Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)

Abstract

Background: Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI.

Methods: This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Other outcomes include exploratory investigation of factors that might have benefits for the treatment or might influence its results, such as genetic background, clinical progression, electroencephalographic abnormalities, health-related quality of life and neuropsychological status. Analyses will be conducted following the safety, intention-to-treat and efficacy concepts.

Discussion: We hypothesize that biperiden treatment will be effective to prevent or mitigate the development of post-traumatic epilepsy in TBI patients. Other health measures from this population also may benefit from treatment with biperiden.

Trial registration: ClinicalTrials.gov, NCT04945213. Registered on June 30, 2021.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Biperiden study plan including the schedule of enrolment, intervention, and assessments*.

*Standard protocol items recommendations for Interventional Trials (SPIRIT) diagram [13]. CT computerized tomography; ECG electrocardiogram, βHCG human chorionic gonadotropin β; PTE post-traumatic epilepsy; SAS symptomatic acute seizures; EEG electroencephalography; mRS modified Rankin scale; EQ-5D-3L EuroQol three-level; EQ VAS EuroQol visual analogue scale; WAIS Wechsler Intelligence Scale; RAVLT Rey Auditory Verbal Learning Test; FDT Five Digit Test; polymorphic ε4 allele of the apolipoprotein E gene. Time deviations in days (d) allowed for follow up visits in months(m): a 1m ± 5d; b 3, 6, 9, 12, 18, 24m ± 15d.