Aug. 26, 2023
Mayo Clinic researchers are collaborating to define markers for future clinical trials of therapies for a rare but disabling cerebrovascular malformation. Several candidate medications have been proposed for the treatment of cavernous angioma with symptomatic hemorrhage (CASH). But the small number of patients with CASH precludes traditional clinical trials with symptomatic hemorrhage as a primary endpoint.
"Different clinical trial structures or different measures of outcome would help bring candidate drugs to clinical practice more quickly," says Kelly D. Flemming, M.D., a neurologist at Mayo Clinic in Rochester, Minnesota.
Mayo Clinic co-led a recently completed CASH trial readiness study. Funded by the National Institutes of Health, the multicenter study sought to determine whether imaging biomarkers and patient-reported outcomes might be used as endpoints in future clinical trials.
"Our findings indicate that quantitative susceptibility mapping (QSM) might be an imaging marker that would allow clinical trials for CASH therapies to reach conclusions with smaller numbers of patients," says Dr. Flemming, who was a site principal investigator in the trial readiness study.
QSM is a noninvasive MRI technique that assesses iron content by quantifying the magnetic susceptibility of local tissues. QSM can also provide excellent depiction of brain lesions with iron deposition.
A second imaging modality — dynamic contrast-enhanced quantitative perfusion (DCEQP) — was also assessed in the trial readiness study. However, DCEQP had lower sensitivity compared with QSM.
The study also found that patient-reported outcomes such as sleep disturbance, fatigue and social function can be negatively impacted when patients have a repeated brain hemorrhage.
"Although patient-reported outcomes aren't sensitive enough to be primary endpoints in a trial, they might be interesting as a secondary endpoint," Dr. Flemming says.
The risk of first symptomatic hemorrhage from a cavernous angioma is very low. But CASH carries a tenfold risk of re-bleeding, with serious clinical sequelae. Asymptomatic bleeds in lesions can also herald future hemorrhage.
The only treatments now available for CASH are observation and surgery. "Both provoke understandable anxiety, and patients often ask if there's another option," Dr. Flemming says.
Mayo Clinic's campus in Minnesota has been designated a center of excellence by the Alliance to Cure Cerebral Cavernous Malformation, a patient advocacy group.
"As a major neurological center, Mayo Clinic has the patient volume, clinical expertise and research capability to study this rare condition," Dr. Flemming says.
For more information
Clinical trials: Study of trial readiness in cavernous angiomas with symptomatic hemorrhage (CASH). Mayo Clinic.
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