Clinical trials based on the neurodevelopmental outcome of babies are inefficient for developing new treatments, due to the long gap between an intervention and a meaningful outcome evaluation.

The MARBLE trial results recently published in the Lancet Neurology (November 2018) suggests that thalamic N-acetyl aspartate (NAA) levels acquired on 3 Tesla magnetic resonance (MR) spectroscopy predicts neurodevelopmental outcome at 2 years with a 99% accuracy. Thalamic NAA as a surrogate endpoint will increase the power of clinical trials, whilst reducing their duration by several years. 


Ongoing studies

Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) Study: (Funding: NIHR)

We recruited 223 babies with neonatal encephalopathy across eight neonatal intensive care units in the UK and USA and compared the accuracy of various MR biomarkers that predict neurodevelopmental outcomes at 2 years of age.

The study results published in the Lancet Neurology (https://www.thelancet.com/action/showPdf?pii=S1474-4422%2818%2930325-9) suggest that Thalamic N-acetyl aspartate (NAA) level at 1 week after birth, predicts the neurodevelopment at 2 years with 99% accuracy. The accuracy of thalamic NAA was far higher than MR spectroscopy peak area metabolite ratios, conventional MRI and diffusion tensor imaging biomarkers. Thalamic NAA as a surrogate outcome measure can reduce the sample size and trial duration of early phase neuroprotection trials, thus accelerating drug development in neonatal encephalopathy.

Funding: National Institute of Health Research (UK)
Sponsor: Imperial College London

Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): Protocol

Recruitment
Recruitment

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Centres
NoHospitalPrincipal InvestigatorMRI Scanner
 1  University College Hospital, London, UK  Dr Angela Heurtas  3T Philips
 2   Imperial Healthcare NHS Trust, UK  Dr Sudhin Thayyil  3T Philips
 3  Medway NHS Hospital Foundation Trust, UK  Dr Aung Soe  3T GE
 4  Coventry University Hospital, UK  Dr Prakash Satodia  3T GE
 5  Norwich University Hospital, UK  Dr Paul Clarke  3T GE
 6  Liverpool Women's Hospital, UK  Dr Kiran Yajamanyam  3T Philips
 7  Royal Victoria Infirmary, Newcastle, UK  Dr Sundeep Harigopal   3T Siemens
 8  Wayne State University, USA  Professor Seetha Shankaran  3T GE
Recruitment is now complete
Summary of the table's contents

Cooling in Mild Neonatal Encephalopathy (COMET): (Funding NIHR)

Although cooling therapy is an established treatment for babies with moderate or severe neonatal encephalopathy, the risk benefits and optimal duration of this therapy for babies with encephalopathy is not known.

COMET trial uses a novel study design, with proton MR spectroscopy thalamic N-acetyl aspartate level, as the primary outcome measure. COMET is a sequential study that includes a feasibility phase, phase II randomised controlled trial to identify the ‘optimal cooling duration’, and then a final confirmatory phase III clinical trial to examine if cooling therapy at this optimal duration improves neurodevelopmental outcomes after mild encephalopathy.

First COMET baby recruited at Queen Charlottes and Chelsea Hospital (15 October 2018)

Funding: National Institute of Health Research (UK), and Weston Garfield Foundation

Sponsor: Imperial College London

Cooling in Mild Encephalopathy (COMET) Trial: Protocol
Cooling in Mild Encephalopathy (COMET): Parent Information Sheet
Cooling in Mild Encephalopathy (COMET): REC Approval
Cooling in Mild Encephalopathy (COMET): HRA Approval

Cooling in Mild Encephalopathy (COMET) Trial: Case Report Form
Cooling in Mild Encephalopathy (COMET) Trial: Blood Collection SOP

Standard Operating Procedures 3T MRI

COMET presentation

Click here to RANDOMISE


NoCentrePrincipal investigator 
 1 Imperial Healthcare NHS trust Dr Sudhin Thayyil
 2 Medway NHS Trust Dr Aung Soe
 3 Homerton NHS Trust Dr Narendra Alangady
 4 Coventry NHS Hospital Dr Prakash Satodia
 5 St Michaels Hospital, Bristol Dr Ela Chakrapani 
 6 Norwich NHS Hospital Dr Paul Clarke
 7 Birmingham Women's Hospital Dr Manobi Boorah
 8 Queens, Nottingham  Dr Dulip Jayasinghe 
 9 Liverpool Women's Hospital Dr Kiran Yajamanuym
 10 Royal Victoria Infirmary, Newcastle Dr Sundeep Harigopal
PARTICIPATING CENTRES
Summary of the table's contents

Early Xenon plus cooling in neonatal encephalopathy (Cool Xenon) (Funding: Action Medical Research)

Although the results of the TOBY Xenon trial were dissappointing, Xenon was delivered late (after 6 hours of age) in this trial, and hence might have missed a treatment effect.

In pre-clinical models, early high dose xenon therapy augments the neuroprotection offered by cooling therapy. Babies with neonatal encephalopathy are being randomised to cooling alone or cooling with inhaled Xenon within 5 hours of birth, in this phase II trial led by Professor Thoresen and Ela Chakkarapani at Bristol University. This study will be completed by 2018.

Magnetic Resonance Imaging in Neonatal Encephalopathy and N-acetyl cysteine (MARINAC) Study (Funding: NIHR and BRC)

N-acetyl cysteine (NAC) therapy augments hypothermic neuroprotection in animal models. We are undertaking the early phase studies of this therapy in neonatal encephalopathy, in collaboration with Dr Doe Jenkins at the Medical University of South Carolina. In the first phase of MARINAC, we examined if cerebral glutathione (GSH) levels (via MR spectroscopy), and serum oxidative stress markers (via mass spectrometry), were altered by N-acetyl cysteine. A phase II randomised controlled trial will begin in 2019.

Magnetic Resonance Imaging in Infection Associated Neonatal Encephalopathy (MARINE) (Funding: NIHR)

In this study, we have developed a rapid acquisition method (reduced from 30min to 10min) which could be used across all clinical 3T MRI scanners in the NHS, without the need for specialist software or research agreements with the scanner vendor (this is usually a significant barrier to the widespread implementation of locally developed techniques). We have also developed automated analysis software for the accurate and rapid quantification of the MR spectroscopy data, which will enable all NHS hospitals to use MR spectroscopy in babies with neonatal encephalopathy without the need for a local MR spectroscopy expert.

MARINE study is now complete and the results will be published soon.