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

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 therapy (NBO) within six hours 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 hours (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 hours, 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 are 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 hours on follow-up imaging reduces potential bias 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.

Evolving Clinical–Translational Investigations of Cerebroprotection in Ischemic Stroke

“…Evidence for oxygenation supplementation, whether at hyperbaric or normobaric pressures, has hit a roadblock due to futility [58,59] and imbalances of deaths despite biological plausibility. Consequently, the PROOF trial attempted to enroll patients to determine a role for penumbral protection before EVT but was ultimately terminated for futility [60]. Studies then progressed to study low-dose oxygen supplementation (rather than hyperbaric or normobaric pressure), with a pragmatic trial design showing no benefit in non-hypoxic stroke patients [61].…”