TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia

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 Overview

• Status: Completed
• Conditions: Hypoxia; Seizures; Asphyxia Neonatorum; Encephalopathy
• Intervention / Treatment: Procedure: Whole body mild induced hypothermia

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.

• Study Type: Interventional
• Enrollment (Actual): 325
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W12 0NN
    • Hammersmith Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 6 hours (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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
NO_INTERVENTION: non-cooled; Standard intensive care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors	Severe neurodevelopmental disability was defined as a score of less than 70 on the Mental Developmental Index of the Bayley Scales of Infant Development II (BSID-II) (on which the standardization mean [± standard deviation (SD)] is 100±15 and higher scores indicate better performance), a score of 3 to 5 on the Gross Motor Function Classification System (GMFCS) (on which scores can range from 1 to 5, with higher scores indicating greater impairment), or bilateral cortical visual impairment with no useful vision.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		18 months
Intracranial Haemorrhage	Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).	Duration of hospital stay, on average 22 days
Persistent Hypotension	Hypotension was defined as a mean blood pressure of 40 mm Hg or less and was persistent if causes of hypotension had been sought and appropriate treatment provided, without success.	Duration of hospital stay, on average 22 days
Pulmonary Haemorrhage		Duration of hospital stay, on average 22 days
Pulmonary Hypertension		Duration of hospital stay, on average 22 days
Prolonged Blood Coagulation Time		Duration of hospital stay, on average 22 days
Culture Proven Sepsis		Duration of hospital stay, on average 22 days
Necrotising Enterocolitis		Duration of hospital stay, on average 22 days
Cardiac Arrhythmia	Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia.	Duration of hospital stay, on average 22 days
Thrombocytopenia		Duration of hospital stay, on average 22 days
Major Venous Thrombosis		Duration of hospital stay, on average 22 days
Renal Failure Treated With Dialysis		Duration of hospital stay, on average 22 days
Pneumonia		Before discharge from hospital
Pulmonary Airleak		Duration of hospital stay, on average 22 days
Duration of Hospitalisation	Total duration of hospital care	Duration of hospital stay, on average 22 days
Severe Neurodevelopmental Disability		18 months
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
Bayley Psychomotor Developmental Index Score (PDI)	Bayley Psychomotor Developmental Index score (PDI) <70	18 months
Sensorineural Hearing Loss	Normal or near normal hearing, no sensorineural hearing loss	18 months
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)		18 months
Microcephaly	Head circumference at follow-up >2 standard deviations below the mean	18 months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Medical Research Council
• Investigators: Principal Investigator: Denis Azzopardi, MD; FRCPCH, Imperial College London

Publications and helpful links

General Publications

• 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. 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. doi: 10.1016/S1474-4422(09)70295-9. Epub 2009 Nov 5.

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (ACTUAL): November 1, 2006
• Study Completion (ACTUAL): August 1, 2008

Study Registration Dates

• First Submitted: September 5, 2005
• First Submitted That Met QC Criteria: September 5, 2005
• First Posted (ESTIMATE): September 7, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): May 11, 2016
• Last Update Submitted That Met QC Criteria: April 6, 2016
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Hypoxia; Hypothermia; Cooling; Neonatal; Encephalopathy; Perinatal; Ischaemia; Whole/Total Body
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Wounds and Injuries; Infant, Newborn, Diseases; Signs and Symptoms, Respiratory; Death; Body Temperature Changes; Seizures; Brain Diseases; Hypoxia; Hypothermia; Asphyxia; Asphyxia Neonatorum
• Other Study ID Numbers: ISRCTN89547571(1)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO