Prospective Management of Plaque Instability With Statins and Extra Folic Acid

Official title

A Prospective, Exploratory, Cohort Clinical Study Comparing the Effects of Oral Statins With or Without Folic Acid on Carotid Plaque Stability.

Overview

This is a prospective, exploratory, cohort clinical study aiming to further investigate the direct impact of folic acid on the stability of carotid atherosclerotic plaques, building upon substantial clinical evidence confirming that folic acid supplementation reduces the risk of stroke in hypertensive patients, thereby providing a basis for subsequent confirmatory randomized controlled trials. The study will enroll patients with carotid plaques who have not undergone carotid endarterectomy or stent implantation, with lesions defined-according to the Expert Consensus on Standardized Ultrasound Operation and Reporting of Carotid Atherosclerotic Plaques (2025, Shanghai)-as the presence of at least one site with a carotid intima-media thickness (cIMT) ≥ 1.5 mm or visible plaque formation. Participants will be allocated into Cohort 1 (statin therapy) and Cohort 2 (statin therapy plus folic acid); Cohort 1 will receive oral atorvastatin 20 mg daily, while Cohort 2 will receive an additional oral folic acid 5 mg daily on top of the 20 mg oral atorvastatin regimen, both for a continuous duration of 6 months. Statin therapy in both groups will be standardized and managed in accordance with current clinical guidelines, and all subjects will undergo comprehensive evaluations at baseline and after the 6-month intervention. The primary endpoint is the change in carotid plaque thickness at 6 months post-treatment, while secondary endpoints encompass changes in maximum plaque diameter, analysis of plaque composition ratio, and the regulatory effects on serum metabolic markers and the peripheral immune microenvironment, alongside continuous monitoring of treatment-related adverse events throughout the study to comprehensively evaluate overall safety and tolerability.

Interventions

• Drug Atorvastatin plus folic acid
  Patients will receive oral folic acid 5 mg daily plus 20 mg atorvastatin regimen, with both treatments continuing for a duration of 6 months
• Drug Atorvastatin
  Patients will receive 20 mg atorvastatin regimen for a duration of 6 months

Primary outcome measures

• Effects of oral folic acid combined with statins on carotid plaque thickness [Time frame: 6 months]

Secondary outcome measures (4)

• To investigate the effect of oral folic acid combined with statins on the maximum diameter of carotid plaques; [Time frame: 6 months]
• To investigate the changes in plaque composition ratios following the administration of oral folic acid combined with statins-including changes in intraplaque calcification area, fibrous cap thickness, intraplaque neovascularization, echo intensity. [Time frame: 6 months]
• To evaluate the impact on the proportions of peripheral blood B-cell subsets (via flow cytometry) and serum IgM/IgG titers (via ELISA) [Time frame: 6 months]
• Safety and Tolerability: To monitor the incidence of adverse events (AEs) during the treatment period. This includes, but is not limited to, drug-specific safety profiles (e.g., gastrointestinal reactions, hepatic and renal dysfunction, and allergic reac [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Signed and dated written informed consent form (version approved by the Ethics Committee);
• Voluntary participation and commitment to comply with the study protocol;
• Aged 18 to 75 years, regardless of sex;
• Confirmed carotid plaque by ultrasound or computed tomography angiography (CTA), defined-according to the Expert Consensus on Standardized Ultrasound Operation and Reporting of Carotid Atherosclerotic Plaques (2025, Shanghai)-as the presence of at least one lesion with a carotid intima-media thickness (cIMT) ≥ 1.5 mm or plaque formation;
• Able to cooperate and complete the 6-month study follow-up, including regular imaging examinations and blood sample collections.

Exclusion criteria

• History of plaque excision or interventional procedures, such as carotid endarterectomy (CEA) or carotid artery stenting (CAS);
• History of severe hepatic or renal impairment, malignancies, autoimmune diseases, or psychiatric disorders;
• Pregnant or lactating women;
• Hypersensitivity (or allergy) to any components of the study medications;
• Current or long-term regular use of any dietary supplements or medications that may significantly affect the folate metabolic cycle (e.g., vitamin B6, vitamin B12, multivitamins, etc.).

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

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Shanghai Jiao Tong University Medical School Affiliated Ruijing Hospital — Shanghai

Publications

• Zeng Y, Chen YB, Pan BZ, Zhang DW. Complete mitochondrial genome of Schizopygopsis malacanthus (Teleostei: Cypriniformes: Cyprinidae). Mitochondrial DNA A DNA Mapp Seq Anal. 2016;27(2):1405-6. doi: 10.3109/19401736.2014.947602. Epub 2014 Aug 8. PMID 25103444
• Hartert M, Mann WJ, Senbaklavaci O. Relocation of an infected tracheostoma: anterior mediastinal tracheostomy as Mission:Impossible. Interact Cardiovasc Thorac Surg. 2021 Jul 26;33(2):319-321. doi: 10.1093/icvts/ivab071. PMID 33792686
• Yang YY, Gao ZX, Mao ZH, Liu DW, Liu ZS, Wu P. Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy. Front Endocrinol (Lausanne). 2023 Jan 18;13:1079465. doi: 10.3389/fendo.2022.1079465. eCollection 2022. PMID 36743936
• Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, Khan NS, Wong CK, Shamailova R, Hill CA, Wang Z, Remark R, Li JR, Pina C, Faries C, Awad AJ, Moss N, Bjorkegren JLM, Kim-Schulze S, Gnjatic S, Ma'ayan A, Mocco J, Faries P, Merad M, Giannarelli C. Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019 Oct;25(10):1576-1588. doi: 10.1038/s41591-019-0590-4 PMID 31591603
• Shibata H, Yasumi T, Shimodera S, Hiejima E, Izawa K, Kawai T, Shirakawa R, Wada T, Nishikomori R, Horiuchi H, Ohara O, Ishii E, Heike T. Human CTL-based functional analysis shows the reliability of a munc13-4 protein expression assay for FHL3 diagnosis. Blood. 2018 May 3;131(18):2016-2025. doi: 10.1182/blood-2017-10-812503. Epub 2018 Mar 16. PMID 29549174
• Clasca F, Rubio-Garrido P, Jabaudon D. Unveiling the diversity of thalamocortical neuron subtypes. Eur J Neurosci. 2012 May;35(10):1524-32. doi: 10.1111/j.1460-9568.2012.08033.x. PMID 22606998
• Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, Tang G, Wang B, Chen D, He M, Fu J, Cai Y, Shi X, Zhang Y, Cui Y, Sun N, Li X, Cheng X, Wang J, Yang X, Yang T, Xiao C, Zhao G, Dong Q, Zhu D, Wang X, Ge J, Zhao L, Hu D, Liu L, Hou FF; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. J PMID 25771069
• Qin X, Xu M, Zhang Y, Li J, Xu X, Wang X, Xu X, Huo Y. Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012 Jun;222(2):307-13. doi: 10.1016/j.atherosclerosis.2011.12.007. Epub 2011 Dec 9. PMID 22209480

Identifiers

NCT: NCT07680595 · RX-2006-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗