BiHiVE2 Study. The Investigation and Validation of Predictive Biomarkers in Hypoxic-ischaemic Encephalopathy. (BiHiVE2)

July 4, 2018 updated by: Dr. Deirdre Murray, University College Cork

BiHiVE 2 Study. The Investigation and Validation of Predictive Biomarkers in Hypoxic-ischaemic Encephalopathy.

Despite recent advances in the care of mothers and newborn infants, many infants (approximately 20 per 1000 live births) continue to need resuscitation at birth. A proportion of these infants will have sustained significant injury through interruption of their blood and oxygen supply prior to delivery (perinatal asphyxia). In 2-3 babies per 1000 this will lead to brain swelling and the risk of long term brain injury called neonatal hypoxic-ischaemic encephalopathy (HIE). HIE remains a cause of neonatal death and long term disability. Early and accurate prediction of outcome would allow us to intervene during the window of the first 6 hours following birth, prior to secondary reperfusion and secondary brain injury. Estimating severity of injury can be difficult in newborn infants. Condition at birth does not predict neonatal, or longer term outcome. Biomarkers which could be measured at the time of birth and analysed at the bedside would offer these infants the best chance of timely and effective intervention. Through the BIHIVE study we have identified a number of predictive biomarkers in hypoxic-ischaemic encephalopathy. These markers are present in umbilical cord blood and have been identified through proteomic and metabolomic analysis of a stored biobank of samples from a recruited cohort of infants with perinatal asphyxia and hypoxic-ischaemic encephalopathy. We now wish to validate these biomarkers in an additional cohort, and will continue to explore new biomarkers in our stored biobank of umbilical cord samples. In addition we wish to assess our ability to predict neurodevelopmental and behavioural outcome in these infants. In this way we will determine the most robust biochemical and clinical markers for the prediction of early and medium term outcome in HIE. This study will establish the evidence base and validation of these biomarkers to the point where they can be developed into a bedside diagnostic algorithm which can be used in the labour ward to immediately identify those infants at risk of HIE in time to prevent secondary damage.

Study Overview

Status

Completed

Conditions

Detailed Description

Background and current knowledge in the area:

Perinatal asphyxia is one of the commonest causes of neonatal death and long term disability, occurring in 20 per 1000 live births. Of these, approximately 2-3 per 1000 will go on to develop hypoxic-ischaemic encephalopathy (HIE) (1). In Ireland and the UK HIE is the third commonest cause of neonatal mortality, accounting for 9% of all deaths, and 21% of term deaths, while globally it is estimated to cause over 1 million neonatal deaths each year. For the survivors there is significant secondary morbidity associated, including cerebral palsy (15%), severe cognitive delay (11%), seizure disorders (8%), sensori-neural deafness (7%), and visual loss (3%)(2).

HIE is an evolving process, which can be simplified into two insults. The initial insult is significant cerebral hypoxia and/or ischaemia which is followed by energy depletion, from anaerobic metabolism leading to the accumulation of lactate, and loss of cellular integrity. This sets in motion a cascade of events with the resultant formation of free radicals, proteases and caspases leading to cell damage and apoptosis, the secondary insult(3). The secondary energy failure has been shown to occur between 6-48 hours after the initial insult.

Until recently no therapeutic intervention which could reduce the associated morbidity or mortality existed. However the recent publications of several international trials, and their subsequent meta-analysis has shown that early induced hypothermia is beneficial in HIE, improving survival and reducing neurological disability (4-5). Induced hypothermia has now become a standard of care in moderate/severe HIE. However to be effective it must be commenced within 6 hours of delivery, before the secondary energy failure occurs. In this narrow window of time the population who would benefit from treatment must be identified, resuscitated, stabilised and cooled.

Unfortunately the ability to recognise and diagnose those who would benefit from therapy is not always possible within this time period. We have shown that the current standard methods to identify those at risk of HIE such as acid-base balance, lactate and Apgar score and initial neurological assessment are unreliable (6). Neonatal electroencephalography (EEG) is useful for the grading of encephalopathy and is an excellent predictor of long term outcome. In particular its evolution over the first 24 hours following delivery strongly correlates with outcome (7). However it requires a highly specialised skill set that is rarely available to the neonatologist in the acute setting. Amplitude integrated EEG is more widely used by clinicians, but its interpretation is user dependent, and the majority of neonatologists report they are not confident in their own interpretive ability (8). The need for early and reliable prediction of outcome in HIE has never been greater. A quick, cheap, reproducible, non-user dependent method for quantifying severity of HIE and likely prognosis is an urgent need. Many biochemical and haematological markers have been proposed in perinatal asphyxia, but none have led to clinical advances, or commercially viable bedside tests (9).

Over the last 2 years, here in the Cork University Maternity Hospital, through the BIHIVE study (Biomarkers in Hypoxic-Ischaemic Encephalopathy study) we have identified potential biochemical markers in umbilical cord blood which can accurately identify those infants who will progress to moderate/severe encephalopathy (10,11). The BIHIVE study has adopted a multifaceted approach to identifying blood-borne biomarkers in HIE through 1) targeted proteomic profiling using Luminex technology 2) miRNA profiling 3) comprehensive mapping of the blood metabolome using both Mass Spectrometry and Nuclear Magnetic Resonance techniques.

Our aim is to recruit a cohort of infants with clearly defined perinatal asphyxia and HIE, classified using both repeated neurological assessment and multichannel EEG. At the time of birth, umbilical cord blood will be drawn, processed and banked, using strict standard operating procedures (SOPs) which we have developed for this purpose. These procedures will ensure that all specimens will be suitable for later proteomic, metabolomic, transcriptomic and genomic analysis. Using a systems biology approach we have studied multiple proposed markers in the stored umbilical cord blood from our discovery cohort, initially focusing on the proteome and metabolome. Through this work we have already identified a number of biomarkers present in umbilical cord blood with the potential to predict the development of moderate/severe HIE. Our early data is extremely promising. Our initial metabolomic analysis has shown that we can differentiate between HIE and controls with an area under the curve (AUROC) of 0.92. Further analysis will be required to identify and quantify the exact metabolite peaks which produce this differentiation. We now wish to validate these findings in a further cohort of infants with perinatal asphyxia and HIE, and to validate our ability to predict longer term neurological outcome. Our pilot work examining microRNA changes in the cord blood of infants with moderate/severe HIE is also very encouraging with significant upregulation of a multiple studied miRNAs in both asphyxia and HIE. The most promising miRNAs are now being quantified using polymerase chain reaction (PCR) amplication and will be validated in the discovery cohort.

Future cohort-BIHIVE2: To develop these markers further to the point where we have validated a marker with >90% sensitivity and specificity for moderate/severe HIE we will need to recruit a further cohort of carefully recruited infants with high quality biobanking at birth and detailed clinical phenotyping. This is the main work of this current application. We will require a further cohort of 300 infants with perinatal asphyxia, of whom 60 will develop HIE and 30 will develop moderate to severe HIE. We will also need to recruit 300 contemporary control infants. To recruit this number of infants with perinatal asphyxia we will need to study 30,000 live births. We have therefore expanded our study centres to include Karolinska University Hospital, Stockholm, a large state of the art maternity hospital with 10,000 live births per annum.

Further validation will allow us to develop an algorithm of clinical and biochemical markers which will provide a sensitive and specific predictive test for moderate/severe HIE. Neurodevelopmental follow up of both cohorts will allow us to assess our ability to predict neurodevelopmental and behavioural outcome at 2 years.

Lastly we will examine the exact timing of biomarker alteration using a timed animal model of hypoxic-ischaemic injury (HI). In clinical studies hypoxic-ischaemic injury is unpredictable and its timing is often impossible to estimate. Dr Tracey Bjorkmann in Queen's University, Brisbane has developed a piglet model of HI which produces HI induces seizures and a level of injury equating to moderate to severe HIE (12). She has agreed to collaborate with our programme and will provide piglet samples of serum taken at 0,1,2 and 12 hours following HI. These samples will be invaluable in examining the progression of biomarker derangement and will help us to time neonatal brain injury after delivery.

Study Type

Observational

Enrollment (Actual)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ireland
      • Cork, Ireland, 00000
        • Cork University Maternity Hospital
  • Sweden
      • Stockholm, Sweden
        • Karolinska University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 hour (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Term Neonates born in hospital

Description

Inclusion Criteria:

Term infants defined at greater than 36 weeks gestation

All infants with one or more of the following clinical markers of HIE:

Apgar score less than or equal to 6 at 5 minutes pH < 7.1 on cord blood, Requiring intubation or CPR at birth -

Exclusion Criteria:

Outborn babies Less than 36 weeks gestation

-

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Term Hypoxic Ischaemic Encephalopathy
Term Hypoxic Ischaemic Encephalopathy (HIE)
Healthy Term Neonates
Controls

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
EEG confirmed hypoxic-ischaemic brain injury in the first 72 hours of life
Time Frame: 24 hours
Clinical examination using the Thompson Encephalopathy score and visual interpretation of multichannel EEG
24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurodevelopmental outcome at 2 years of age assessed using BSID III
Time Frame: 18-24 months
Bayley's Scales of infant Development Version III
18-24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University College Cork

Collaborators

Karolinska Institutet

Investigators

  • Principal Investigator: Deirdre Murray, MD, University College Cork, Ireland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2012

Primary Completion (Actual)

August 1, 2017

Study Completion (Actual)

August 1, 2017

Study Registration Dates

First Submitted

November 6, 2013

First Submitted That Met QC Criteria

December 17, 2013

First Posted (Estimate)

December 24, 2013

Study Record Updates

Last Update Posted (Actual)

July 6, 2018

Last Update Submitted That Met QC Criteria

July 4, 2018

Last Verified

July 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DM0113UCC

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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