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  • Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial

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Paediatrics
Protocol
Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial
  1. Geraldine Favrais1,2,
  2. Moreno Ursino3,
  3. Catherine Mouchel4,5,
  4. Estelle Boivin6,
  5. Vincent Jullien7,
  6. Sarah Zohar3,
  7. Elie Saliba1,2
  1. 1 Neonatal Intensive Care Unit, CHRU de Tours, Tours, France
  2. 2 UMR 1253, iBrain, Université de Tours, INSERM, Tours, France
  3. 3 INSERM, UMRS 1138, team 22, CRC, Université Paris 5, Université Paris 6, Paris, France
  4. 4 INSERM CIC-1414, Clinical investigation Center, Université Rennes 1, Rennes, France
  5. 5 Department of Clinical Pharmacology, CHRU de Rennes, Rennes, France
  6. 6 Research Clinical and Innovation Delegation, CHRU de Tours, Tours, France
  7. 7 INSERM U1129, Department of Pharmacology, Université Paris Descartes, Hôpital Européen Georges Pompidou, Paris, France
  1. Correspondence to Dr Geraldine Favrais; g.favrais{at}chu-tours.fr

Abstract

Introduction Therapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED). The aim of this phase II trial is to determine the benefits of LEV by applying a strict methodology and to estimate the optimal dose of LEV as a first-line AED to treat seizures in newborns suffering from hypoxic-ischaemic encephalopathy.

Methods and analysis LEVNEONAT-1 is an open and sequential LEV dose-finding study. The optimal dose is that which is estimated to be associated with a toxicity not exceeding 10% and an efficacy higher than 60%. Efficacy is defined by a seizure burden reduction of 80% after the loading dose. Four increasing dose regimens will be assessed including one loading dose of 30, 40, 50 or 60 mg/kg followed by eight maintenance doses (ie, a quarter of the loading dose) injected every 8 hours. A two-patient cohort will be necessary at each dose level to consider an upper dose level assignment. The maximal sample size expected is 50 participants with a minimum of 24 patients or fewer in the case of a high rate of toxicity. Patients will be recruited in five neonatal intensive care units beginning in October 2017 and continuing for 2 years. In parallel, the LEV pharmacokinetics will be measured five times (ie, 30 min; 4 and 7 hours after the loading dose; 1–3 hours and 12–18 hours after the last maintenance dose).

Ethics and dissemination Ethics approval has been obtained from the regional ethical committee (2016-R25) and the French Drug Safety Agency (160652A-31). The results will be published in a peer-reviewed journal. The results will also be presented at medical meetings.

Trial registration number NCT02229123; Pre-results.

  • levetiracetam
  • newborn
  • seizure
  • phase li trial
  • hypoxic-ischaemic encephalopathy

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2018-022739

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    Footnotes

    • Patient consent for publication Obtained.

    • Contributors GF and ES were responsible for the study design including aims, assessment criteria and intervention schedule. SZ and MU provided statistical expertise in trial design, developed the dose-finding model and conducted the statistical analysis. CM and GF assumed the pharmacovigilance procedure. EB handled the legal aspects and authorisations and helped with implementation. VJ designed the pharmacokinetic analysis and performed the LEV pharmacokinetic measurements. All authors contributed to the refinement of the study protocol and approved the final manuscript.

    • Funding This work was supported by a grant from the French Ministry of Health (LEVNEONAT-1, 2013, PHRCI 2013 API13/T/065). No financial support from industry took part in the LEVNEONAT-1 funding. Levetiracetam will not be provided by industry. SZ and MU were supported by the InSPiRe (innovative methodology for small populations research) project, which was funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration, under grant agreement number FP HEALTH 2013-602144.

    • Disclaimer This funding source had no role in the design of the study and will not have any role during the study execution, analyses, interpretation of the data or decision to submit results.

    • Competing interests None declared.

    • Ethics approval Regional Ethical Committee (CPP Ouest 1).

    • Provenance and peer review Not commissioned; externally peer reviewed.