TY - JOUR
T1 - Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
AU - Polster, Sean P.
AU - Stadnik, Agnieszka
AU - Akers, Amy L.
AU - Cao, Ying
AU - Christoforidis, Gregory A.
AU - Fam, Maged D.
AU - Flemming, Kelly D.
AU - Girard, Romuald
AU - Hobson, Nicholas
AU - Koenig, James I.
AU - Koskimäki, Janne
AU - Lane, Karen
AU - Liao, James K.
AU - Lee, Cornelia
AU - Lyne, Seán B.
AU - McBee, Nichol
AU - Morrison, Leslie
AU - Piedad, Kristina
AU - Shenkar, Robert
AU - Sorrentino, Matthew
AU - Thompson, Richard E.
AU - Whitehead, Kevin J.
AU - Zeineddine, Hussein A.
AU - Hanley, Daniel F.
AU - Awad, Issam A.
N1 - Publisher Copyright:
© 2018 by the Congress of Neurological Surgeons.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Atorvastatin
KW - Cavernous angioma
KW - Cavernous angioma with symptomatic hemorrhage (CASH)
KW - Cerebral cavernous malformation (CCM)
KW - Clinical trial
KW - Symptomatic hemorrhage
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U2 - 10.1093/neuros/nyy539
DO - 10.1093/neuros/nyy539
M3 - Article
C2 - 30476251
AN - SCOPUS:85076365790
SN - 0148-396X
VL - 85
SP - 843
EP - 853
JO - Clinical neurosurgery
JF - Clinical neurosurgery
IS - 6
ER -