Rationale:
Neonatal seizures affect 1 in 300 infants with high rates of permanent disabilities such as cerebral palsy, global developmental delay, and epilepsy. Mounting evidence indicates that seizures contribute to brain injury and neurodevelopmental disability; better treatment may improve long-term neurodevelopmental outcomes.
Methods:
This FDA-funded NEOLEV3 clinical trial aims to refine the standard clinical paradigm for neonatal seizure treatment utilizing a stratified approach; using Levetiracetam (LEV) with its significantly improved side effect profile, targeted at reducing mild to moderate seizure burden, reserving Phenobarbital (PHB) with its associated side effects for neonates with high seizure burden. This dose escalation and safety study will determine the maximum safe tolerated dose of LEV (primary endpoint). Infants who continue to have seizures following standard dose LEV will receive either higher dose LEV or the control drug PHB, randomized in a 3:1 allocation ratio. Dose escalation will proceed in 3 phases to the maximal LEV loading dose of 150mg/kg. A minimum of 10 subjects will be studied at each dosing level phase, with evaluation of dose-limiting toxicity. Secondary endpoints include: additional efficacy of higher doses of LEV, pharmacokinetics of high-dose LEV in neonates, and the usefulness of Persyst neonatal seizure detection. We hypothesize that optimal dosing of Levetiracetam (LEV) to treat neonatal seizures is significantly greater than 60mg/kg. Phase 1 of this study has been completed. Phase 2 is ongoing.
Results:
In Phase 1, we consented 78 neonates and treated 26 neonates with the first standard loading dose of LEV. Fourteen neonates continued to have seizures and were randomized to either a higher dose of LEV or Phenobarbital. Ten neonates received LEV. Four neonates received Phenobarbital. No unexpected adverse events were found in Phase 1. Phase 2 is in progress. One Phase 2 participant was randomized to the higher dose of LEV and received a total of 120mg/kg in loading doses.
Conclusions: Phase 1 results were reviewed by the Data Safety Monitoring Board and demonstrated that LEV loading doses up to 90 mg/kg are safe for neonatal seizure treatment. In Phase 2, the first participant randomized to a 120 mg/kg total loading dose achieved seizure cessation without any unexpected adverse events, suggesting both the safety and potential efficacy of this higher dose; however, Phase 2 recruitment, data collection, and analyses are still in process.
Funding: The FDA Orphan Drug Division funds this study: R01FD006335.