Updated recommendations for the design of therapeutic trials for neonatal seizures
Janet S Soul1, Sonya Wang2, Cia Sharpe3,4
1Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Janet.Soul@childrens.harvard.edu.
Insights
Updated guidelines for neonatal seizure clinical trials emphasize exploring new efficacy endpoints and improving patient recruitment. These recommendations aim to enhance trial design and feasibility for treating neonatal seizures effectively.
Area of Science:
- Neonatal Neurology
- Clinical Trial Design
- Pharmacology
Background:
- Neonatal seizures pose significant challenges in clinical management and research.
- Previous recommendations for neonatal seizure trial design require updates based on recent experiences.
Purpose of the Study:
- To provide updated recommendations for the design of clinical trials investigating treatments for neonatal seizures.
- To address challenges in efficacy endpoint definition, recruitment, and operational feasibility.
Main Methods:
- Review of recent clinical trial experiences and developments in neonatal seizure treatment.
- Formulation of updated recommendations by the International Neonatal Consortium Seizure Working Group.
Main Results:
- Recommendations for including alternate seizure burden reduction measures as exploratory endpoints.
- Inclusion of key covariates like seizure timing, randomization, and anti-seizure medication (ASM) administration.
- Guidance on trial masking, reporting of concomitant medications, adverse events, and genetic testing.
- Strategies for improved recruitment and consent, including novel technologies and patient advocacy group involvement.
- Considerations for trial infrastructure, operational feasibility, and regulatory accommodations.
Conclusions:
- Updated recommendations aim to refine neonatal seizure trial design for greater clinical meaningfulness and feasibility.
- Emphasis on exploratory endpoints, robust covariate inclusion, and enhanced recruitment strategies.
- Adaptability to local regulations and resources is crucial for successful trial conduct.
Abstract:
The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren't sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated. IMPACT: This review provides an update to the initial recommendations for neonatal seizure treatment trial design, with recommendations regarding: (1) exploratory endpoints to inform future trials, (2) additional key covariates to include, (3) considerations regarding masking of investigators, (3) inclusion of concomitant medications and adverse events, (4) genetic testing, (5) strategies for recruitment and consent, and (6) infrastructure and operational feasibility.
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