Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project

Abstract

Background and purpose: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH.

Methods: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion.

Results: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites.

Conclusions: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Keywords: biomarkers; clinical trial; intracranial hemorrhage; magnetic resonance imaging; quality of life; vascular malformations.

Figure 1.. Baseline PROMIS-29 domain scores for 110 enrolled patients in the CASH TR Project.

Box plots represent the distribution of standardized T-scores. The box indicates the interquartile range, blue vertical line is the median, whiskers represent lower and upper quartiles, and dots indicate outliers. Red vertical line at 50 indicates mean T-score of reference population (SD 10). Scores are oriented so that higher scores are worse across domains.

Figure 2.. Magnetic resonance image thumbnails of 73 cases enrolled in CASH TR Project.

T2 images of CASH lesion in 73 consecutively enrolled FUBV cases through May 2020. Images obtained at enrollment, cropped to the region highlighting the CASH lesion at similar scale (bar = 12.8 cm). A diagnostic CASH event must have occurred within the prior 12 months (images of diagnostic hemorrhage not shown).

Figure 3.. Baseline mean lesional QSM (A) and DCEQP Permeability Index Ki (B) obtained at enrollment in CASH TR FUBV Study.

QSM data is shown from 72 cases and DCEQP data from 70 cases among 73 cases enrolled in CASH TR FUBV through May 2020. These represent successfully executed and analyzed data in 98.6% and 95.9% of cases for QSM and DCEQP, respectively. Data points are color coded for participating sites. For reference, historical pilot data is shown from 46 satisfactorily completed QSM and 61 satisfactorily completed DCEQP on CASH cases at the University of Chicago prior to initiation of the CASH TR project.