Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study.
BACKGROUND
Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy.


METHODS
The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis.


CONCLUSIONS
In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia.


BACKGROUND
Clinical Trials, protocol registration system: NCT00189007.
Kaandorp
Joepe J
JJ
Perinatal Center, University Medical Center, Utrecht, the Netherlands. j.j.kaandorp@gmail.com
Benders
Manon J N L
MJ
Rademaker
Carin M A
CM
Torrance
Helen L
HL
Oudijk
Martijn A
MA
de Haan
Timo R
TR
Bloemenkamp
Kitty W M
KW
Rijken
Monique
M
van Pampus
Maria G
MG
Bos
Arie F
AF
Porath
Martina M
MM
Oetomo
Sidarto Bambang
SB
Willekes
Christine
C
Gavilanes
A W Danilo
AW
Wouters
Maurice G A J
MG
van Elburg
Ruurd M
RM
Huisjes
Anjoke J M
AJ
Bakker
Saskia C M J E R
SC
van Meir
Claudia A
CA
von Lindern
Jeannette
J
Boon
Janine
J
de Boer
Inge P
IP
Rijnders
Robbert Jp
RJ
Jacobs
Corrie J W F M
CJ
Uiterwaal
Cuno S P M
CS
Mol
Ben Willem J
BW
Visser
Gerard H A
GH
van Bel
Frank
F
Derks
Jan B
JB
D000493:Allopurinol / Q000627:therapeutic use*; D001238:Asphyxia Neonatorum / Q000097:blood / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005311:Fetal Hypoxia / Q000097:blood / Q000150:complications / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D007231:Infant, Newborn; D015999:Multivariate Analysis; D009414:Nerve Growth Factors / Q000097:blood; D009426:Netherlands / Q000453:epidemiology; D010751:Phosphopyruvate Hydratase / Q000097:blood; D010865:Pilot Projects; D011247:Pregnancy; D011295:Prenatal Care / Q000379:methods*; D011446:Prospective Studies; D012044:Regression Analysis; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D015415:Biomarkers; D016166:Free Radical Scavengers; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D000493:Allopurinol; D014969:Xanthine Oxidase; D010751:Phosphopyruvate Hydratase