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.
RCT Entities:
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.
Authors: Lisa McKerracher; Robert Shenkar; Matthew Abbinanti; Ying Cao; Amy Peiper; James K Liao; Rhonda Lightle; Thomas Moore; Nicholas Hobson; Carol Gallione; Joerg Ruschel; Janne Koskimäki; Romuald Girard; Kenneth Rosen; Douglas A Marchuk; Issam A Awad Journal: Transl Stroke Res Date: 2019-08-24 Impact factor: 6.829
Authors: Marc C Mabray; Arvind Caprihan; Jeffrey Nelson; Charles E McCulloch; Atif Zafar; Helen Kim; Blaine L Hart; Leslie Morrison Journal: Transl Stroke Res Date: 2019-10-23 Impact factor: 6.829
Authors: Nicholas Hobson; Sean P Polster; Ying Cao; Kelly Flemming; Yunhong Shu; John Huston; Chandra Y Gerrard; Reed Selwyn; Marc Mabray; Atif Zafar; Romuald Girard; Julián Carrión-Penagos; Yu Fen Chen; Todd Parrish; Xiaohong Joe Zhou; James I Koenig; Robert Shenkar; Agnieszka Stadnik; Janne Koskimäki; Alexey Dimov; Dallas Turley; Timothy Carroll; Issam A Awad Journal: J Magn Reson Imaging Date: 2019-09-12 Impact factor: 4.813
Authors: Abhinav Srinath; Ying Li; Romuald Girard; Issam A Awad; Sharbel G Romanos; Bingqing Xie; Chang Chen; Yan Li; Thomas Moore; Dehua Bi; Je Yeong Sone; Rhonda Lightle; Nick Hobson; Dongdong Zhang; Janne Koskimäki; Le Shen; Sara McCurdy; Catherine Chinhchu Lai; Agnieszka Stadnik; Kristina Piedad; Julián Carrión-Penagos; Abdallah Shkoukani; Daniel Snellings; Robert Shenkar; Dinanath Sulakhe; Yuan Ji; Miguel A Lopez-Ramirez; Mark L Kahn; Douglas A Marchuk; Mark H Ginsberg Journal: Transl Stroke Res Date: 2022-06-17 Impact factor: 6.829
Authors: Romuald Girard; Yan Li; Agnieszka Stadnik; Robert Shenkar; Nicholas Hobson; Sharbel Romanos; Abhinav Srinath; Thomas Moore; Rhonda Lightle; Abdallah Shkoukani; Amy Akers; Timothy Carroll; Gregory A Christoforidis; James I Koenig; Cornelia Lee; Kristina Piedad; Steven M Greenberg; Helen Kim; Kelly D Flemming; Yuan Ji; Issam A Awad Journal: Neurosurgery Date: 2021-02-16 Impact factor: 4.654
Authors: Helen Kim; Kelly D Flemming; Jeffrey A Nelson; Avery Lui; Jennifer J Majersik; Michael Dela Cruz; Joseph Zabramski; Odilette Trevizo; Giuseppe Lanzino; Atif Zafar; Michel Torbey; Marc C Mabray; Myranda Robinson; Jared Narvid; Janine Lupo; Richard E Thompson; Daniel F Hanley; Nichol McBee; Kevin Treine; Noeleen Ostapkovich; Agnieszka Stadnik; Kristina Piedad; Nicholas Hobson; Timothy Carroll; Abdallah Shkoukani; Julián Carrión-Penagos; Carolina Mendoza-Puccini; James I Koenig; Issam Awad Journal: Stroke Date: 2021-09-16 Impact factor: 7.914
Authors: Daniel A Snellings; Courtney C Hong; Aileen A Ren; Miguel A Lopez-Ramirez; Romuald Girard; Abhinav Srinath; Douglas A Marchuk; Mark H Ginsberg; Issam A Awad; Mark L Kahn Journal: Circ Res Date: 2021-06-24 Impact factor: 23.213