Efficacy of Probucol Combined with Statins Treatment for Ischemic Stroke

NCT ID: NCT06604117

Last Updated: 2025-03-25

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

200 participants

Study Classification

OBSERVATIONAL

Study Start Date

2024-10-17

Study Completion Date

2027-10-31

Brief Summary

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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

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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.

Conditions

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Ischemic Stroke Atherosclerosis of Artery Lipid Disorder Statin

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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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.

Statin

Intervention Type 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.

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.

Probucol

Intervention Type 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.

Interventions

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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 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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Conventional Lipid-Lowering Therapy Probucol and Statin Combination Therapy

Eligibility Criteria

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Inclusion Criteria

1. Aged 18 years or older.
2. Diagnosed with ischemic stroke (IS) confirmed by cranial CT/MRI.
3. Onset of stroke within the last 30 days.
4. 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.
5. Signed informed consent.

Exclusion Criteria

1. History of allergy to Probucol or statins.
2. Non-atherosclerotic arterial stenosis, such as vasculitis, moyamoya disease, or arterial dissection.
3. Potential cardiac embolic sources, such as atrial fibrillation, artificial heart valves, endocarditis, or patent foramen ovale.
4. Known bleeding tendencies or hemorrhagic diseases, such as thrombocytopenia (platelet count \< 100 × 10\^9/L), hemorrhagic stroke, or gastrointestinal bleeding.
5. Severe myocardial diseases such as myocardial infarction (MI) or myocarditis.
6. 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.
7. Ventricular tachycardia, bradycardia, torsades de pointes, or syncopal episodes of cardiac origin.
8. Prolonged QT interval or conditions that may prolong the QT interval, such as certain medications.
9. Suffering from a severe illness with a life expectancy of less than one year or unable to cooperate due to cognitive or psychological issues.
10. 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.
11. Pregnant or breastfeeding individuals, those trying to conceive.
12. Concurrent participation in another clinical trial involving investigational drugs or devices within the past 30 days.
13. Planned surgery or intervention that would require discontinuation of the study medication during the study period.
14. Any reason, known to the participant and investigator, that would prevent the participant from adhering to the study protocol or follow-up.
15. Other conditions determined by the investigator that may require exclusion.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Xuanwu Hospital, Beijing

OTHER

Sponsor Role lead

Responsible Party

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Xin Ma

Chief Doctor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Jing Dong, Doctor

Role: PRINCIPAL_INVESTIGATOR

Xuanwu Hospital, Beijing

Locations

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Xuanwu Hospital

Xicheng District, Beijing Municipality, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Xin Ma, Doctor

Role: CONTACT

+86 13501390691

Facility Contacts

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Xin Ma

Role: primary

+86 13501390691

References

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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.

Reference Type BACKGROUND
PMID: 32336234 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 33867420 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 21852751 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 1435295 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29115480 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 21747278 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 35583875 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 33883728 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 34024117 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 35508321 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26892955 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 37471501 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 34487721 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 35143758 (View on PubMed)

Other Identifiers

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IRB [2024]275-001

Identifier Type: -

Identifier Source: org_study_id

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