Study to Evaluate Phenobarbital Sodium Injection for the Treatment of Neonatal Seizures

Overview

This is a randomized, double-blind, parallel-group, Phase 3 study to evaluate the efficacy of the administration of phenobarbital Sodium Injection, United States Pharmacopeia, (USP), in participants who have suffered from a clinical seizure. As neonatal seizures can have long-term adverse effects, including death, placebo-controlled studies are not appropriate for this population. This study is designed to show phenobarbital is effective at preventing subsequent seizures by demonstrating greater efficacy at the higher (40 mg/kg) dose compared to the lower dose (20 mg/kg). It is important to note that, although phenobarbital is not approved for the treatment of neonatal seizures, it is commonly used for this indication and is considered the first-line therapy in the US and by the World Health Organization. The minimum recommended dose of phenobarbital used to treat neonatal seizures is 20 mg/kg. Therefore, the lower dose of phenobarbital used in this study is considered an "effective" dose for the treatment of neonatal seizures. The design of this study allows for assessment of the minimum recommended dose with the maximum recommended dose to show the increased efficacy of the high dose in various measures of reduction in seizures.

This is a randomized, double-blind, parallel-group, Phase 3 study to evaluate the efficacy of the administration of Phenobarbital Sodium Injection, USP in participants who have suffered from a clinical seizure. As neonatal seizures can have long-term adverse effects, including death, placebo-controlled studies are not appropriate for this population. This study is designed to show phenobarbital is effective at preventing subsequent seizures by demonstrating greater efficacy at the higher (40 mg/kg) dose compared to the lower dose (20 mg/kg). It is important to note that, although phenobarbital is not approved for the treatment of neonatal seizures, it is commonly used for this indication and is considered the first-line therapy in the United States, (US), and by the World Health Organization. The minimum recommended dose of phenobarbital used to treat neonatal seizures is 20 mg/kg. Therefore, the lower dose of phenobarbital used in this study is considered an "effective" dose for the treatment of neonatal seizures. The design of this study allows for assessment of the minimum recommended dose with the maximum recommended dose to show the increased efficacy of the high dose in various measures of reduction in seizures. Study participants undergoing electrographic or electroclinical seizures lasting 10 seconds or longer will be randomized in a 1:1 fashion between the 2 treatment arms. Participants will receive either a 20-mg/kg or 40-mg/kg loading dose of Phenobarbital Sodium Injection, USP upon confirmation that the seizure was not due to metabolic imbalances. Randomization of participants with hypoxic-ischemic encephalopathy, (HIE), will be stratified between the dosing groups. Participants will further be stratified by treatment group for pharmacokinetics, (PK), analysis timepoints due to the limitations on the number of pharmacokinetics, (PK), samples that can be taken from each patient. After cessation of seizures the participants will remain in the hospital for 24 hours for continuous monitoring by electroencephalogram, (EEG). According to recommended dosing of phenobarbital, participants in the 20-mg/kg treatment arm in whom seizure activity does not resolve after the first dose (20 mg/kg) will be given phenobarbital in 10-mg/kg increments (each hour) until the seizure activity resolves, up to a maximum total dose of 40 mg/kg. If the seizure activity is still not resolved, participants will be given a second-line anticonvulsant. The second-line therapy given will be determined by the attending physician and recorded in the study documentation. Participants in the 40-mg/kg treatment arm in whom seizure activity does not resolve after the initial loading dose of phenobarbital will be given a second-line anticonvulsant. The second therapy given will be determined by the attending physician and recorded in the study documentation.