Evaluation of Pelacarsen (TQJ230) in Reducing Major Cardiovascular Events in Patients with Established Cardiovascular Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to demonstrate the **superiority** of pelacarsen (TQJ230) compared to placebo in reducing the risk of expanded major adverse cardiovascular events (MACE), which include cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, and urgent coronary re-vascularization requiring hospitalization. This evaluation is conducted in two groups: the overall study population with established cardiovascular disease (CVD) and lipoprotein(a) levels of 70 mg/dL or higher, and a subpopulation with established CVD and lipoprotein(a) levels of 90 mg/dL or higher. The clinical relevance of this objective lies in its potential to provide a novel therapeutic option for reducing cardiovascular risk in patients with elevated lipoprotein(a), a known risk factor for cardiovascular events.

Secondary objectives include:

• Demonstrating the superiority of pelacarsen compared to placebo in reducing the risk of the MACE composite of cardiovascular death, non-fatal MI, and non-fatal stroke.
• Demonstrating the superiority of pelacarsen compared to placebo in reducing the risk of the composite of coronary heart disease (CHD) outcomes, including death due to CHD, non-fatal MI, and urgent coronary re-vascularization requiring hospitalization.
• Evaluating the rate of all-cause death.
• Demonstrating the superiority of pelacarsen compared to placebo in lowering the lipoprotein(a) level at 1 year.

The clinical trial involves a total of **4206 participants** diagnosed with **cardiovascular disease**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having a lipoprotein(a) level of at least 70 mg/dL at the screening visit and being on optimal LDL-cholesterol lowering treatment. The trial also considers individuals with a history of myocardial infarction or ischemic stroke within a specified timeframe, as well as those with clinically significant symptomatic peripheral artery disease. The study population includes a vulnerable population, indicating that additional ethical considerations are in place. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants have established cardiovascular disease, aligning with the study's objective to assess the efficacy of pelacarsen in reducing major adverse cardiovascular events.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **pelacarsen** (TQJ230) in reducing major adverse cardiovascular events (MACE) in patients with established **cardiovascular disease**. The trial will span an estimated duration from December 2019 to July 2025, with a maximum treatment period of 52 weeks for each participant. The study involves the administration of TQJ230 or a placebo via **subcutaneous injection** using a pre-filled syringe with a needle safety device. The primary objective is to demonstrate the superiority of TQJ230 over placebo in reducing the risk of expanded MACE, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as lipoprotein(a) levels of ≥ 70 mg/dL and a history of myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease. Following successful screening, participants will be randomized to receive either TQJ230 or placebo. Follow-up visits will be scheduled periodically to monitor safety, efficacy, and any changes in lipoprotein(a) levels. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.

The expected length of participant involvement is approximately one year, with conditions for early termination including significant adverse events or withdrawal of consent. The primary endpoints focus on the time to the first occurrence of expanded MACE, while secondary endpoints include changes in lipoprotein(a) levels and time to all-cause death. The trial aims to provide robust data on the potential benefits of TQJ230 in managing cardiovascular risk in patients with elevated lipoprotein(a) levels.

The clinical trial involves the administration of **TQJ230**, an experimental medication, which is a **solution for injection in a pre-filled syringe**. The active substance in TQJ230 is **pelacarsen**, classified as an antisense oligonucleotide of nucleic acid origin. The pharmaceutical form is a solution for injection, and it is administered via the **subcutaneous route**. The dosage is set at 80 mg per injection, with a maximum total dose of 4080 mg over a treatment period of 52 weeks. The administration frequency is determined by the study protocol, ensuring participant compliance through regular monitoring. The product is manufactured by Novartis Pharma AG.

The study also includes a **placebo** treatment, which is designed to match the TQJ230 in appearance and administration method. The placebo is a solution for injection in a pre-filled syringe with a needle safety device, ensuring blinding of the study. The placebo is administered subcutaneously, following the same dosing schedule as the experimental medication. This placebo control is essential for assessing the efficacy and safety of TQJ230 in reducing major cardiovascular events in patients with established cardiovascular disease.

Efficacy in this clinical trial will be assessed by evaluating the impact of **pelacarsen** (TQJ230) on major cardiovascular events in patients with established cardiovascular disease. The primary endpoints include the time to the first occurrence of CEC-confirmed expanded MACE, which encompasses cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, and urgent coronary revascularization requiring hospitalization. This will be measured in two populations: patients with elevated lipoprotein(a) [Lp(a)] levels of ≥ 70 mg/dL and a subpopulation with Lp(a) levels of ≥ 90 mg/dL.

Secondary endpoints will include the time to the first occurrence of the CEC-confirmed composite endpoint of MACE, which includes cardiovascular death, non-fatal MI, and non-fatal stroke. Additionally, the time to the first occurrence of the CEC-confirmed composite endpoint of coronary heart disease (CHD), which includes CHD death, non-fatal MI, and urgent coronary revascularization requiring hospitalization, will be assessed. Changes in Lp(a) levels on a log scale from baseline at one year and the time to CEC-confirmed all-cause death will also be evaluated.

The trial is designed as a randomized, double-blind, placebo-controlled, multicenter study. The efficacy parameters will be collected and analyzed at specified time points throughout the study duration, which is estimated to conclude by July 2025. The trial aims to demonstrate the superiority of pelacarsen over placebo in reducing the risk of expanded MACE in the specified patient populations.