The FP7 Cooperation Work Programme "Health" lists two essential impacts for the call:
1. Evidence for better use in paediatric populations.
2. To aim at eventual new Paediatric Use Marketing Authorisations (PUMAs).
The findings of NEMO1 suggest that at the doses that were studied and in the investigated population, bumetanide did not show signs of clinical efficacy for the treatment of neonatal seizures. In addition, it was associated with a higher risk of ototoxicity. Due to this adverse benefit-risk ratio, further efficacy trials using bumetanide at this dose regimen cannot be recommended thus we propose to move from the planned RCT of bumetanide. We are currently writing up these results as well as a publication on ‘How to conduct clinical trials for neonatal seizures - lessons learned from NEMO’.
One of the most important results of NEMO1 is the fact that traditional ways of measuring seizure burden is not reliable for neonatal seizures. The results of NEMO1 will be used to develop a new outcome measure for clinical trials of neonatal seizures (WP6). We anticipate that this will have far reaching implications on how drug trials into neonatal seizures will be performed in the future.
Recent research has shown that MRI can be used as a biomarker for neurodevelopmental outcome (Miller et al 2020; Glass et al 2012; van Rooij et al 2011; Shah et al 2014). A new deliverable is planned to use this knowledge to further analyse our data (WP7).
As stated in our contingency plan in the original application to the EU, if an RCT of bumetanide was not supported by the results of NEMO-1 we would move to an alternative neonatal AED. While we had originally stated that we would consider midazolam, more compelling evidence has emerged for the use of lidocaine as a neonatal AED thereby justifying an RCT. We appreciate that a full RCT is not feasible given the time remaining in this project; however we do wish to develop a neonatal formulation for lidocaine and generate all of the supporting evidence for a PIP application to the EMA.
Lidocaine is on the EMA priority list and there are a number of reports of lidocaine’s success as an AED (Hellstrom-Westas et al 1988; Kobayashi et al 1999; Boylan et al, 2004; van den Broek et al 2013). Recent publications from UMCU have included PK data for lidocaine in term neonates undergoing therapeutic hypothermia and focused on novel dosing regimens based on simulations using data from a pharmacokinetic model (van den Broek et al 2011; van den Broek et al 2013). In addition, recent as yet unpublished research has indicated that in a human neural stem cell model, cooling attenuates AED apoptosis for phenobarbitone and lidocaine but not for levetiracetam. As cooling is now established as a standard of care for HIE in all tertiary referral centres, our choice of lidocaine as a first choice second line AED is based not only on a novel dosing regimen which has a proven short term safety profile but on emerging data that lidocaine has a reduced apoptotic effect under cooling. The Consortium will collaborate to refine novel neonatal dosing regimens that have been developed for lidocaine and pool the expertise and knowledge that currently exists within the group in order the support the PIP approval process.
The NEMO consortium has gained considerable international reputation during the last 4 years and is considered as the strongest consortium to evaluate neonatal seizures in Europe, maybe even worldwide. We are aiming to apply for further funding in Horizon 2020 to evaluate lignocaine in a randomised controlled trial (NEMOLido). In order not to lose momentum and risk the knowledge, expertise and collaboration developed in NEMO1 we propose to use the remaining time to build the ground work for this new trial with lignocaine over the next 12 months.