Pemafibrate for Symptomatic ICAS RCT

Official title

Triglyceride-lowering Therapy With Pemafibrate for Prevention of Atherosclerotic Cardiovascular Disease in Patients With Symptomatic Intracranial Artery Stenosis: a Multi-center, Open-label, Randomized Controlled Trial (PPAR-ICAS)

Overview

The goal of this clinical trial is to learn whether pemafibrate can help prevent worsening of intracranial arterial stenosis (ICAS) in patients who have symptomatic ICAS and high triglycerides (TG) levels after ischemic stroke or transient ischemic attack (TIA). The main questions this study aims to answer are: 1. Does pemafibrate lower the chance that ICAS gets worse over 12 months? 2. Does pemafibrate improve TG levels and other vascular risk markers? 3. What are the effects of pemafibrate on vascular events, functional outcomes, and safety over 12 months? Researchers will compare a pemafibrate group with a non-pemafibrate group to see whether pemafibrate helps prevent progression of ICAS. This is an open-label, randomized, parallel-group trial. That means participants are assigned by chance to 1 of 2 groups, and both the researchers and participants know which group was assigned. Participants in both groups will continue to receive standard stroke care, including antithrombotic therapy and management of vascular risk factors such as blood pressure, low-density lipoprotein cholesterol, diabetes, and smoking. Participants may be eligible if they are 18 years or older, have clinically stable ischemic stroke or TIA, have 50% to 99% stenosis in a symptomatic intracranial artery on contrast-enhanced CT angiography (CTA), and have elevated fasting (\>=150 mg/dL) or non-fasting (\>=175 mg/dL) TG levels. Some people will not be eligible, such as those with ICAS due to non-atherosclerotic arterial disease, severe extracranial carotid stenosis, recent intravenous thrombolysis or mechanical thrombectomy, planned revascularization, contraindications to pemafibrate or iodinated contrast media, dialysis, or pregnancy. Participants will: * Be randomly assigned to a pemafibrate group or a non-pemafibrate group * Take pemafibrate for 12 months if assigned to the pemafibrate group, with possible dose adjustment based on TG levels and kidney function * Have blood tests and clinical assessments at baseline and during follow-up * Undergo brain CTA at study entry and again at 12 months * Undergo brain MRI/MRA and vascular tests such as ankle brachial index, cardio ankle vascular index, and pulse wave velocity according to the study schedule * Be followed for vascular events, functional outcome, and adverse events for 1 year

Interventions

• Drug Pemafibrate
  Participants in this arm will receive pemafibrate in addition to standard medical therapy.

Primary outcome measures

• Progression in intracranial arterial stenosis on CTA at 12 months from enrollment (progression vs. no progression [no change or improvement]) [Time frame: Baseline and 12 months]

Secondary outcome measures (12)

• Key secondary endpoint (supplementary analyses of the primary endpoint): Change in intracranial arterial stenosis on CTA at 12 months from enrollment (three categories: progression, no change, improvement) [Time frame: Baseline and 12 months]
• Key secondary endpoint (supplementary analyses of the primary endpoint): Improvement in intracranial arterial stenosis on CTA at 12 months from enrollment (improvement vs. no improvement [progression or no change]) [Time frame: Baseline and 12 months]
• Change in percent stenosis by the WASID method [Time frame: Baseline and 12 months]
• Proportion of intracranial arterial stenosis progression/improvement per the TOSS and TOSS-2 criteria [Time frame: Baseline and 12 months]
• Proportion of intracranial arterial stenosis progression/improvement per the Wong KS criteria [Time frame: Baseline and 12 months]
• Major cardiovascular events (MACE) [Time frame: From enrollment to the end of treatment at 12 months]
• All-cause mortality [Time frame: From enrollment to the end of treatment at 12 months]
• Activities of daily living by mRS score (mRS 0-1, 0-2, and 0-3 proportions, and the overall mRS score distribution) [Time frame: Baseline and 12 months]
• Change in Fazekas scale on brain MRI [Time frame: Baseline and 12 months]
• Change in number of cerebral microbleeds on brain MRI [Time frame: Baseline and 12 months]
• Change in total cerebral small vessel disease score on brain MRI [Time frame: Baseline and 12 months]
• Changes in ankle-brachial index (ABI) [Time frame: Baseline and 12 months]

Eligibility criteria

Inclusion criteria

• Clinically stable ischemic stroke or high-risk TIA (ABCD2 score >=4) between 24 hours and 3 years from onset at enrollment.
• Contrast-enhanced CT angiography (CTA) within 3 months prior to consent demonstrating 50-99% stenosis (WASID criteria) in a symptomatic intracranial artery: intracranial internal carotid artery, middle cerebral artery (M1/M2), anterior cerebral artery (A1), vertebral artery (V4), basilar artery, or posterior cerebral artery (P1).
• Fasting triglycerides (TG) 150-499 mg/dL, or non-fasting TG 175-499 mg/dL, measured within 4 weeks prior to consent.
• Men or women aged >=18 years at the time of consent.
• Ability to obtain written informed consent from the patient or a legally authorized representative.

Exclusion criteria

• Patients with intracranial arterial stenosis due to non-atherosclerotic disorders (e.g., vasculitis, moyamoya disease, intracranial arterial dissection).
• Patients with >=70% stenosis of the extracranial carotid artery (NASCET criteria).
• Patients with neurological deterioration within 24 hours prior to enrollment.
• Patients who received intravenous thrombolysis or mechanical thrombectomy within 24 hours prior to enrollment.
• Patients scheduled to undergo revascularization procedures (percutaneous transluminal angioplasty, stent placement, carotid endarterectomy, or cerebral bypass surgery).
• Patients who meet any contraindication to pemafibrate, including:

(1) History of hypersensitivity to pemafibrate; (2) Severe hepatic impairment or liver cirrhosis classified as Child-Pugh B or C; (3) Cholelithiasis; (4) Pregnancy or suspected pregnancy; (5) Concomitant use of cyclosporine or rifampin. 7. Patients who have taken pemafibrate or any fibrate within 12 weeks prior to consent.

8\. Patients with contraindications to iodinated contrast media. 9. Patients on dialysis. 10. Patients with a history of pancreatitis attributable to hypertriglyceridemia.

11\. Patients with severe systemic comorbidities with an expected survival <12 months.

12\. Patients who may be pregnant, are pregnant, or are breastfeeding. 13. Any other condition for which the principal or sub-investigator judges participation to be inappropriate.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Japan · 37 centers

• Fujita Health University Hospital — Toyoake
• Tokyo Women's Medical University Yachiyo Medical Center — Yachiyo
• Brain Attack Center Ota Memorial Hospital — Fukuyama
• Hiroshima City Hiroshima Citizens Hospital — Hiroshima
• Kobe City Medical Center General Hospital — Kobe
• University of Tsukuba Hospital — Tsukuba
• Iwate Medical University Hospital — Hizume
• Kagoshima Medical Center — Kagoshima
• … and 29 more centers

Publications

• Wong KS, Lam WW, Liang E, Huang YN, Chan YL, Kay R. Variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis. Stroke. 1996 Jun;27(6):1084-7. doi: 10.1161/01.str.27.6.1084. PMID 8650718
• Kwon SU, Hong KS, Kang DW, Park JM, Lee JH, Cho YJ, Yu KH, Koo JS, Wong KS, Lee SH, Lee KB, Kim DE, Jeong SW, Bae HJ, Lee BC, Han MK, Rha JH, Kim HY, Mok VC, Lee YS, Kim GM, Suwanwela NC, Yun SC, Nah HW, Kim JS. Efficacy and safety of combination antiplatelet therapies in patients with symptomatic intracranial atherosclerotic stenosis. Stroke. 2011 Oct;42(10):2883-90. doi: 10.1161/STROKEAHA.110.60 PMID 21799173
• Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, Lee JH, Kim JS. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke. 2005 Apr;36(4):782-6. doi: 10.1161/01.STR.0000157667.06542.b7. Epub 2005 Mar 3. PMID 15746463
• Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, Sila CA, Jovin TG, Romano JG; Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005 Mar 31;352(13):1305-16. doi: 10.1056/NEJMoa043033. PMID 15800226

Identifiers

NCT: NCT07562178 · JIHS-C-005243-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗