Efficacy of Probucol Combined with Statins Treatment for Ischemic Stroke

NCT06604117 | Recruiting DMC

• 1 other identifier: IRB [2024]275-001
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Ischemic Stroke; Atherosclerosis of Artery; Lipid Disorder; Statin

Keywords

Probucol; Statin; Atherosclerosis; Ischemic stroke; Plaque burden; Lipid-lowering treatment

Outcome Measures

Primary Outcomes (1)

• Change in Plaque Burden from Baseline to 12-Month Follow-up

  The primary outcome is the change in atherosclerotic plaque burden, measured as the percentage of stenosis at the most severe location of atherosclerotic plaque on computed tomography angiography (CTA). Plaque burden is calculated as 100% × (diameter of the plaque at its most severe point/diameter of the arterial lumen). The difference between the baseline and the 12-month follow-up measurement will be used to assess the effectiveness of the treatment.

  Baseline to 12 months

Secondary Outcomes (4)

• Change in High-Risk Plaque Count from Baseline to 12-Month Follow-up

  Baseline to 12 months

• Change in Atherosclerotic Burden Score from Baseline to 12-Month Follow-up

  Baseline to 12 months

• Occurrence of Cardiovascular Events at 12-Month and 24-Month Follow-up

  12 months and 24 months

• Poor Functional Outcome at 1-Month Follow-up

  1 month and 3 months

Other Outcomes (1)

• Changes in Biomarkers from Baseline to 12-Month Follow-up

  Baseline to 12 months

Study Arms (2)

Conventional Lipid-Lowering Therapy Group

Participants who choose this group will receive conventional lipid-lowering therapy following current clinical guidelines, which may include statins, ezetimibe, or PCSK9 inhibitors. The treatment regimen will be tailored to the participants' individual needs but will not include Probucol.

Drug: Statin

Combined Lipid-Lowering Therapy with Probucol Group

Participants who choose this group will receive a combination of conventional lipid-lowering therapy following current clinical guidelines (statins, ezetimibe, or PCSK9 inhibitors) and additional treatment with Probucol 0.5g twice daily. This regimen aims to further reduce atherosclerotic plaque burden and improve cardiovascular outcomes.

Drug: Probucol

Interventions

Statin DRUG

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 primary treatment. If LDL-C levels are not adequately controlled, ezetimibe will be added. If lipid levels remain unsatisfactory, the addition of PCSK9 inhibitors will be considered. Moderate-intensity statins are defined as atorvastatin 10-20 mg or rosuvastatin 5-10 mg.

Also known as: Conventional Lipid-Lowering Therapy

Conventional Lipid-Lowering Therapy Group

Probucol DRUG

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.

Also known as: Probucol and Statin Combination Therapy

Combined Lipid-Lowering Therapy with Probucol Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of hospitalized individuals diagnosed with ischemic stroke at the Stroke Center of Xuanwu Hospital. Participants will be adults aged 18 years and older who meet the inclusion criteria specified for the study.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Xuanwu Hospital, Beijing: lead

Study Sites (1)

Xuanwu Hospital

Xicheng District, Beijing Municipality, China

RECRUITING

Related Publications (14)

• 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 BACKGROUND

• 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. Epub 2021 Apr 18.

  PMID: 33867420 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, Kamel H, Kernan WN, Kittner SJ, Leira EC, Lennon O, Meschia JF, Nguyen TN, Pollak PM, Santangeli P, Sharrief AZ, Smith SC Jr, Turan TN, Williams LS. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021 Jul;52(7):e364-e467. doi: 10.1161/STR.0000000000000375. Epub 2021 May 24. No abstract available.

  PMID: 34024117 BACKGROUND

• Khan SU, Yedlapati SH, Lone AN, Hao Q, Guyatt G, Delvaux N, Bekkering GET, Vandvik PO, Riaz IB, Li S, Aertgeerts B, Rodondi N. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis. BMJ. 2022 May 4;377:e069116. doi: 10.1136/bmj-2021-069116.

  PMID: 35508321 BACKGROUND

• Libby P, Bornfeldt KE, Tall AR. Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res. 2016 Feb 19;118(4):531-4. doi: 10.1161/CIRCRESAHA.116.308334. No abstract available.

  PMID: 26892955 BACKGROUND

• Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, Dixon DL, Fearon WF, Hess B, Johnson HM, Kazi DS, Kolte D, Kumbhani DJ, LoFaso J, Mahtta D, Mark DB, Minissian M, Navar AM, Patel AR, Piano MR, Rodriguez F, Talbot AW, Taqueti VR, Thomas RJ, van Diepen S, Wiggins B, Williams MS; Peer Review Committee Members. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023 Aug 29;148(9):e9-e119. doi: 10.1161/CIR.0000000000001168. Epub 2023 Jul 20.

  PMID: 37471501 BACKGROUND

• GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021 Oct;20(10):795-820. doi: 10.1016/S1474-4422(21)00252-0. Epub 2021 Sep 3.

  PMID: 34487721 BACKGROUND

• Gutierrez J, Turan TN, Hoh BL, Chimowitz MI. Intracranial atherosclerotic stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2022 Apr;21(4):355-368. doi: 10.1016/S1474-4422(21)00376-8. Epub 2022 Feb 7.

  PMID: 35143758 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood

MeSH Terms

Conditions

Ischemic Stroke; Lipid Metabolism Disorders; Atherosclerosis

Interventions

Hydroxymethylglutaryl-CoA Reductase Inhibitors; Probucol

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases

Intervention Hierarchy (Ancestors)

Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Jing Dong, Doctor

  Xuanwu Hospital, Beijing

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xin Ma, Doctor

CONTACT

+86 13501390691; maxin@xwh.ccmu.edu.cn

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Doctor

Study Record Dates

• First Submitted: September 15, 2024
• First Posted: September 19, 2024
• Study Start: October 17, 2024
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: March 25, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

CN (1)