INTRODUCTION:Ongoing research endeavors seek to identify neuroprotective drugs capable of mitigating brain cell necrosis and reperfusion injury by protecting the ischemic penumbra. Despite these efforts, the quest for effective neuroprotective agents remains elusive. Encouragingly, preliminary investigations, including basic experiments and single-center exploratory studies, have demonstrated the neuroprotective properties of normobaric hyperoxia (NBO). In pursuit of validating and expanding upon these findings, we have conducted a multicenter, prospective, randomized, controlled clinical trial known as OPENS-2. However, the OPENS-2 study only assessed outcomes at a 90-day endpoint, leaving uncertainties regarding the potential long-term benefits of NBO in stroke management. Thus, to address this gap in knowledge, we will initiate a long-term follow-up trial, OPENS-2L, building upon the foundation laid by the OPENS-2 study.MATERIALS AND METHODS:This prospective, randomized controlled clinical trial will enroll 280 patients at a 1:1 ratio. Patients will be randomly divided into the NBO combined with the endovascular treatment group, where they will receive 10 L/min of oxygen through a mask, or the control group, where they will receive 1 L/min of oxygen.RESULTS:The primary endpoint of this study is the modified Rankin Scale (mRS) score at 1 year. Secondary endpoints include mRS 0-2, mRS 0-3, mRS 0-1 scores, Barthel index, and the EuroQol-5 Dimension score at 1 year. Safety endpoints encompass all-cause mortality at 1 year and the incidence of major vascular events.CONCLUSION:If this trial yields positive outcomes, it would furnish crucial evidence for guiding future neuroprotective research endeavors. Overall, the insights gained from this study hold the potential to illuminate the long-term benefits of NBO combined with endovascular treatment in improving stroke outcomes, thereby shaping the landscape of stroke management practices.TRIAL REGISTRATION:ClinicalTrials.gov NCT05039697.