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: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

Center for Rare Diseases Eberhard Karls University Tubingen Germany

Centre Hospital Regional Universitaire de Nancy Nancy France

Coordinating Centre for Clinical Trials University of Heidelberg Heidelberg Germany

Department of Anaesthesia and Critical Care CHU Grenoble Alpes Grenoble France

Department of Anesthesiology and Intensive Care Medicine Eberhard Karls University Tubingen Germany

Department of Brain Sciences Imperial College London London UK

Department of Cardiology Universitatsspital Basel Basel Switzerland

Department of Clinical Neuroscience Institute of Neuroscience and Physiology Sahlgrenska Academy at University of Gothenburg Gothenburg Sweden

Department of Diagnostic and Interventional Neuroradiology Eberhard Karls University Tubingen Germany

Department of Diagnostic and Therapeutic Neuroradiology Centre Hospital Regional Universitaire de Nancy Universite de Lorraine INSERM U1254 Nancy France

Department of Infectiology Eberhard Karls University Tuebingen Germany

Department of Neurology Alfried Krupp Hospital Essen Germany

Department of Neurology and Center for Stroke Research Berlin Charite Universitatsmedizin Berlin Berlin Germany

Department of Neurology and Stroke Center Hopital fondation Adolphe de Rothschild Paris France

Department of Neurology and Stroke Eberhard Karls University University Hospital Tubingen Germany

Department of Neurology Boston Medical Center Boston MA USA

Department of Neurology Duke University School of Medicine Durham NC USA

Department of Neurology Ghent University Hospital Ghent Belgium

Department of Neurology GHU Paris Psychiatrie et Neurosciences INSERM U1266 Universite Paris Cite FHU NeuroVasc Paris France

Department of Neurology Heidelberg University Hospital Heidelberg Germany

Department of Neurology Helsinki University Hospital and University of Helsinki Helsinki Finland

Department of Neurology Hopital Sainte Anne Universite de Paris Paris France

Department of Neurology Hospital University de Bellvitge Barcelona Spain

Department of Neurology KSA Kantonsspital Aarau and University of Bern Bern Switzerland

Department of Neurology Ludwig Maximilian University Munich Germany

Department of Neurology Massachusetts General Hospital Harvard Medical School Boston MA USA

Department of Neurology Sahlgrenska University Hospital Gothenburg Sweden

Department of Neurology St Anne's University Hospital Brno and Masaryk University Brno Czech Republic

Department of Neurology St Anne's University Hospital in Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Neurology St John's Hospital Vienna Austria

Department of Neurology University Hospital Essen Essen Germany

Department of Neurology University Hospital Hamburg Eppendorf Hamburg Germany

Department of Neurology University Hospital of Ulm Ulm Germany

Department of Neurology University Hospital Schleswig Holstein Kiel Germany

Department of Neurology University Hospitals Leuven Leuven Belgium

Department of Neurology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Neurology Vall d'Hebron University Hospital Barcelona Spain

Department of Neuroradiology GHU Paris Psychiatrie et Neurosciences INSERM U1266 Universite Paris Cite FHU NeuroVasc Paris France

Department of Neuroradiology University Hospital Hamburg Eppendorf Hamburg Germany

Department of Neurosciences Experimental Neurology KU Leuven University of Leuven Leuven Belgium

Department of Radiology Boston Medical Center Boston MA USA

Department of Vascular and Interventional Radiology Ghent University Hospital Ghent Belgium

Duke Clinical Research Institute Durham NC USA

Duke University School of Medicine Durham NC USA

Eppdata GmbH Hamburg Germany

European Clinical Research Infrastructure Network Paris France

German Center for Neurodegenerative Diseases Munich Germany

German Centre for Cardiovascular Research Munich Germany

Hertie Institute for Clinical Brain Research Eberhard Karls University Tubingen Germany

Hospital Clinico Universitario de Valladolid Valladolid Spain

Inserm U1216 Grenoble Institut Neurosciences Université Grenoble Alpes Grenoble France

Institute for Stroke and Dementia Research University Hospital LMU Munich Munich Germany

International Clinical Research Centre St Anne's University Hospital in Brno Brno Czech Republic

Landeskrebsregister Nordrhein Westfalen Bochum Germany

Munich Cluster for Systems Neurology Munich Germany

Neurology CHU Grenoble Alpes Grenoble France

Neuroradiology MRI Department CHU Grenoble Alpes Grenoble France

Neuroradiology University Hospital Hamburg Eppendorf Hamburg Germany

Neurosciences Cliniques Centre Hospitalier Universitaire Vaudois Lausanne Switzerland

Vall d'Hebron Institut de Recerca Neurovascular Research Lab Barcelona Spain

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ClinicalTrials.gov
NCT03500939