Condition category
Pregnancy and Childbirth
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Plain English Summary

Not provided at time of registration

Trial website

Contact information



Primary contact

Dr Denis Azzopardi


Contact details

Department of Paediatrics
ICSTM at Hammersmith
Du Cane Road
W12 0NN
United Kingdom

Additional identifiers

EudraCT number 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


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

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


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Patient information can be found at:


Perinatal asphyxial encephalopathy, child development, cerebral palsy


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



Not Applicable

Drug names

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 trial start date


Overall trial end date


Reason abandoned (if study stopped)


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


Age group




Target number of participants


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


Recruitment end date



Countries of recruitment

Finland, Hungary, Ireland, Israel, Sweden, United Kingdom

Trial participating centre

ICSTM at Hammersmith
W12 0NN
United Kingdom

Sponsor information


Imperial College London (UK)

Sponsor details

Research Services
Research Services Division
Faculty Building
South Kensington Campus
South Kensington
United Kingdom

Sponsor type




Funder type

Research council

Funder name

Medical Research Council (MRC) (UK) (ref: G0100126)

Alternative name(s)


Funding Body Type

government organisation

Funding Body Subtype

National government


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


Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)


Publication list

2009 results in:
2009 results of nested trial in:
2014 results in:

Publication citations

  1. Results of nested trial

    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, 9, 1, 39-45, doi: 10.1016/S1474-4422(09)70295-9.

  2. Results

    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, , Moderate hypothermia to treat perinatal asphyxial encephalopathy., N. Engl. J. Med., 2009, 361, 14, 1349-1358, doi: 10.1056/NEJMoa0900854.

  3. Results

    Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, Goodwin J, Halliday HL, Juszczak E, Kapellou O, Levene M, Linsell L, Omar O, Thoresen M, Tusor N, Whitelaw A, Edwards AD; TOBY Study Group, Effects of hypothermia for perinatal asphyxia on childhood outcomes, N Engl J Med, 2014 , 371, 2, 140-149, doi: 10.1056/NEJMoa1315788.

Additional files

Editorial Notes

21/03/2016: added link to results - basic reporting. 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). On 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.