Asphyxiated newborn infants evolving to moderate-to-severe hypoxic ischemic encephalopathy
Conditions
Interventions
Trade Name: Topiramato ratiopharm 200
Product Name: Topiramate
Pharmaceutical Form: Spot-on suspension
INN or Proposed INN: Topiramate
CAS Number: 97240-79-4
Other descriptive name: TOPIRAMATE
Concent
Sponsors
Instituto de Investigacion Sanitaria La Fe
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Signed informed consent by parents or legal guardians. ? Term near term gestation (?36weeks) ? Birth weight ? 2000g ? Significant moderate to severe Hypoxic Ischemic Encephalopathy, estimated with the modified Sarnat classification (see Annex 2) ? Evident signs of asphyxia during labor: meconium and/or alteration of fetal heart rate. ? Inborn in referral center or arrival to referral center within the acceptable timeframe for initiating hypothermia (6 hours after birth). ? The patient must meet at least, one criteria of A and one of B: A. Existence of perinatal data compatible with peripartum hypoxic ischemia: - Non-reassuring fetal status during fetal monitoring - Pathological scalp pH (=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: ? Gestational age <36weeks? gestation ? Birth weight < 2000g ? Any pathology requiring surgery prior to discharge ? Major congenital malformations ? Imminent death ? Chromosomopathies ? Rejection to participate or to sign inform consent ? Erroneous or impossibility for randomization ? Incapability of initiating active or passive hypothermia (rectal temperature ? 34ºC) within the 6 hours timeframe ? Use of another investigational agent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effectiveness of Topiramate administered immediately after birth, on the reduction of HIE-associated seizures and consequently, the neurodevelopmental outcome in newly born infants with birth asphyxia evolving to hypoxic ischemic encephalopathy;Timepoint(s) of evaluation of this end point: From birth until hospital discharge.;Secondary Objective: To evaluate the effectiveness of Topiramate in the long term neurodevelopmental outcome at 24 months of age. ? To enhance our knowledge about pharmacokinetics and pharmacodynamics of TPM in newborn infants treated with mild whole body hypothermia. ? To compare the need for additional anticonvulsivant drugs during the acute period with those patients randomized to TPM Arm. ? To compare the abnormal brain ultrasounds and MRI findings at 7 days and 6 months (sub-study) after birth with those patients treated with TPM. ? To evaluate the histological brain lesions in deceased patients. To evaluate possible reductions in the need for anticonvulsive therapy after discharge. ? To compare the effects of TPM on biomarkers of neuronal damage and oxidative stress. ? To evaluate the tolerance/toxicity of TPM in the newborn period;Primary end point(s): The primary outcome is a reduction in a 50% of HIE-associated seizure activity (clinical and/or electrical) in number, frequency, intensity and/or duration, during the acute phase of hypoxic ischemic encephalopathy (first 7 days after birth, aprox) in those patients randomized to Topiramate group. Primary Outcome: Seizures will be measured by continuous registration of amplitude integrated EEG (aEEG): subjects will be continuously monitored starting immediately after birth and ceasing at discharge. An experienced neonatologist per shift will evaluate the readings and decide if additional medication is needed. A specially trained neonatologist and/or pediatric neurologist will review daily aEEG registers and evaluate brain activity, number, duration and inten | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): o Improved neurodevelopmental outcome at 24 months of age (22-26 limits) using the Bayley III scale. Secondary Outcomes: o Need for additional anticonvulsivants during the acute period. They will be evaluated before discharge by reviewing the patient?s medical records. o Topiramate pharmacokinetic and pharmacodynamic behavior in newborn infants treated with mild whole body hypothermia. o Neuronal damage measured by MRI and US imaging at 7 days (MRI includes Spectroscopy) and 6 months (MRI without Spectroscopy) after birth. o Histological brain lesions in deceased patients, measured by histology and histochemistry of the Central Nervous System. o Measurement of Oxidative Stress biomarkers in plasma at birth, 24h, 48h and 72h since first study treatment administration. They will be measured to evaluate relationship with the study intervention. o Measurement of CNS damage biomarkers in urine at birth, 12h, 24h, 48h, 72h and 96h since first study treatment administration. They will be measured to evaluate relationship with the study intervention. o Evaluation of brain electrical activity by conventional multichannel EEG. o Neurological status during the acute phase (hospitalization) and after discharge. o Evaluation of clinical laboratory parameters (to be evaluated and corrected by the neonatologist in charge or on call. o Reduction of seizures during re-warming. o Survival.;Timepoint(s) of evaluation of this end point: -At 24 months of age as measured by Bayley III scale | — |
Countries
Spain
Contacts
Public ContactUREC
Instituto de Investigacion Sanitaria La Fe
Outcome results
None listed