Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.
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Poli Sven, Mbroh Joshua, Baron Jean-Claude, Singhal Aneesh B, Strbian Daniel, Molina Carlos, Lemmens Robin, Turc Guillaume, Mikulik Robert, Michel Patrik, Tatlisumak Turgut, Audebert Heinrich J, Dichgans Martin, Veltkamp Roland, Hüsing Johannes, Graessner Holm, Fiehler Jens, Montaner Joan, Adeyemi Adedolapo Kamaldeen, Althaus Katharina, Arenillas Juan F, Bender Benjamin, Benedikt Frank, Broocks Gabriel, Burghaus Ina, Cardona Pere, Deb-Chatterji Milani, Cviková Martina, Defreyne Luc, De Herdt Veerle, Detante Olivier, Ernemann Ulrike, Flottmann Fabian, García Guillamón Lídia, Glauch Monika, Gomez-Exposito Alexandra, Gory Benjamin, Sylvie Grand Sylvie, Haršány Michal, Hauser Till Karsten, Heck Olivier, Hemelsoet Dimitri, Hennersdorf Florian, Hoppe Julia, Kalmbach Pia, Kellert Lars, Köhrmann Martin, Kowarik Markus, Lara-Rodríguez Blanca, Legris Loic, Lindig Tobias, Luntz Steffen, Lusk Jay, Mac Grory Brian, Manger Andreas, Martinez-Majander Nicolas, Mengel Annerose, Meyne Johannes, Müller Susanne, Mundiyanapurath Sibu, Naggara Olivier, Nedeltchev Krassen, Nguyen Thanh N, Nilsson Maike A, Obadia Michael, Poli Khouloud, Purrucker Jan C, Räty Silja, Richard Sebastien, Richter Hardy, Schilte Clotilde, Schlemm Eckhard, Stöhr Linda, Stolte Benjamin, Sykora Marek, Thomalla Götz, Tomppo Liisa, van Horn Noel, Zeller Julia, Ziemann Ulf, Zuern Christine S, Härtig Florian, Tuennerhoff Johannes, PROOF investigators
Аннотация
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: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.