Back to resultsTOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia
Primary Purpose
Asphyxia Neonatorum, Hypoxia, Encephalopathy
Status
Completed
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Whole body mild induced hypothermia
Sponsored by
About this trial
This is an interventional treatment trial for Asphyxia Neonatorum focused on measuring Hypoxia, Ischaemia, Encephalopathy, Neonatal, Hypothermia, Perinatal, Cooling, Whole/Total Body
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
Sites / Locations
- Hammersmith Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
No Intervention
Arm Label
cooled
non-cooled
Arm Description
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.
Standard intensive care
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Intracranial Haemorrhage
Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).
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.
Pulmonary Haemorrhage
Pulmonary Hypertension
Prolonged Blood Coagulation Time
Culture Proven Sepsis
Necrotising Enterocolitis
Cardiac Arrhythmia
Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia.
Thrombocytopenia
Major Venous Thrombosis
Renal Failure Treated With Dialysis
Pneumonia
Pulmonary Airleak
Duration of Hospitalisation
Total duration of hospital care
Mortality
Severe Neurodevelopmental Disability
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
Bayley Psychomotor Developmental Index Score (PDI)
Bayley Psychomotor Developmental Index score (PDI) <70
Sensorineural Hearing Loss
Normal or near normal hearing, no sensorineural hearing loss
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
Microcephaly
Head circumference at follow-up >2 standard deviations below the mean
Full Information
NCT ID
NCT00147030
First Posted
September 5, 2005
Last Updated
April 6, 2016
Sponsor
Imperial College London
Collaborators
Medical Research Council
1. Study Identification
Unique Protocol Identification Number
NCT00147030
Brief Title
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
2. Study Status
Record Verification Date
November 2013
Overall Recruitment Status
Completed
Study Start Date
December 2002 (undefined)
Primary Completion Date
November 2006 (Actual)
Study Completion Date
August 2008 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
Collaborators
Medical Research Council
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asphyxia Neonatorum, Hypoxia, Encephalopathy, Seizures
Keywords
Hypoxia, Ischaemia, Encephalopathy, Neonatal, Hypothermia, Perinatal, Cooling, Whole/Total Body
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
325 (Actual)
8. Arms, Groups, and Interventions
Arm Title
cooled
Arm Type
Active Comparator
Arm Description
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.
Arm Title
non-cooled
Arm Type
No Intervention
Arm Description
Standard intensive care
Intervention Type
Procedure
Intervention Name(s)
Whole body mild induced hypothermia
Intervention Description
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
Primary Outcome Measure Information:
Title
Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors
Description
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.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Intracranial Haemorrhage
Description
Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).
Time Frame
Duration of hospital stay, on average 22 days
Title
Persistent Hypotension
Description
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.
Time Frame
Duration of hospital stay, on average 22 days
Title
Pulmonary Haemorrhage
Time Frame
Duration of hospital stay, on average 22 days
Title
Pulmonary Hypertension
Time Frame
Duration of hospital stay, on average 22 days
Title
Prolonged Blood Coagulation Time
Time Frame
Duration of hospital stay, on average 22 days
Title
Culture Proven Sepsis
Time Frame
Duration of hospital stay, on average 22 days
Title
Necrotising Enterocolitis
Time Frame
Duration of hospital stay, on average 22 days
Title
Cardiac Arrhythmia
Description
Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia.
Time Frame
Duration of hospital stay, on average 22 days
Title
Thrombocytopenia
Time Frame
Duration of hospital stay, on average 22 days
Title
Major Venous Thrombosis
Time Frame
Duration of hospital stay, on average 22 days
Title
Renal Failure Treated With Dialysis
Time Frame
Duration of hospital stay, on average 22 days
Title
Pneumonia
Time Frame
Before discharge from hospital
Title
Pulmonary Airleak
Time Frame
Duration of hospital stay, on average 22 days
Title
Duration of Hospitalisation
Description
Total duration of hospital care
Time Frame
Duration of hospital stay, on average 22 days
Title
Mortality
Time Frame
18 months
Title
Severe Neurodevelopmental Disability
Time Frame
18 months
Title
Multiple Handicap
Description
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
Time Frame
18 months
Title
Bayley Psychomotor Developmental Index Score (PDI)
Description
Bayley Psychomotor Developmental Index score (PDI) <70
Time Frame
18 months
Title
Sensorineural Hearing Loss
Description
Normal or near normal hearing, no sensorineural hearing loss
Time Frame
18 months
Title
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
Time Frame
18 months
Title
Microcephaly
Description
Head circumference at follow-up >2 standard deviations below the mean
Time Frame
18 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Hour
Maximum Age & Unit of Time
6 Hours
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Denis Azzopardi, MD; FRCPCH
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hammersmith Hospital
City
London
ZIP/Postal Code
W12 0NN
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
19797281
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. Erratum In: N Engl J Med. 2010 Mar 18;362(11):1056.
Results Reference
result
PubMed Identifier
19896902
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.
Results Reference
result
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TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia
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