Neonatal EncephalopathyMARBLENCT01309711
Magnetic Resonance Biomarkers in Neonatal Encephalopathy
An observational study of Neonatal Encephalopathy, run by Imperial College London at 1 site in United Kingdom.
Trial summary
N-acetylaspartate (NAA) is a surrogate neuronal marker and its proton magnetic resonance spectroscopy (1H MRS) signal decreases with increasing neuronal mortality associated with cerebral hypoxia-ischaemia. Read more about this study
- Who is it for?
- Ages 1 day to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Neonatal Encephalopathy
- How many people
- 180 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 30 Mar 2011to 31 Dec 2017
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 45 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: Healthy control infants, Infants with Neonatal encephalopathy, Healthy adult volunteers
Who may be able to join
- Group I (Controls): Healthy newborn infants (gestation 36 to 43 weeks, birth weight >2.7 kg)
- Group II (NE): Infants 36 to 43 weeks gestation with at least one of the following:
- Evidence of perinatal asphyxia as indicated by
- Apgar score of <5 at 5 minutes after birth
- Continued need for resuscitation, including endotracheal or mask ventilation, at 5 minutes after birth
- Acidosis defined as pH <7.00 and/or base deficit >16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood) AND
- Moderate to severe encephalopathy consisting of altered state of consciousness (reduced or absent response to stimulation) and hypotonia, and abnormal primitive reflexes (weak or absent suck or Moro response). Clinical NE severity will be assessed by Thompson encephalopathy score.
- Group III (Healthy adult volunteers): Same individual will be scanned multiple times at each of the centres to examine intra and inter-centre variability of thalamic [NAA].
Who cannot join
- Life threatening congenital malformations
- Syndromic infants
- Metabolic disorders
- Meningitis or encephalitis
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Multicentre Prospective Study on Magnetic Resonance Biomarkers in Neonatal Encephalopathy
N-acetylaspartate (NAA) is a surrogate neuronal marker and its proton magnetic resonance spectroscopy (1H MRS) signal decreases with increasing neuronal mortality associated with cerebral hypoxia-ischaemia. The MRS lactate (Lac)/NAA peak-area ratio increases during and after severe cerebral hypoxia-ischaemia reflecting mitochondrial injury and impaired oxidative phosphorylation.
Aims: (1) To establish normative ranges for thalamic 1H MRS NAA concentration and Lac/NAA in healthy newborn infants (2) To examine the accuracies of thalamic 1H MRS NAA concentration and Lac/NAA for predicting adverse neurodevelopmental outcome in neonatal encephalopathy (NE)
Read more
Design: Prospective observational study Methods: Year 1: Following 1H MRS methodology optimisation 40 healthy control infants will be recruited to collect normative data. Year 2 to 3: 115 infants with NE, undergoing therapeutic hypothermia will be recruited. MRS will be performed aged less than 4 days and 7 to 14 days and thalamic NAA levels and Lac/NAA will be quantified; Qualitative interviews to evaluate parental understanding of this biomarker. Year 4, 5: Outcome assessment by BSID III at 18 months.
Outcomes: Mean thalamic NAA levels and Lac/NAA and appropriate confidence intervals in normal infants, and thalamic NAA levels and Lac/NAA in infants with NE according to neurodevelopmental outcome. Areas under curves for thalamic NAA and Lac/NAA will be examined separately for early \& late MRS. Accuracy of early MRS will inform utility of this investigation in decisions about withdrawal of life support; late MRS will inform about efficacy as a surrogate end point in clinical trials. Qualitative interviews will be thematically analysed and reported.
Read the detailed description
- 1 PRIMARY OBJECTIVE To examine the accuracy of 1H MRS thalamic [NAA] for predicting adverse neurodevelopment in infants with NE undergoing therapeutic hypothermia
2.2 SECONDARY OBJECTIVE 2.2.1 To examine inter and intra-center variability of thalamic [NAA] levels in healthy adult volunteers 2.2.2 To further develop normative ranges for 1H MRS thalamic [NAA] and other quantitative measures of potential utility in healthy term newborn infants 2.2.3 To compare the prognostic accuracy of 1H MRS thalamic [NAA] and other MRS quantities with that of the Lactate/NAA peak-area ratio acquired early (aged ≤ 4 days) and with that acquired late (aged 5 to 14 days) 2.2.4 To examine parental attitudes towards MR use in decisions about withdrawal of life support and counselling about long term outcomes
- METHODS Prospective observational study; the index test (1H MRS) and gold-standard test (neurological outcome at 18 months) will be performed independently and blinded to each other.
3.3 Recruitment Control infants will be recruited from the postnatal wards at the participating hospitals. The MR scans will be performed before the infant is first discharged from hospital as far as possible (for example following a Caesarean delivery) i.e. within the first week of life. A lead research midwife will be identified in each of the participating hospitals who will approach the parents for recruitment and informed consent.
NE infants will be recruited from neonatal intensive care units. MR scans will be performed twice after informed parental consent. The first scan at less than 4 days of age (if clinically feasible) and the second scan between 5 to 14 days of age. The first scan will be performed while the infant is still in the intensive care unit at the participating centre. At the time of the second MR scan, it is likely most babies would be off the ventilator. Sedation would be used if required in these babies.
3.4 Neurodevelopmental evaluation Neurodevelopmental outcomes will be assessed at 18 months of age using Bayley Scale of Infant Development® (Version 3) blinded to the MRS information. Favourable outcome will be defined as survival without disability, no disability being defined as all of: developmental quotient (DQ) >84 (BSID III), no neuromotor impairment (neurological exam score ≥73 and Gross Motor Function Classification System (GMFCS) ≤I) [19], and normal vision and hearing on clinical examination. Unfavourable outcome will be defined as death or, in survivors, moderate or severe disability.
3.5 Post-mortem evaluation If the infant dies (UCH cases only), parents will be given options of conventional autopsy or minimally invasive autopsy (MIA) at Great Ormond Street Hospital (GOSH) using the protocol established for the MaRIAS (Magnetic Resonance Imaging Autopsy Study)[20].
3.6 Qualitative interviews About 6 months after death or discharge a parental sub group from 20 NE cases recruited by stratified purposeful sampling from Royal Victoria Infirmary (Newcastle) will be invited to participate in an interview by a psychology Research Fellow. The parental understanding of, and attitudes towards use of, MR techniques for predicting long term outcomes and making decisions about withdrawal of life support (during hospital stay), will be collected thematically and analysed (aim 2.2.3). Tape recorded transcripts of parental interviews will be analysed and emerging themes grouped.
- ENDPOINTS AND DATA ANALYSIS
1H MRS thalamic [NAA] (mean (SD); mmol/kg wet weight brain tissue) in NE infants will be compared with outcome. Sensitivity and specificity with 95% CI and area under the curve (Standard Error) will be reported for [NAA] and Lac/NAA peak-area ratio and the clinical significances of unit changes in these measures in terms of unit changes in motor and cognitive outcome scores examined. The prognostic accuracy of early acquisition 1H MRS will be compared with late acquisition using area under curve and diagnostic odds ratios. The accuracy of [NAA] for prediction of outcome will be compared with conventional MRI. 1H MRS thalamic [NAA] (mean (SD)) in healthy term infants will be reported.
- Conditions
- Neonatal Encephalopathy
- Keywords
- MRI, Biomarkers, Neonatal encephalopathy, Therapeutic hypothermia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| HIE | Moderate of severe neonatal encephalopathy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Prognostic accuracy of [NAA]
Assessed by BSID 3
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Mar 2011 (estimated)
- Study start30 Mar 2011
- Primary completion13 Aug 2017
- Study completion31 Dec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Neonatal EncephalopathyStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 180 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01309711
- Sponsor's protocol ID
- MARBLE
- Acronym
- MARBLE
- Status last verified
- Mar 2024
- First submitted
- 3 Mar 2011
- Last updated
- 19 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
Publications
Lally PJ, Pauliah S, Montaldo P, Chaban B, Oliveira V, Bainbridge A, Soe A, Pattnayak S, Clarke P, Satodia P, Harigopal S, Abernethy LJ, Turner MA, Huertas-Ceballos A, Shankaran S, Thayyil S. Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study. BMJ Open. 2015 Sep 30;5(9):e008912. doi: 10.1136/bmjopen-2015-008912.
PubMed 26423856Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil S; MARBLE consortium. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 2019 Jan;18(1):35-45. doi: 10.1016/S1474-4422(18)30325-9. Epub 2018 Nov 15.
PubMed 30447969Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, Thayyil S. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2018 Jul;103(4):F383-F387. doi: 10.1136/archdischild-2017-313321. Epub 2017 Sep 21.
PubMed 28935718
Study at a glance
From the registry record, last updated by the sponsor on 19 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicentre Prospective Study on Magnetic Resonance Biomarkers in Neonatal Encephalopathy
- ClinicalTrials.gov ID
- NCT01309711
- Acronym / sponsor ID
- MARBLE / MARBLE
- Conditions
- Neonatal Encephalopathy
- Keywords
- MRI, Biomarkers, Neonatal encephalopathy, Therapeutic hypothermia
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 180 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Study start
- 30 Mar 2011 (actual)
- Primary completion
- 13 Aug 2017 (actual)
- Study completion
- 31 Dec 2017 (actual)
- First posted
- 7 Mar 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
N-acetylaspartate (NAA) is a surrogate neuronal marker and its proton magnetic resonance spectroscopy (1H MRS) signal decreases with increasing neuronal mortality associated with cerebral hypoxia-ischaemia. The MRS lactate (Lac)/NAA peak-area ratio increases during and after severe cerebral hypoxia-ischaemia reflecting mitochondrial injury and impaired oxidative phosphorylation.
Aims: (1) To establish normative ranges for thalamic 1H MRS NAA concentration and Lac/NAA in healthy newborn infants (2) To examine the accuracies of thalamic 1H MRS NAA concentration and Lac/NAA for predicting adverse neurodevelopmental outcome in neonatal encephalopathy (NE)
Design: Prospective observational study Methods: Year 1: Following 1H MRS methodology optimisation 40 healthy control infants will be recruited to collect normative data. Year 2 to 3: 115 infants with NE, undergoing therapeutic hypothermia will be recruited. MRS will be performed aged less than 4 days and 7 to 14 days and thalamic NAA levels and Lac/NAA will be quantified; Qualitative interviews to evaluate parental understanding of this biomarker. Year 4, 5: Outcome assessment by BSID III at 18 months.
Outcomes: Mean thalamic NAA levels and Lac/NAA and appropriate confidence intervals in normal infants, and thalamic NAA levels and Lac/NAA in infants with NE according to neurodevelopmental outcome. Areas under curves for thalamic NAA and Lac/NAA will be examined separately for early \& late MRS. Accuracy of early MRS will inform utility of this investigation in decisions about withdrawal of life support; late MRS will inform about efficacy as a surrogate end point in clinical trials. Qualitative interviews will be thematically analysed and reported.
Detailed description
- 1 PRIMARY OBJECTIVE To examine the accuracy of 1H MRS thalamic [NAA] for predicting adverse neurodevelopment in infants with NE undergoing therapeutic hypothermia
2.2 SECONDARY OBJECTIVE 2.2.1 To examine inter and intra-center variability of thalamic [NAA] levels in healthy adult volunteers 2.2.2 To further develop normative ranges for 1H MRS thalamic [NAA] and other quantitative measures of potential utility in healthy term newborn infants 2.2.3 To compare the prognostic accuracy of 1H MRS thalamic [NAA] and other MRS quantities with that of the Lactate/NAA peak-area ratio acquired early (aged ≤ 4 days) and with that acquired late (aged 5 to 14 days) 2.2.4 To examine parental attitudes towards MR use in decisions about withdrawal of life support and counselling about long term outcomes
- METHODS Prospective observational study; the index test (1H MRS) and gold-standard test (neurological outcome at 18 months) will be performed independently and blinded to each other.
3.3 Recruitment Control infants will be recruited from the postnatal wards at the participating hospitals. The MR scans will be performed before the infant is first discharged from hospital as far as possible (for example following a Caesarean delivery) i.e. within the first week of life. A lead research midwife will be identified in each of the participating hospitals who will approach the parents for recruitment and informed consent.
NE infants will be recruited from neonatal intensive care units. MR scans will be performed twice after informed parental consent. The first scan at less than 4 days of age (if clinically feasible) and the second scan between 5 to 14 days of age. The first scan will be performed while the infant is still in the intensive care unit at the participating centre. At the time of the second MR scan, it is likely most babies would be off the ventilator. Sedation would be used if required in these babies.
3.4 Neurodevelopmental evaluation Neurodevelopmental outcomes will be assessed at 18 months of age using Bayley Scale of Infant Development® (Version 3) blinded to the MRS information. Favourable outcome will be defined as survival without disability, no disability being defined as all of: developmental quotient (DQ) >84 (BSID III), no neuromotor impairment (neurological exam score ≥73 and Gross Motor Function Classification System (GMFCS) ≤I) [19], and normal vision and hearing on clinical examination. Unfavourable outcome will be defined as death or, in survivors, moderate or severe disability.
3.5 Post-mortem evaluation If the infant dies (UCH cases only), parents will be given options of conventional autopsy or minimally invasive autopsy (MIA) at Great Ormond Street Hospital (GOSH) using the protocol established for the MaRIAS (Magnetic Resonance Imaging Autopsy Study)[20].
3.6 Qualitative interviews About 6 months after death or discharge a parental sub group from 20 NE cases recruited by stratified purposeful sampling from Royal Victoria Infirmary (Newcastle) will be invited to participate in an interview by a psychology Research Fellow. The parental understanding of, and attitudes towards use of, MR techniques for predicting long term outcomes and making decisions about withdrawal of life support (during hospital stay), will be collected thematically and analysed (aim 2.2.3). Tape recorded transcripts of parental interviews will be analysed and emerging themes grouped.
- ENDPOINTS AND DATA ANALYSIS
1H MRS thalamic [NAA] (mean (SD); mmol/kg wet weight brain tissue) in NE infants will be compared with outcome. Sensitivity and specificity with 95% CI and area under the curve (Standard Error) will be reported for [NAA] and Lac/NAA peak-area ratio and the clinical significances of unit changes in these measures in terms of unit changes in motor and cognitive outcome scores examined. The prognostic accuracy of early acquisition 1H MRS will be compared with late acquisition using area under curve and diagnostic odds ratios. The accuracy of [NAA] for prediction of outcome will be compared with conventional MRI. 1H MRS thalamic [NAA] (mean (SD)) in healthy term infants will be reported.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| HIE | – | –Moderate of severe neonatal encephalopathy |
Who may qualify
- Ages
- 1 day to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- Healthy control infants, Infants with Neonatal encephalopathy, Healthy adult volunteers
Key inclusion criteria (8 listed)
- Group I (Controls): Healthy newborn infants (gestation 36 to 43 weeks, birth weight >2.7 kg)
- Group II (NE): Infants 36 to 43 weeks gestation with at least one of the following:
- Moderate to severe encephalopathy consisting of altered state of consciousness (reduced or absent response to stimulation) and hypotonia, and abnormal primitive reflexes (weak or absent suck or Moro response). Clinical NE severity will be assessed by Thompson encephalopathy score.
- Group III (Healthy adult volunteers): Same individual will be scanned multiple times at each of the centres to examine intra and inter-centre variability of thalamic [NAA].
Key exclusion criteria (4 listed)
- Life threatening congenital malformations
- Syndromic infants
- Metabolic disorders
- Meningitis or encephalitis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Prognostic accuracy of [NAA]
Time frame: 18 months
Assessed by BSID 3
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2024.
- Background: PubMed 26423856Lally PJ, Pauliah S, Montaldo P, Chaban B, Oliveira V, Bainbridge A, Soe A, Pattnayak S, Clarke P, Satodia P, Harigopal S, Abernethy LJ, Turner MA, Huertas-Ceballos A, Shankaran S, Thayyil S. Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study. BMJ Open. 2015 Sep 30;5(9):e008912. doi: 10.1136/bmjopen-2015-008912.
- Derived from this study: PubMed 30447969Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil S; MARBLE consortium. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 2019 Jan;18(1):35-45. doi: 10.1016/S1474-4422(18)30325-9. Epub 2018 Nov 15.
- Derived from this study: PubMed 28935718Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, Thayyil S. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2018 Jul;103(4):F383-F387. doi: 10.1136/archdischild-2017-313321. Epub 2017 Sep 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Neonatal Encephalopathy, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Prognostic accuracy of [NAA] (time frame: 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01309711, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2024.