis;
- •Severe pulmonary disease requiring continuous home oxygen therapy;
- •Interstitial lung disease;
- •Concomitant disorder of calcium-phosphate metabolism;
- •Current use of warfarin;
- •ALT and AST ≥ 3 times the upper limit of normal, or severe hepatic insufficiency (e.g., cirrhosis, chronic active liver disease);
- •Inability to undergo contrast-enhanced CT, or contrast media allergy;
- •Concomitant acute myocarditis, cardiac amyloidosis, cardiac sarcoidosis, or stress (takotsubo) cardiomyopathy;
- •Presence of acute coronary syndrome (including unstable angina, non-ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction) within 60 days prior to randomization, or an indication for coronary revascularization (percutaneous intervention/bypass surgery); or a need for coronary revascularization identified at the time of randomization;
- •History of cerebrovascular accident (including TIA or stroke) within 60 days prior to randomization;
- •Psychiatric disorder or legal incapacity precluding the ability to provide informed consent;
- •Any medical condition, circumstance, or history that, in the investigator's judgment, would compromise the participant's ability to participate in or complete the study.
研究组 & 干预措施
Placebo
Matching placebo tablets orally once daily
干预措施: Placebo (Drug)
Vericiguat
Vericiguat orally once daily.
干预措施: Vericiguat (BAY1021189) (Drug)
结局指标
主要结局
Hierarchical Composite Endpoint including Time to all-cause death, Time to aortic valve-related clinical events and Change in aortic valve calcification (AVC) score from baseline at 24 months (log-transformed).
时间窗: Up to 24 months
A three-tier hierarchical composite endpoint, compared using the Win Ratio method, ranked by clinical importance: Tier 1: Time to all-cause death. Tier 2: Time to aortic valve-related clinical events (aortic valve replacement \[TAVR or SAVR\] or first hospitalization for aortic stenosis). Tier 3: Change in aortic valve calcification (AVC) score from baseline at 24 months (log-transformed). A smaller increase (slower calcification progression) is favored.
Change in Aortic Valve Calcium (AVC) Score at 24 months
时间窗: At 24 months
Change in log-transformed aortic valve calcium score from baseline, measured by non-contrast electrocardiographic-gated cardiac CT (Agatston method). Higher scores mean worse outcome.
次要结局
- Change in Aortic Valve Calcium (AVC) Score at 12 Months(At 12 months and 24 months)
- Change in Aortic Valve Peak Velocity(At 6, 12, 18, and 24 months)
- Change in Aortic Valve Mean Pressure Gradient(At 6, 12, 18, and 24 months)
- Change in Aortic Valve Area(At 6, 12, 18, and 24 months)
- Time to First Aortic Valve-Related Clinical Event(Up to 24 months)
- Time to Aortic Valve Replacement(Up to 24 months)
- Time to all-cause death(Up to 24 months)
- Time to First Major Adverse Cardiovascular and Cerebrovascular Event(Up to 24 months)
- Hierarchical Composite of Adverse Cardiovascular Events(Up to 24 months)
- Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score(At 6, 12, 18, and 24 months)
- Change in NYHA Functional Classification(At 6, 12, 18, and 24 months)
- Incidence of Adverse Events and Serious Adverse Events(Baseline through 24 months)
- Incidence of Events of Clinical Interest: Liver Function Abnormalities(Baseline through 24 months)
- Incidence of Events of Clinical Interest: Symptomatic Hypotension(Baseline through 24 months)
- Incidence of Events of Clinical Interest: Syncope(Baseline through 24 months)
- Incidence of Permanent Discontinuation of Study Drug Due to Adverse Events(Baseline through 24 months)
- Change from baseline in aortic valve calcium volume(At 12 and 24 months)
- Hierarchical Composite Endpoint including Time to all-cause death, Time to aortic valve-related clinical events and Change in aortic valve calcification (AVC) score from baseline at 24 months (log-transformed).(Up to 24 months)
- Change in Aortic Valve Calcium (AVC) Score at 12 Months(At 12 months)
- Time to all-cause death and cumulative all-cause mortality(Up to 24 months)
- Change in New York Heart Association (NYHA) Functional Classification(At 6, 12, 18, and 24 months)
研究者
Mao Chen
Director of Department of Cardiology
West China Hospital