Clinical trial NCT00147030: TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia
Official title: Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Asphyxia Neonatorum
Hypoxia
Encephalopathy
Seizures
Keywords: Hypoxia
Ischaemia
Encephalopathy
Neonatal
Hypothermia
Perinatal
Cooling
Whole/Total Body
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Medical Research Council
First posted: 2005-09-07
Enrollment: 325
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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 Neonatal Intensive Care Unit (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 amplitude-integrated electroencephalogram (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

Primary outcomes:
measure: Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors
timeFrame: 18 months
Secondary outcomes:
measure: Intracranial Haemorrhage
timeFrame: Duration of hospital stay, on average 22 days
measure: Persistent Hypotension
timeFrame: Duration of hospital stay, on average 22 days
measure: Pulmonary Haemorrhage
timeFrame: Duration of hospital stay, on average 22 days
measure: Pulmonary Hypertension
timeFrame: Duration of hospital stay, on average 22 days
measure: Prolonged Blood Coagulation Time
timeFrame: Duration of hospital stay, on average 22 days
measure: Culture Proven Sepsis
timeFrame: Duration of hospital stay, on average 22 days
measure: Necrotising Enterocolitis
timeFrame: Duration of hospital stay, on average 22 days
measure: Cardiac Arrhythmia
timeFrame: Duration of hospital stay, on average 22 days
measure: Thrombocytopenia
timeFrame: Duration of hospital stay, on average 22 days
measure: Major Venous Thrombosis
timeFrame: Duration of hospital stay, on average 22 days
measure: Renal Failure Treated With Dialysis
timeFrame: Duration of hospital stay, on average 22 days
measure: Pneumonia
timeFrame: Before discharge from hospital
measure: Pulmonary Airleak
timeFrame: Duration of hospital stay, on average 22 days
measure: Duration of Hospitalisation
timeFrame: Duration of hospital stay, on average 22 days
measure: Mortality
timeFrame: 18 months
measure: Severe Neurodevelopmental Disability
timeFrame: 18 months
measure: Multiple Handicap
timeFrame: 18 months
measure: Bayley Psychomotor Developmental Index Score (PDI)
timeFrame: 18 months
measure: Sensorineural Hearing Loss
timeFrame: 18 months
measure: Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
timeFrame: 18 months
measure: Microcephaly
timeFrame: 18 months
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith Hospital
Study officials:
affiliation: Imperial College London
name: Denis Azzopardi, MD; FRCPCH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1056/NEJMoa0900854.
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 of a randomised controlled trial. Lancet Neurol. 2010 Jan;9(1):39-45. doi: 10.1016/S1474-4422(09)70295-9. Epub 2009 Nov 5.