Evaluation of Preemptive Genotyping Strategy on Statin-Induced Musculoskeletal Adverse Events in Cardiovascular Risk Patients Using Atorvastatin and Drug Combination

The primary objective of this study is to assess the efficacy of a **statin** preemptive genotyping strategy in reducing statin-associated musculoskeletal adverse events. This is clinically relevant as it aims to minimize the occurrence of musculoskeletal symptoms, which are common side effects of statin therapy, thereby potentially improving patient outcomes and adherence to treatment.

Secondary objectives include:

• Assessing the efficacy of a statin preemptive genotyping strategy in optimizing dyslipidemia management compared to Standard of Care (SoC) treatment/dosing.
• Evaluating the pharmacoeconomic feasibility of implementing a preemptive pharmacogenetic strategy to address adverse musculoskeletal symptoms.
• Identifying novel prognostic and predictive genetic biomarkers of statin-related adverse events and efficacy.
• Assessing the efficacy of a statin preemptive genotyping strategy in reducing major ischemic cardiovascular events.
• Evaluating the effect of a statin preemptive genotyping strategy in improving patient therapeutic adherence.
• Assessing the effect of a statin preemptive genotyping strategy in reducing perceived pain of statin-associated musculoskeletal symptoms (SAMS).

The clinical trial involves **participants** at risk of cardiovascular disease who are susceptible to receiving high or moderate-intensity doses of statins. The study population includes both male and female subjects aged 18 years and older. Participants are required to be in general good health, with the ability to understand the study's purpose and risks, and to provide informed consent. The trial does not involve a vulnerable population. Participants must be naïve to any genotyping test of specific genes and willing to comply with treatment plan modifications. Women of childbearing potential must commit to not becoming pregnant and use highly effective contraceptive methods or practice sexual abstinence during the study. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, single-blind, controlled, adaptive phase IV study to evaluate the efficacy, safety, and cost-efficacy of a pre-emptive genotyping strategy in patients at risk of cardiovascular disease who are susceptible to receiving high or moderate-intensity doses of statins. The trial will involve a 9-month follow-up period, with the primary objective being to assess the efficacy of this genotyping strategy in reducing statin-associated musculoskeletal adverse events. The trial will include several key phases, starting with an inclusion (screening) visit, followed by regular follow-up visits, and concluding with an end-of-study visit.

Participants will be involved in the study for a maximum of 9 months. The inclusion visit will determine eligibility based on criteria such as age (≥18 years), willingness to comply with the study protocol, and susceptibility to be prescribed specific statins, including **atorvastatin**, **simvastatin**, **pitavastatin**, **rosuvastatin**, **pravastatin**, **lovastatin**, and **fluvastatin**. Participants must also be naïve to genotyping tests for specific genes and agree to use effective contraceptive methods if applicable. Follow-up visits will monitor the incidence of musculoskeletal symptoms, changes in LDL cholesterol levels, and any necessary modifications to the treatment plan. The end-of-study visit will assess the overall outcomes and any adverse events experienced during the trial.

Participants may be terminated early from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The primary endpoint is a composite variable that includes the incidence of clinically relevant statin-associated musculoskeletal symptoms or elevated serum CPK levels. Secondary endpoints include changes in LDL cholesterol levels, the need for statin dose modifications, and the cost-efficacy of the intervention. The trial is expected to start recruitment in April 2024 and conclude by January 2025.

The clinical trial involves the administration of several **statins** as part of the experimental treatment regimen. **Atorvastatin**, marketed as Atorvastatina NORMON 40 mg, is provided in the form of a film-coated tablet. The maximum daily dose is 80 mg, with a total maximum dose of 21,600 mg over a treatment period of up to 9 months. The route of administration is oral, and the medication is intended for cardiovascular risk prevention.

**Pitavastatin calcium**, available as pitavastatina cinfa 2 mg, is also administered as a film-coated tablet. The maximum daily dose is 4 mg, with a total maximum dose of 1,080 mg over the same treatment period. This medication is administered orally and is used for cardiovascular risk prevention.

**Simvastatin**, under the brand name simvastatina cinfa 20 mg, is provided in a film-coated tablet form. The maximum daily dose is 80 mg, with a total maximum dose of 21,600 mg over 9 months. It is administered orally for the purpose of cardiovascular risk prevention.

**Lovastatin**, marketed as lovastatina cinfa 40 mg, is available in tablet form. The maximum daily dose is 80 mg, with a total maximum dose of 21,600 mg over the treatment period. The route of administration is oral, and it is used for cardiovascular risk prevention.

**Rosuvastatin**, available as Rosuvastatina ratiopharm 20 mg, is provided in a film-coated tablet form. The maximum daily dose is 40 mg, with a total maximum dose of 10,800 mg over 9 months. It is administered orally for cardiovascular risk prevention.

**Fluvastatin**, marketed as Fluvastatina ratiopharm 80 mg, is provided in a prolonged-release tablet form. The maximum daily dose is 80 mg, with a total maximum dose of 21,600 mg over the treatment period. The route of administration is oral, and it is used for cardiovascular risk prevention.

**Pravastatin sodium**, available as Pravastatina Cinfamed 40 mg, is administered in tablet form. The maximum daily dose is 40 mg, with a total maximum dose of 10,800 mg over 9 months. It is administered orally for cardiovascular risk prevention.

All medications are chemically derived and are not formulated for pediatric use. The trial does not include any non-experimental treatments such as placebo or comparator treatments. Participant compliance with the dosing schedule is monitored throughout the trial period to ensure adherence to the prescribed regimen.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is a composite variable that includes the incidence of patients experiencing clinically relevant statin-associated musculoskeletal symptoms, defined by a **SAMS-CI** score of 7 or higher and a **Numeric Pain Rating Scale (NPRS)** score of 3 or higher, or a serum **CPK** level exceeding three times the upper limit of normality as specified by each center's laboratory, within a 9-month follow-up period. Secondary endpoints include the 9-month change in percentual **LDLc**, defined as the percentage difference between LDLc values at 9 months and baseline LDLc, and the percentage of patients requiring statin dose modification, withdrawal, or additional lipid-lowering therapy to meet LDLc goals after 9 months.

Additional secondary endpoints involve the cost-efficacy analysis, comparing the costs of the intervention and related procedures with the costs derived from events in the control arm over the 9-month follow-up period. The trial will also assess novel prognostic and predictive genetic biomarkers of statin-related adverse events and efficacy in outlier subjects or for quality control reasons, using techniques available at CNIO, including genome-wide association studies. Furthermore, the percentage of participants experiencing a 4-component exploratory endpoint, consisting of cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina, will be evaluated. Differences in adherence levels, as measured by the **Morisky-Green (MMAS-8)** questionnaire, and differences in **NPRS** scores between study arms will also be assessed.