Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Abstract

Background Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods This study on the effects of AL lopurinol in addition to hypothermia treatment for hypoxic-ischemic B rain I njury on N eurocognitive O utcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance

“…A second dose of either allopurinol or mannitol (both 10 mg/kg, intravenous over 10 min) was administered 12 h after the first dose in neonates who subsequently underwent TH. The primary endpoint of this study is death or severe neurodevelopmental impairment vs survival without severe neurodevelopmental impairment at the age of 2 years [ 12 ].…”

“…Patients were eligible for the ALBINO trial if they fulfilled at least one of the perinatal asphyxia criteria: (1) pH < 7 or base deficit ≥ 16 mmol/L, (2) need for ongoing cardiac massage for ≥ 5 min postpartum; (3) need for adrenalin administration during resuscitation; and (4) Apgar score ≤ 5 after 10 min postpartum; in combination with two or more early signs of evolving encephalopathy: (1) altered state of consciousness; (2) hypotonia or hypertonia; (3) absent/insufficient spontaneous respiration requiring respiratory support for at least 10 min postpartum; and (4) abnormal primitive reflexes/abnormal movements (i.e., seizures). Further details of the study protocol have been published [ 12 ]. The most important exclusion criteria were a gestational age < 36 weeks, an estimated birth weight < 2500 g, or severe congenital abnormalities.…”

“…Consequently, mannitol clearance (CL) has been used to describe GFR, including maturation and growth from term neonatal age onwards [9][10][11]. The ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial is a randomized blinded placebo-controlled trial with mannitol administration in the placebo group, as this enabled visual blinding [12]. As pharmacokinetics was a predefined secondary endpoint of this trial, this provided us with the possibility to describe mannitol pharmacokinetics and its covariates as a GFR indicator and its variability in this specific population of neonates.…”

The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status

“…Doycheva et al [ 30 ] demonstrated that G-CSF + Ab improved body weight, reduced brain tissue damage, and improved long-term neurological function when assessed at 96 h and 5 weeks post HI in the neonatal rat pups, as well as conferring greater neuroprotection by depleting neutrophil accumulation, while G-CSF + metyrapone treatment not only lower caspase-3 expression level but also reduce corticosterone levels in neonates after HI injury [ 89 ]. Surprisingly, there has not been any study evaluating combinational therapy of G-CSF and therapeutic hypothermia (TH), as other modalities have been tried and underwent and/or are undergoing clinical trials in neonatal HIE, such as with epo and TH [ 120 – 122 ], xenon and TH [ 51 , 123 , 124 ], melatonin and TH [ 46 , 47 ], and allopurinol and TH [ 125 ]. Thus, more study is needed to explore and evaluate the neuroprotective effect of G-CSF in combination with therapeutic hypothermia as well as other emerging agents.…”

Neurotoxicity of Unconjugated Bilirubin in Neonatal Hypoxic-Ischemic Brain Injury in vitro

“…In particular, it was recently demonstrated in animal experiments that these drugs confer neuroprotection against cerebral ischemia, by activating several mechanisms that involve both anti-oxidant and anti-inflammatory effects (25,26). Most importantly, the therapeutic potential of pioglitazone has been shown in patients after ischemic stroke or transient ischemic attack events (27) and allopurinol has been recently tested in neonates for HIE (28). In addition, the beneficial action of pioglitazone was also evidentiated in models of spinal cord injury (29) and amyotrophic lateral sclerosis (30), demonstrating their neuroprotective effect.…”