Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000669695
Ethics application status
Approved
Date submitted
16/06/2014
Date registered
25/06/2014
Date last updated
19/08/2022
Date data sharing statement initially provided
22/02/2019
Date results information initially provided
17/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
PAEAN – Erythropoietin for hypoxic ischaemic encephalopathy in newborns
Scientific title
Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy with Erythropoietin: A Phase III Randomised Placebo Controlled Multicentre Clinical Trial
Secondary ID [1] 284741 0
NCT03079167
Universal Trial Number (UTN)
Trial acronym
PAEAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
neonatal hypoxic ischaemic encephalopathy 292108 0
Condition category
Condition code
Reproductive Health and Childbirth 292440 292440 0 0
Complications of newborn
Neurological 292589 292589 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Erythropoetin (epoetin alpha) 1000 IU/kg intravenous infusion once daily on days 1, 2, 3, 5 & 7 of life
Intervention code [1] 289526 0
Treatment: Drugs
Comparator / control treatment
Saline infusion
Control group
Placebo

Outcomes
Primary outcome [1] 292295 0
To compare composite of death or moderate/severe disability in infants treated with either erythropoietin or control group (placebo) using death and disability assessments such as paediatric review (Any CP), GMFCS score (greater than or equal to 2) and Bayley Scale of Infant Development III (2 or more stand deviations below the mean)
Timepoint [1] 292295 0
2 years of age
Secondary outcome [1] 308665 0
Death (at any time from day 1 of treatment to 2 years of age)
Timepoint [1] 308665 0
2 years
Secondary outcome [2] 308666 0
Cerebral palsy assessed by paediatric assessment
Timepoint [2] 308666 0
2 years of age
Secondary outcome [3] 308667 0
Moderate-severe motor deficit is defined as any incident of cerebral palsy (any of quadriplegia (QP); triplegia; hemiplegia (HP), diplegia (DP) or monoplegia) plus any level of functional impairment using the Gross Motor Function Classification Scale (GMFCS) greater than or equal to 2.0.
Timepoint [3] 308667 0
2 years of age
Secondary outcome [4] 308668 0
Cognitive deficit (Bayley III Cognitive Score)
Timepoint [4] 308668 0
2 years of age
Secondary outcome [5] 308669 0
Need for supplementary respiratory or nutritional support
Timepoint [5] 308669 0
2 years of age
Secondary outcome [6] 308670 0
Cortical visual impairment by paediatric exam
Timepoint [6] 308670 0
2 years of age
Secondary outcome [7] 308671 0
Hearing impairment by paediatric exam
Timepoint [7] 308671 0
2 years of age
Secondary outcome [8] 308672 0
Removal of secondary outcome [8].
Timepoint [8] 308672 0
Removal of secondary outcome [8].
Secondary outcome [9] 308673 0
Epilepsy by paediatric exam
Timepoint [9] 308673 0
2 years of age
Secondary outcome [10] 308674 0
Cost of healthcare and service utilisation by parent completed questionnaire and Medicare service use
Timepoint [10] 308674 0
2 years of age

Eligibility
Key inclusion criteria
1. 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.

2. One or more of the following indications of perinatal depression:
a. Apgar less than or equal to 5 at 10 minutes after birth OR
b. receiving ongoing resuscitation eg assisted ventilation (positive pressure ventilation or CPAP) or chest compressions at 10 minutes after birth OR
c. on cord blood or arterial or venous blood obtained at less 60 minutes after birth the following values: pH less than 7.00 OR base deficit greater than or equal to 12

3. Moderate to severe encephalopathy, defined between one and six hours after birth by one or both of the following
a. 3 out of 6 modified Sarnat criteria indicating moderate/severe encephalopathy
OR
b. 2 out of 6 modified Sarnat criteria plus seizure(s) requiring anticonvulsant treatment (diagnosed either clinically or using EEG monitoring)

4. Hypothermia treatment initiated by 6 hours of age; i.e. controlled whole-body cooling for 72 hours, to a target temperature (adjusted manually or with a device) and subsequent controlled re-warming

5. Study treatment both planned and able to start within 24 hours after birth (as soon as feasible after randomisation)

6. One parent greater than or equal to 18 years of age

7. Anticipated ability to collect primary endpoint at 2 years of age

8. Signed, written informed parental consent
Minimum age
35 Weeks
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications to investigational product

2. Indication prior to randomisation for erythropoietin or any other erythropoietic stimulating agent to be given during the first two weeks of life.

3. Severe intrauterine growth restriction (birth weight less than 1800g)

4. Suspected major chromosomal or congenital anomalies

5. Head circumference less than 3rd centile below the mean for gestation and gender.

6. Infant for whom imminent withdrawal of care is being planned.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment allocation will be balanced using minimisation for the following characteristics: a. study site and b. severity of encephalopathy (moderate vs severe, as measured by modified Sarnat score between 1 and 6 hours of age)
Participants will be allocated to the treatment group in a ratio of 1:1.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size of 150 per treatment group is large enough to detect a 19% absolute risk reduction in the combined endpoint of death or severe/moderate motor/cognitive deficit assuming a control event rate of 46%, (decrease from 46% to 27%) and allowing for a 10% non-compliance/lost to follow-up rate with 90% power and a two-sided Type I error of 0.05. Three hundred infants will be recruited. Each infant will be followed for 24 months to assess the primary and secondary outcomes.

Analyses of the primary and secondary outcomes will adhere to the Intention to Treat (ITT) principle, where all neonates randomised will be included. Analysis of safety endpoints will be according to treatment received, including only neonates who received at least one dose of treatment. All p-values will be two tailed without adjustment. A nominal significance level of 0.05 will be applied.
The proportion of neonates who have death or severe/moderate motor/cognitive deficit at 2 years will be compared using a chi-squared test. Continuous outcomes will be compared using t-tests where appropriate. Time-to-event outcomes will be displayed using Kaplan-Meier curves and comparisons where appropriate using the log-rank test.

Multivariable comparisons using regression methods will be used to explore the impact of key prognostic variables on outcomes.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
2/05/2016
Actual
14/05/2016
Date of last participant enrolment
Anticipated
31/12/2020
Actual
31/03/2021
Date of last data collection
Anticipated
31/03/2023
Actual
Sample size
Target
300
Accrual to date
Final
313
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 2549 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 2550 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [3] 2551 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [4] 2552 0
The Royal Women's Hospital - Parkville
Recruitment hospital [5] 2553 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [6] 5669 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [7] 5670 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [8] 5671 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [9] 5672 0
Nepean Hospital - Kingswood
Recruitment hospital [10] 5673 0
Westmead Hospital - Westmead
Recruitment hospital [11] 5675 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [12] 5676 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [13] 5677 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [14] 5678 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [15] 7690 0
The Canberra Hospital - Garran
Recruitment hospital [16] 7691 0
Royal Hobart Hospital - Hobart
Recruitment hospital [17] 10085 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [18] 13228 0
Royal Hospital for Women - Randwick
Recruitment hospital [19] 15930 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 8232 0
4101 - South Brisbane
Recruitment postcode(s) [2] 8233 0
3052 - Parkville
Recruitment postcode(s) [3] 8234 0
2145 - Westmead
Recruitment postcode(s) [4] 8235 0
5042 - Bedford Park
Recruitment postcode(s) [5] 13155 0
2305 - New Lambton
Recruitment postcode(s) [6] 13156 0
2050 - Camperdown
Recruitment postcode(s) [7] 13157 0
2065 - St Leonards
Recruitment postcode(s) [8] 13158 0
2747 - Kingswood
Recruitment postcode(s) [9] 13160 0
3168 - Clayton
Recruitment postcode(s) [10] 13161 0
5006 - North Adelaide
Recruitment postcode(s) [11] 13162 0
4006 - Herston
Recruitment postcode(s) [12] 15611 0
2605 - Garran
Recruitment postcode(s) [13] 15612 0
7000 - Hobart
Recruitment postcode(s) [14] 21621 0
3084 - Heidelberg
Recruitment postcode(s) [15] 25785 0
2031 - Randwick
Recruitment postcode(s) [16] 29397 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 6096 0
New Zealand
State/province [1] 6096 0
Auckland
Country [2] 24131 0
Singapore
State/province [2] 24131 0

Funding & Sponsors
Funding source category [1] 289355 0
Government body
Name [1] 289355 0
NHMRC
Country [1] 289355 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
The University of Sydney
NSW 2006
Australia
Country
Australia
Secondary sponsor category [1] 288040 0
None
Name [1] 288040 0
None
Address [1] 288040 0
Country [1] 288040 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291127 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 291127 0
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 291127 0
Australia
Date submitted for ethics approval [1] 291127 0
06/06/2014
Approval date [1] 291127 0
28/11/2014
Ethics approval number [1] 291127 0
EC00113
Ethics committee name [2] 294882 0
Womens and Newborn Health Service Ethics Committee
Ethics committee address [2] 294882 0
c/o Ethics Committee Secretary, Ethics Office, Princess Margaret Hospital for Children, SUBIACO WA 6008
Ethics committee country [2] 294882 0
Australia
Date submitted for ethics approval [2] 294882 0
02/04/2015
Approval date [2] 294882 0
Ethics approval number [2] 294882 0
EC00350
Ethics committee name [3] 297228 0
Tasmania Health and Medical HREC
Ethics committee address [3] 297228 0
Office of Research Services, University of Tasmania, Private Bag 1, Hobart TAS 7001
Ethics committee country [3] 297228 0
Australia
Date submitted for ethics approval [3] 297228 0
19/12/2016
Approval date [3] 297228 0
28/02/2017
Ethics approval number [3] 297228 0
H0016260
Ethics committee name [4] 297229 0
ACT Health Human Research Ethics Committee
Ethics committee address [4] 297229 0
PO Box 11, Woden ACT 2606
Ethics committee country [4] 297229 0
Australia
Date submitted for ethics approval [4] 297229 0
08/09/2016
Approval date [4] 297229 0
16/08/2016
Ethics approval number [4] 297229 0
ETH.8.16.162E
Ethics committee name [5] 297230 0
Southern Health and Disability Ethics Committee
Ethics committee address [5] 297230 0
Health and Disability Ethics Committees, Ministry of Health, PO Box 5013, Wellington 6011, New Zealand
Ethics committee country [5] 297230 0
New Zealand
Date submitted for ethics approval [5] 297230 0
29/05/2015
Approval date [5] 297230 0
08/09/2015
Ethics approval number [5] 297230 0
15/STH/83
Ethics committee name [6] 299706 0
Mercy Health Human Research Ethics Committee
Ethics committee address [6] 299706 0
Level 2, 12 Shelley Street, Richmond VIC 3121
Ethics committee country [6] 299706 0
Australia
Date submitted for ethics approval [6] 299706 0
Approval date [6] 299706 0
31/01/2018
Ethics approval number [6] 299706 0
2017-038

Summary
Brief summary
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 nearterm
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 48982 0
Prof Helen Liley
Address 48982 0
Mater Health Services
Aubigny 1
Raymond Terrace
South Brisbane Qld 4101
Country 48982 0
Australia
Phone 48982 0
+61 7 3163 2733
Fax 48982 0
Email 48982 0
[email protected]
Contact person for public queries
Name 48983 0
Ms PAEAN Trial Coordinator
Address 48983 0
NHMRC Clinical Trials Centre
PAEAN Trial Coordinator
Locked Bag 77
Camperdown NSW 2050
Country 48983 0
Australia
Phone 48983 0
+61 2 9562 5000
Fax 48983 0
Email 48983 0
[email protected]
Contact person for scientific queries
Name 48984 0
Prof Helen Liley
Address 48984 0
Mater Health Services
Aubigny 1
Raymond Terrace
South Brisbane Qld 4101
Country 48984 0
Australia
Phone 48984 0
+61 7 3163 2733
Fax 48984 0
Email 48984 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
6974Study protocol    It is intended that the study protocol will be pub... [More Details]
6975Statistical analysis plan    It is intended that the statistical analysis plan ... [More Details]
6976Informed consent form    It is intended that the informed consent form will... [More Details]
6977Ethical approval    It is intended that the ethical approval will be p... [More Details]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEarly, accurate diagnosis and early intervention in cerebral palsy: Advances in diagnosis and treatment.2017https://dx.doi.org/10.1001/jamapediatrics.2017.1689
EmbaseErythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome.2017https://dx.doi.org/10.1016/j.jpeds.2017.03.053
N.B. These documents automatically identified may not have been verified by the study sponsor.