Phase I Study in Patients Supporting IV TPM for Neonatal Seizures (9/07, IND7899)

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DESCRIPTION (provided by applicant): The aim of this first-in-humans, Phase 1 study in adults taking oral topiramate (TPM) is to provide information essential to the further development of TPM as an orphan product for the treatment of neonatal seizures in newborns with HIE, a rare medical disorder. The results from this study will set the stage for Phase 2/3 clinical trials of IV TPM in newborns with HIE. Hypoxic-ischemic encephalopathy occurs in approximately 0.5-0.75 babies per 1,000 deliveries, or an estimated 2,500 cases per year. Seizures and brain injury arising from HIE often result in life-long morbidity including cognitive impairment. The current drugs of choice, phenobarbital and phenytoin, have never been subjected to adequately controlled clinical trials. In uncontrolled studies, fewer than 50% of babies respond to therapy and both drugs are associated with serious adverse effects including further brain injury, acute systemic toxicity, and significant drug interactions. The National Institute of Neurological Disorders and Stroke has identified improved treatment of neonatal seizures as a significant unmet need. Topiramate is an antiepileptic drug used in adults and children to treat epilepsy. Recent research has shown that TPM is highly effective in controlling seizures and is neuroprotective in newborn laboratory animals in models of status epilepticus and cerebral ischemia. The proven safety and effectiveness of TPM for seizures in older children and adults together with substantial laboratory evidence showing benefit in models of HIE strongly suggest TPM would be useful in the treatment of neonatal seizures resulting from HIE and provide neuroprotection. Prior to studies of investigational drugs in newborns, the Food and Drug Administration (FDA) requires that studies first be done in adults. The investigators propose to carry out a pharmacokinetic and safety study of a novel IV TPM formulation in adult patients taking oral TPM. A small (25 mg) dose of a stable-labeled (non-radioactive) IV TPM will be administered at the same time as the patient takes his or her usual morning oral dose. Plasma TPM concentrations from both oral and IV TPM doses can be measured and a full pharmacokinetic profile can be determine without interrupting patients' maintenance regimen. The investigators state that the results from this pilot study will inform the design of subsequent studies, including controlled clinical trials intended to determine the efficacy and safety of IV TPM for neuroprotection and seizure control in neonates.