Antenatal Allopurinol During Fetal Hypoxia

Does Antenatal Allopurinol Administration Reduce Post-hypoxic-ischemic Reperfusion Damage During Fetal Hypoxia in the Newborn?

A former study (submitted) in 32 severely asphyxiated infants participating in a randomized double blind study, in which early postnatal allopurinol or a placebo (within 4 hours after birth) was administered to reduce free radical formation and consequently reperfusion/reoxygenation injury to the newborn brain, showed an unaltered high mortality and no clinically relevant improvement in morbidity in infants treated with allopurinol. It was hypothesized that postnatal allopurinol treatment started too late to reduce reperfusion-induced free radical surge and that initiating allopurinol treatment of the fetus with (imminent) hypoxia already via the mother during labor will be more effective to reduce free radical-induced post-asphyxial brain damage.

Study Overview

• Status: Unknown
• Conditions: Reperfusion Injury; Fetal Hypoxia
• Intervention / Treatment: Drug: Allopurinol sodium; Drug: Mannitol

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • AMC
  • Amsterdam, Netherlands
    • VUMC
  • Apeldoorn, Netherlands
    • Gelre Hospitals
  • Den Bosch, Netherlands
    • Jeroen Bosch Hospital
  • Gouda, Netherlands
    • Groene Hart Hospital
  • Groningen, Netherlands
    • UMCG
  • Leiden, Netherlands
    • LUMC
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • Utrecht, Netherlands
    • Diakonessenhuis
  • Utrecht, Netherlands, 3508AB
    • Wilhelmina Children's Hospital/UMC Utrecht
  • Veldhoven, Netherlands
    • Maxima Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age of 36 weeks or more
• Non-reassuring CTG, significant events on the STAN-monitor AND/OR FBS < 7.20

Exclusion Criteria:

• Chromosomal abnormalities

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Allopurinol; 500 mg allopurinol/ 50 mL water for injection intravenously	Drug: Allopurinol sodium; Allopurinol sodium 500 mg / 50 mL, intravenously, single dose; Other Names: Acepurin
Placebo Comparator: Placebo; 500 mg mannitol/50 mL water for injection intravenously	Drug: Mannitol; Mannitol 500 mg/50 mL water for injection, intravenously, single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Free radical production and markers of neuronal damage	Up to 24 hours postpartum

Secondary Outcome Measures

Outcome Measure	Time Frame
Developmental outcome	Up to 5 years of age
Mortality	Up to 28 days postpartum
Severe composite morbidity	Up to 28 days postpartum

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Study Director: Frank van Bel, Prof MD PhD, Wilhelmina Children's Hospital/UMC Utrecht; Principal Investigator: Manon JN Benders, MD, PhD, UMC Utrecht; Principal Investigator: Jan B Derks, MD, PhD, UMC Utrecht; Principal Investigator: Joepe J Kaandorp, MD, UMC Utrecht; Principal Investigator: Gerard H Visser, MD, PhD, UMC Utrecht; Principal Investigator: Ben WJ Mol, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Carin MA Rademaker, PhD, Clinical Pharmacy, UMCU

Publications and helpful links

General Publications

• Kaandorp JJ, Benders MJ, Rademaker CM, Torrance HL, Oudijk MA, de Haan TR, Bloemenkamp KW, Rijken M, van Pampus MG, Bos AF, Porath MM, Oetomo SB, Willekes C, Gavilanes AW, Wouters MG, van Elburg RM, Huisjes AJ, Bakker SC, van Meir CA, von Lindern J, Boon J, de Boer IP, Rijnders RJ, Jacobs CJ, Uiterwaal CS, Mol BW, Visser GH, van Bel F, Derks JB. Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study. BMC Pregnancy Childbirth. 2010 Feb 18;10:8. doi: 10.1186/1471-2393-10-8.
• Klumper J, Kaandorp JJ, Schuit E, Groenendaal F, Koopman-Esseboom C, Mulder EJH, Van Bel F, Benders MJNL, Mol BWJ, van Elburg RM, Bos AF, Derks JB; ALLO-trial study group. Behavioral and neurodevelopmental outcome of children after maternal allopurinol administration during suspected fetal hypoxia: 5-year follow up of the ALLO-trial. PLoS One. 2018 Aug 23;13(8):e0201063. doi: 10.1371/journal.pone.0201063. eCollection 2018.
• Kaandorp JJ, Benders MJ, Schuit E, Rademaker CM, Oudijk MA, Porath MM, Oetomo SB, Wouters MG, van Elburg RM, Franssen MT, Bos AF, de Haan TR, Boon J, de Boer IP, Rijnders RJ, Jacobs CJ, Scheepers LH, Gavilanes DA, Bloemenkamp KW, Rijken M, van Meir CA, von Lindern JS, Huisjes AJ, Bakker SC, Mol BW, Visser GH, Van Bel F, Derks JB. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015 May;100(3):F216-23. doi: 10.1136/archdischild-2014-306769. Epub 2014 Dec 15.
• Kaandorp JJ, van den Broek MP, Benders MJ, Oudijk MA, Porath MM, Bambang Oetomo S, Wouters MG, van Elburg R, Franssen MT, Bos AF, Mol BW, Visser GH, van Bel F, Rademaker CM, Derks JB; ALLO-trial Study Group. Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour. Arch Dis Child Fetal Neonatal Ed. 2014 Mar;99(2):F144-8. doi: 10.1136/archdischild-2013-304876. Epub 2013 Dec 18.
• Torrance HL, Benders MJ, Derks JB, Rademaker CM, Bos AF, Van Den Berg P, Longini M, Buonocore G, Venegas M, Baquero H, Visser GH, Van Bel F. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B. Pediatrics. 2009 Jul;124(1):350-7. doi: 10.1542/peds.2008-2228.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): December 1, 2011
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: September 11, 2005
• First Submitted That Met QC Criteria: September 11, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Estimate): March 29, 2012
• Last Update Submitted That Met QC Criteria: March 28, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: allopurinol; neuroprotection; reperfusion injury; fetal hypoxia; post hypoxic-ischemic reperfusion damage
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Signs and Symptoms, Respiratory; Fetal Diseases; Pregnancy Complications; Reperfusion Injury; Hypoxia; Fetal Hypoxia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Antioxidants; Free Radical Scavengers; Gout Suppressants; Mannitol; Allopurinol
• Other Study ID Numbers: ZonMw 170991001; ALLO-trial (Other Identifier: Dutch Consortium for Studies in Obstetrics and Gynaecology); 2006-005796-18 (EudraCT Number); 170991001 (Other Grant/Funding Number: ZonMw); NTR-1383 (Registry Identifier: Dutch Trial Register); NL26516.000.09 (Other Identifier: The Central Committee on Research Involving Human Subjects (CCMO))