A randomized double-blind, placebo-controlled, multicenter trial assessing the impact of lipoprotein(a) lowering with pelacarsen (TQJ230) on the progression of calcific aortic valve stenosis [Lp(a)FRONTIERS CAVS]

The primary objective of this study is to demonstrate the superiority of **pelacarsen** (TQJ230) versus placebo in slowing the progression of **calcific aortic valve stenosis**. This will be evaluated by assessing the change from baseline to month 36 in peak aortic jet velocity using echocardiography and in aortic valve calcium score via computed tomography. The clinical relevance of this objective lies in its potential to provide a therapeutic option for patients with calcific aortic valve stenosis, a condition that can lead to significant morbidity and mortality if left untreated.

Secondary objectives include:

• Assessing the effect of pelacarsen versus placebo on the reduction of **lipoprotein(a)** levels from baseline to month 12.
• Evaluating the effect of pelacarsen versus placebo in slowing the progression of calcific aortic valve stenosis by measuring the change from baseline to month 36 in fibrocalcific thickening of the aortic valve using contrast computed tomography.
• Assessing the effect of pelacarsen versus placebo in reducing the risk of a composite clinical endpoint.
• Evaluating the safety and tolerability of lipoprotein(a) lowering therapy with pelacarsen.

The clinical trial involves a total of **244 participants** diagnosed with **calcific aortic valve stenosis**. The study population includes both male and female subjects aged between 50 and 79 years. Participants were selected based on specific criteria, including a lipoprotein(a) level of at least 175 nmol/L and mild to moderate calcific aortic valve stenosis, characterized by a peak aortic jet velocity between 2.5 m/s and 3.5 m/s. At the time of randomization, participants are required to be optimally treated for existing cardiovascular risk factors such as LDL-C, diabetes mellitus, and hypertension, in accordance with local practices or guidelines. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are considered in the context of managing cardiovascular risk factors. The selection process ensures a representative sample of the target demographic, focusing on individuals who meet the inclusion criteria and are likely to benefit from the intervention being studied.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **pelacarsen** (TQJ230) in slowing the progression of **calcific aortic valve stenosis**. The trial will involve participants aged 50 to 79 years with mild to moderate calcific aortic valve stenosis and elevated lipoprotein(a) levels. The study will span approximately 36 months, with the estimated recruitment start date in June 2024 and an estimated end date in July 2029.

Participants will be randomly assigned to receive either pelacarsen or a placebo, administered as a solution for injection in a pre-filled syringe. The primary endpoints include changes in peak aortic jet velocity and aortic valve calcium score from baseline to month 36. Secondary endpoints will assess changes in lipoprotein(a) levels, fibrocalcific thickening of the aortic valve, and the time to the first occurrence of a composite clinical endpoint event, including unplanned hospital admissions related to calcific aortic valve stenosis, aortic valve interventions, or death related to the condition. Safety endpoints will also be monitored throughout the study.

The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, lipoprotein(a) levels, and aortic valve stenosis severity. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety parameters. The end-of-study visit will occur at the conclusion of the 36-month treatment period, where final assessments will be conducted.

Participant involvement is expected to last for the entire 36-month duration unless early termination is warranted. Conditions for early termination may include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide robust data on the potential benefits of pelacarsen in managing calcific aortic valve stenosis, contributing to the understanding of treatment options for this condition.

The clinical trial involves the administration of the experimental medication **TQJ230**, which contains the active substance **pelacarsen**. This medication is formulated as a **solution for injection in a pre-filled syringe** and is administered via **subcutaneous use**. The maximum daily dose of TQJ230 is 80 mg, with a total maximum dose of 3040 mg over the course of the trial. The treatment period extends up to 36 months. TQJ230 is classified as an **antisense oligonucleotide** and is provided in a pre-filled syringe equipped with a needle safety device. The medication is not a pediatric formulation and is not designated as an orphan drug. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

The study also includes a **placebo** treatment, which is designed to match the TQJ230 80 mg/0.8 mL solution for injection in a pre-filled syringe with a needle safety device. The placebo is used as a comparator to evaluate the efficacy of TQJ230 in slowing the progression of calcific aortic valve stenosis. The placebo is administered in the same manner as the experimental medication, ensuring that the study remains double-blind. The placebo does not contain any active substance and serves to maintain the integrity of the trial's control group.

Efficacy in this clinical trial will be assessed by evaluating the impact of **pelacarsen** (TQJ230) on the progression of calcific aortic valve stenosis. The primary endpoints for efficacy evaluation include the change in peak aortic jet velocity and the change in aortic valve calcium score, both measured from baseline to month 36. These parameters will be assessed using echocardiography and computed tomography, respectively. Secondary endpoints include the change in lipoprotein(a) levels from baseline to month 12, change in fibrocalcific thickening of the aortic valve from baseline to month 36, and the time from randomization to the first occurrence of a composite clinical endpoint event, which includes unplanned hospital admission related to calcific aortic valve stenosis, aortic valve intervention, or death related to the condition. Safety endpoints, including adverse events, serious adverse events, safety laboratory parameters, and vital signs, will be collected from baseline to the end of the study. The trial is designed as a randomized, double-blind, placebo-controlled, multicenter study, with assessments scheduled at specific timepoints to ensure comprehensive data collection and analysis.