Efficacy of Probucol Combined with Statins Treatment for Ischemic Stroke

Official title

A Prospective, Open-label Study Evaluating the Effects of Probucol Combined with Statins on Atherosclerotic Characteristics and Prognosis in Patients with Ischemic Stroke

Overview

The goal of this clinical trial is to evaluate whether the combination of Probucol with statin therapy can reduce the risk of vascular events and improve atherosclerosis outcomes in adults with ischemic stroke and confirmed atherosclerosis. The main questions it aims to answer are: Does adding Probucol to statin therapy reduce plaque burden more effectively than statins alone? Does the combination therapy lead to fewer cardiovascular and cerebrovascular events compared to statins alone? Researchers will compare participants receiving standard statin therapy to those receiving statins combined with Probucol to assess differences in plaque burden and the occurrence of vascular events. Participants will: Choose either standard statin therapy (with possible addition of ezetimibe or PCSK9 inhibitors) or the same therapy combined with Probucol 0.5g twice daily. Attend regular follow-up visits for monitoring atherosclerosis features and cardiovascular health over a 3-year period. Undergo imaging studies to evaluate changes in atherosclerosis and blood tests to monitor lipid levels and other biomarkers.

Detailed description

This single-center, prospective, open-label study will assess the effects of combining Probucol with statin therapy on the progression of atherosclerosis and the risk of vascular events in people with ischemic stroke. The primary hypothesis is that, in participants receiving guideline-recommended statin therapy, the addition of Probucol will reduce cardiovascular and cerebrovascular event risk, enhance plaque stability, and be well-tolerated.

The study will include participants aged 18 years or older who have experienced an ischemic stroke within the past 30 days and have confirmed atherosclerosis in any major artery (carotid, coronary, aortic, renal, or peripheral arteries). Participants will either follow a guideline-recommended lipid-lowering regimen (statins, with or without ezetimibe or PCSK9 inhibitors as needed) or a similar regimen combined with Probucol 0.5g twice daily. The study will enroll at least 100 participants in both the standard therapy group and the Probucol combination group.

Primary outcomes will include changes in plaque burden, while secondary outcomes will cover atherosclerotic features, composite vascular events (ischemic stroke, ischemic heart disease, vascular death), stroke recurrence, and poor functional prognosis (mRS ≥ 3). Exploratory outcomes will include changes in biochemical markers such as LDL-C, Ox-LDL, and Lp(a). Safety will be assessed by monitoring adverse events and serious adverse events.

Statistical analysis will include a multivariate linear regression model for primary outcomes, adjusted for baseline characteristics such as LDL-C levels and previous cardiovascular events. For time-to-event endpoints, Kaplan-Meier curves will be used, with Cox proportional hazards models providing hazard ratios. Subgroup analyses and repeated measures will further refine the understanding of treatment effects.

Interventions

• Drug Statin
  Participants who opt for this group will receive guideline-recommended conventional lipid-lowering therapy. For those with a history of ischemic stroke (IS), myocardial infarction (MI), acute coronary syndrome within the past year, symptomatic peripheral artery disease, or two or more high-risk factors, the target LDL-C level will be set at 1.4 mmol/L. For other IS participants, the LDL-C target will be set at 1.8 mmol/L. All participants will receive moderate-intensity statin therapy as the pri
• Drug Probucol
  Participants who choose this group will receive Probucol in combination with guideline-recommended lipid-lowering therapy. Specifically, participants in this group will take 0.5 grams of Probucol twice daily alongside the conventional lipid-lowering therapy mentioned in Group 1. The combination of Probucol and conventional therapy aims to further improve lipid profile and address atherosclerosis.

Primary outcome measures

• Change in Plaque Burden from Baseline to 12-Month Follow-up [Time frame: Baseline to 12 months]

Secondary outcome measures (4)

• Change in High-Risk Plaque Count from Baseline to 12-Month Follow-up [Time frame: Baseline to 12 months]
• Change in Atherosclerotic Burden Score from Baseline to 12-Month Follow-up [Time frame: Baseline to 12 months]
• Occurrence of Cardiovascular Events at 12-Month and 24-Month Follow-up [Time frame: 12 months and 24 months]
• Poor Functional Outcome at 1-Month Follow-up [Time frame: 1 month and 3 months]

Eligibility criteria

Inclusion criteria

• Aged 18 years or older.
• Diagnosed with ischemic stroke (IS) confirmed by cranial CT/MRI.
• Onset of stroke within the last 30 days.
• Evidence of atherosclerosis (AS) in at least one artery (carotid, coronary, aorta, renal, or peripheral arteries) identified through neck CTA, coronary CTA, or ultrasound examination of lower extremity arteries.
• Signed informed consent.

Exclusion criteria

• History of allergy to Probucol or statins.
• Non-atherosclerotic arterial stenosis, such as vasculitis, moyamoya disease, or arterial dissection.
• Potential cardiac embolic sources, such as atrial fibrillation, artificial heart valves, endocarditis, or patent foramen ovale.
• Known bleeding tendencies or hemorrhagic diseases, such as thrombocytopenia (platelet count \< 100 × 10\^9/L), hemorrhagic stroke, or gastrointestinal bleeding.
• Severe myocardial diseases such as myocardial infarction (MI) or myocarditis.
• Liver (ALT or AST \> twice the upper limit of normal) or kidney (creatinine \> 1.5 times the upper limit of normal or glomerular filtration rate \< 50 ml/min) dysfunction.
• Ventricular tachycardia, bradycardia, torsades de pointes, or syncopal episodes of cardiac origin.
• Prolonged QT interval or conditions that may prolong the QT interval, such as certain medications.
• Suffering from a severe illness with a life expectancy of less than one year or unable to cooperate due to cognitive or psychological issues.
• Use of Probucol or any lipid-lowering medication other than statins, ezetimibe, and PCSK9 inhibitors within the 30 days prior to enrollment, including bile acid sequestrants, fibrates, and other similar drugs.
• Pregnant or breastfeeding individuals, those trying to conceive.
• Concurrent participation in another clinical trial involving investigational drugs or devices within the past 30 days.
• Planned surgery or intervention that would require discontinuation of the study medication during the study period.
• Any reason, known to the participant and investigator, that would prevent the participant from adhering to the study protocol or follow-up.
• Other conditions determined by the investigator that may require exclusion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 1 center

• Xuanwu Hospital — Xicheng District

Publications

• Kong Q, Ma X, Wang C, Du X, Ren Y, Wan Y. Total Atherosclerosis Burden of Baroreceptor-Resident Arteries Independently Predicts Blood Pressure Dipping in Patients With Ischemic Stroke. Hypertension. 2020 Jun;75(6):1505-1512. doi: 10.1161/HYPERTENSIONAHA.120.15036. Epub 2020 Apr 27. PMID 32336234
• Arai H, Bujo H, Masuda D, Ishibashi T, Nakagawa S, Tanabe K, Kagimura T, Kang HJ, Kim MH, Sung J, Kim SH, Kim CH, Park JE, Ge J, Oh BH, Kita T, Saito Y, Fukushima M, Matsuzawa Y, Yamashita S. Integrated Analysis of Two Probucol Trials for the Secondary Prevention of Atherosclerotic Cardiovascular Events: PROSPECTIVE and IMPACT. J Atheroscler Thromb. 2022 Jun 1;29(6):850-865. doi: 10.5551/jat.62821 PMID 33867420
• Li T, Chen W, An F, Tian H, Zhang J, Peng J, Zhang Y, Guo Y. Probucol attenuates inflammation and increases stability of vulnerable atherosclerotic plaques in rabbits. Tohoku J Exp Med. 2011 Sep;225(1):23-34. doi: 10.1620/tjem.225.23. PMID 21852751
• Naruszewicz M, Selinger E, Dufour R, Davignon J. Probucol protects lipoprotein (a) against oxidative modification. Metabolism. 1992 Nov;41(11):1225-8. doi: 10.1016/0026-0495(92)90013-z. PMID 1435295
• Zhu BB, Wang H, Chi YF, Wang YM, Yao XM, Liu S, Qiu H, Fang J, Yin PH, Zhang XM, Peng W. Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX-1/ROS/MAPK signaling. Mol Med Rep. 2018 Jan;17(1):1289-1296. doi: 10.3892/mmr.2017.7935. Epub 2017 Nov 2. PMID 29115480
• Mitra S, Deshmukh A, Sachdeva R, Lu J, Mehta JL. Oxidized low-density lipoprotein and atherosclerosis implications in antioxidant therapy. Am J Med Sci. 2011 Aug;342(2):135-42. doi: 10.1097/MAJ.0b013e318224a147. PMID 21747278
• Duarte Lau F, Giugliano RP. Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review. JAMA Cardiol. 2022 Jul 1;7(7):760-769. doi: 10.1001/jamacardio.2022.0987. PMID 35583875
• Libby P. The changing landscape of atherosclerosis. Nature. 2021 Apr;592(7855):524-533. doi: 10.1038/s41586-021-03392-8. Epub 2021 Apr 21. PMID 33883728

Identifiers

NCT: NCT06604117 · IRB [2024]275-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗