TOBY: a Study of Treatment for Perinatal Asphyxia

Hypoxia Clinical Trial

Official title:

Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00147030
• Other study ID #: ISRCTN89547571(1)
• Status: Completed
• Phase: N/A
• First received: September 5, 2005
• Last updated: November 25, 2013
• Start date: December 2002
• Est. completion date: August 2008

Study information

• Verified date: November 2013
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 325
• Est. completion date: August 2008
• Est. primary completion date: November 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 6 Hours

Eligibility

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 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 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asphyxia
• Asphyxia Neonatorum
• Brain Diseases
• Encephalopathy
• Hypoxia
• Seizures

Intervention

Procedure:
• Whole body mild induced hypothermia
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

Locations

Country	Name	City	State
United Kingdom	Hammersmith Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
Imperial College London	Medical Research Council

Country where clinical trial is conducted

United Kingdom, 

References & Publications (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; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 O — View Citation

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 o — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Combined incidence of mortality and severe neurodevelopmental disability in survivors		18 months	No
Secondary	Intracranial haemorrhage		Before discharge from hospital	No
Secondary	Persistent hypotension		Before discharge from hospital	No
Secondary	Pulmonary haemorrhage		Before discharge from hospital	No
Secondary	Pulmonary hypertension		Before discharge from hospital	No
Secondary	Prolonged blood coagulation time		Before discharge from hospital	No
Secondary	Culture proven sepsis		Before discharge from hospital	No
Secondary	Necrotising enterocolitis		Before discharge from hospital	No
Secondary	Cardiac arrhythmia		Before discharge from hospital	No
Secondary	Thrombocytopenia		Before discharge from hospital	No
Secondary	Major venous thrombosis		Before discharge from hospital	No
Secondary	Renal failure treated with dialysis		Before discharge from hospital	No
Secondary	Pneumonia		Before discharge from hospital	No
Secondary	Pulmonary airleak		Before discharge from hospital	No
Secondary	Duration of hospitalisation		Before discharge from hospital	No
Secondary	Mortality		18 months	No
Secondary	Severe neurodevelopmental disability		18 months	No
Secondary	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	No
Secondary	Bayley Psychomotor Developmental Index score (PDI)		18 months	No
Secondary	Sensorineural hearing loss: 40 deciBels		18 months	No
Secondary	Epilepsy (defined as recurrent seizures beyond the neonatal period, requiring anticonvulsant therapy at the time of assessment)		18 months	No
Secondary	Microcephaly (head circumference more than 2 standard deviations below the mean).		18 months	No

External Links

•   The TOBY study website