There are fewer than 200,000 cases of brain cavernous angiomas in North America today who have suffered a symptomatic hemorrhage. Cavernous angiomas with symptomatic hemorrhage (CASH) are likely to re-bleed, causing further neurologic sequelae, and are thus the primary focus of drug development. CASH patients include different genotypes and lesion locations, potentially portending variable disease severity or prospective risk. Candidate therapeutics have emerged in recent years from mechanistic studies, and some were already shown to prevent lesion development or hemorrhage in preclinical experiments meeting the most stringent NINDS criteria of objectivity and translational rigor. Several agents are being pursued by the pharmaceutical industry specifically for this disease, and are currently at various stages of development. Other drugs in current clinical use are being explored for proof of concept effect, with the aim of repurposing for this disease. All these candidate agents will ultimately require testing of safety and efficacy in multi-site clinical trials. Much progress has been made in understanding the epidemiology and natural history of CASH, and several outcome assessment tools have been proposed, including novel biomarkers linked to the biologic mechanisms and clinical activity in the lesions. Yet, the ability to screen, enroll and risk-stratify CASH cases has never been assessed prospectively at multiple sites. Biomarkers and other outcomes instruments have not been evaluated for their relative sensitivity and reliability, nor have they been harmonized at multiple sites. This project assembles leading cavernous angioma researchers, clinical centers of excellence, and experienced trialists who propose to address these knowledge gaps. They aim to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization and follow-up of CASH using common clinical data elements, (2) the reliability of advanced imaging biomarkers at multiple sites, and (3) the relative rates of recurrent hemorrhage and change in functional status, quality of life and biomarker measurements during prospective follow-up of eligible cases. Senior statisticians have been recruited to construct workable models for multi-site trials based on emerging results. The project insures the most stringent rigor in trial assumptions, defining realistic enrollment rates and validating baseline features of eligible subjects. It promises to endorse or reject outcome instruments and/or biomarkers based on empiric observations, hypothesizing a clinically meaningful impact of putative therapies. And it will determine the sample size, length of follow-up, and number of sites needed to test trial hypotheses. An Advisory Committee will provide guidance and prioritization of workable trials by industry or academia. Corollary goals are to ready pilot sites with expertise in these facets of disease evaluation and follow-up, to be deployed and emulated in prospectiv...