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

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ClinicalTrials.gov Identifier: NCT03079167
Recruitment Status : Recruiting
First Posted : March 14, 2017
Last Update Posted : July 8, 2019
Sponsor:
Collaborator:
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
University of Sydney

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.

Condition or disease Intervention/treatment Phase
Hypoxic-Ischemic Encephalopathy Drug: Epoetin Alfa Drug: Normal saline Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy With Erythropoietin: A Phase III Randomised Placebo Controlled Multicentre Clinical Trial
Actual Study Start Date : May 14, 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Erythropoietin
Erythropoietin (epoetin alfa) 1000 IU/kg birth weight (capped at 4000IU daily) IV infusion, on Days 1, 2, 3, 5 and 7 of age
Drug: Epoetin Alfa
Other Names:
  • Epogen
  • Procrit

Placebo Comparator: Placebo
IV normal saline (equiv. volume), on Days 1, 2, 3, 5 and 7 of age
Drug: Normal saline
Other Name: 0.9% NaCl




Primary Outcome Measures :
  1. Composite measure of death or moderate/severe disability [ Time Frame: 2 years of age ]
    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 :
  1. Death [ Time Frame: Any time from Day 1 of treatment to 2 years of age ]
  2. Cerebral palsy (CP), assessed by paediatric assessment [ Time Frame: 2 years of age ]
  3. Moderate/severe motor deficit [ Time Frame: 2 years of age ]
    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

  4. Moderate/severe cognitive deficit [ Time Frame: 2 years of age ]
    Defined as a BSDIII cognitive score less than or equal to 80

  5. Need for supplemental respiratory support (includes tracheostomy, ventilator, high flow nasal cannula, CPAP or oxygen dependency) [ Time Frame: 2 years of age ]
  6. Need for nutritional support (includes gastrostomy or nasogastric feeds) [ Time Frame: 2 years of age ]
  7. Major cortical visual impairment by paediatric examination [ Time Frame: 2 years of age ]
  8. Hearing impairment status by paediatric examination - requirement for hearing aids [ Time Frame: 2 years of age ]
  9. Autism spectrum disorder, assessed by Modified Checklist for Autism in Toddlers (M-CHAT) parent questionnaire [ Time Frame: 2 years of age ]
  10. 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). [ Time Frame: 2 years of age ]
  11. Cost of healthcare and service utilisation [ Time Frame: 2 years of age ]
    Defined as a composite of parent completed questionnaire data and Medicare service use

  12. Frequency of selected adverse events (AEs) of interest, including deaths [ Time Frame: Up to 30 days post study treatment ]

Other Outcome Measures:
  1. Distribution of overall disability [ Time Frame: 2 years of age ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 23 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03079167


Contacts
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Contact: PAEAN Coordinator +61295625000 paean@ctc.usyd.edu.au

Locations
Show Show 25 study locations
Sponsors and Collaborators
University of Sydney
National Health and Medical Research Council, Australia
Investigators
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Study Chair: Helen Liley, BHB, MBChB University of Sydney
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Responsible Party: University of Sydney
ClinicalTrials.gov Identifier: NCT03079167    
Other Study ID Numbers: CTC0119
12614000669695 ( Registry Identifier: Australian New Zealand Clinical Trials Registry )
First Posted: March 14, 2017    Key Record Dates
Last Update Posted: July 8, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Ischemia
Hypoxia
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Hypoxia, Brain
Epoetin Alfa
Hematinics