Asphyxia NeonatorumNCT00147030
TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia
A study testing Whole body mild induced hypothermia in people with Asphyxia Neonatorum and Hypoxia, run by Imperial College London at 1 site in United Kingdom.
Trial 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… Read more about this study
- Who is it for?
- Ages 1 hour to 6 hours
- Conditions the study is for
- Asphyxia Neonatorum, Hypoxia, Encephalopathy
- What is being tested?
- Whole body mild induced hypothermia
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 325 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Dec 2002to Aug 2008
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 hour to 6 hours
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- The infant will be assessed sequentially by criteria A, B and C listed below:
- 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
Show all 18Show fewer
- Infants that meet criteria A will be assessed for whether they meet the neurological abnormality entry criteria (B) by trained personnel:
- 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):
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Asphyxia Neonatorum, Hypoxia, Encephalopathy, Seizures
- Being tested
- Whole body mild induced hypothermia
- Keywords
- Hypoxia, Ischaemia, Encephalopathy, Neonatal, Hypothermia, Perinatal, Cooling, Whole/Total Body
- Medical subject headings
- Asphyxia Neonatorum, Hypoxia, Brain Diseases, Seizures, Ischemia, Hypothermia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Whole body mild induced hypothermiaProcedure or surgery
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
| Study group | Role | What they receive |
|---|---|---|
| cooled | Active comparator | 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. Receives: Procedure: Whole body mild induced hypothermia |
| non-cooled | No intervention | Standard intensive care |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 18 months
Secondary outcomes (21)
Intracranial Haemorrhage
Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).
Measured: 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.
Measured: Duration of hospital stay, on average 22 days
Pulmonary Haemorrhage
Measured: Duration of hospital stay, on average 22 days
Pulmonary Hypertension
Measured: Duration of hospital stay, on average 22 days
Prolonged Blood Coagulation Time
Measured: Duration of hospital stay, on average 22 days
Culture Proven Sepsis
Measured: Duration of hospital stay, on average 22 days
Necrotising Enterocolitis
Measured: 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.
Measured: Duration of hospital stay, on average 22 days
Thrombocytopenia
Measured: Duration of hospital stay, on average 22 days
Major Venous Thrombosis
Measured: Duration of hospital stay, on average 22 days
Renal Failure Treated With Dialysis
Measured: Duration of hospital stay, on average 22 days
Pneumonia
Measured: Before discharge from hospital
Pulmonary Airleak
Measured: Duration of hospital stay, on average 22 days
Duration of Hospitalisation
Total duration of hospital care
Measured: Duration of hospital stay, on average 22 days
Mortality
Measured: 18 months
Severe Neurodevelopmental Disability
Measured: 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
Measured: 18 months
Bayley Psychomotor Developmental Index Score (PDI)
Bayley Psychomotor Developmental Index score (PDI) <70
Measured: 18 months
Sensorineural Hearing Loss
Normal or near normal hearing, no sensorineural hearing loss
Measured: 18 months
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
Measured: 18 months
Microcephaly
Head circumference at follow-up >2 standard deviations below the mean
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Sep 2005 (estimated)
- Study startDec 2002
- Primary completionNov 2006
- Study completionAug 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Asphyxia NeonatorumStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 325 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- Medical Research Council
- Responsible party
- Sponsor
- Investigators
- Denis Azzopardi, MD; FRCPCH, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00147030
- Sponsor's protocol ID
- ISRCTN89547571(1)
- Status last verified
- Nov 2013
- First submitted
- 5 Sep 2005
- Last updated
- 11 May 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
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.
PubMed 19797281Rutherford 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.
PubMed 19896902
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy
- ClinicalTrials.gov ID
- NCT00147030
- Acronym / sponsor ID
- ISRCTN89547571(1)
- Conditions
- Asphyxia Neonatorum, Hypoxia, Encephalopathy, Seizures
- Keywords
- Hypoxia, Ischaemia, Encephalopathy, Neonatal, Hypothermia, Perinatal, Cooling, Whole/Total Body
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 325 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- Medical Research Council
- Study start
- Dec 2002
- Primary completion
- Nov 2006 (actual)
- Study completion
- Aug 2008 (actual)
- First posted
- 7 Sep 2005 (estimated)
- Results
- Posted 11 May 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| cooled | Active comparator | Procedure: Whole body mild induced hypothermiaWhole 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. |
| non-cooled | No intervention | –Standard intensive care |
Who may qualify
- Ages
- 1 hour to 6 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (18 listed)
- 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
Key exclusion criteria (2 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Whole body mild induced hypothermiaTarget rectal temperature 33-34°C for 72 hours, commencing by 6 hours of age; followed by re-warming at 0.5°C to normothermia | Procedure or surgery | cooled |
Primary outcome
Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors
Time frame: 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.
21 secondary outcomes
Intracranial Haemorrhage
Time frame: Duration of hospital stay, on average 22 days
Persistent Hypotension
Time frame: Duration of hospital stay, on average 22 days
Pulmonary Haemorrhage
Time frame: Duration of hospital stay, on average 22 days
Pulmonary Hypertension
Time frame: Duration of hospital stay, on average 22 days
Prolonged Blood Coagulation Time
Time frame: Duration of hospital stay, on average 22 days
Culture Proven Sepsis
Time frame: Duration of hospital stay, on average 22 days
Necrotising Enterocolitis
Time frame: Duration of hospital stay, on average 22 days
Cardiac Arrhythmia
Time frame: Duration of hospital stay, on average 22 days
Thrombocytopenia
Time frame: Duration of hospital stay, on average 22 days
Major Venous Thrombosis
Time frame: Duration of hospital stay, on average 22 days
Renal Failure Treated With Dialysis
Time frame: Duration of hospital stay, on average 22 days
Pneumonia
Time frame: Before discharge from hospital
Pulmonary Airleak
Time frame: Duration of hospital stay, on average 22 days
Duration of Hospitalisation
Time frame: Duration of hospital stay, on average 22 days
Mortality
Time frame: 18 months
Severe Neurodevelopmental Disability
Time frame: 18 months
Multiple Handicap
Time frame: 18 months
Bayley Psychomotor Developmental Index Score (PDI)
Time frame: 18 months
Sensorineural Hearing Loss
Time frame: 18 months
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
Time frame: 18 months
Microcephaly
Time frame: 18 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 19797281Azzopardi 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.
- Results publication: PubMed 19896902Rutherford 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Denis Azzopardi, MD; FRCPCH principal investigator
Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Whole body mild induced hypothermia in people with Asphyxia Neonatorum and Hypoxia, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 May 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors (time frame: 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00147030, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2016.