Recommendations for the design of therapeutic trials for neonatal seizures

Abstract

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

“…Given the steep dependence of neuronal excitability on brain pH, it is reasonable to assume that the large pH changes which take place during and following birth asphyxia in human neonates (Uria-Avellanal and Robertson, 2014) are likely to contribute to the multiple mechanisms that lead to the generation of post-asphyxia seizures. Using an inhaled gas mixture with elevated (5 %) CO 2 might be difficult in the NICU, especially when fast decisions regarding therapeutic interventions have to be made (see Soul et al, 2019). Therefore, additional strategies targeting post-asphyxia changes in brain pH should be examined in future work.…”

“…The period of recovery after asphyxia is often marked by seizures, some of which are considered to promote HIE-related trauma (Bennet et al, 2007;Glass et al, 2009;Kharoshankaya et al, 2016;McBride et al, 2000;Miller et al, 2002;Pressler and Mangum, 2013;Soul et al, 2019;van Rooij et al, 2010;Wirrell et al, 2001). Suppression of seizures has been notoriously unsuccessful with current pharmacological approaches.…”

“…On the contrary, a large number of preclinical studies suggest that many anticonvulsants used in the neonatal intensive care unit (NICU) may have deleterious actions on the developing brain (Bittigau et al, 2002;Ikonomidou and Turski, 2010). Thus, designing novel approaches to suppress neonatal seizures is an unmet and urgent goal (Pressler and Lagae, 2019;Soul et al, 2019).…”

The probability of seizures during continuous EEG monitoring in high‐risk neonates

“…Burst suppression has consistently been found to be a significant predictor of seizure risk in prior studies. 45 Although prior studies have focused on the well-studied and homogenous ANE population, our data suggest that enrolling neonates across etiologies may be feasible, as seizure risk was high in all groups. The presence of excessive sharp transients in SCE and excessive discontinuity in ANE modestly decreased seizure risk.…”

“…44 Advances in neonatal seizure care are limited by the time, expense, and challenges inherent in designing successful clinical trials in this population. 45 Although prior studies have focused on the well-studied and homogenous ANE population, our data suggest that enrolling neonates across etiologies may be feasible, as seizure risk was high in all groups. When epileptiform activity was present, this risk was increased 4-to 56-fold and over 99% of neonates with seizures were captured within the first 24 hours of monitoring, suggesting that targeting this population may produce more powerful and shorter clinical trials.…”