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 language | English (US) |
|---|---|
| Pages (from-to) | 843-853 |
| Number of pages | 11 |
| Journal | Clinical Neurosurgery |
| Volume | 85 |
| Issue number | 6 |
| DOIs | |
| State | Published - 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
Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial. / Polster, Sean P.; Stadnik, Agnieszka; Akers, Amy L.; Cao, Ying; Christoforidis, Gregory A.; Fam, Maged D.; Flemming, Kelly D.; Girard, Romuald; Hobson, Nicholas; Koenig, James I.; Koskimäki, Janne; Lane, Karen; Liao, James K.; Lee, Cornelia; Lyne, Seán B.; McBee, Nichol; Morrison, Leslie; Piedad, Kristina; Shenkar, Robert; Sorrentino, Matthew; Thompson, Richard E.; Whitehead, Kevin J.; Zeineddine, Hussein A.; Hanley, Daniel F.; Awad, Issam A.
In: Clinical Neurosurgery, Vol. 85, No. 6, 01.12.2019, p. 843-853.Research output: Contribution to journal › Article
}
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.
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
UR - http://www.scopus.com/inward/record.url?scp=85076365790&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076365790&partnerID=8YFLogxK
U2 - 10.1093/neuros/nyy539
DO - 10.1093/neuros/nyy539
M3 - Article
C2 - 30476251
AN - SCOPUS:85076365790
VL - 85
SP - 843
EP - 853
JO - Neurosurgery
JF - Neurosurgery
SN - 0148-396X
IS - 6
ER -