. 2024 Jan;19(1):120-126.

doi: 10.1177/17474930231185275. Epub 2023 Aug 18.

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^{1

2}, Joshua Mbroh¹, Jean-Claude Baron³, Aneesh B Singhal⁴, Daniel Strbian⁵, Carlos Molina⁶, Robin Lemmens^{7

8}, Guillaume Turc^{3

9}, Robert Mikulik¹⁰, Patrik Michel¹¹, Turgut Tatlisumak^{5

12

13}, Heinrich J Audebert¹⁴, Martin Dichgans^{15

16

17

18}, Roland Veltkamp^{19

20}, Johannes Hüsing^{21

22}, Holm Graessner²³, Jens Fiehler^{24

25}, Joan Montaner²⁶, Adedolapo Kamaldeen Adeyemi¹, Katharina Althaus²⁷, Juan F Arenillas²⁸, Benjamin Bender²⁹, Frank Benedikt³⁰, Gabriel Broocks³¹, Ina Burghaus²¹, Pere Cardona³², Milani Deb-Chatterji³³, Martina Cviková³⁴, Luc Defreyne³⁵, Veerle De Herdt³⁶, Olivier Detante^{37

38}, Ulrike Ernemann²⁹, Fabian Flottmann³¹, Lídia García Guillamón²⁶, Monika Glauch²³, Alexandra Gomez-Exposito¹, Benjamin Gory³⁹, Sylvie Sylvie Grand^{38

40}, Michal Haršány^{34

41}, Till Karsten Hauser²⁹, Olivier Heck⁴⁰, Dimitri Hemelsoet³⁶, Florian Hennersdorf²⁹, Julia Hoppe³³, Pia Kalmbach¹, Lars Kellert⁴², Martin Köhrmann³⁰, Markus Kowarik^{1

2}, Blanca Lara-Rodríguez³², Loic Legris^{37

38}, Tobias Lindig²⁹, Steffen Luntz²¹, Jay Lusk⁴³, Brian Mac Grory^{43

44

45}, Andreas Manger⁴⁶, Nicolas Martinez-Majander⁵, Annerose Mengel¹, Johannes Meyne⁴⁷, Susanne Müller²⁷, Sibu Mundiyanapurath⁴⁸, Olivier Naggara⁴⁹, Krassen Nedeltchev⁵⁰, Thanh N Nguyen^{51

52}, Maike A Nilsson²¹, Michael Obadia⁵³, Khouloud Poli¹, Jan C Purrucker⁴⁸, Silja Räty⁵, Sebastien Richard⁵⁴, Hardy Richter⁵⁵, Clotilde Schilte⁵⁶, Eckhard Schlemm⁵⁷, Linda Stöhr⁵⁸, Benjamin Stolte³⁰, Marek Sykora⁵⁹, Götz Thomalla³³, Liisa Tomppo⁵, Noel van Horn³¹, Julia Zeller¹, Ulf Ziemann^{1

2}, Christine S Zuern⁶⁰, Florian Härtig⁴⁶, Johannes Tuennerhoff^{1

2}; PROOF investigators

Collaborators, Affiliations

Affiliations

¹ Department of Neurology & Stroke, Eberhard-Karls University, University Hospital, Tubingen, Germany.
² Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tubingen, Germany.
³ Department of Neurology, Hopital Sainte-Anne, Universite de Paris, Paris, France.
⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁶ Department of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain.
⁷ Department of Neurosciences, Experimental Neurology, KU Leuven, University of Leuven, Leuven, Belgium.
⁸ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁹ Department of Neurology, GHU Paris Psychiatrie et Neurosciences INSERM U1266 Universite Paris Cite FHU NeuroVasc, Paris, France.
¹⁰ Department of Neurology, St. Anne's University Hospital Brno and Masaryk University, Brno, Czech Republic.
¹¹ Neurosciences Cliniques, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
¹² Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
¹³ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁴ Department of Neurology and Center for Stroke Research Berlin, Charite Universitatsmedizin Berlin, Berlin, Germany.
¹⁵ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
¹⁶ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁷ German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.
¹⁸ German Centre for Cardiovascular Research (DZHK, Munich), Munich, Germany.
¹⁹ Department of Neurology, Alfried Krupp Hospital, Essen, Germany.
²⁰ Department of Brain Sciences, Imperial College London, London, UK.
²¹ Coordinating Centre for Clinical Trials, University of Heidelberg, Heidelberg, Germany.
²² Landeskrebsregister Nordrhein-Westfalen, Bochum, Germany.
²³ Center for Rare Diseases, Eberhard-Karls University, Tubingen, Germany.
²⁴ Neuroradiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
²⁵ Eppdata GmbH, Hamburg, Germany.
²⁶ Vall d'Hebron Institut de Recerca, Neurovascular Research Lab, Barcelona, Spain.
²⁷ Department of Neurology, University Hospital of Ulm, Ulm, Germany.
²⁸ Hospital Clinico Universitario de Valladolid, Valladolid, Spain.
²⁹ Department of Diagnostic and Interventional Neuroradiology, Eberhard-Karls University, Tubingen, Germany.
³⁰ Department of Neurology, University Hospital Essen, Essen, Germany.
³¹ Department of Neuroradiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
³² Department of Neurology, Hospital University de Bellvitge, Barcelona, Spain.
³³ Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
³⁴ Department of Neurology, St. Anne's University Hospital in Brno, Faculty of Medicine Masaryk University, Brno, Czech Republic.
³⁵ Department of Vascular and Interventional Radiology, Ghent University Hospital, Ghent, Belgium.
³⁶ Department of Neurology, Ghent University Hospital, Ghent, Belgium.
³⁷ Neurology, CHU Grenoble Alpes, Grenoble, France.
³⁸ Inserm, U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France.
³⁹ Department of Diagnostic and Therapeutic Neuroradiology, Centre Hospital Regional Universitaire de Nancy, Universite de Lorraine, INSERM U1254, Nancy, France.
⁴⁰ Neuroradiology / MRI Department, CHU Grenoble Alpes, Grenoble, France.
⁴¹ International Clinical Research Centre, St. Anne's University Hospital in Brno, Brno, Czech Republic.
⁴² Department of Neurology, Ludwig Maximilian University (LMU), Munich, Germany.
⁴³ Duke University School of Medicine, Durham, NC, USA.
⁴⁴ Duke Clinical Research Institute, Durham, NC, USA.
⁴⁵ Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
⁴⁶ Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University, Tubingen, Germany.
⁴⁷ Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.
⁴⁸ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
⁴⁹ Department of Neuroradiology, GHU Paris Psychiatrie et Neurosciences INSERM U1266 Universite Paris Cite FHU NeuroVasc, Paris, France.
⁵⁰ Department of Neurology, KSA Kantonsspital Aarau and University of Bern, Bern, Switzerland.
⁵¹ Department of Radiology, Boston Medical Center, Boston, MA, USA.
⁵² Department of Neurology, Boston Medical Center, Boston, MA, USA.
⁵³ Department of Neurology and Stroke Center, Hopital fondation Adolphe de Rothschild, Paris, France.
⁵⁴ Centre Hospital Regional Universitaire de Nancy, Nancy, France.
⁵⁵ Department of Infectiology, Eberhard-Karls-University, Tuebingen, Germany.
⁵⁶ Department of Anaesthesia and Critical Care, CHU Grenoble Alpes, Grenoble, France.
⁵⁷ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁸ European Clinical Research Infrastructure Network (ECRIN), Paris, France.
⁵⁹ Department of Neurology, St. John's Hospital, Vienna, Austria.
⁶⁰ Department of Cardiology, Universitatsspital Basel, Basel, Switzerland.

PMID: 37515459
PMCID: PMC10759237
DOI: 10.1177/17474930231185275

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 et al. Int J Stroke. 2024 Jan.

. 2024 Jan;19(1):120-126.

doi: 10.1177/17474930231185275. Epub 2023 Aug 18.

Authors

Affiliations

¹ Department of Neurology & Stroke, Eberhard-Karls University, University Hospital, Tubingen, Germany.
² Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tubingen, Germany.
³ Department of Neurology, Hopital Sainte-Anne, Universite de Paris, Paris, France.
⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁶ Department of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain.
⁷ Department of Neurosciences, Experimental Neurology, KU Leuven, University of Leuven, Leuven, Belgium.
⁸ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁹ Department of Neurology, GHU Paris Psychiatrie et Neurosciences INSERM U1266 Universite Paris Cite FHU NeuroVasc, Paris, France.
¹⁰ Department of Neurology, St. Anne's University Hospital Brno and Masaryk University, Brno, Czech Republic.
¹¹ Neurosciences Cliniques, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
¹² Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
¹³ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁴ Department of Neurology and Center for Stroke Research Berlin, Charite Universitatsmedizin Berlin, Berlin, Germany.
¹⁵ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
¹⁶ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁷ German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.
¹⁸ German Centre for Cardiovascular Research (DZHK, Munich), Munich, Germany.
¹⁹ Department of Neurology, Alfried Krupp Hospital, Essen, Germany.
²⁰ Department of Brain Sciences, Imperial College London, London, UK.
²¹ Coordinating Centre for Clinical Trials, University of Heidelberg, Heidelberg, Germany.
²² Landeskrebsregister Nordrhein-Westfalen, Bochum, Germany.
²³ Center for Rare Diseases, Eberhard-Karls University, Tubingen, Germany.
²⁴ Neuroradiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
²⁵ Eppdata GmbH, Hamburg, Germany.
²⁶ Vall d'Hebron Institut de Recerca, Neurovascular Research Lab, Barcelona, Spain.
²⁷ Department of Neurology, University Hospital of Ulm, Ulm, Germany.
²⁸ Hospital Clinico Universitario de Valladolid, Valladolid, Spain.
²⁹ Department of Diagnostic and Interventional Neuroradiology, Eberhard-Karls University, Tubingen, Germany.
³⁰ Department of Neurology, University Hospital Essen, Essen, Germany.
³¹ Department of Neuroradiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
³² Department of Neurology, Hospital University de Bellvitge, Barcelona, Spain.
³³ Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
³⁴ Department of Neurology, St. Anne's University Hospital in Brno, Faculty of Medicine Masaryk University, Brno, Czech Republic.
³⁵ Department of Vascular and Interventional Radiology, Ghent University Hospital, Ghent, Belgium.
³⁶ Department of Neurology, Ghent University Hospital, Ghent, Belgium.
³⁷ Neurology, CHU Grenoble Alpes, Grenoble, France.
³⁸ Inserm, U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France.
³⁹ Department of Diagnostic and Therapeutic Neuroradiology, Centre Hospital Regional Universitaire de Nancy, Universite de Lorraine, INSERM U1254, Nancy, France.
⁴⁰ Neuroradiology / MRI Department, CHU Grenoble Alpes, Grenoble, France.
⁴¹ International Clinical Research Centre, St. Anne's University Hospital in Brno, Brno, Czech Republic.
⁴² Department of Neurology, Ludwig Maximilian University (LMU), Munich, Germany.
⁴³ Duke University School of Medicine, Durham, NC, USA.
⁴⁴ Duke Clinical Research Institute, Durham, NC, USA.
⁴⁵ Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
⁴⁶ Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University, Tubingen, Germany.
⁴⁷ Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.
⁴⁸ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
⁴⁹ Department of Neuroradiology, GHU Paris Psychiatrie et Neurosciences INSERM U1266 Universite Paris Cite FHU NeuroVasc, Paris, France.
⁵⁰ Department of Neurology, KSA Kantonsspital Aarau and University of Bern, Bern, Switzerland.
⁵¹ Department of Radiology, Boston Medical Center, Boston, MA, USA.
⁵² Department of Neurology, Boston Medical Center, Boston, MA, USA.
⁵³ Department of Neurology and Stroke Center, Hopital fondation Adolphe de Rothschild, Paris, France.
⁵⁴ Centre Hospital Regional Universitaire de Nancy, Nancy, France.
⁵⁵ Department of Infectiology, Eberhard-Karls-University, Tuebingen, Germany.
⁵⁶ Department of Anaesthesia and Critical Care, CHU Grenoble Alpes, Grenoble, France.
⁵⁷ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁸ European Clinical Research Infrastructure Network (ECRIN), Paris, France.
⁵⁹ Department of Neurology, St. John's Hospital, Vienna, Austria.
⁶⁰ Department of Cardiology, Universitatsspital Basel, Basel, Switzerland.

PMID: 37515459
PMCID: PMC10759237
DOI: 10.1177/17474930231185275

Abstract

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.

Keywords: NBO; Normobaric oxygen therapy; hyperoxygenation; ischemic stroke; neuroprotection; penumbra; thrombectomy.

PubMed Disclaimer

Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

**Figure 1.**
Study flow. MT: mechanical thrombectomy, NBO: normobaric oxygen.

See this image and copyright information in PMC

References

1. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994; 36: 557–565. - PubMed
1. Emberson J, Lees KR, Lyden P, et al.. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; 384: 1929–1935. - PMC - PubMed
1. Goyal M, Menon BK, van Zwam WH, et al.. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387: 1723–1731. - PubMed
1. Baron JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nat Rev Neurol 2018; 14: 325–337. - PubMed
1. Poli S, Veltkamp R. Oxygen therapy in acute ischemic stroke—experimental efficacy and molecular mechanisms. Curr Mol Med 2009; 9: 227–241. - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical