Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome — a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)
Authors: Engel Corinna , Rüdiger Mario , Benders Manon J. N. L. , van Bel Frank , Allegaert Karel , Naulaers Gunnar , Bassler Dirk , Klebermaß-Schrehof Katrin , Vento Maximo , Vilan Ana , Falck Mari , Mauro Isabella , Metsäranta Marjo , Vanhatalo Sampsa , Mazela Jan , Metsvaht Tuuli , van der Vlught Roselinda , Franz Axel R. ,   for the ALBINO Study Group, Poets Christian F. , Guimarães Hercilia , Stiri Tom , Cattarossi Luigi , van Veldhuizen Cees K. W. , Maiwald Christian A. , Bergmann Iris , Weiss Monika , Eichhorn Andreas , Raubuch Michael , Schuler Birgit , Laméris Bas , van Ramshorst Thirza , Kliniken Tirol , Brandner Johannes , Tackoen Marie , Reibel Ruth , Ilmoja Mari-Liis , Saik Pille , Käär Ruth , Andresson Pille , der J. W. Goethe Klinikum , Schloesser Main Rolf , Carus Carl Gustav , Winkler Stefan , Hoehn Thomas , Teig Norbert , Schroth Michael , Fusch Christoph , Thome Ulrich H. , Ehrhardt Harald , Carnielli Ancona Virgilio , Napolitano Marcello , Faldini Francesca , “V.Buzzi” Bambini , Lista Milano Gianluca , Barbarini Mario , Pagani Laura , Mastretta Emmanuele , Vento Giovanni , Fumagalli Monica , van Weissenbruch Mirjam M. , van Straaten Henrica L. M. , Annink Kim V. , Dudink Jeroen , Derks Jan B. , de Boer Inge P. , Meijssen Clemens B. , de Haan Timo R. , van Rooij Linda G. , van Hillegersberg Jacqueline L. , van Dongen Minouche , Dijkman Koen P. , van Houten Marlies A. , van der Schoor Sophie R. D. , Schneider Moritz , Nestaas Eirik , Nakstad Britt , Karpinski Lukas , Gulczynska Ewa , Ferraz Claudia , Pereira Almerinda , Barroso Rosalina , da Graça Mendes , Tomé Teresa , Pinto Filomena , Rodilla Juan Martínez , Pico Maria Luz.Couce , Suazo José Antonio Hurtado , Valverde Eva , Lorenzo José Ramón Fernández , Boix Héctor , Parrilla Francisco Jimenez , Blanco Dorotea , Loureiro Begoña , Moral-Pumarega Maria Teresa , Maletzki Julia , Knoepfli Claudia , Hagmann Cornelia , Kleber Michael , Stocker Martin , Riedel Thomas 
Published: January 2024

Background

Despite therapeutic hypothermia (TH) and neonatal intensive care, 45–50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants.

Allopurinol — a xanthine oxidase inhibitor — reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult.

This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE.

Methods/design

The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE.

Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years.

Results

The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and .”will be stratified for the two treatment groups.

Discussion

The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Trial registration

ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.