Clinical trials of prevention of acquired epilepsy: New proof-of-concept approach to restart trials.

Approximately 20% of epilepsy is caused by acute central nervous system insults such as traumatic brain injury (TBI), stroke, and infection. There is a latent period of weeks to years between the insult and epilepsy onset, which offers an opportunity to prevent epilepsy. No preventive treatments exist. Their development is a major unmet need in neurology. For logistical reasons, epilepsy acquired after TBI, posttraumatic epilepsy (PTE), is most suitable for epilepsy prevention studies. In the past 20 years, preclinical PTE research has flourished, offering potential treatments to prevent PTE, but clinical development has been dormant. The major barrier in the development of PTE preventive treatment is the lack of a viable proof of concept (POC) trial design. PTE trials use the first late unprovoked posttraumatic seizure as an outcome measure, which necessitates a long (~2-year) follow-up and makes POC studies nonfeasible. A reliable biomarker of early PTE detection would allow shorter follow-up duration and facilitate POC studies, but such a biomarker is not yet available. Biomarker, POC, and randomized clinical trial studies have virtually identical designs in terms of patient inclusion and follow-up. Done sequentially, the studies would take a generation to complete. We propose a novel trial design for studies of PTE prevention that combines discovery of biomarker(s) of early PTE detection with POC study and uses an adaptive study POC-phase 3 continuation design approach to incorporate POC study into phase 3 study following an interim futility analysis after 6 months of treatment of the first 25% of the cohort, the POC population. This approach would establish a POC model for treatment of PTE prevention, shorten development of PTE prevention treatment, and reopen the door to clinical trials to prevent epilepsy.