Workpackage 04

Workpackage leads and partners

Academic Lead: Dr. Ronit Pressler (UCL)

WP partners: UCC, O4CP, INSERM, HUS, UNIVLEEDS, UU, UMCU, AP-HP, KI, GOSHFCNT, EMC

Workpackage objectives

• Perform two clinical trials according to GCP guidelines and to the highest ethical standards:

                NEMO1: dose finding, feasibility and pharmacokinetic study
                NEMO2: randomised, placebo-controlled, double-blind clinical

• To enrol adequate number of babies in both clinical trials
• To accurately assess safety and efficacy of bumetanide
• Provide information on safety and efficacy of bumetanide in babies as required for a PUMA application

Workpackage description

Two clinical trials are planned:

NEMO 1 -  phase I/IIa: dose finding, feasibility and pharmacokinetic study of bumetanide for the treatment of neonatal seizures not responding to phenobarbitone with the aim to estimate the optimal dose of bumetanide as an antiepileptic drug in neonatal seizures. 

NEMO 2 - phase IIb/III, randomised, placebo-controlled, double-blind, clinical trial to evaluate the efficacy and safety of the optimal dose of bumetanide for treatment of neonatal seizures not responding to phenobarbitone.

The aim of this work package is to perform the two clinical trails of NEMO iwith the aim to evaluate the efficacy and safety of bumetanide for treatment of neonatal seizures not responding to phenobarbitone. The results will provide detailed information relating to the safety and efficacy of bumetanide in the newborn which is required for a PUMA application (WP 10). This pivotal trial will need to take account of information required for regulatory processes and the particular issues relating to trials of antiepileptic drug in newborn infants with seizures.

These studies will be the largest multicenter European studies of neonatal seizures and their treatment to date. The trials will be conducted according to the highest ethical standards and following Good Clinical Practice (GCP) in European accredited centres. Together with WP 05, WP 10 and WP 11 we will ensure that the rights, safety and well-being of enrolled babies are the most important consideration of everybody involved in the study.

EEG monitoring is considered to be the gold standard for seizure diagnosis and treatment monitoring. The study will use continuous EEG for diagnosis and monitoring in all enrolled newborns (simultaneous video monitoring will also be used if available). This will enable accurate seizure detection during the clinical trial which is the primary outcome measure.

The responsibilities and duties of WP 04 during the clinical trials are:

• Medical advice for pharmacovigilance
• Review of annual safety reports
• Review of recruitment numbers
• End of trial documents

Several tasks in the clinical trials are the responsibility of the local principal investigators and scientific leads. We will support local trial centres in these activities:

• Recruitment of babies meeting all inclusion criteria, obtaining written informed consent form parents, data collection, monitoring and trial interventions of adequate number of babies according to the protocol and GCP.
• Data collection and transfer of forms to the electronic database has to be performed in a timely manner
• Blood samples for PK assessments will be taken and will stored according to guidelines from the lead investigator of WP 09.
• Site file: keep updated on a regular basis and be available for inspection.
• Drug accountability is the responsibility of each local principal investigator.