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)

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2024年1月24日

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

摘要

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.