Clinical trial NCT03079167: PAEAN - Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns
Official title: Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy With Erythropoietin: A Phase III Randomised Placebo Controlled Multicentre Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypoxic-Ischemic Encephalopathy
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
First posted: 2017-03-14
Enrollment: 313
Sex: ALL
Maximum age (years): 23
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Composite measure of death or moderate/severe disability
timeFrame: 2 years of age
Secondary outcomes:
measure: Death
timeFrame: Any time from Day 1 of treatment to 2 years of age
measure: Cerebral palsy (CP), assessed by paediatric assessment
timeFrame: 2 years of age
measure: Moderate/severe motor deficit
timeFrame: 2 years of age
measure: Moderate/severe cognitive deficit
timeFrame: 2 years of age
measure: Need for supplemental respiratory support (includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency)
timeFrame: 2 years of age
measure: Need for nutritional support (includes gastrostomy or nasogastric feeds)
timeFrame: 2 years of age
measure: Major cortical visual impairment by paediatric examination
timeFrame: 2 years of age
measure: Hearing impairment status by paediatric examination - requirement for hearing aids
timeFrame: 2 years of age
measure: 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).
timeFrame: 2 years of age
measure: Cost of healthcare and service utilisation
timeFrame: 2 years of age
measure: Frequency of selected adverse events (AEs) of interest, including deaths
timeFrame: Up to 30 days post study treatment
Other outcomes:
measure: Distribution of overall disability
timeFrame: 2 years of age
Locations:
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: New Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Royal Hospital for Women
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Women's & Brisbane Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Mothers' Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: North Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Heidelberg
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Parkville
country: Australia
facility: The Royal Children's Hospital
state: Victoria
city: Parkville
country: Australia
facility: The Royal Women's Hospital
state: Victoria
city: Subiaco
country: Australia
facility: King Edward Memorial Hospital
state: Western Australia
city: Subiaco
country: Australia
facility: Princess Margaret Hospital
state: Western Australia
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
Study officials:
affiliation: University of Sydney
name: Helen Liley, BHB, MBChB
role: STUDY_CHAIR
References: