Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling

Abstract

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project.

Methods: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted.

Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05.

Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Keywords: biomarkers; hemorrhage; iron; perfusion; permeability.

Figure 1.

Illustration of conventional MRI axial images with (left to right) T1-weighted sequence, T2-weighted sequence, QSM, and DCEQP assessments of CM lesion with SH. The regions of interest for QSM and DCQEP assessments include the whole lesion as delineated on T2-weighted sequence. Note the maximal QSM values in the hemosiderin ring at the lesion periphery, while the maximal permeability values are within the core of the lesion.

Figure 2.

Flow chart of screened, excluded and enrolled subjects with yearly follow-up and contribution to research imaging acquisitions, usability and QSM/DCEQP pairs analyzed.

Figure 3.

QSM percent change during the 1^st and 2^nd follow-up years. QSM yearly-change during epoch 1 (mean +16.33; SD 74.93) was significantly lower (p=0.033) than in epoch 2 (mean +19.61; SD 70.96). Red dots represent SH; blue dots represent AC; and black dots represent no clinical event detected.

Figure 4.

QSM yearly percent change for cases with SH, AC and no clinical events detected during the same epoch as paired biomarker assessment. No significant differences in percent yearly-change in mean lesional QSM between cases with SH (mean +34.64; SD 27.17) and AC (mean +38.53; SD 59.36) during the same epoch. QSM changes with SH events were significantly higher than QSM change in cases with no clinical events (p 0.019). Red dots represent QSM pairs that meet the threshold biomarker ΔQSM ≥6%.

Figure 5.

DCEQP percent change during the 1^st and 2^nd follow-up years. DCEQP yearly-change during the epoch 1 (mean +61.62; SD +248.8) was not significantly different from the change during epoch 2 (mean +52.45; SD +206.4). Red dots represent SH; blue dots represent AC; and black dots represent no clinical event detected.

Figure 6.

DCEQP yearly percent change for SH, AC and no clinical events detected during the same epoch as paired biomarker assessment. There was significantly higher percent change in mean lesional DCEQOP (mean +179.9; SD +237.4) in cases with SH events than in those without detected clinical events (mean +49.92; SD +235.5) (p 0.030). No significant difference in yearly DCEQP change between AC events (mean +52.45; SD +175.8) and either SH events or cases with no clinical events. Orange dots represent DCEQP pairs that meet the threshold biomarker ΔDCEQP ≥40%.