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

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ClinicalTrials.gov Identifier: NCT00147030
Recruitment Status : Completed
First Posted : September 7, 2005
Results First Posted : May 11, 2016
Last Update Posted : May 11, 2016
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
Imperial College London

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Asphyxia Neonatorum
Hypoxia
Encephalopathy
Seizures
Intervention Procedure: Whole body mild induced hypothermia
Enrollment 325
Recruitment Details Infants who met trial entry criteria were recruited at 40 Neonatal Intensive Care Units mainly in the United Kingdom and also in Europe. Recruitment took place over 4 years, from December 2006 to November 2006.
Pre-assignment Details 494 infants were assessed for eligibility; 94 did not meet inclusion criteria, 30 declined to participate 45 were not enrolled for other reasons. 325 underwent randomization.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care at normothermia
Period Title: Overall Study
Started 163 162
Completed 163 162
Not Completed 0 0
Arm/Group Title Cooled Non-cooled Total
Hide Arm/Group Description Whole body mild induced hypothermia 72 hours, commencing by 6 hours of age followed by re-warming to normothermia. Standard intensive care Total of all reporting groups
Overall Number of Baseline Participants 163 162 325
Hide Baseline Analysis Population Description
Infants who were less than 6 hours of age who had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy confirmed by 30 minutes’ amplitude-integrated electro-encephalography that showed abnormal background activity or seizures.
Age, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 163 participants 162 participants 325 participants
Age 0-4 hours 48 57 105
Age 4-6 hours 115 105 220
[1]
Measure Description: All participants were < 6 hours of age at randomization.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 163 participants 162 participants 325 participants
Female
62
  38.0%
74
  45.7%
136
  41.8%
Male
101
  62.0%
88
  54.3%
189
  58.2%
1.Primary Outcome
Title Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors
Hide 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
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[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
74 86
2.Secondary Outcome
Title Intracranial Haemorrhage
Hide Description Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).
Time Frame Duration of hospital stay, on average 22 days
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[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 64 67
Measure Type: Number
Unit of Measure: participants
25 21
3.Secondary Outcome
Title Persistent Hypotension
Hide 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
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[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
126 134
4.Secondary Outcome
Title Pulmonary Haemorrhage
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
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[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
5 3
5.Secondary Outcome
Title Pulmonary Hypertension
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
16 9
6.Secondary Outcome
Title Prolonged Blood Coagulation Time
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 161
Measure Type: Number
Unit of Measure: participants
67 72
7.Secondary Outcome
Title Culture Proven Sepsis
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
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[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
20 20
8.Secondary Outcome
Title Necrotising Enterocolitis
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
1 0
9.Secondary Outcome
Title Cardiac Arrhythmia
Hide 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
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
8 3
10.Secondary Outcome
Title Thrombocytopenia
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours; followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 161
Measure Type: Number
Unit of Measure: participants
94 80
11.Secondary Outcome
Title Major Venous Thrombosis
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
2 1
12.Secondary Outcome
Title Renal Failure Treated With Dialysis
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group Description:
Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.
Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
0 0
13.Secondary Outcome
Title Pneumonia
Hide Description [Not Specified]
Time Frame Before discharge from hospital
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
5 5
14.Secondary Outcome
Title Pulmonary Airleak
Hide Description [Not Specified]
Time Frame Duration of hospital stay, on average 22 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
9 3
15.Secondary Outcome
Title Duration of Hospitalisation
Hide Description Total duration of hospital care
Time Frame Duration of hospital stay, on average 22 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 163 162
Median (Inter-Quartile Range)
Unit of Measure: days
12
(8 to 18)
13
(9 to 25)
16.Secondary Outcome
Title Mortality
Hide Description [Not Specified]
Time Frame 18 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 163 162
Measure Type: Number
Unit of Measure: participants
42 44
17.Secondary Outcome
Title Severe Neurodevelopmental Disability
Hide Description [Not Specified]
Time Frame 18 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 120 117
Measure Type: Number
Unit of Measure: participants
32 42
18.Secondary Outcome
Title Multiple Handicap
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 112 110
Measure Type: Number
Unit of Measure: participants
21 33
19.Secondary Outcome
Title Bayley Psychomotor Developmental Index Score (PDI)
Hide Description Bayley Psychomotor Developmental Index score (PDI) <70
Time Frame 18 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 114 109
Measure Type: Number
Unit of Measure: participants
27 37
20.Secondary Outcome
Title Sensorineural Hearing Loss
Hide Description Normal or near normal hearing, no sensorineural hearing loss
Time Frame 18 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 120 117
Measure Type: Number
Unit of Measure: participants
110 97
21.Secondary Outcome
Title Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
Hide Description [Not Specified]
Time Frame 18 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 116 116
Measure Type: Number
Unit of Measure: participants
12 16
22.Secondary Outcome
Title Microcephaly
Hide Description Head circumference at follow-up >2 standard deviations below the mean
Time Frame 18 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
Overall Number of Participants Analyzed 114 112
Measure Type: Number
Unit of Measure: participants
24 28
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cooled Non-cooled
Hide Arm/Group 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.

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

Standard intensive care
All-Cause Mortality
Cooled Non-cooled
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Cooled Non-cooled
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/163 (4.91%)      3/162 (1.85%)    
Blood and lymphatic system disorders     
Major venous thrombosis not related to an infusion line.   2/163 (1.23%)  2 0/162 (0.00%)  0
Cardiac disorders     
Hypotension  [1]  2/163 (1.23%)  2 2/162 (1.23%)  2
Cardia arrhythmia   3/163 (1.84%)  3 2/162 (1.23%)  2
Surgical and medical procedures     
Collapse * [2]  1/163 (0.61%)  1 0/162 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[1]
Severe hypotension (mean arterial pressure less than 25mmHg), despite full inotrope support and volume replacement.
[2]
Collapse during lumbar puncture
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cooled Non-cooled
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   126/163 (77.30%)      134/162 (82.72%)    
Blood and lymphatic system disorders     
Prolonged coagulation time   67/163 (41.10%)  72/162 (44.44%) 
Thrombocytopenia   94/163 (57.67%)  80/162 (49.38%) 
Cardiac disorders     
Persistent hypotension  [1]  126/163 (77.30%)  134/162 (82.72%) 
Gastrointestinal disorders     
Necrotizing enterocolitis   1/163 (0.61%)  0/162 (0.00%) 
Infections and infestations     
Culture-proven sepsis   20/163 (12.27%)  20/162 (12.35%) 
Nervous system disorders     
Intracranial hemorrhage   25/163 (15.34%)  21/162 (12.96%) 
Respiratory, thoracic and mediastinal disorders     
Pneumonia   5/163 (3.07%)  5/162 (3.09%) 
Pulmonary air leak   9/163 (5.52%)  3/162 (1.85%) 
Pulmonary hemorrhage   5/163 (3.07%)  3/162 (1.85%) 
Pulmonary hypertension   16/163 (9.82%)  9/162 (5.56%) 
Indicates events were collected by systematic assessment
[1]
Hypotension was defined as a mean blood pressure of 40 mm Hg or less.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Director of NPEU Clinical Trials Unit
Organization: National Perinatal Epidemiology Unit, University of Oxford
Phone: 01865 289700 ext 89728
Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT00147030     History of Changes
Other Study ID Numbers: ISRCTN89547571(1)
First Submitted: September 5, 2005
First Posted: September 7, 2005
Results First Submitted: March 8, 2016
Results First Posted: May 11, 2016
Last Update Posted: May 11, 2016