TOBY: a Study of Treatment for Perinatal Asphyxia

Brief Summary

Official Title: “Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy”

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.

  • Study Type: Interventional
  • Study Design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: November 2006

Detailed Clinical Trial 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.

Interventions Used in this Clinical Trial

  • 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

Arms, Groups and Cohorts in this Clinical Trial

  • Active Comparator: cooled
    • Whole body mild induced hypothermia for 72 hours, starting by 6 hours of age, in addition to standard intensive care. After 72 hours of cooling, rewarming by a maximum of 0.5 degree C / hour to normothermia.
  • No Intervention: non-cooled
    • Standard intensive care

Outcome Measures for this Clinical Trial

Primary Measures

  • Combined incidence of mortality and severe neurodevelopmental disability in survivors
    • Time Frame: 18 months
      Safety Issue?: No

Secondary Measures

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

Criteria for Participation in this Clinical Trial

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 6 Hours

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • Imperial College London
  • Collaborator
    • Medical Research Council
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Denis Azzopardi, MD; FRCPCH, Principal Investigator, Imperial College London

Citations Reporting on 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; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. Erratum in: N Engl J Med. 2010 Mar 18;362(11):1056.

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 Jan;9(1):39-45. Epub 2009 Nov 5.

Source

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http://clinicaltrialsfeeds.org/clinical-trials/show/NCT00147030