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

TY - JOUR

T1 - Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial

AU - Poli, Sven

AU - Mbroh, Joshua

AU - Baron, Jean-Claude

AU - Singhal, Aneesh B

AU - Strbian, Daniel

AU - Molina, Carlos

AU - Lemmens, Robin

AU - Turc, Guillaume

AU - Mikulik, Robert

AU - Michel, Patrik

AU - Tatlisumak, Turgut

AU - Audebert, Heinrich J

AU - Dichgans, Martin

AU - Veltkamp, Roland

AU - Hüsing, Johannes

AU - Graessner, Holm

AU - Fiehler, Jens

AU - Montaner, Joan

AU - Adeyemi, Adedolapo Kamaldeen

AU - Althaus, Katharina

AU - Arenillas, Juan F

AU - Bender, Benjamin

AU - Benedikt, Frank

AU - Broocks, Gabriel

AU - Burghaus, Ina

AU - Cardona, Pere

AU - Deb-Chatterji, Milani

AU - Cviková, Martina

AU - Defreyne, Luc

AU - De Herdt, Veerle

AU - Detante, Olivier

AU - Ernemann, Ulrike

AU - Flottmann, Fabian

AU - García Guillamón, Lídia

AU - Glauch, Monika

AU - Gomez-Exposito, Alexandra

AU - Gory, Benjamin

AU - Sylvie Grand, Sylvie

AU - Haršány, Michal

AU - Hauser, Till Karsten

AU - Heck, Olivier

AU - Hemelsoet, Dimitri

AU - Hennersdorf, Florian

AU - Hoppe, Julia

AU - Kalmbach, Pia

AU - Kellert, Lars

AU - Köhrmann, Martin

AU - Kowarik, Markus

AU - Lara-Rodríguez, Blanca

AU - Legris, Loic

AU - Lindig, Tobias

AU - Luntz, Steffen

AU - Lusk, Jay

AU - Mac Grory, Brian

AU - Manger, Andreas

AU - Martinez-Majander, Nicolas

AU - Mengel, Annerose

AU - Meyne, Johannes

AU - Müller, Susanne

AU - Mundiyanapurath, Sibu

AU - Naggara, Olivier

AU - Nedeltchev, Krassen

AU - Nguyen, Thanh N

AU - Nilsson, Maike A

AU - Obadia, Michael

AU - Poli, Khouloud

AU - Purrucker, Jan C

AU - Räty, Silja

AU - Richard, Sebastien

AU - Richter, Hardy

AU - Schilte, Clotilde

AU - Schlemm, Eckhard

AU - Stöhr, Linda

AU - Stolte, Benjamin

AU - Sykora, Marek

AU - Thomalla, Götz

AU - Tomppo, Liisa

AU - van Horn, Noel

AU - Zeller, Julia

AU - Ziemann, Ulf

AU - Zuern, Christine S

AU - Härtig, Florian

AU - Tuennerhoff, Johannes

AU - PROOF investigators

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

U2 - 10.1177/17474930231185275

DO - 10.1177/17474930231185275

M3 - SCORING: Journal article

C2 - 37515459

VL - 19

SP - 120

EP - 126

JO - INT J STROKE

JF - INT J STROKE

SN - 1747-4930

IS - 1

ER -