• Neurosurgery · Dec 2019

    Randomized Controlled Trial

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

    • Sean P Polster, Agnieszka Stadnik, Amy L Akers, Ying Cao, Gregory A Christoforidis, Maged D Fam, Kelly D Flemming, Romuald Girard, Nicholas Hobson, James I Koenig, Janne Koskimäki, Karen Lane, James K Liao, Cornelia Lee, Seán B Lyne, Nichol McBee, Leslie Morrison, Kristina Piedad, Robert Shenkar, Matthew Sorrentino, Richard E Thompson, Kevin J Whitehead, Hussein A Zeineddine, Daniel F Hanley, and Issam A Awad.
    • Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois.
    • Neurosurgery. 2019 Dec 1; 85 (6): 843-853.

    BackgroundMore 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.ObjectiveTo 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.MethodsThe 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 OutcomesThe 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.DiscussionWith firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.Copyright © 2018 by the Congress of Neurological Surgeons.

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