NEMO1:NEonatal Seizure Using Medication Off-patent (NEMO1)

NEMO1: An Open Label Exploratory Dose Finding and Pharmacokinetic Clinical Trial of Bumetanide for the Treatment of Neonatal Seizure Using Medication Off-patent

NEMO is a multicentre pan European clinical trial with the aim to develop new treatment strategies for the treatment of neonatal seizures using the loop diuretic bumetanide. There is evidence that bumetanide improves GABAergic function of the current standard drug, phenobarbitone. Bumetanide has been used as a diuretic in term and preterm babies for around thirty years. This trial should confirm that Bumetanide in addition to standard treatment will result in better seizures control.

Study Overview

• Status: Completed
• Conditions: Neonatal Seizures
• Intervention / Treatment: Drug: Bumetanide

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Ireland
  • Cork, Ireland
    • Cork University Maternity Hospital
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus Universitair Medisch Centrum Rotterdam
  • Utrecht, Netherlands, 3508 AB
    • University Medical Centre Utrecht
• Sweden
  • Stockholm, Sweden
    • Karolinska Institutet and University Hospital
  • Uppsala, Sweden
    • Uppsala University Hospital
• United Kingdom
  • Leeds, United Kingdom
    • Leeds General Infirmary
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:-

• Male or female term baby with gestational age of 37-43 weeks and postnatal age <48 hours
• One or more of the following:
• APGAR score < 5 at 5 mins.
• Umbilical cord or first arterial blood sample pH < 7.1 or base deficit >16 mmol/L.

• Postnatal resuscitation still required 10 minutes after birth

  • Clinically evolving encephalopathy
  • Received one dose of standard anticonvulsive therapy (phenobarbitone,20mg/kg) for clinical or electrographic seizures.
  • EEG: equal to or more than 3 min cumulative seizures, or 2 or more seizures of >30 sec duration over 2 hr period within first 48 hr of life
  • Written informed consent of parent or guardian.
  • EEG monitoring has commenced within the first 48 hours of birth.

Exclusion Criteria:

• Suspected or confirmed brain malformation, inborn error of metabolism,genetic syndrome, or major congenial malformation

• Congenital (in utero) infection (TORCH).

  • Babies who have received diuretics such as furosemide or bumetanide in routine clinical management within the last 24 hours.
  • Total serum bilirubin > 15 mg/dl (255 micromol/l) at inclusion.
  • On any other anticonvulsive medication other than phenobarbitone or bolus of midazolam / pentobarbitone for intubation.
  • Anuria/renal failure defined as serum creatinine > 200 micromol/l.
  • Severe electrolyte depletion (Na <120 mmol/L, K <3.0 mmol/L)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bumetanide; Bumetanide - Standard Phenobarbital plus either 0.05 mg/kg,0.1 mg/kg, 0.2 mg/kg, or 0.3 mg/kg of bumetanide as determined by the the dose escalation design Maximum dose allowed is 0.3mg/kg given up to 4 times at 12 hourly intervals (total of 1.2mg/kg).	Drug: Bumetanide; Bumetanide - Standard Phenobarbital plus either 0.05 mg/kg,0.1 mg/kg, 0.2 mg/kg, or 0.3 mg/kg of bumetanide as determined by the the dose escalation design Maximum dose allowed is 0.3mg/kg given up to 4 times at 12 hourly intervals (total of 1.2mg/kg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optimal dose finding	The optimal dose is defined as achieving effective seizure reduction: Reduction of electrographic seizure (measuresd by EEG) burden by >80% during the 3rd and 4th hour after the first bumetanide administration compared to a 2 hour epoch prior to Bumetanide administration.; No need for rescue AED within 48 hours	6 months

Collaborators and Investigators

• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Collaborators: Karolinska University Hospital; University College London Hospitals; Helsinki University Central Hospital; UMC Utrecht; Erasmus Medical Center; The Leeds Teaching Hospitals NHS Trust; Uppsala University Hospital; Cork University Hospital; Hôpital Necker-Enfants Malades; Only For Children Pharmaceuticals
• Investigators: Principal Investigator: Ronit Pressler, Dr, Great Ormond Street Hospital for Children NHS foundation trust

Publications and helpful links

General Publications

• Pressler RM, Boylan GB, Marlow N, Blennow M, Chiron C, Cross JH, de Vries LS, Hallberg B, Hellstrom-Westas L, Jullien V, Livingstone V, Mangum B, Murphy B, Murray D, Pons G, Rennie J, Swarte R, Toet MC, Vanhatalo S, Zohar S; NEonatal seizure treatment with Medication Off-patent (NEMO) consortium. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 2015 May;14(5):469-77. doi: 10.1016/S1474-4422(14)70303-5. Epub 2015 Mar 10.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: September 9, 2011
• First Submitted That Met QC Criteria: September 13, 2011
• First Posted (Estimate): September 14, 2011

Study Record Updates

• Last Update Posted (Estimate): September 14, 2015
• Last Update Submitted That Met QC Criteria: September 11, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Hypoxic Ischemic Encephalopathy; Electroencephalography; Neonatal seizures; Bumetanide
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Bumetanide
• Other Study ID Numbers: 08NR26