PAEAN - Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns

Hypoxic-Ischemic Encephalopathy Clinical Trial

— PAEAN  

Official title:

Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy With Erythropoietin: A Phase III Randomised Placebo Controlled Multicentre Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03079167
• Other study ID #: CTC0119
• Secondary ID: 12614000669695
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 14, 2016
• Est. completion date: March 2023

Study information

• Verified date: May 2022
• Source: University of Sydney
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 313
• Est. completion date: March 2023
• Est. primary completion date: March 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 23 Hours

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypoxia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy
• Ischemia

Intervention

Drug:
• Epoetin Alfa

• Normal saline

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Canberra Hospital	Garran	Australian Capital Territory
Australia	Mercy Hospital for Women	Heidelberg	Victoria
Australia	Royal Women's & Brisbane Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	John Hunter Hospital	New Lambton	New South Wales
Australia	Women's and Children's Hospital	North Adelaide	South Australia
Australia	The Royal Children's Hospital	Parkville	Victoria
Australia	The Royal Women's Hospital	Parkville	Victoria
Australia	Royal Hospital for Women	Randwick	New South Wales
Australia	Mater Mothers' Hospital	South Brisbane	Queensland
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	King Edward Memorial Hospital	Subiaco	Western Australia
Australia	Princess Margaret Hospital	Subiaco	Western Australia
Australia	Westmead Hospital	Westmead	New South Wales
New Zealand	Auckland City Hospital	Auckland
New Zealand	Middlemore Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Waikato Hospital	Hamilton
New Zealand	Wellington Hospital	Wellington
Singapore	KK Women's and Children's Hospital	Singapore

Sponsors (2)

Lead Sponsor	Collaborator
University of Sydney	National Health and Medical Research Council, Australia

Countries where clinical trial is conducted

Australia,  New Zealand,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Distribution of overall disability	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	2 years of age
Primary	Composite measure of death or moderate/severe disability	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	2 years of age
Secondary	Death	Death from any cause	Any time from Day 1 of treatment to 2 years of age
Secondary	Cerebral palsy (CP), assessed by paediatric assessment	Any incidence of CP (any of quadriplegia, triplegia, hemiplegia, diplegia or monoplegia)	2 years of age
Secondary	Moderate/severe motor deficit	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	2 years of age
Secondary	Moderate/severe cognitive deficit	Defined as a BSDIII cognitive score less than or equal to 80	2 years of age
Secondary	Need for supplemental respiratory support (includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency)	Supplemental respiratory support includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency	2 years of age
Secondary	Need for nutritional support (includes gastrostomy or nasogastric feeds)	Nutritional support includes gastrostomy or nasogastric feeds	2 years of age
Secondary	Major cortical visual impairment by paediatric examination	Impairment as assessed by paediatric assessment	2 years of age
Secondary	Hearing impairment status by paediatric examination - requirement for hearing aids	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)	2 years of age
Secondary	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).	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	2 years of age
Secondary	Cost of healthcare and service utilisation	Defined as a composite of parent completed questionnaire data and Medicare service use	2 years of age
Secondary	Frequency of selected adverse events (AEs) of interest, including deaths	Frequency of selected adverse events (AEs) of interest up to 30 days after the last study dose	Up to 30 days post study treatment