Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

作者：Sean P. Polster, Agnieszka Stadnik, Amy L. Akers, Ying Jun Cao, Gregory A. Christoforidis, Maged D Fam, Kelly D. Flemming, Romuald Girard, Nicholas M. Hobson, James I. Koenig, Janne Koskimäki, Karen T. Lane, James K. Liao, Cornelia Lee, Sean B. Lyne, Nichol A. McBee, Leslie A. Morrison, Kristina Piedad, Robert Shenkar, Matthew J. Sorrentino, Richard E. Thompson, Kevin J. Whitehead, Hussein A. Zeineddine, Daniel F. Hanley, Issam A. Awad · 发表于：Neurosurgery · 年份：2018 · DOI：10.1093/neuros/nyy539 · 被引用次数：88 · 研究领域：Vascular Malformations Diagnosis and Treatment、Intracerebral and Subarachnoid Hemorrhage Research、Glioma Diagnosis and Treatment

BACKGROUND: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof...