TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy

Conditions
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Asphyxia Neonatorum, Hypoxia, Encephalopathy, Seizures

Intervention / Treatment
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* Procedure: Whole body mild induced hypothermia


Participation Criteria
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Eligibility Criteria
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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: Apgar score of =<5 at 10 minutes after birth Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial or capillary pH <7.00) Base Deficit =>16 mmol/L in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth 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: hypotonia abnormal reflexes including oculomotor or pupillary abnormalities absent or weak suck clinical seizures 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: normal background with some seizure activity moderately abnormal activity suppressed activity continuous seizure activity Exclusion criteria Infants expected to be > 6 hours of age at the time of randomisation Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cooled<br>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. | Procedure: Whole body mild induced hypothermia<br>* 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<br>|
| No Intervention: non-cooled<br>Standard intensive care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxia, Ischaemia, Encephalopathy, Neonatal, Hypothermia, Perinatal, Cooling, Whole/Total Body