Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial

  • Sven Poli
  • Joshua Mbroh
  • Jean-Claude Baron
  • Aneesh B Singhal
  • Daniel Strbian
  • Carlos Molina
  • Robin Lemmens
  • Guillaume Turc
  • Robert Mikulik
  • Patrik Michel
  • Turgut Tatlisumak
  • Heinrich J Audebert
  • Martin Dichgans
  • Roland Veltkamp
  • Johannes Hüsing
  • Holm Graessner
  • Jens Fiehler
  • Joan Montaner
  • Adedolapo Kamaldeen Adeyemi
  • Katharina Althaus
  • Juan F Arenillas
  • Benjamin Bender
  • Frank Benedikt
  • Gabriel Broocks
  • Ina Burghaus
  • Pere Cardona
  • Milani Deb-Chatterji
  • Martina Cviková
  • Luc Defreyne
  • Veerle De Herdt
  • Olivier Detante
  • Ulrike Ernemann
  • Fabian Flottmann
  • Lídia García Guillamón
  • Monika Glauch
  • Alexandra Gomez-Exposito
  • Benjamin Gory
  • Sylvie Sylvie Grand
  • Michal Haršány
  • Till Karsten Hauser
  • Olivier Heck
  • Dimitri Hemelsoet
  • Florian Hennersdorf
  • Julia Hoppe
  • Pia Kalmbach
  • Lars Kellert
  • Martin Köhrmann
  • Markus Kowarik
  • Blanca Lara-Rodríguez
  • Loic Legris
  • Tobias Lindig
  • Steffen Luntz
  • Jay Lusk
  • Brian Mac Grory
  • Andreas Manger
  • Nicolas Martinez-Majander
  • Annerose Mengel
  • Johannes Meyne
  • Susanne Müller
  • Sibu Mundiyanapurath
  • Olivier Naggara
  • Krassen Nedeltchev
  • Thanh N Nguyen
  • Maike A Nilsson
  • Michael Obadia
  • Khouloud Poli
  • Jan C Purrucker
  • Silja Räty
  • Sebastien Richard
  • Hardy Richter
  • Clotilde Schilte
  • Eckhard Schlemm
  • Linda Stöhr
  • Benjamin Stolte
  • Marek Sykora
  • Götz Thomalla
  • Liisa Tomppo
  • Noel van Horn
  • Julia Zeller
  • Ulf Ziemann
  • Christine S Zuern
  • Florian Härtig (Geteilte/r Letztautor/in)
  • Johannes Tuennerhoff (Geteilte/r Letztautor/in)
  • PROOF investigators


RATIONALE: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs.

AIMS: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion.

METHODS AND DESIGN: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial.

STUDY OUTCOMES: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted.

SAMPLE SIZE: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation.

DISCUSSION: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia.

TRIAL REGISTRATIONS: NCT03500939; EudraCT: 2017-001355-31.

Bibliografische Daten

StatusVeröffentlicht - 01.2024
PubMed 37515459