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

James K Liao, Issam A Awad, Daniel F Hanley, Hussein A Zeineddine, Kevin J Whitehead, Richard E Thompson, Matthew Sorrentino, Robert Shenkar, Kristina Piedad, Leslie Morrison, Nichol McBee, Seán B Lyne, Cornelia Lee, Sean P Polster, Karen Lane, Janne Koskimäki, James I Koenig, Nicholas Hobson, Romuald Girard, Kelly D Flemming, Maged D Fam, Gregory A Christoforidis, Ying Cao, Amy L Akers, Agnieszka Stadnik

Journal: Neurosurgery 2020;85(6):843-853

PMID: 30476251

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Abstract

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 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.

Address: Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois.; Angioma Alliance, Norfolk, Virginia.; Department of Diagnostic Radiology, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.; Division of Brain Injury Outcomes, Department of Neurology, Johns Hopkins University Medical Institutions, Baltimore, Maryland.; Section of Cardiology, Department of Medicine, The University of Chicago Medical Center, Illinois.; Department of Neurology, University of New Mexico, Albuquerque, New Mexico.; Department of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah.

DOI: 10.1093/neuros/nyy539

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MeSH Terms: Atorvastatin, Cerebral Hemorrhage, Double-Blind Method, Female, Follow-Up Studies, Hemangioma, Cavernous, Hemangioma, Cavernous, Central Nervous System, Humans, Magnetic Resonance Imaging, Male, Proof of Concept Study, Prospective Studies, Protein Kinase Inhibitors, Treatment Outcome, rhoA GTP-Binding Protein