Plain English Summary
Not provided at time of registration
Study website
Contact information
Type
Scientific
Contact name
Dr Denis Azzopardi
ORCID ID
Contact details
Department of Paediatrics
ICSTM at Hammersmith
Du Cane Road
London
W12 0NN
United Kingdom
-
abc@email.com
Additional identifiers
EudraCT/CTIS number
IRAS number
ClinicalTrials.gov number
NCT00147030, NCT01092637
Protocol/serial number
MRC ref: G0100126; G0801320
Study information
Scientific title
Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial
Acronym
TOBY (TOtal Body hYpothermia)
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
The TOBY Children Study: School age outcomes following a newborn cooling trial (TCS) 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.
Ethics approval(s)
1. London Multi-centre Research Ethics Committee (MREC), 08/01/2002, ref: MREC 00/02/73
2. TCS study: Charing Cross Hospital Research Ethics Committee, 10/02/2010, ref: 10/H0711/13
Study design
Randomised controlled trial; subsequent cohort study at school age follow up
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Study setting(s)
Hospital
Study type
Treatment
Patient information sheet
Patient information can be found at: http://www.npeu.ox.ac.uk/TOBY/toby_downloads/toby_pil1.pdf
Condition
Perinatal asphyxial encephalopathy, child development, cerebral palsy
Intervention
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.
TCS study:
No intervention, comparison of outcomes at school age in the treatment and control groups.
Intervention type
Other
Primary outcome measure
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 measures
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
Overall study start date
01/09/2002
Overall study end date
01/09/2008
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type(s)
Patient
Age group
Neonate
Sex
Both
Target number of participants
325
Participant 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.
Recruitment start date
01/09/2002
Recruitment end date
30/11/2006
Locations
Countries of recruitment
England, Finland, Hungary, Ireland, Israel, Sweden, United Kingdom
Study participating centre
ICSTM at Hammersmith
London
W12 0NN
United Kingdom
Sponsor information
Organisation
Imperial College London (UK)
Sponsor details
Research Services
Medicine
Research Services Division
Faculty Building
South Kensington Campus
South Kensington
London
SW7 2AZ
England
United Kingdom
Sponsor type
University/education
Website
ROR
Funders
Funder type
Research council
Funder name
Medical Research Council (MRC) (UK) (ref: G0100126)
Alternative name(s)
UK Medical Research Council, MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
The TCS study has also been funded by the Medical Research Council (MRC) (UK) (ref: G0801320)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Individual participant data (IPD) sharing plan
IPD sharing plan summary
Not provided at time of registration
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | No | No | |||
| Results article | results | 01/10/2009 | Yes | No | |
| Results article | results of nested trial | 01/01/2010 | Yes | No | |
| Results article | results | 10/07/2014 | Yes | No |