Introduction: Cavernous angiomas with symptomatic hemorrhage are likely to re-bleed with neurologic sequelae. CASH patients include different genotypes and lesion locations, portending variable disease severity/prospective risk. Several agents are being pursued and are at various stages of development. These agents will ultimately require testing of safety and efficacy in multi-site clinical trials. 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 biologic mechanisms and clinical activity. Yet, the ability to screen, enroll and risk-stratify CASH cases has never been assessed prospectively at multiple sites.
Methods: Outcome instruments have not been evaluated for their relative sensitivity and reliability, nor been harmonized across multiple sites. This project assembles leading researchers, clinical centers of excellence, and experienced trialists who propose to address these knowledge gaps.
Results: They aim to assess (1) the feasibility of screening, enrollment rates, baseline categorization and follow-up of CASH using common clinical data elements, (2) novel biomarkers, including quantitative susceptibility mapping and perfusion measures which have been shown to correlation with lesion activity, and (3) the relative rates of recurrent hemorrhage and change in functional status, quality of life and biomarker measurements during prospective follow-up.
Conclusions: It promises to endorse/reject outcome instruments and/or biomarkers based on empiric observations, hypothesizing a clinically meaningful impact of putative therapies. It will determine sample size, length of follow-up, and number of sites needed to test trial hypotheses. Corollary goals are to ready pilot sites with expertise in these facets of disease evaluation, to be deployed and emulated in prospective clinical trials. Other goals are to complete preparatory and regulatory milestones needed for launching actual trials and to assemble research core teams who would oversee and manage these prospective trials. This project (U01 NS104157) is funded by the NIH/NINDS, 2017-2022.
Patient Care: Brain cavernous angiomas with symptomatic hemorrhage are rare, but they exact a heavy burden of neurologic disability from recurrent bleeding, for which there is no proven therapy. This trial readiness project aims to address current critical obstacles in identifying cases at multiple sites, characterizing their relevant features, and measuring their outcome. The timing cannot be more opportune, with therapeutic targets already identified, exceptional collaboration among researchers and with the patient community, and several drugs ready to benefit from a track to clinical testing in the next five years.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Describe the importance of trial readiness in CASH
2) Discuss the specific aims for enrollment/harmonization, biomarkers, and validation of outcomes.