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

This study has been completed.
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT00147030
First received: September 5, 2005
Last updated: April 6, 2016
Last verified: November 2013
  Purpose

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.


Condition Intervention
Asphyxia Neonatorum
Hypoxia
Encephalopathy
Seizures
Procedure: Whole body mild induced hypothermia

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
    Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).

  • Persistent Hypotension [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Pulmonary Hypertension [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Prolonged Blood Coagulation Time [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Culture Proven Sepsis [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Necrotising Enterocolitis [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Cardiac Arrhythmia [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
    Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia.

  • Thrombocytopenia [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Major Venous Thrombosis [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Renal Failure Treated With Dialysis [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Pneumonia [ Time Frame: Before discharge from hospital ] [ Designated as safety issue: No ]
  • Pulmonary Airleak [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
  • Duration of Hospitalisation [ Time Frame: Duration of hospital stay, on average 22 days ] [ Designated as safety issue: No ]
    Total duration of hospital care

  • Mortality [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Severe Neurodevelopmental Disability [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Multiple Handicap [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Bayley Psychomotor Developmental Index score (PDI) <70

  • Sensorineural Hearing Loss [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Microcephaly [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Head circumference at follow-up >2 standard deviations below the mean


Enrollment: 325
Study Start Date: December 2002
Study Completion Date: August 2008
Primary Completion Date: November 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   up to 6 Hours   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00147030

Locations
United Kingdom
Hammersmith Hospital
London, United Kingdom, W12 0NN
Sponsors and Collaborators
Imperial College London
Medical Research Council
Investigators
Principal Investigator: Denis Azzopardi, MD; FRCPCH Imperial College London
  More Information

Additional Information:
Publications:
Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT00147030     History of Changes
Other Study ID Numbers: ISRCTN89547571(1) 
Study First Received: September 5, 2005
Results First Received: March 8, 2016
Last Updated: April 6, 2016
Health Authority: United Kingdom: Research Ethics Committee
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Imperial College London:
Hypoxia
Ischaemia
Encephalopathy
Neonatal
Hypothermia
Perinatal
Cooling
Whole/Total Body

Additional relevant MeSH terms:
Seizures
Hypothermia
Anoxia
Brain Diseases
Asphyxia
Asphyxia Neonatorum
Epilepsy
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Body Temperature Changes
Signs and Symptoms, Respiratory
Death
Pathologic Processes
Wounds and Injuries
Infant, Newborn, Diseases

ClinicalTrials.gov processed this record on July 24, 2016