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PAEAN - Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns (PAEAN)

Primary Purpose

Hypoxic-Ischemic Encephalopathy

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Epoetin Alfa
Normal saline
Sponsored by
University of Sydney
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxic-Ischemic Encephalopathy

Eligibility Criteria

undefined - 23 Hours (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Canberra Hospital
  • Royal Prince Alfred Hospital
  • Nepean Hospital
  • John Hunter Hospital
  • Royal Hospital for Women
  • Royal North Shore Hospital
  • Westmead Hospital
  • Royal Women's & Brisbane Hospital
  • Mater Mothers' Hospital
  • Flinders Medical Centre
  • Women's and Children's Hospital
  • Royal Hobart Hospital
  • Monash Medical Centre
  • Mercy Hospital for Women
  • The Royal Children's Hospital
  • The Royal Women's Hospital
  • King Edward Memorial Hospital
  • Princess Margaret Hospital
  • Auckland City Hospital
  • Middlemore Hospital
  • Christchurch Hospital
  • Waikato Hospital
  • Wellington Hospital
  • KK Women's and Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Erythropoietin

Placebo

Arm Description

Erythropoietin (epoetin alfa) 1000 IU/kg birth weight (capped at 4000IU daily) IV infusion, on Days 1, 2, 3, 5 and 7 of age

IV normal saline (equiv. volume), on Days 1, 2, 3, 5 and 7 of age

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Death
Death from any cause
Cerebral palsy (CP), assessed by paediatric assessment
Any incidence of CP (any of quadriplegia, triplegia, hemiplegia, diplegia or monoplegia)
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
Moderate/severe cognitive deficit
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)
Supplemental respiratory support includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency
Need for nutritional support (includes gastrostomy or nasogastric feeds)
Nutritional support includes gastrostomy or nasogastric feeds
Major cortical visual impairment by paediatric examination
Impairment as assessed by paediatric assessment
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)
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
Cost of healthcare and service utilisation
Defined as a composite of parent completed questionnaire data and Medicare service use
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

Full Information

First Posted
February 20, 2017
Last Updated
September 20, 2022
Sponsor
University of Sydney
Collaborators
National Health and Medical Research Council, Australia
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1. Study Identification

Unique Protocol Identification Number
NCT03079167
Brief Title
PAEAN - Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns
Acronym
PAEAN
Official Title
Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy With Erythropoietin: A Phase III Randomised Placebo Controlled Multicentre Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
May 14, 2016 (Actual)
Primary Completion Date
March 2023 (Anticipated)
Study Completion Date
March 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Sydney
Collaborators
National Health and Medical Research Council, Australia

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic-Ischemic Encephalopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
313 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Erythropoietin
Arm Type
Experimental
Arm Description
Erythropoietin (epoetin alfa) 1000 IU/kg birth weight (capped at 4000IU daily) IV infusion, on Days 1, 2, 3, 5 and 7 of age
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
IV normal saline (equiv. volume), on Days 1, 2, 3, 5 and 7 of age
Intervention Type
Drug
Intervention Name(s)
Epoetin Alfa
Other Intervention Name(s)
Epogen, Procrit
Intervention Type
Drug
Intervention Name(s)
Normal saline
Other Intervention Name(s)
0.9% NaCl
Primary Outcome Measure Information:
Title
Composite measure of death or moderate/severe disability
Description
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
Time Frame
2 years of age
Secondary Outcome Measure Information:
Title
Death
Description
Death from any cause
Time Frame
Any time from Day 1 of treatment to 2 years of age
Title
Cerebral palsy (CP), assessed by paediatric assessment
Description
Any incidence of CP (any of quadriplegia, triplegia, hemiplegia, diplegia or monoplegia)
Time Frame
2 years of age
Title
Moderate/severe motor deficit
Description
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
Time Frame
2 years of age
Title
Moderate/severe cognitive deficit
Description
Defined as a BSDIII cognitive score less than or equal to 80
Time Frame
2 years of age
Title
Need for supplemental respiratory support (includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency)
Description
Supplemental respiratory support includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency
Time Frame
2 years of age
Title
Need for nutritional support (includes gastrostomy or nasogastric feeds)
Description
Nutritional support includes gastrostomy or nasogastric feeds
Time Frame
2 years of age
Title
Major cortical visual impairment by paediatric examination
Description
Impairment as assessed by paediatric assessment
Time Frame
2 years of age
Title
Hearing impairment status by paediatric examination - requirement for hearing aids
Description
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)
Time Frame
2 years of age
Title
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).
Description
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
Time Frame
2 years of age
Title
Cost of healthcare and service utilisation
Description
Defined as a composite of parent completed questionnaire data and Medicare service use
Time Frame
2 years of age
Title
Frequency of selected adverse events (AEs) of interest, including deaths
Description
Frequency of selected adverse events (AEs) of interest up to 30 days after the last study dose
Time Frame
Up to 30 days post study treatment
Other Pre-specified Outcome Measures:
Title
Distribution of overall disability
Description
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
Time Frame
2 years of age

10. Eligibility

Sex
All
Maximum Age & Unit of Time
23 Hours
Accepts Healthy Volunteers
No
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: Apgar less than or equal to 5 at 10 minutes after birth, OR Receiving ongoing resuscitation e.g. assisted ventilation (positive pressure ventilation or CPAP) or chest compressions at 10 minutes after birth, OR 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: 3 out of 6 modified Sarnat criteria indicating moderate/severe encephalopathy, OR 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Helen Liley, BHB, MBChB
Organizational Affiliation
University of Sydney
Official's Role
Study Chair
Facility Information:
Facility Name
Canberra Hospital
City
Garran
State/Province
Australian Capital Territory
ZIP/Postal Code
2605
Country
Australia
Facility Name
Royal Prince Alfred Hospital
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
Nepean Hospital
City
Kingswood
State/Province
New South Wales
ZIP/Postal Code
2747
Country
Australia
Facility Name
John Hunter Hospital
City
New Lambton
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
Royal Hospital for Women
City
Randwick
State/Province
New South Wales
ZIP/Postal Code
2031
Country
Australia
Facility Name
Royal North Shore Hospital
City
St Leonards
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Facility Name
Westmead Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Royal Women's & Brisbane Hospital
City
Herston
State/Province
Queensland
ZIP/Postal Code
4006
Country
Australia
Facility Name
Mater Mothers' Hospital
City
South Brisbane
State/Province
Queensland
ZIP/Postal Code
4101
Country
Australia
Facility Name
Flinders Medical Centre
City
Bedford Park
State/Province
South Australia
ZIP/Postal Code
5042
Country
Australia
Facility Name
Women's and Children's Hospital
City
North Adelaide
State/Province
South Australia
ZIP/Postal Code
5006
Country
Australia
Facility Name
Royal Hobart Hospital
City
Hobart
State/Province
Tasmania
ZIP/Postal Code
7000
Country
Australia
Facility Name
Monash Medical Centre
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Facility Name
Mercy Hospital for Women
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Facility Name
The Royal Children's Hospital
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Facility Name
The Royal Women's Hospital
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Facility Name
King Edward Memorial Hospital
City
Subiaco
State/Province
Western Australia
ZIP/Postal Code
6008
Country
Australia
Facility Name
Princess Margaret Hospital
City
Subiaco
State/Province
Western Australia
ZIP/Postal Code
6008
Country
Australia
Facility Name
Auckland City Hospital
City
Auckland
ZIP/Postal Code
1023
Country
New Zealand
Facility Name
Middlemore Hospital
City
Auckland
ZIP/Postal Code
2104
Country
New Zealand
Facility Name
Christchurch Hospital
City
Christchurch
ZIP/Postal Code
8140
Country
New Zealand
Facility Name
Waikato Hospital
City
Hamilton
ZIP/Postal Code
3204
Country
New Zealand
Facility Name
Wellington Hospital
City
Wellington
ZIP/Postal Code
6021
Country
New Zealand
Facility Name
KK Women's and Children's Hospital
City
Singapore
ZIP/Postal Code
229899
Country
Singapore

12. IPD Sharing Statement

Plan to Share IPD
No

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PAEAN - Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns

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