Preventing Epilepsy Using Vigabatrin in Infants with Tuberous Sclerosis Complex (PREVeNT Trial)

Tuberous sclerosis complex (TSC) is a multi-system genetic disorder, in which 90-95% of effected individuals have CNS involvement. Clinically, epilepsy is manifested in 80-90% of people diagnosed with TSC, and around half of these cases are drug-resistant. In most individuals, the onset of epilepsy is within the first 2 years of life. Intellectual disability, autism spectrum disorder, developmental delays, and psychiatric disorders are prevalent in this population and are strongly associated with early-onset epilepsy. Today, many TSC patients are diagnosed before birth or at the time of birth due to the presence of cardiac rhabdomyomas, which can be found using fetal ultrasound, and genetic testing. The underlying molecular basis of TSC is known, arising from deficiency in proteins encoded by the TSC1 and TSC2 genes that play a ritical role in the regulation of mTOR. Pharmacological inhibitors of mTOR have been shown to reduce the size of various tumor types, and many studies have also suggested these drugs may have a beneficial impact on other TSC manifestations, including seizures and neurocognition. Although there is limited data on the efficacy of most current antiepileptic medications for the treatment of epilepsy in individuals with TSC, vigabatrin, an FDA approved drug for use in TSC, is a clear exception. Many published studies have validated the efficacy of vigabatrin for the treatment of infantile spasms and partial-onset seizures in children with TSC. Current standard of care applies to patients only after clinical spasms are manifested, and there is presently no indication for pre-symptomatic treatment or treatment based solely on EEG findings. The scientific basis for using vigabatrin as a potential treatment intervention to slow progression of epileptogenesis, rather than its efficacy in seizure control, is based on a recent publication by Zhang et al. The results provided evidence that vigabatrin decreased seizure frequency and increased survival in a rat model. Russo et al. also reported that early treatment with vigabatrin had “antiepileptogenic” effects in a genetic rat model of absence epilepsy. The exact mechanism of vigabatrin in TSC is uncertain, but together with its established clinical efficacy in treatment of epilepsy, these data are the basis for our proposal to investigate vigabatrin as an  antiepileptogenesis treatment for children with TSC. The central hypothesis to the current trial is that early identification of electroencephalography (EEG) biomarkers and early treatment versus delayed treatment with vigabatrin in infants with TSC will have a positive impact on developmental outcomes at 24 months of age. The primary outcome measure for this objective will be the cognitive assessment score of the Bayley-III at 24 months of age. This approach is expected to result in more favorable long-term cognitive, behavioral, developmental and psychiatric outcomes and significantly improve overall quality of life. It is a prospective multi-center, randomized, placebo-controlled, double-blind clinical trial design, with a goal of enrolling 80 infants with TSC who are less than 6 months of age and without a history of seizures. Advanced EEG technology, validated neurodevelopmental assessment tools, genetic analysis, and standardized clinical measurements will be utilized. The clinical consortium will be supported by a centralized Data Coordinating Center at University of Alabama at Birmingham with experience in another rare disease (neurofibromatosis).