Trial Outcomes & Findings for TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia (NCT NCT00147030)

NCT ID: NCT00147030

Last Updated: 2016-05-11

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 325 participants
• Primary outcome timeframe: 18 months
• Results posted on: 2016-05-11

Participant Flow

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.

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.

Participant milestones

Measure	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. 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	Non-cooled Standard intensive care at normothermia
Overall Study STARTED	163	162
Overall Study COMPLETED	163	162
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Cooled n=163 Participants Whole body mild induced hypothermia 72 hours, commencing by 6 hours of age followed by re-warming to normothermia.	Non-cooled n=162 Participants Standard intensive care	Total n=325 Participants Total of all reporting groups
Age, Customized Age 0-4 hours	48 participants n=5 Participants	57 participants n=7 Participants	105 participants n=5 Participants
Age, Customized Age 4-6 hours	115 participants n=5 Participants	105 participants n=7 Participants	220 participants n=5 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	74 Participants n=7 Participants	136 Participants n=5 Participants
Sex: Female, Male Male	101 Participants n=5 Participants	88 Participants n=7 Participants	189 Participants n=5 Participants

PRIMARY outcome

Timeframe: 18 months

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.

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors	74 participants	86 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).

Outcome measures

Measure	Cooled n=64 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=67 Participants Standard intensive care
Intracranial Haemorrhage	25 participants	21 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

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.

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Persistent Hypotension	126 participants	134 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Pulmonary Haemorrhage	5 participants	3 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Pulmonary Hypertension	16 participants	9 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=161 Participants Standard intensive care
Prolonged Blood Coagulation Time	67 participants	72 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Culture Proven Sepsis	20 participants	20 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Necrotising Enterocolitis	1 participants	0 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia.

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Cardiac Arrhythmia	8 participants	3 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=161 Participants Standard intensive care
Thrombocytopenia	94 participants	80 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Major Venous Thrombosis	2 participants	1 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Renal Failure Treated With Dialysis	0 participants	0 participants

SECONDARY outcome

Timeframe: Before discharge from hospital

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Pneumonia	5 participants	5 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Pulmonary Airleak	9 participants	3 participants

SECONDARY outcome

Timeframe: Duration of hospital stay, on average 22 days

Total duration of hospital care

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Duration of Hospitalisation	12 days Interval 8.0 to 18.0	13 days Interval 9.0 to 25.0

SECONDARY outcome

Timeframe: 18 months

Outcome measures

Measure	Cooled n=163 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=162 Participants Standard intensive care
Mortality	42 participants	44 participants

SECONDARY outcome

Timeframe: 18 months

Population: 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.

Outcome measures

Measure	Cooled n=120 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=117 Participants Standard intensive care
Severe Neurodevelopmental Disability	32 participants	42 participants

SECONDARY outcome

Timeframe: 18 months

Population: 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.

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

Outcome measures

Measure	Cooled n=112 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=110 Participants Standard intensive care
Multiple Handicap	21 participants	33 participants

SECONDARY outcome

Timeframe: 18 months

Population: 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.

Bayley Psychomotor Developmental Index score (PDI) <70

Outcome measures

Measure	Cooled n=114 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=109 Participants Standard intensive care
Bayley Psychomotor Developmental Index Score (PDI)	27 participants	37 participants

SECONDARY outcome

Timeframe: 18 months

Population: 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.

Normal or near normal hearing, no sensorineural hearing loss

Outcome measures

Measure	Cooled n=120 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=117 Participants Standard intensive care
Sensorineural Hearing Loss	110 participants	97 participants

SECONDARY outcome

Timeframe: 18 months

Population: 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.

Outcome measures

Measure	Cooled n=116 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=116 Participants Standard intensive care
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)	12 participants	16 participants

SECONDARY outcome

Timeframe: 18 months

Population: 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.

Head circumference at follow-up >2 standard deviations below the mean

Outcome measures

Measure	Cooled n=114 Participants Whole body mild induced hypothermia commencing by 6 hours of age for 72 hours, followed by normothermia.	Non-cooled n=112 Participants Standard intensive care
Microcephaly	24 participants	28 participants

Adverse Events

Cooled

Serious events: 8 serious events

Other events: 126 other events

Deaths: 0 deaths

Non-cooled

Serious events: 3 serious events

Other events: 134 other events

Deaths: 0 deaths

Serious adverse events

Measure	Cooled n=163 participants at risk 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	Non-cooled n=162 participants at risk Standard intensive care
Cardiac disorders Hypotension	1.2% 2/163 • Number of events 2	1.2% 2/162 • Number of events 2
Cardiac disorders Cardia arrhythmia	1.8% 3/163 • Number of events 3	1.2% 2/162 • Number of events 2
Blood and lymphatic system disorders Major venous thrombosis not related to an infusion line.	1.2% 2/163 • Number of events 2	0.00% 0/162
Surgical and medical procedures Collapse	0.61% 1/163 • Number of events 1	0.00% 0/162

Other adverse events

Measure	Cooled n=163 participants at risk 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	Non-cooled n=162 participants at risk Standard intensive care
Cardiac disorders Persistent hypotension	77.3% 126/163	82.7% 134/162
Blood and lymphatic system disorders Prolonged coagulation time	41.1% 67/163	44.4% 72/162
Blood and lymphatic system disorders Thrombocytopenia	57.7% 94/163	49.4% 80/162
Nervous system disorders Intracranial hemorrhage	15.3% 25/163	13.0% 21/162
Respiratory, thoracic and mediastinal disorders Pneumonia	3.1% 5/163	3.1% 5/162
Respiratory, thoracic and mediastinal disorders Pulmonary air leak	5.5% 9/163	1.9% 3/162
Respiratory, thoracic and mediastinal disorders Pulmonary hemorrhage	3.1% 5/163	1.9% 3/162
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	9.8% 16/163	5.6% 9/162
Gastrointestinal disorders Necrotizing enterocolitis	0.61% 1/163	0.00% 0/162
Infections and infestations Culture-proven sepsis	12.3% 20/163	12.3% 20/162

Additional Information

Director of NPEU Clinical Trials Unit

National Perinatal Epidemiology Unit, University of Oxford

Phone: 01865 289700

Email: ctu@npeu.ox.ac.uk

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place