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Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy
ISRCTN ISRCTN89547571
DOI 10.1186/ISRCTN89547571
ClinicalTrials.gov identifier NCT00147030
EudraCT number
Public title Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy
Scientific title Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial
Acronym TOBY (TOtal Body hYpothermia)
Serial number at source MRC ref: G0100126; G0801320
Study hypothesis 1. To determine whether whole body cooling for 72 hours in term infants with perinatal asphyxial encephalopathy improves survival without neurological or neurodevelopmental disability at 18 months
2. To confirm the safety of prolonged whole body cooling in full term infants with perinatal asphyxial encephalopathy

Please note that, as of 06/06/2006, the target number of participants has been updated from 236 to 325. The original target (n = 236) was achieved earlier than expected. Ethics approval for a revised target of 400 was obtained to continue recruitment.

The TOBY Children Study: School age outcomes following a newborn cooling trial (TCS) -
As of 23/03/2010 this record was updated to include the details of a nested children study. All details can be found under the relevant field with the title: 'TCS study'. The TCS study took place in Israel, Hungary, Sweden, Finland and Ireland as well as the United Kingdom. The trial ran from 01/09/2009 to 31/08/2013 and anticipates recruiting 239 participants (survivors of the TOBY trial at 18 months).

TCS study hypothesis:
The aim of this cross-sectional cohort study is to determine the effect of therapeutic hypothermia following perinatal asphyxia on neurological and neuropsychological outcomes and also to assess academic attainment and any additional health, societal or educational costs associated with changes in outcome as a result of the intervention.
Lay summary
Ethics approval London Multi-centre Research Ethics Committee (MREC) approved on the 8th January 2002 (ref: MREC 00/02/73)

TCS study:
Charing Cross Hospital Research Ethics Committee approved on the 10th February 2010 (ref: 10/H0711/13)
Study design Randomised controlled trial; subsequent cohort study at school age follow up
Countries of recruitment Finland, Hungary, Ireland, Israel, Sweden, United Kingdom
Disease/condition/study domain Perinatal asphyxial encephalopathy, child development, cerebral palsy
Participants - inclusion criteria Infants will be assessed sequentially by criteria 1, 2 and 3 listed below:

1. Infants greater than or equal to 36 weeks gestation admitted to the Neonatal Intensive Care Unit (NICU) with ONE of the following:
1.1. Apgar score of less than five at ten minutes after birth
1.2. Continued need for resuscitation, including endotracheal or mask ventilation, at ten minutes after birth
1.3. Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes of birth less than pH 7.00
1.4. Base deficit greater than or equal to 16 mmol/l in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood)

If the infant meets criteria 1 then assess for neurological abnormality (by trained study personnel):

2. Moderate to severe encephalopathy consisting of altered state of consciousness (lethargy, stupor or coma) and at least one or more of hypotonia, abnormal reflexes including oculomotor or pupillary abnormalities, an absent or weak suck or clinical seizures, as recorded by study personnel.

If the infant meets criteria 1 & 2 then assess by amplitude-integrated electroencephalography (aEEG) (read by trained study personnel):

3. 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:
3.1. Normal background with some seizure activity
3.2. Moderately abnormal activity
3.3. Suppressed activity
3.4. Continuous seizure activity

TCS study:
1. Previously specified that they do not want to be contacted again
2. Previously recruited in the TOBY study within 6 hours of birth
3. Confirmed moderate or severe neonatal encephalopathy
Participants - exclusion criteria 1. Infants expected to be greater than 5.5 hours of age at the time of randomization
2. Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis

TCS study:
Non-participation will only occur if consent is not obtained or contact with the family cannot be achieved. Children who did not take part in the TOBY study are not eligible.
Anticipated start date 01/09/2002
Anticipated end date 01/09/2008
Status of trial Completed
Patient information material Patient information can be found at: http://www.npeu.ox.ac.uk/TOBY/toby_downloads/toby_pil1.pdf
Target number of participants 325
Interventions Full term infants will be randomised within six hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2 degrees celsius or to whole body cooling with the rectal temperature kept at 33.5 +/- 0.5 degrees celsius for 72 hours followed by slow rewarming.
Relevant physiological parameters will be monitored and outcome assessed at 18 months of age by survival and neurological and neurodevelopmental testing.

Recruitment closed at the end of the planned recruitment phase on 30/11/2006.

TCS study:
No intervention, comparison of outcomes at school age in the treatment and control groups.
Primary outcome measure(s) The primary outcome for this trial is a combined endpoint: death in the first 18 months of life OR Severe neurodevelopmental disability.

TCS study:
Frequency of survival with an IQ greater than 84; timepoint: 6 years to 7 years and 4 months.
Secondary outcome measure(s) Secondary outcome measures added as of 16/10/2007:
Short term (before discharge from hospital):
1. Intracranial haemorrhage
2. Persistent hypotension
3. Pulmonary haemorrhage
4. Pulmonary hypertension
5. Prolonged blood coagulation time
6. Culture proven sepsis
7. Necrotising enterocolitis
8. Cardiac arrhythmia
9. Thrombocytopenia
10. Major venous thrombosis
11. Renal failure treated with dialysis
12. Pneumonia
13. Pulmonary airleak
14. Duration of hospitalisation

Long term (at 18 months):
1. Mortality
2. Severe neurodevelopmental disability
3. Multiple handicap, defined as the presence of any two of the following in an infant:
3.1. Neuromotor disability (Level 3-5 on General Motor Function (GMF) Assessment Scale classification), mental delay (the Bayley Scales of Infant Development - Mental Development Indices (MDI) score less than 70), epilepsy, cortical visual impairment, sensorineural hearing loss
4. The Bayley Scales of Infant Development - Psychomotor Development Indices (PDI) score
5. Sensorineural hearing loss: greater than or equal to 40 dB
6. Epilepsy (defined as recurrent seizures beyond the neonatal period, requiring anticonvulsant therapy at the time of assessment)
7. Microcephaly (head circumference more than 2 standard deviations below the mean)

TCS study:
1. Overall IQ from Wechsler Preschool and Primary Scale of Intelligence tests (WPPSI III)
2. Overall Working Memory Test Battery for Children (WMTB-C) Scale
3. Overall Strengths and Difficulties Quotient score (SDQ) for behavioural problems
4. Overall ADHD Score (Du Paul RS IV)
5. Prevalence of Cerebral Palsy
6. Gross Motor Function Classification System level GMFCS)
7. Unimpaired outcome and overall grade of disability
8. Teachers academic achievement score
9. Health Utility Index (HUI-III)
10. Overall number of deaths in each group to age 7 years and 4 months
Sources of funding Medical Research Council (MRC) (UK) (ref: G0100126)

The TCS study has also been funded by the Medical Research Council (MRC) (UK) (ref: G0801320)
Trial website http://www.npeu.ox.ac.uk/TOBY/
Publications 1. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19797281
2. 2009 results of nested trial in http://www.ncbi.nlm.nih.gov/pubmed/19896902
Contact name Dr  Denis  Azzopardi
  Address Department of Paediatrics
ICSTM at Hammersmith
Du Cane Road
  City/town London
  Zip/Postcode W12 0NN
  Country United Kingdom
  Email
Sponsor Imperial College London (UK)
  Address Research Services, Medicine
Research Services Division
Faculty Building
South Kensington Campus
South Kensington
  City/town London
  Zip/Postcode SW7 2AZ
  Country United Kingdom
  Sponsor website: http://www.imperial.ac.uk/
Date applied 21/09/2000
Last edited 23/03/2010
Date ISRCTN assigned 21/09/2000
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