Changes in plaque characteristics after short-term statin therapy assessed with coronary CT

The primary objective of this study is to evaluate the change in non-calcified plaque volume during a 3-month follow-up period in patients with coronary artery disease undergoing statin therapy. This objective addresses the critical need to assess early plaque modification effects of lipid-lowering treatment, which may provide insights into the mechanisms of cardiovascular risk reduction and guide therapeutic decision-making in patients with stable chest pain.

The secondary objectives include:

• Change in total plaque volume at 3-month, 24-month, and between 3- and 24-month follow-up periods.

• Change in low attenuation non-calcified plaque volume during 3-month and 24-month follow-up periods.

• Change in non-calcified plaque volume between 3- and 24-month follow-up period and during 24-month follow-up period.

• Change in plaque composition during 3-month and 24-month follow-up periods.

• Change in per-vessel fractional flow reserve (FFRCT) during 3-month and 24-month follow-up periods.

• Change in the prevalence of high-risk plaque features during 3-month and 24-month follow-up periods.

• Change in radiomic features during 3-month and 24-month follow-up periods.

• Prevalence of major adverse cardiac event and clinical adverse event.

• Changes in blood lipid profile, inflammatory markers, and markers of glucose homeostasis.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population included both **male** and **female** subjects, with males aged 40 to 75 years and females aged 45 to 75 years. Participants were patients with **coronary artery disease** presenting with **stable chest pain** who required clinically indicated **coronary CT angiography**. The trial population consisted of **statin-naive patients** who had at least one partially-calcified or **non-calcified plaque** identified on imaging, with fractional flow reserve derived from CT (**FFRCT**) greater than 0.75 distal to stenosis. Subjects were required to have no contraindications to CT angiography and to provide informed consent. No vulnerable populations were included in the study.

This clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate changes in coronary artery **plaque characteristics** following short-term **statin therapy** in patients with **coronary artery disease**. The trial employs **coronary computed tomography angiography** (coronary CT) as the primary imaging modality to assess plaque morphology and composition. The study involves **statin-naive** patients aged 45-75 years for females and 40-75 years for males who present with stable chest pain and have a clinically indicated coronary CT angiography. Eligible participants must have at least one partially-calcified or **non-calcified plaque** identified on imaging and demonstrate **fractional flow reserve** (FFR-CT) greater than 0.75 distal to the stenosis. Participants must have no contraindications to CT angiography and must provide informed consent by understanding and signing the consent form.

The trial investigates the active substance **rosuvastatin**, administered as a 10 mg **film-coated tablet** via the **oral route**, compared against a lactose-free **placebo** capsule. The maximum daily dose of rosuvastatin is 40 mg, with a maximum total dose of 3600 mg over a treatment period of 12 weeks. The primary objective is to measure the change in non-calcified plaque volume during a 3-month follow-up period, expressed in cubic millimeters. Secondary endpoints include assessment of plaque composition measured at both 3-month and 24-month visits, with components categorized by **Hounsfield units** (HU): **low attenuation plaque** (−100 to 30 HU), non-calcified plaque (30 to 350 HU), and **calcified plaque** (>350 HU). Additional secondary endpoints encompass total plaque volume, low-attenuation non-calcified plaque volume, CT-based fractional flow reserve, visual presence of **high-risk plaque features** including **positive remodeling**, **napkin-ring sign**, **spotty calcification**, minimal luminal area, and plaque burden ≥70%, as well as radiomic features at both follow-up time points.

The study timeline extends from an estimated recruitment start date of July 1, 2025, to an estimated end date of December 31, 2029, representing an overall trial duration of approximately 4.5 years. Participant involvement includes an initial screening visit where eligibility is confirmed through coronary CT angiography and baseline assessments. Following enrollment and randomization, participants receive either rosuvastatin or placebo for a period of 12 weeks. A follow-up visit is scheduled at 3 months post-baseline for repeat coronary CT angiography and evaluation of primary and secondary endpoints. An extended follow-up visit occurs at 24 months to assess long-term plaque changes and additional imaging parameters. The end-of-study visit coincides with the completion of the 24-month assessment, at which point final data collection is performed.

Throughout the trial, safety monitoring includes assessment of **major adverse events** such as death, **cardiovascular death**, fatal and nonfatal **myocardial infarction**, fatal and nonfatal **stroke** or **transient ischemic attack** (TIA), **unstable angina**, and hospitalization. Minor adverse events are also recorded, including muscle pain, constipation, abdominal pain or meteorismus, nausea, headache, vertigo, fatigue, skin rash, and pruritus. Laboratory parameters are monitored and include **total cholesterol**, **low-density lipoprotein** (LDL) cholesterol, **high-density lipoprotein** (HDL) cholesterol, **triglycerides**, **lipoprotein(a)** (Lp(a)), **apolipoprotein A1** (apoA1), **apolipoprotein B** (apoB), **high-sensitivity C-reactive protein** (hs-CRP), **ferritin**, and **hemoglobin A1c**. Conditions that may lead to early termination from the study include the occurrence of major adverse events, development of contraindications to continued study participation, withdrawal of consent by the participant, or at the discretion of the investigator if continuation poses unacceptable risk to the participant.

The trial is classified as a **low-intervention clinical trial** because the investigational medicinal product is authorized for marketing and is used in accordance with the terms of its marketing authorization and approved clinical indications. The additional diagnostic procedures, such as coronary CT and blood sampling, pose only minimal additional risk to the safety of study participants when compared to standard clinical practice. This study is sponsored by Semmelweis University and the National Research, Development and Innovation Office (Hungarian Scientific Research Fund), utilizing commercially available statin therapy to ensure minimal additional risk compared to routine care.

The experimental treatment in this clinical trial is Xeter 10 mg film-coated tablet, containing rosuvastatin as the active substance. Rosuvastatin is a chemical substance classified under ATC code C10AA07. The medicinal product is manufactured by Gedeon Richter PLC and is authorized in Hungary under the marketing authorization number OGYI-T-21173/03. The pharmaceutical form is a film-coated tablet administered via the oral route. The maximum daily dose is 40 mg, with a maximum total dose of 3600 mg over the treatment period. The maximum treatment duration is 12 weeks. This product serves as the test medication in the trial, which aims to evaluate changes in non-calcified plaque volume during a 3-month follow-up period using coronary computed tomography.

The comparator treatment consists of a placebo formulation presented as a white, lactose-free capsule containing 0.2 g of inactive ingredients. The placebo does not contain any active pharmaceutical substance and is designed to match the experimental treatment regimen. Administration details for the placebo follow the same schedule as the active treatment to maintain blinding and ensure methodological rigor throughout the trial duration.

The primary efficacy endpoint is **non-calcified plaque volume** at 3 months follow-up, expressed in cubic millimeters. Secondary efficacy endpoints include **total plaque volume** measured at both 3-month and 24-month follow-up visits, expressed in cubic millimeters. **Plaque composition** will be assessed at the 3-month and 24-month visits, with each component expressed in cubic millimeters and categorized by attenuation levels: low attenuation (−100 to 30 HU), non-calcified (30 to 350 HU), and calcified (greater than 350 HU). **Low-attenuation non-calcified plaque volume** will be evaluated during both the 3-month and 24-month follow-up periods, expressed in cubic millimeters.

Additional secondary endpoints include **CT-based Fractional Flow Reserve** (FFR-CT) measured at 3 months and 24 months follow-up. Visual presence of **high-risk plaque features** will be assessed at both the 3-month and 24-month follow-up, including low attenuation plaque, positive remodeling, napkin-ring sign, spotty calcification, minimal luminal area, or plaque burden equal to or greater than 70 percent. **Radiomic features** will be evaluated at both 3-month and 24-month follow-up visits. Laboratory parameters assessed include **total cholesterol**, **low-density lipoprotein cholesterol**, **high-density lipoprotein cholesterol**, **triglycerides**, **lipoprotein(a)**, **apolipoprotein A1**, **apolipoprotein B**, **high-sensitivity C-reactive protein**, **ferritin**, and **hemoglobin A1c**.

Safety assessments include monitoring for major adverse events such as death, cardiovascular death, fatal and nonfatal myocardial infarction, fatal and nonfatal stroke or transient ischemic attack, unstable angina, and hospitalization. Minor adverse events monitored include muscle pain, constipation, abdominal pain or meteorismus, nausea, headache, vertigo, fatigue, skin rash, and pruritus.