Hypoxic-Ischemic Encephalopathy
Conditions
Brief summary
Double-blind, placebo controlled Phase III trial of erythropoietin for hypoxic ischaemic encephalopathy in infants receiving hypothermia. The study aim is to determine whether Epo in conjunction with hypothermia in infants with moderate/severe hypoxic ischaemic encephalopathy (HIE) will improve neurodevelopmental outcomes at 2 years of age, without significant adverse effects, when compared to hypothermia alone.
Detailed description
A lack of oxygen (hypoxia) or low blood supply (ischaemia) before or during birth can destroy cells in a newborn baby's brain. The damage caused by the lack of oxygen continues for some time afterwards. One way to try to reduce this damage is to induce hypothermia cooling the baby or just the baby's head for hours to days. Erythropoietin (Epo) given in the first week after birth shows promise as a treatment that may also help. This study is to find out whether Epo plus induced hypothermia (cooling) of near-term newborn babies who have suffered from low blood or oxygen supply to the brain at birth reduces death and disability in survivors at two years of age. The target population is 300 newborn term or near term infants (greater than or equal to 35+0 weeks gestation) with hypoxic ischaemic encephalopathy who are receiving, or planned to receive hypothermia and who are able to be recruited in time to allow study treatment to commence before 24 hours of age. This is a double blind, placebo controlled, parallel, 2 arm randomised, phase III multicentre trial, stratified by study site and by severity of encephalopathy at study entry. The treatment group of 150 infants will receive human recombinant Epo, 1000 IU/kg IV on days 1, 2, 3, 5 & 7 of life. The control group will receive 0.9% sodium chloride as a placebo on days 1, 2, 3, 5 & 7 of life. Families will be followed up every 6 months until the primary assessment of death and disability at 2 years of age.
Interventions
DRUGEpoetin Alfa
DRUGNormal saline
Sponsors
National Health and Medical Research Council, Australia
University of Sydney
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 23 Hours
Healthy volunteers
No
Inclusion criteria
* Male or female infants born greater than or equal to 35+0 weeks gestation and able to be randomised less than 23 hours after birth * One or more of the following indicators of perinatal depression: 1. Apgar less than or equal to 5 at 10 minutes after birth, OR 2. Receiving ongoing resuscitation e.g. assisted ventilation (positive pressure ventilation or CPAP) or chest compressions at 10 minutes after birth, OR 3. on cord blood or arterial or venous blood obtained at less than 60 minutes after birth, either pH less than 7.00 OR base deficit greater than or equal to 12.0 mmol/L * Moderate to severe encephalopathy, defined between one and six hours after birth by one or both of the following: 1. 3 out of 6 modified Sarnat criteria indicating moderate/severe encephalopathy, OR 2. 2 out of 6 modified Sarnat criteria plus seizure(s) requiring anticonvulsant treatment (diagnosed either clinically or using EEG monitoring) at any time prior to randomisation * Hypothermia treatment initiated by 6 hours ofa ge; i.e. controlled whole-body cooling planned to continue for 72 hours to a target temperature (adjusted manually or with a device) and subsequent controlled re-warming * Study treatment planned to start within 24 hours after birth (as soon as feasible after randomisation) * At least one parent greater than or equal to 18 years of age * Anticipated ability to collect primary endpoint at 2 years of age * Signed, written informed parental consent
Exclusion criteria
* Contraindications to investigational product * Indication prior to randomisation for erythropoietin or any other erythropoietic stimulating agent to be given during the first two weeks of life * Severe intrauterine growth restriction (birth weight less than 1800g) * Suspected major chromosomal or congenital anomalies * Head circumference less than 3rd centile below the mean for gestation and gender * Infant for whom imminent withdrawal of care is being planned
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite measure of death or moderate/severe disability | 2 years of age | Moderate/severe disability is defined as any cerebral palsy and a Gross Motor Function Classification Scale (GMFCS) score greater than or equal to 1), or Bayley Scale of Infant Development III (BSDIII) less than or equal to 80 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death | Any time from Day 1 of treatment to 2 years of age | Death from any cause |
| Cerebral palsy (CP), assessed by paediatric assessment | 2 years of age | Any incidence of CP (any of quadriplegia, triplegia, hemiplegia, diplegia or monoplegia) |
| Moderate/severe motor deficit | 2 years of age | Composite of any incidence of CP (any of quadriparesis, CP, hemiparesis or diparesis) AND any level of functional impairment using the GMFCS greater than or equal to 1.0 |
| Moderate/severe cognitive deficit | 2 years of age | Defined as a BSDIII cognitive score less than or equal to 80 |
| Need for supplemental respiratory support (includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency) | 2 years of age | Supplemental respiratory support includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency |
| Major cortical visual impairment by paediatric examination | 2 years of age | Impairment as assessed by paediatric assessment |
| Hearing impairment status by paediatric examination - requirement for hearing aids | 2 years of age | Defined as the requirement for hearing aids (either diagnosis of: Hears well or with only a little difficulty WITH a hearing aid OR Has severe hearing difficulty even with a hearing aid or hearing is not helped with an aid) |
| Epilepsy (history of 2 or more afebrile unprovoked seizures since discharge from neonatal unit where PAEAN study treatment was provided, or use of anticonvulsants at 2 years of age). | 2 years of age | Defined by history of 2 or more afebrile unprovoked seizures since discharge from neonatal unit where PAEAN study treatment was provided, or use of anticonvulsants at 2 years of age |
| Cost of healthcare and service utilisation | 2 years of age | Defined as a composite of parent completed questionnaire data and Medicare service use |
| Frequency of selected adverse events (AEs) of interest, including deaths | Up to 30 days post study treatment | Frequency of selected adverse events (AEs) of interest up to 30 days after the last study dose |
| Need for nutritional support (includes gastrostomy or nasogastric feeds) | 2 years of age | Nutritional support includes gastrostomy or nasogastric feeds |
Other
| Measure | Time frame | Description |
|---|---|---|
| Distribution of overall disability | 2 years of age | Distribution of overall severity across 4 domains: 1) normal, 2) mild motor or cognitive deficit, 3) moderate/severe motor or cognitive deficit, and 4) death |
Countries
Australia, New Zealand, Singapore
Outcome results
None listed