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| Name | Class |
|---|---|
| Medical Research Council | OTHER_GOV |
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Hypothesis: Prolonged whole body cooling in term infants with perinatal asphyxial encephalopathy reduces death and severe neurodevelopmental disability.
This study aims to determine whether whole body cooling to 33-34°C is a safe treatment that improves survival, without severe neurological or neurodevelopmental impairments at 18 months, of term infants suffering perinatal asphyxial encephalopathy.
This is a multicentre prospective randomised controlled trial to determine whether a reduction of body temperature by 3-4°C following perinatal asphyxia improves survival without neurodevelopmental disability.
Full term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 ± 0.2°C or to whole body cooling with the rectal temperature kept at 33.5 ± 0.5°C for 72 hours followed by slow rewarming.
The outcome will be assessed at 18 months of age by survival and neurological and neurodevelopmental testing.
Eligibility criteria:
Term infants less than 6 hours after birth with moderate or severe perinatal asphyxia (a combination of clinical and EEG criteria).
Exclusion criteria:
Infants expected to be 6 hours of age at the time of randomisation or infants with major congenital abnormalities.
Intervention:
Intensive care with whole body cooling versus intensive care without whole body cooling (babies are cooled to 33.5°C for 72 hours)
Main Outcomes:
Death and severe neurodevelopmental impairment at 18 months of age
Secondary Outcomes:
Cerebral thrombosis or haemorrhage, persistent hypotension, pulmonary hypertension, abnormal coagulation, arrhythmia and sepsis in the neonatal period. Neurological impairments at 18 months
Number of patients required: 236.
On 30th November 2006, when recruitment closed, 325 babies had been recruited.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| cooled | Active Comparator | Whole body mild induced hypothermia for 72 hours, starting by 6 hours of age, in addition to standard intensive care. After 72 hours of cooling, rewarming by a maximum of 0.5 degree C / hour to normothermia. |
|
| non-cooled | No Intervention | Standard intensive care |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Whole body mild induced hypothermia | Procedure | Target rectal temperature 33-34°C for 72 hours, commencing by 6 hours of age; followed by re-warming at 0.5°C to normothermia |
|
| Measure | Description | Time Frame |
|---|---|---|
| Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors | Severe neurodevelopmental disability was defined as a score of less than 70 on the Mental Developmental Index of the Bayley Scales of Infant Development II (BSID-II) (on which the standardization mean [± standard deviation (SD)] is 100±15 and higher scores indicate better performance), a score of 3 to 5 on the Gross Motor Function Classification System (GMFCS) (on which scores can range from 1 to 5, with higher scores indicating greater impairment), or bilateral cortical visual impairment with no useful vision. | 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Intracranial Haemorrhage | Intracranial hemorrhage was identified on magnetic resonance imaging (MRI). | Duration of hospital stay, on average 22 days |
| Persistent Hypotension | Hypotension was defined as a mean blood pressure of 40 mm Hg or less and was persistent if causes of hypotension had been sought and appropriate treatment provided, without success. |
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Inclusion criteria
The infant will be assessed sequentially by criteria A, B and C listed below:
A. Infants =>36 completed weeks gestation admitted to the Neonatal Intensive Care Unit (NICU) with at least one of the following:
Infants that meet criteria A will be assessed for whether they meet the neurological abnormality entry criteria (B) by trained personnel:
B. Moderate to severe encephalopathy, consisting of altered state of consciousness (lethargy, stupor or coma) AND at least one of the following:
Infants that meet criteria A & B will be assessed by amplitude-integrated electroencephalogram (aEEG) (read by trained personnel):
C. At least 30 minutes duration of amplitude integrated EEG recording that shows abnormal background aEEG activity or seizures. There must be one of the following:
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Denis Azzopardi, MD; FRCPCH | Imperial College London | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hammersmith Hospital | London | W12 0NN | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19797281 | Result | Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854. | |
| 19896902 | Result |
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494 infants were assessed for eligibility; 94 did not meet inclusion criteria, 30 declined to participate 45 were not enrolled for other reasons. 325 underwent randomization.
Infants who met trial entry criteria were recruited at 40 Neonatal Intensive Care Units mainly in the United Kingdom and also in Europe. Recruitment took place over 4 years, from December 2006 to November 2006.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cooled | Whole body mild induced hypothermia for 72 hours, starting by 6 hours of age, in addition to standard intensive care. After 72 hours of cooling, rewarming by a maximum of 0.5 degree C / hour to normothermia. Whole body mild induced hypothermia: Target rectal temperature 33-34°C for 72 hours, commencing by 6 hours of age; followed by re-warming at 0.5°C to normothermia |
| FG001 | Non-cooled | Standard intensive care at normothermia |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Infants who were less than 6 hours of age who had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy confirmed by 30 minutes' amplitude-integrated electro-encephalography that showed abnormal background activity or seizures.
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| ID | Title | Description |
|---|---|---|
| BG000 | Cooled | Whole body mild induced hypothermia 72 hours, commencing by 6 hours of age followed by re-warming to normothermia. |
| BG001 | Non-cooled | Standard intensive care |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | All participants were < 6 hours of age at randomization. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors | Severe neurodevelopmental disability was defined as a score of less than 70 on the Mental Developmental Index of the Bayley Scales of Infant Development II (BSID-II) (on which the standardization mean [± standard deviation (SD)] is 100±15 and higher scores indicate better performance), a score of 3 to 5 on the Gross Motor Function Classification System (GMFCS) (on which scores can range from 1 to 5, with higher scores indicating greater impairment), or bilateral cortical visual impairment with no useful vision. | Posted | Number | participants | 18 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cooled | Whole body mild induced hypothermia for 72 hours, starting by 6 hours of age, in addition to standard intensive care. After 72 hours of cooling, rewarming by a maximum of 0.5 degree C / hour to normothermia. Whole body mild induced hypothermia: Target rectal temperature 33-34°C for 72 hours, commencing by 6 hours of age; followed by re-warming at 0.5°C to normothermia |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Cardiac disorders | Systematic Assessment | Severe hypotension (mean arterial pressure less than 25mmHg), despite full inotrope support and volume replacement. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Persistent hypotension | Cardiac disorders | Systematic Assessment | Hypotension was defined as a mean blood pressure of 40 mm Hg or less. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of NPEU Clinical Trials Unit | National Perinatal Epidemiology Unit, University of Oxford | 01865 289700 | 89728 | ctu@npeu.ox.ac.uk |
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| ID | Term |
|---|---|
| D001238 | Asphyxia Neonatorum |
| D000860 | Hypoxia |
| D001927 | Brain Diseases |
| D012640 | Seizures |
| D007511 | Ischemia |
| D007035 | Hypothermia |
| ID | Term |
|---|---|
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
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| Duration of hospital stay, on average 22 days |
| Pulmonary Haemorrhage | Duration of hospital stay, on average 22 days |
| Pulmonary Hypertension | Duration of hospital stay, on average 22 days |
| Prolonged Blood Coagulation Time | Duration of hospital stay, on average 22 days |
| Culture Proven Sepsis | Duration of hospital stay, on average 22 days |
| Necrotising Enterocolitis | Duration of hospital stay, on average 22 days |
| Cardiac Arrhythmia | Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia. | Duration of hospital stay, on average 22 days |
| Thrombocytopenia | Duration of hospital stay, on average 22 days |
| Major Venous Thrombosis | Duration of hospital stay, on average 22 days |
| Renal Failure Treated With Dialysis | Duration of hospital stay, on average 22 days |
| Pneumonia | Before discharge from hospital |
| Pulmonary Airleak | Duration of hospital stay, on average 22 days |
| Duration of Hospitalisation | Total duration of hospital care | Duration of hospital stay, on average 22 days |
| Mortality | 18 months |
| Severe Neurodevelopmental Disability | 18 months |
| Multiple Handicap | defined as the presence of any two of the following in an infant; neuromotor disability (Level 3-5 on Gross Motor Function classification), mental delay (Bayley Mental Developmental Index (MDI) score < 70), epilepsy, cortical visual impairment, sensorineural hearing loss | 18 months |
| Bayley Psychomotor Developmental Index Score (PDI) | Bayley Psychomotor Developmental Index score (PDI) <70 | 18 months |
| Sensorineural Hearing Loss | Normal or near normal hearing, no sensorineural hearing loss | 18 months |
| Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment) | 18 months |
| Microcephaly | Head circumference at follow-up >2 standard deviations below the mean | 18 months |
| Rutherford M, Ramenghi LA, Edwards AD, Brocklehurst P, Halliday H, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 2010 Jan;9(1):39-45. doi: 10.1016/S1474-4422(09)70295-9. Epub 2009 Nov 5. |
| BG002 | Total | Total of all reporting groups |
| Number |
| participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Standard intensive care |
|
|
| Secondary | Intracranial Haemorrhage | Intracranial hemorrhage was identified on magnetic resonance imaging (MRI). | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Persistent Hypotension | Hypotension was defined as a mean blood pressure of 40 mm Hg or less and was persistent if causes of hypotension had been sought and appropriate treatment provided, without success. | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Pulmonary Haemorrhage | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Pulmonary Hypertension | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Prolonged Blood Coagulation Time | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Culture Proven Sepsis | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Necrotising Enterocolitis | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Cardiac Arrhythmia | Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia. | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Thrombocytopenia | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Major Venous Thrombosis | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Renal Failure Treated With Dialysis | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Pneumonia | Posted | Number | participants | Before discharge from hospital |
|
|
|
| Secondary | Pulmonary Airleak | Posted | Number | participants | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Duration of Hospitalisation | Total duration of hospital care | Posted | Median | Inter-Quartile Range | days | Duration of hospital stay, on average 22 days |
|
|
|
| Secondary | Mortality | Posted | Number | participants | 18 months |
|
|
|
| Secondary | Severe Neurodevelopmental Disability | Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented. | Posted | Number | participants | 18 months |
|
|
|
| Secondary | Multiple Handicap | defined as the presence of any two of the following in an infant; neuromotor disability (Level 3-5 on Gross Motor Function classification), mental delay (Bayley Mental Developmental Index (MDI) score < 70), epilepsy, cortical visual impairment, sensorineural hearing loss | Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented. | Posted | Number | participants | 18 months |
|
|
|
| Secondary | Bayley Psychomotor Developmental Index Score (PDI) | Bayley Psychomotor Developmental Index score (PDI) <70 | Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented. | Posted | Number | participants | 18 months |
|
|
|
| Secondary | Sensorineural Hearing Loss | Normal or near normal hearing, no sensorineural hearing loss | Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented. | Posted | Number | participants | 18 months |
|
|
|
| Secondary | Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment) | Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented. | Posted | Number | participants | 18 months |
|
|
|
| Secondary | Microcephaly | Head circumference at follow-up >2 standard deviations below the mean | Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented. | Posted | Number | participants | 18 months |
|
|
|
| 8 |
| 163 |
| 126 |
| 163 |
| EG001 | Non-cooled | Standard intensive care | 3 | 162 | 134 | 162 |
|
| Cardia arrhythmia | Cardiac disorders | Systematic Assessment |
|
| Major venous thrombosis not related to an infusion line. | Blood and lymphatic system disorders | Systematic Assessment |
|
| Collapse | Surgical and medical procedures | Non-systematic Assessment | Collapse during lumbar puncture |
|
|
| Prolonged coagulation time | Blood and lymphatic system disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Intracranial hemorrhage | Nervous system disorders | Systematic Assessment |
|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary air leak | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary hemorrhage | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary hypertension | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Necrotizing enterocolitis | Gastrointestinal disorders | Systematic Assessment |
|
| Culture-proven sepsis | Infections and infestations | Systematic Assessment |
|
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D009461 | Neurologic Manifestations |
| D010335 | Pathologic Processes |
| D001832 | Body Temperature Changes |