Condition category
Pregnancy and Childbirth
Date applied
21/09/2000
Date assigned
21/09/2000
Last edited
23/03/2010
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

http://www.npeu.ox.ac.uk/TOBY/

Contact information

Type

Scientific

Primary contact

Dr Denis Azzopardi

ORCID ID

Contact details

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

Additional identifiers

EudraCT number

ClinicalTrials.gov number

NCT00147030

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

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.

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

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial 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.

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.

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

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

01/09/2002

Overall trial end date

01/09/2008

Reason abandoned

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

Patient

Age group

Neonate

Gender

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

01/09/2008

Locations

Countries of recruitment

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

Trial participating centre

Department of Paediatrics
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
United Kingdom

Sponsor type

University/education

Website

http://www.imperial.ac.uk/

Funders

Funder type

Research council

Funder name

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

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

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

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

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

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. 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.

Additional files

Editorial Notes