A Randomized, Double-Blind, Cross-Over Trial Assessing Rosuvastatin Calcium and Placebo in Statin-Intolerant Patients with High Cardiovascular Risk

The primary objective of this study is to evaluate whether an **n=1 study**—a randomized, double-blind, cross-over trial with counseling on patients' individual treatment results—will enhance the use of statins and decrease the prescription of PCSK9 inhibitors compared to standard care at 12 months post-randomization. This is clinically relevant as it aims to optimize treatment strategies for patients with high cardiovascular risk and **statin-intolerance**, potentially improving patient outcomes and reducing healthcare costs.

Secondary objectives include:

• Assessing statin use at 6, 24, 36, and 48 months after randomization.
• Evaluating PCSK9 inhibitor use at 6, 12, 24, 36, and 48 months.
• Monitoring LDL cholesterol levels at 6, 12, 24, 36, and 48 months.
• Assessing quality of life at 6, 12, 24, 36, and 48 months.
• Evaluating reported side effects at 6, 12, 24, 36, and 48 months.
• Assessing cost-effectiveness at 6, 12, and 24 months.
• Evaluating patients' acceptability to participate in n=1 trials.
• Assessing applicability in clinical care, focusing on healthcare professionals' workload.
• Evaluating patients' perceived treatment concordance during n=1 trials.
• Assessing physical and mental complaints during placebo and statin therapy.
• Evaluating differences in patients' views on medication and decisional conflict regarding lipid-lowering therapy before and after the n=1 intervention.
• Assessing differences in the level of physician trust among patients before and after the n=1 intervention.
• Evaluating biopsychosocial differences between statin-intolerant and nocebo-intolerant patients, focusing on views on medication and decisional conflict.

The clinical trial involves participants with **high cardiovascular risk**, including those with previous cardiovascular disease or familial hypercholesterolemia, and individuals who are statin-intolerant. The study population comprises adults aged 18 years or older, encompassing both male and female subjects. Participants have previously taken two or more statins and discontinued use due to perceived side effects. They have a clinical indication for lipid-lowering therapy related to the prevention of cardiovascular disease. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. All participants have provided full informed consent. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, cross-over** study aimed at evaluating the impact of an 'n=1 study' on increasing **statin** use and reducing the prescription of PCSK9 inhibitors in patients with **statin-intolerance**. The trial will involve participants who are 18 years or older, have previously discontinued two or more statins due to perceived side effects, and have a clinical indication for lipid-lowering therapy related to secondary prevention of cardiovascular disease or familial hypercholesterolemia. The study will utilize **rosuvastatin calcium** tablets and a placebo, both administered orally, to assess the primary endpoint of self-reported statin use 12 months post-inclusion.

The trial is expected to commence recruitment on August 1, 2024, and conclude by July 31, 2030. Participants will be involved in the study for a maximum treatment period of 24 weeks. The sequence of study visits includes an initial screening visit to confirm eligibility, followed by randomization into treatment arms. Participants will undergo multiple follow-up visits to monitor adherence, side effects, and efficacy of the treatment. The end-of-study visit will evaluate the primary endpoint and gather final data on statin use.

Participants may be withdrawn from the study if they experience significant adverse effects, withdraw consent, or if the investigator deems it necessary for safety reasons. The trial is categorized as a low-intervention phase IV study, given the established safety profile of rosuvastatin from previous research. The study aims to provide insights into optimizing therapy for individuals with high cardiovascular risk and statin-intolerance, potentially improving patient outcomes through personalized treatment strategies.

The clinical trial involves the administration of **rosuvastatin** in the form of a 10 mg tablet, produced by Apotheek A15. The active substance in this experimental medication is **rosuvastatin calcium**, a chemical compound. The pharmaceutical form of the medication is a tablet, and it is administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 20 mg over a treatment period of up to 24 weeks. The trial aims to assess the effects of this medication in a randomized, double-blind, cross-over design. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental medication, a placebo is used as a comparator treatment. The placebo is also a 10 mg tablet, produced by Apotheek A15, and is designed to mimic the appearance and administration route of the rosuvastatin tablet. The placebo is administered orally, following the same dosing schedule as the active medication, to maintain the blinding of the study. The use of a placebo allows for the assessment of the nocebo effect in participants who are statin-intolerant. Compliance with the placebo administration will be monitored in the same manner as the active treatment.

Efficacy in the clinical trial titled "N=1-studies In Statin-intolerance; Objectifying Nocebo Effects (NISONE)" will be assessed primarily through the measurement of **statin use** 12 months after inclusion. This endpoint is self-reported by participants, providing insight into the long-term adherence to statin therapy following the intervention. The trial employs a randomized, double-blind, cross-over design, which includes counseling on patients' individual treatment results to potentially enhance statin use and reduce the prescription of PCSK9 inhibitors compared to usual care. The study aims to determine if this approach can effectively increase statin utilization among participants who have previously withdrawn from statins due to perceived side effects. The trial is categorized as a low-intervention, phase IV study, focusing on the practical application of rosuvastatin and its placebo in a real-world setting.