Awad, Issam A.

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.

Abstract BACKGROUND Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Abstract BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.

Background and Purpose— The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography–based planimetry (CTP). Methods— In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. Results— In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC ( r 2 =0.93) than with site-ABC ( r 2 =0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm 3 ; CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P <0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. Conclusions— ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.