Quantitative surrogate MR biomarkers for neuroprotection
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.
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 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
|No||Hospital||Principal Investigator||MRI 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|
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 phase of the COMET has been completed, and the Second phase started in October 2019.
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) Trial: Cohort 1 Parent Information Sheet
Cooling in Mild Encephalopathy (COMET) Trial: Cohort 2 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
|1||Imperial Healthcare NHS trust||Dr Gaurav Atreja|
|2||Medway NHS Trust||Dr Aung Soe|
|3||Homerton NHS Trust||Dr Narendra Alangady|
|4||Liverpool Women's Hospital||Dr Balamurugan Palaniswamy|
|5||Royal Victoria Infirmary, Newcastle||Dr Sundeep Harigopal|
|6||Birmingham Women's Hospital||Dr Manobi Boorah|
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.
Erythropoietin versus Darbepoetin in Neonatal Encephalopathy (EDEN) Trial (Funding: NIHR)
Erythropoietin and Darbepoetin alfa are FDA approved drugs for treating anemia, with a proven safety profile in newborn infants and have potential neuroprotective benefits in neonatal encephalopathy. Darbe has similar effects to erythropoietin and requires less frequent administration.
The EDEN trial is a 3 arm randomised control trial and aims to examine the physiological effects of erythropoietin and darbepoetin therapy on proton magnetic resonance spectroscopy thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing cooling therapy. The trial is aming to start in September 2020.
Funding: National Institute of Health Research (UK).
Sponsor: Imperial College London
Erythropoietin and Darbepoetin in Neonatal Encephalopathy: Protocol
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.