Term newborns delivered at gestational age higher than 36 weeks and with birth weight higher than 1800 g admitted for HIE to the Neonatal Intensive Care Units (NICUs) of A. Meyer University Children’s Hospital, Florence, of the Santa Chiara University Hospital of Pisa and of the La Sapienza University of Rome.
Multicenter interventional pilot randomized controlled trial to compare the safety and efficacy of TPM add-on therapy associated to the conventional approach (treatment with whole-body moderate hypothermia).
All newborns who will satisfy admission criteria will be treated with moderate (33.5°C) hypothermia for 72 hours. Outborn patients will be initially cooled to 35°C at the birth hospital, avoiding heating and using ice packs during the transfer to NICU. In all the centers a cooling blanket with an esophageal probe will be used to induce hypothermia; the esophageal temperature will be lowered by the blanket’s servomechanism. Rectal temperature will be monitored by a rectal probe connected to cardiomonitor. After 72 hours of hypothermia, all newborns will be gradually re-warmed up to 36.5-37°C over the following 6–12 hours (0.5°C/h). Vital parameters will be continuously monitored under hypothermia.
Half of these newborns will be subjected to additional treatment with oral topiramate.
TPM (Topamax, Janssen-Cilag, Cologno Monzese, Milan, Italy) will be administered by orogastric tube as enteric-coated granules mixed with water at the beginning of hypothermia for the first three days of life, for a total amount of 3 doses per patient. Newborns will receive 10 mg/kg once a day, a dosage usually used in infants
] and neonates
]. TPM plasma concentrations will be measured as previously reported
The following respiratory and hemodynamic parameters will be registered before starting hypothermia and then at hours 0, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 of hypothermia, and after the re-warming process: respiratory rate, oxygen saturation (SaO2), fractional inspired oxygen (FiO2), systolic, diastolic and mean arterial pressures, heart rate. The following blood tests will be performed in all newborns at hypothermia hours 0, 24, 48, 72 and after re-warming process: blood gas analysis (corrected for body temperature), serum electrolytes, liver and renal function tests, creatine-kinase, creatine-kinase MB isoenzyme, lactate dehydrogenase, troponin IC, complete cell blood count, C-reactive protein, procalcitonin and coagulation tests.
Clinical course and concomitant treatments
A central venous line will be placed in all patients. Fluid intake will be started at 60–70 mL/kg and increased of 10–20 mL/kg each day, basing on changes in body weight and serum electrolytes levels. Minimal enteral feeding will be allowed with human milk from the first day of life. In case of respiratory failure newborns will be put on patient triggered ventilation. Neonates who will develop seizures will be treated with phenobarbital, (loading dose 20 mg/kg, followed by 1.5-2.5 mg/kg every 12 hours). In case of resistance to phenobarbital, midazolam will be used with a dose-initial bolus of 0.15 mg/kg, followed by a continuous infusion (1 μg/kg/min) increased by 0.5-1 μg/kg/min every 2 minutes until a favourable response and up to a maximum dose of 18 μg/kg/min
]. In case of hypotension, defined as a mean arterial blood pressure <40 mmHg, single or multiple normal saline boluses will be administered (10–20 mL/kg), and in case of refractoriness, dopamine, dobutamine, norepinephrine or terlipressin
] will be progressively added. Newborns will receive analgesia with Fentanyl at a dose of 1 μg/kg/h, since hypothermia causes agitation and reducing the threshold of pain.
The duration of follow-up necessary for possible neuro-motor disabilities and cognitive loss will be 24 months.
Every newborn will be evaluated beyond the neonatal period, at 1, 3, 6, 12, 18 and 24 months of life. Standard EEG will be evaluated within one week and will be repeated if abnormal. Within the first week and three months of age, newborns will be studied with Neonatal Hammersmith neurological examination and General Movement (GMs) assessment
]. The Hammersmith Infant Neurological Examination
] will be performed between 3 and 6 months of life. The mental and motor development will be evaluated with the Bayley Scales of Infant and Toddler Development 3rd
] measure at 12, 18 and 24 months. Bayley scales will be used to measure the major areas of development: cognitive, language, motor, social-emotional and adaptive functioning.
Visual function will be assessed in the first ten days of life by means of a recently published battery of behavioural tests designed to assess various aspects of visual function
], which includes items that assess ocular movements (spontaneous behaviour and in response to a target), the ability to fix and follow a black/white target (horizontally, vertically, and in an arc), the reaction to a colored target, the ability to discriminate between black and white stripes of increasing spatial frequency, and the ability to keep attention on a target that is moved slowly away from the infant. Visual function will be evaluated again at 4 ½, 6 and 12 months with particular regards to binocular visual acuity, measured by means of standardized instruments based on preferential force choice (Teller acuity cards), stereopsis and ocular motricity.
Acoustic function will be monitored until 24 months.
Neurologists responsible of clinical follow-up will be blindfolded about which newborns have been treated with TPM in addition to hypothermia.
Standard cerebral magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and spectroscopy will be performed at the end of the hypothermic treatment within the first week, at three months and at 18 months.
Neuroradiologists responsible of follow-up will be blindfolded about which newborns have been treated with TPM in addition to hypothermia.
The treatment with therapeutic hypothermia will be reserved to newborns with gestational age ≥ 36 weeks and birth weight ≥ 1,800 g who will fulfill the following criteria:
1. Metabolic criteria: Apgar score ≤5 at 10 min, or persisting need for resuscitation, including endotracheal intubation or mask ventilation for more than 10 min after birth, or acidosis (pH ≤7.0 and/or base deficit ≥ −16 mmol/L in umbilical cord blood or arterial, venous, or capillary blood) within 60 min from birth;
2. Neurological criteria (modified from Sarnat and Sarnat
]): moderate to severe encephalopathy consisting of altered state of consciousness (irritability, lethargy, stupor, or coma) and ≥ 1 of the following signs: hypotonia, or abnormal reflexes including oculomotor or pupil abnormalities, or absent or weak suctioning, or clinical seizures;
3. aEEG criteria: “moderately abnormal” indicates a background tracing with upper margin >10 μV and lower margin ≤5 μV; “severely abnormal” pattern refers to a tracing with upper margin <10 μV and lower margin <5 μV; often this is accompanied by bursts of high voltage activity (“burst suppression”). Seizures are identified as periods of sudden increase in voltage, accompanied by narrowing of the band of aEEG activity followed by a brief period of suppression or by a build up of rhythmic activity of increasing amplitude and decreasing frequency
Selection criteria for study subjects
At least one of the parents of the newborns meeting the inclusion criteria will be approached by the study investigator/nurse and informed of the study. A signed parental informed consent must be obtained.
1. Newborns with gestational age less than 36 weeks, with birth weights less than 1800 g, or admitted at the NICU after 6 hours of life.
2. Newborns with major congenital abnormalities or other syndromes that include brain malformations, congenital viral infections or evidence encephalopathy other than HIE.
3. Informed Consent refused.
Allocation of participants to the trial groups (Randomization)
EEG is useful in identifying suitable newborns for hypothermia due to its capability to distinguish newborns with Sarnat grade 2 from those with Sarnat 1. Several studies have demonstrated that aEEG is easier to be interpreted than standard EEG, but equally accurate and reproducible. It correlates well with neurodevelopmental outcome of full-term infants with HIE, and it is considered the best single predictor of neurologic outcome. In some studies aEEG was more specific and exhibited a higher positive predictive value when compared with the neurologic examination performed in the first hours after delivery
In all three recruiting hospitals, randomization will be done stratifying eligible newborns according to aEEG into moderate or severe HIE. Newborns will be assigned to the group of moderate or severe aEEG to ensure maximal clinical homogeneity between the groups.
Newborns will be randomized in blocks of eight for each group, alternating newborns between TPM added to standard hypothermic treatment and standard treatment alone.
Experimental plan and data analysis
Based on the medical literature, the mean incidence of the combined frequency of mortality and severe neurodevelopmental disability in survivors at 18 months of age is approximately 50%. In fact this percentage is 55% in the cool Cap study
], 44% in the NICHD study
], 45% in the TOBY trial
], 51.4% in the ICE trial
], and 50.9% in the neo.nEURO.network study
]. We hypothesize that treatment with TPM may reduce the incidence of the combined frequency of mortality and severe neurodevelopmental disability in survivors at 18 months at 15%. In order to compare the incidence of this primary outcome between newborns receiving TPM plus hypothermia (treated) and those only receiving hypothermia (control group), the estimated sample size was calculated, considering normal distribution, an alpha error of 0.05 and a power of 80 percent. The sample size for each group is 32 participants.
The three units have an overall admission rate of approximately 10 term newborns with HIE per year. Due to the high hypothetical advantages of this treatment, we estimate 90-100% rate of consent and we predict we would recruit the 64 newborns over around 24 months period with a realistic safety margin.
Mortality, the incidence of severe neuromotor disability, cortical vision, sensorineural hearing loss, developmental delay, epilepsy will be evaluated at 18 months of life.
To evaluate TPM safety, cardiac and respiratory parameters (heart frequency, blood pressure, oxygen saturation, respiratory support), will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. Kruskal-Wallis test will be used to assess possible differences between newborns treated or not with TPM. The safety will be also evaluated by means of relative risk (RR)
]. RR will be calculated as the ratio between the probabilities of side effects in the TPM group with respect to the control group. Values of RR lower than 1, will be associated to the efficacy of the treatment.
Finally, we will evaluate the different distribution of any brain lesions on MRI brain highlighted.The RR is calculated for each item studied. An RR <1 indicates an improvement of neurological, neurodevelopmental and neuroradiologic hypothermia due to the association-topiramate.
The neurological and neuroimaging outcome of these two groups of infants will be compared to determine whether adjunctive treatment with TPM improves the neuroprotective effect of hypothermic treatment.
The primary outcome will be the combined frequency of mortality and severe neurodevelopmental disability in survivors at 24 months of age. Severe disability is defined as Bayley III
] cognitive development index 3 SDs below mean or any one of the components of severe sensorimotor disability (e.g. inability to walk, sit, feed using hands, communicate (Bayley III language development index 3 SDs below mean), hear (80 dB sensory neural hearing loss) or see.
The following secondary outcomes will also be assessed at 24 months of life:
•Multiorgan dysfunction (adverse events in three or more organ systems),
•Bilateral sensorineural hearing loss more than 40 dB
•Epilepsy (recurrent seizures beyond the neonatal, period requiring anticonvulsant treatment)
•Multiple Disabilities (epilepsy, cortical visual impairment, sensorineural hearing loss, developmental delay)
Finally, the neuroradiologic outcome will be assessed by comparing the imaging obtained by standard cerebral MRI, DTI and spectroscopy performed within the first 7 days, at 3 months and 18 months of age. Brain injuries will be classified as isolated lesions of the white matter (WM), of basal ganglia and thalami (BGT), with or without involvement of the posterior limb of the internal capsule (PLIC), of cortex (COR), or various combinations of such lesions
A three-centre phase II pilot study entitled “Safety and Efficacy of Topiramate in Neonates With Hypoxic Ischemic Encephalopathy Treated With Hypothermia (NeoNATI)” has been approved by the Ethics Committees of A. Meyer University Children’s Hospital, Florence, of University of Pisa and of La Sapienza University, Rome (prot. 276/2010).
Informed consent will be obtained from at least one parent prior to study entry. Parents will be given full verbal and written information regarding the objective and procedures of the study and the possible risks involved.
TPM is considered safe for use in children. Nevertheless, a careful watch will be kept on all study participants with regard to side effects of drug administration. Parents of participants will be made aware of possible side effects. Infants will be monitored in the Neonatal Intensive Care Unit throughout the study period and their clinical condition will be evaluated daily as part of medical rounds. A letter informing the participant and the family doctor as to which study arm the participant had been randomized to will be sent following completion of the study.
In the presence of adverse events, a reduction of dosage will be taken into account.
For ethical and scientific reasons, an interim analysis after the enrolment of half of the newborns, is planned.
Patients will be withdrawn from the study if parents make specific request for the treatment to be discontinued before 72 hours, in case of severe bleeding, thrombosis, or pulmonary hypertension difficult to treat, arrhythmia, clinical electroencephalographic or neuroimaging evidence of irreversible severe brain damage.
Measurement of outcomes
To evaluate if the TPM administration reduces the cerebral damage of newborns with HIE and treated with therapeutic hypothermia, neurological and neuroradiologic follow-up are planned at different stages.
a. To evaluate the safety of TPM treatment, cardiac and respiratory parameters (heart frequency, blood pressure, oxygen saturation, respiratory support) will be continuously monitored; blood samplings will be performed to check renal, liver and metabolic balance
b. To evaluate if TPM improves the functional and structural outcome, visual function is planned at 40 weeks gestational age, 4 ½, 12, 18 and 24 months corrected age.
The participants’ data collected during this trial will be kept confidential. Study staff will have access to the data as well as the participants’ medical records as they pertain to this study. Published results will not contain any information that would identify individual participants.