ANZCTR - Registration

The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

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

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]

NCT03079167

Universal Trial Number (UTN)

Trial acronym

PAEAN

Linked study record

Health condition

Health condition(s) or problem(s) studied:

neonatal hypoxic ischaemic encephalopathy

Condition category

Condition code

Reproductive Health and Childbirth

Complications of newborn

Neurological

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]

Treatment: Drugs

Comparator / control treatment

Saline infusion

Control group

Placebo

Outcomes

Primary outcome [1]

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]

2 years of age

Secondary outcome [1]

Death (at any time from day 1 of treatment to 2 years of age)

Timepoint [1]

2 years

Secondary outcome [2]

Cerebral palsy assessed by paediatric assessment

Timepoint [2]

2 years of age

Secondary outcome [3]

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]

2 years of age

Secondary outcome [4]

Cognitive deficit (Bayley III Cognitive Score)

Timepoint [4]

2 years of age

Secondary outcome [5]

Need for supplementary respiratory or nutritional support

Timepoint [5]

2 years of age

Secondary outcome [6]

Cortical visual impairment by paediatric exam

Timepoint [6]

2 years of age

Secondary outcome [7]

Hearing impairment by paediatric exam

Timepoint [7]

2 years of age

Secondary outcome [8]

Removal of secondary outcome [8].

Timepoint [8]

Removal of secondary outcome [8].

Secondary outcome [9]

Epilepsy by paediatric exam

Timepoint [9]

2 years of age

Secondary outcome [10]

Cost of healthcare and service utilisation by parent completed questionnaire and Medicare service use

Timepoint [10]

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?

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]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [2]

Mater Mother's Hospital - South Brisbane

Recruitment hospital [3]

The Royal Childrens Hospital - Parkville

Recruitment hospital [4]

The Royal Women's Hospital - Parkville

Recruitment hospital [5]

Flinders Medical Centre - Bedford Park

Recruitment hospital [6]

John Hunter Hospital Royal Newcastle Centre - New Lambton

Recruitment hospital [7]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [8]

Royal North Shore Hospital - St Leonards

Recruitment hospital [9]

Nepean Hospital - Kingswood

Recruitment hospital [10]

Westmead Hospital - Westmead

Recruitment hospital [11]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [12]

Womens and Childrens Hospital - North Adelaide

Recruitment hospital [13]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [14]

King Edward Memorial Hospital - Subiaco

Recruitment hospital [15]

The Canberra Hospital - Garran

Recruitment hospital [16]

Royal Hobart Hospital - Hobart

Recruitment hospital [17]

Mercy Hospital for Women - Heidelberg

Recruitment hospital [18]

Royal Hospital for Women - Randwick

Recruitment hospital [19]

Perth Children's Hospital - Nedlands

Recruitment postcode(s) [1]

4101 - South Brisbane

Recruitment postcode(s) [2]

3052 - Parkville

Recruitment postcode(s) [3]

2145 - Westmead

Recruitment postcode(s) [4]

5042 - Bedford Park

Recruitment postcode(s) [5]

2305 - New Lambton

Recruitment postcode(s) [6]

2050 - Camperdown

Recruitment postcode(s) [7]

2065 - St Leonards

Recruitment postcode(s) [8]

2747 - Kingswood

Recruitment postcode(s) [9]

3168 - Clayton

Recruitment postcode(s) [10]

5006 - North Adelaide

Recruitment postcode(s) [11]

4006 - Herston

Recruitment postcode(s) [12]

2605 - Garran

Recruitment postcode(s) [13]

7000 - Hobart

Recruitment postcode(s) [14]

3084 - Heidelberg

Recruitment postcode(s) [15]

2031 - Randwick

Recruitment postcode(s) [16]

6009 - Nedlands

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Country [2]

Singapore

State/province [2]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

University of Sydney

Address

The University of Sydney
NSW 2006
Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

SLHD Ethics Review Committee (RPAH Zone)

Ethics committee address [1]

c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/06/2014

Approval date [1]

28/11/2014

Ethics approval number [1]

EC00113

Ethics committee name [2]

Womens and Newborn Health Service Ethics Committee

Ethics committee address [2]

c/o Ethics Committee Secretary, Ethics Office, Princess Margaret Hospital for Children, SUBIACO WA 6008

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

02/04/2015

Approval date [2]

Ethics approval number [2]

EC00350

Ethics committee name [3]

Tasmania Health and Medical HREC

Ethics committee address [3]

Office of Research Services, University of Tasmania, Private Bag 1, Hobart TAS 7001

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

19/12/2016

Approval date [3]

28/02/2017

Ethics approval number [3]

H0016260

Ethics committee name [4]

ACT Health Human Research Ethics Committee

Ethics committee address [4]

PO Box 11, Woden ACT 2606

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

08/09/2016

Approval date [4]

16/08/2016

Ethics approval number [4]

ETH.8.16.162E

Ethics committee name [5]

Southern Health and Disability Ethics Committee

Ethics committee address [5]

Health and Disability Ethics Committees, Ministry of Health, PO Box 5013, Wellington 6011, New Zealand

Ethics committee country [5]

New Zealand

Date submitted for ethics approval [5]

29/05/2015

Approval date [5]

08/09/2015

Ethics approval number [5]

15/STH/83

Ethics committee name [6]

Mercy Health Human Research Ethics Committee

Ethics committee address [6]

Level 2, 12 Shelley Street, Richmond VIC 3121

Ethics committee country [6]

Australia

Date submitted for ethics approval [6]

Approval date [6]

31/01/2018

Ethics approval number [6]

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

Prof Helen Liley

Address

Mater Health Services
Aubigny 1
Raymond Terrace
South Brisbane Qld 4101

Country

Australia

Phone

+61 7 3163 2733

Fax

[email protected]

Contact person for public queries

Name

PAEAN Trial Coordinator

Address

NHMRC Clinical Trials Centre
PAEAN Trial Coordinator
Locked Bag 77
Camperdown NSW 2050

Country

Australia

Phone

+61 2 9562 5000

Fax

[email protected]

Contact person for scientific queries

Name

Helen Liley

Address

Mater Health Services
Aubigny 1
Raymond Terrace
South Brisbane Qld 4101

Country

Australia

Phone

+61 7 3163 2733

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

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

Source	Title	Year of Publication	DOI
Embase	Early, accurate diagnosis and early intervention in cerebral palsy: Advances in diagnosis and treatment.	2017	https://dx.doi.org/10.1001/jamapediatrics.2017.1689
Embase	Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome.	2017	https://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.

Trial Review

Documents added manually

Documents added automatically