The toby trial

Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : January 21, Last Update Posted : January 21, Study Description. Detailed Description:. FDA Resources. Child was allocated standard intensive care only within 6 hours of birth. Outcome Measures. Number of participants diagnosed with Cerebral Palsy.

Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. All participants were recruited to the TOBY randomised controlled trial as newborns, with confirmed moderate or severe hypoxic ischaemic encephalopathy.

Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.

More Information. Effects of hypothermia for perinatal asphyxia on childhood outcomes. FB Tweet More. You'll get the latest updates on this topic in your browser notifications. Toby Willis. Credit: Cheatham County Jail. All rights reserved. The metabolic rate is reduced during hypothermia and this results in bradycardia and prolonged PR and QT intervals. There are few data on the safety of mild or moderate hypothermia in newborn infants since previous studies employed hypothermia for brief periods in the treatment of failed resuscitation [ 39 - 42 ].

These early studies appeared to demonstrate improved outcomes without side effects but few controls were included. No clinically significant adverse effects due to cooling were observed in the recent pilot studies of whole body cooling following encephalopathy [ 34 , 35 ]. As expected, the heart rate reduced to below bpm with cooling but this was not accompanied by arrhythmia, and the blood pressure and perfusion were maintained.

Although some experimental evidence suggests that selective head cooling may be effective [ 25 , 43 ], it is uncertain whether head cooling alone effectively lowers deep brain temperature. In adults, a steep temperature gradient has been observed between the surface of the head and deep brain structures and the deep brain temperature remains very close to core temperature even when extreme cold is applied to the surface of the head [ 45 ].

The possibility of temperature gradients within the brain and the importance of damage to deep structures in causing severe neurodevelopmental impairment [ 46 ] and the lack of precise, non-invasive methods for measuring regional brain temperature pose major difficulties with selective head cooling. Pilot studies of prolonged whole body cooling in infants with perinatal asphyxial encephalopathy have been carried out [ 34 , 35 ].

Infants were selected on staged criteria based on the clinical condition at birth and abnormal amplitude integrated EEG aEEG. Selection was completed, written informed consent was obtained and hypothermic treatment started within six hours of birth, including the infants born outside the study centres. An increase in blood pressure and a reduction in heart rate with cooling were noted, but these were not clinically significant, unless there was an inadvertent rapid change in body temperature [ 34 ].

A mild hypokalaemia was commonly observed. No disturbance in coagulation or viscosity attributable to cooling was seen. Magnetic resonance imaging MRI was performed repeatedly. Sinus thrombosis was observed in two infants and one infant developed delayed haemorrhagic cerebral infarction. These three infants died after intensive care was withdrawn according to parental wishes when the clinical, EEG and MRI findings indicated severe, irreversible cerebral injury.

Since the TOBY trial was started in , three other trials of hypothermia for the management of neonatal encephalopathy NE one using selective head cooling and two using whole body cooling , have been published [ 73 - 75 ]. The results of these trials are summarised here with a reminder of the assumptions that were made when calculating the required sample size of the TOBY study:. Despite the promising results which are beginning to emerge from the completed studies, none of the completed or on-going studies including TOBY are large enough to allow assessment of moderate differences after 18 months of age.

There is increasing concern that therapeutic hypothermia may be introduced into clinical practice without any knowledge of whether these apparent initial benefits are maintained in the longer term, such as at 6 years of age. There is broad support for continuing to recruit to the on going trials: a meeting convened by the NIH in Washington to assess future studies of treatment with hypothermia in neonates concluded that:.

Perinatal asphyxial encephalopathy is reported to occur in between one and two infants per thousand deliveries, and much more frequently in countries without adequate obstetric facilities. Early identification by clinical features of infants at risk of developing encephalopathy is difficult. Fetal heart rate patterns are not very helpful [ 48 , 49 ] and neither the Apgar scores recorded immediately after birth [ 50 , 51 ] nor umbilical cord blood gas analysis [ 52 , 53 ] are good predictors of the likelihood or severity of post asphyxial encephalopathy.

Abnormal appearances can be observed on cranial ultrasonography, computerized tomography [ 54 ] and MRI [ 55 ]. However, these abnormalities may not be apparent during the first 24 — 48 hours after birth. Therefore, these techniques may be of use as prognostic indicators but not for early selection of infants for neuroprotective therapies. Standard electroencephalography EEG and measurement of evoked potentials may provide objective evidence for abnormal cerebral function following perinatal asphyxia [ 56 , 57 ].

However, these techniques are difficult to apply very soon after birth. Continuous aEEG during the first six hours after birth provides a more simple objective measure for the presence of encephalopathy [ 57 , 58 ]. It is easier to interpret the aEEG than the conventional EEG, although it gives less information on the underlying type of activity.

There is a good correlation between early continuous amplitude monitoring and the conventional EEG [ 47 , 59 ]. However, only 6 of 37 infants showed a change in aEEG pattern between 3 and 6 hours after birth [ 53 ]. Most of the infants showing a change from the initial aEEG showed an improvement.

Only infants with a moderately or severely abnormal aEEG defined using a semiquantitative classification system [ 47 ] will be recruited to TOBY. There was an excellent correlation Kappa 0. The use of multiple clinical risk factors as entry criteria would ensure that most babies recruited have perinatal asphyxia. However, the sensitivity would be low, so most of the babies with perinatal asphyxia would be missed [ 52 , 60 ].

The minimum duration of follow-up that is required for accurately diagnosing neuromotor, neurosensory and cognitive disability is 18 months. Long-term follow-up to at least 6 years of age will also be desirable, as a secondary study, for detailed assessment of intellectual function.

There is now strong experimental evidence in studies of adult and immature animals that the short term histological and behavioural neuroprotection seen with prolonged post-insult hypothermia [ 61 , 62 ] leads to long lasting neuroprotection associated with corresponding functional improvement [ 17 , 63 - 65 ]. Such long lasting functional neuroprotection has been reported despite up to 6 hours delay in initiating cooling in adult animal models [ 64 - 66 ].

Clinical data from follow-up of adults and children subjected to deep hypothermia during surgery have found no evidence for delayed adverse effects [ 67 , 68 ]. This will be a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling".

Clinical staff will be unblinded because they must know the rectal temperature of the infants in order to adjust the cooling and heating appropriately. The primary outcome measure severe neurodevelopmental disability will be assessed blind to allocation.

The infant will be assessed sequentially by criteria A, B and C listed below:. 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:.

There must be one of the following:. Every effort will be made to ensure entry to the study before 3 hours of age.

Delays should be avoided because there may be rapid attenuation of neuroprotection with delay in the start of cooling [ 69 - 71 ]. Informed written consent will be obtained from a parent after a full verbal and written explanation of the study. The attending physician will meet with parents during the intervention period to ensure that they understand the study procedures and continue to consent to participate in the study. As soon as parental consent has been obtained for an eligible infant, the recruiting TOBY clinician will telephone the randomisation service and obtain treatment assignment, which will be either to "intensive care with cooling" or "intensive care".

Minimisation will be used to ensure balance between the groups with respect to severity of encephalopathy. All infants recruited to the study will be cared for in a tertiary referral centre that has the equipment necessary for providing hypothermia treatment to the "intensive care with cooling" group "Treatment Centres".

Infants may be recruited from hospitals that transfer babies to these centres. Babies that are thought to be eligible will be assessed by trained retrieval teams from the referral centres, who will perform the aEEG, seek consent if eligible, telephone the randomisation service and begin the cooling treatment, if allocated see TOBY Handbook for more details.

All infants who are randomised to this group will receive the present standard of clinical care. Infants will thus receive symptomatic therapy aimed at homeostasis. In particular, the management of the temperature of the infants will aim to maintain normothermia.

All infants will be dried at birth, and kept warm during resuscitation. The infants will be cared for under an overhead radiant heater or in closed incubators, servo controlled to the infants' abdominal skin temperature, to maintain the rectal temperature at Infants born in referring hospitals that are randomised to this group will be transferred to the Treatment Centre. The incubator heater will be adjusted during transport to maintain a rectal temperature as close to All infants randomised to intensive care with cooling will be treated in closed incubators to facilitate cooling.

Hypothermia will be maintained using the Tecotherm cooling system, which induces hypothermia by circulating fluid within a special mattress. A temperature thermostat can be regulated to alter the temperature of the fluid. Infants born outside Treatment Centres who are allocated to intensive care with cooling will be nursed prior to transfer with the overhead radiant warmer turned off.

During transport the infant will be nursed in a transport incubator. Cooled gel packs will be placed around the infant if necessary to maintain the target temperature. Some referring hospitals may have quick access to a Treatment Centre. If it is likely that the infant can be transferred within three hours of birth, assessment and randomisation may be postponed until admission to the Treatment Centre.

When cooling is concluded 72 hours after randomisation, or earlier if clinical circumstances dictate, the rectal temperature will be allowed to rise by no more than 0. The thermostat set point of the Tecotherm system will be adjusted as needed, to rewarm the infants. The infants' temperature will be carefully monitored for at least 4 hours to prevent rebound hyperthermia, as this might be detrimental [ 71 , 72 ].

Reasons will be recorded, and might include clinical, EEG and imaging evidence of severe, irreversible brain injury, or continued inability to maintain rectal temperature in the desired range. If the parents or the attending paediatrician elect to discontinue cooling, then rewarming and follow-up procedures will be commenced. Apparent improvement on continuous aEEG recording, after trial entry, is not an indication for discontinuing cooling.

Treatment centres will provide a uniform standard of clinical care, to minimise potential bias that could arise from differential use of co-interventions. Following resuscitation, ventilatory requirement will be judged by assessing the infant's spontaneous breathing efforts and blood gas analysis.

Infants who appear distressed will receive standard sedation. Seizures whether noted on aEEG or clinically will be treated using a standardised approach. Blood electrolyte analysis, urine volume and analysis and infant weight will be monitored to guide fluid management. Neurodevelopment will be assessed, blind to study group, by a developmental paediatrician. Severe neurodevelopmental disability will be defined as the presence of at least one of:. Epilepsy defined as recurrent seizures beyond the neonatal period, requiring anticonvulsant therapy at the time of assessment.

Microcephaly head circumference more than 2 standard deviations below the mean. Short-term outcomes up to discharge from hospital will be assessed from hospital notes. Major morbidity at 18 months will be assessed by a research paediatrician, blind to study allocation, using a standardised neurological examination and the revised Bayley Scales of Infant Development BSID-II.

The DMEC will be independent of the trial organisers. Interim analyses will be supplied, in strict confidence, to the DMEC, as frequently as its Chair requests. Meetings of the committee will be arranged periodically, as considered appropriate by the Chair.

In the light of interim data on the trial's outcomes, adverse event data, accumulating evidence from the NICHD study see below and any other relevant evidence including updated overviews of the relevant randomised controlled trials , the DMEC will inform the Trial Steering Committee TSC if in their view i there is proof beyond reasonable doubt that the data indicate that any part of the protocol under investigation is either clearly indicated or contra-indicated, either for all infants or for a particular subgroup of trial participants or ii it is evident that no clear outcome will be obtained.

Appropriate criteria for proof beyond reasonable doubt cannot be specified precisely. A difference of at least 3 standard deviations in the interim analysis of a major endpoint may be needed to justify halting, or modifying, such a study prematurely. If this criterion were to be adopted, it would have the practical advantage that the exact number of interim analyses would be of little importance, and so no fixed schedule is proposed.

Unless modification or cessation of the study is recommended by the DMEC, the TSC, investigators, collaborators and administrative staff except those who supply the confidential information will remain ignorant of the results of the interim analysis.

Collaborators and all others associated with the study, may write to the DMEC via the TOBY Co-ordinating Centre, to draw attention to any concern they may have about the possibility of harm arising from the treatment under study, or any other relevant matters. This trial uses the same intervention but different eligibility criteria.

Its results are likely to be relevant to decisions about continuation of recruitment to TOBY. However, this calculation needs to be modified to ensure that meaningful subgroup analyses can be performed for both infants with moderate and severe encephalopathy. Each subgroup needs to be large enough to detect a relative risk between the cooled and non cooled groups of about 0.

Originally, it was the intention in the TOBY study to recruit a similar number of infants as the completed and other on-going studies approximately infants. Although there is an intention to continue further follow-up in the other studies, because of the difficulty of such follow-up, neither study will have recruited sufficient infants to enable assessment of the effect of cooling on outcome beyond 18 months of age.

TOBY was in a unique position to ensure that a sufficient cohort of children is recruited to enable longer-term follow-up at age 6 years. As the aim of whole body cooling in this group of babies is to provide neuroprotection, IQ is the most appropriate primary outcome of a long term follow-up study. IQ is standardised to for "normal" children.

However, in this group of children we can anticipate that IQ in either group is unlikely to approximate to the normal. In the small number of follow up studies that have assessed IQ in children with NE, the degree of later impairment is closely correlated with the degree of encephalopathy.

For example, at age 8 years a group of 56 children born with mild encephalopathy had a mean IQ similar to their peer group versus , using the Wechsler Intelligence Scales. In the 84 children with moderate encephalopathy the mean IQ was 95 standard deviation 23 and for the 5 children with severe encephalopathy the mean IQ was 68 standard deviation 21 [ 76 ].

One standard deviation below the mean for normal children is an IQ of If we assume a mean of 85 in the non-cooled group of TOBY, with a standard deviation of 20, and wish to be able to detect half a "normal" standard deviation difference i. The current mortality of babies recruited to TOBY is approximately thirty per cent.