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 SorrentinoRichard E. Thompson, Kevin J. Whitehead, Hussein A. Zeineddine, Daniel F. Hanley, Issam A. Awad

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)843-853
Number of pages11
JournalClinical neurosurgery
Volume85
Issue number6
DOIs
StatePublished - Dec 1 2019

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Keywords

  • Atorvastatin
  • Cavernous angioma
  • Cavernous angioma with symptomatic hemorrhage (CASH)
  • Cerebral cavernous malformation (CCM)
  • Clinical trial
  • Symptomatic hemorrhage

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Polster, S. P., Stadnik, A., Akers, A. L., Cao, Y., Christoforidis, G. A., Fam, M. D., Flemming, K. D., Girard, R., Hobson, N., Koenig, J. I., Koskimäki, J., Lane, K., Liao, J. K., Lee, C., Lyne, S. B., McBee, N., Morrison, L., Piedad, K., Shenkar, R., ... Awad, I. A. (2019). Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial. Clinical neurosurgery, 85(6), 843-853. https://doi.org/10.1093/neuros/nyy539