Normobaric Hyperoxia With Extended-Window Endovascular Therapy for Acute Ischemic Stroke (OPENS-EXTEND)

Официальное название

Efficacy and Safety of Periprocedural Normobaric Hyperoxia With Endovascular Therapy for Acute Ischemic Stroke 6-24 Hours After Last Known Well: A Multicenter Randomized Sham-Controlled Phase 3 Trial

Обзор

Although endovascular therapy (EVT) has substantially improved recanalization rates and extended the treatment window for acute ischemic stroke, fewer than half of patients achieve functional independence despite successful reperfusion. Growth of the ischemic core before reperfusion and ischemia-reperfusion injury after recanalization may contribute to unfavorable outcomes. Therefore, an adjunctive neuroprotective strategy that preserves the ischemic penumbra before and during EVT may further improve clinical outcomes. Normobaric hyperoxia (NBO) is a noninvasive and readily available treatment that delivers high-concentration oxygen at normal atmospheric pressure. By increasing oxygen delivery to hypoperfused but potentially salvageable brain tissue, NBO may delay infarct growth, preserve the blood-brain barrier, and reduce reperfusion injury. Previous preclinical studies and early clinical trials have suggested that NBO may provide neuroprotection without increasing oxidative stress or other major safety risks. The previous OPENS-1 and OPENS-2 trials showed that periprocedural NBO combined with EVT reduced infarct volume and improved 90-day functional outcomes in patients treated within 6 hours after stroke onset. In addition, a preliminary two-center study involving 120 patients treated 6-24 hours after onset suggested greater early neurological improvement and a potentially favorable 90-day functional outcome with NBO plus EVT compared with EVT alone. OPENS-EXTEND is a prospective, multicenter, randomized controlled trial designed to evaluate the efficacy and safety of periprocedural NBO as an adjunct to EVT in patients with acute ischemic stroke caused by anterior-circulation large-vessel occlusion who present 6-24 hours after symptom onset or last known well and have imaging evidence of salvageable ischemic brain tissue. Participants will be randomly assigned to receive either EVT combined with NBO or EVT with standard medical management alone. The primary hypothesis is that adjunctive NBO will improve functional outcomes at 90 days without increasing safety risks.

Подробное описание

Successful reperfusion after endovascular therapy (EVT) does not always result in favorable functional outcomes in patients with acute ischemic stroke. Infarct growth before reperfusion and ischemia-reperfusion injury after recanalization may contribute to poor outcomes. Normobaric hyperoxia (NBO) may preserve salvageable ischemic brain tissue by increasing oxygen delivery to the ischemic penumbra, delaying infarct growth, and reducing blood-brain barrier injury. Previous studies have suggested potential benefits of periprocedural NBO in patients undergoing EVT within 6 hours; however, its efficacy and safety in the 6- to 24-hour treatment window remain uncertain.

OPENS-EXTEND is a prospective, multicenter, randomized, sham-controlled, phase 3 clinical trial. A total of 314 participants will be randomly assigned in a 1:1 ratio to receive NBO plus EVT or sham NBO plus EVT. Eligible participants will have acute anterior-circulation ischemic stroke caused by an internal carotid artery or middle cerebral artery M1-segment occlusion, an NIHSS score of at least 10, an ASPECTS of at least 6, a pre-stroke modified Rankin Scale score of 0 or 1, and imaging evidence of salvageable ischemic brain tissue. Randomization will occur 6 to 24 hours after the participant was last known well.

All participants will undergo EVT as soon as possible according to current guideline-recommended practice and will receive standard medical care. Randomization and initiation of the study intervention must not cause an avoidable delay in EVT.

Participants in the experimental group will receive 100% medical oxygen through a non-rebreather mask at 10 L/min for 4 hours, initiated within 30 minutes after randomization and covering the periods before, during, and after EVT. For participants requiring endotracheal intubation for airway protection, procedural sedation, or general anesthesia, NBO will be delivered through mechanical ventilation, with FiO₂ initially set and targeted at 1.0. If clinically necessary, FiO₂ may be reduced but should be maintained at 0.80 or greater whenever feasible.

Participants in the sham-control group will wear the same mask model. The respiratory indicator and the green membrane covering the opposite side valve will be removed, allowing ambient air to enter through both open lateral ports. Medical oxygen will be delivered at a nominal flow rate of 1 L/min for 4 hours. For intubated participants, FiO₂ will initially be set at 0.30 and may be increased when clinically necessary, but should remain at 0.40 or lower whenever feasible.

Peripheral oxygen saturation will be continuously monitored. Oxygen flow or FiO₂ may be adjusted to maintain SpO₂ above 94% or to protect participant safety. All adjustments, interruptions, rescue oxygen therapy, and premature discontinuations will be documented.

Participants and clinical outcome assessors will be masked to treatment assignment. Personnel administering the intervention, neurointerventionalists, anesthesiologists, and other staff requiring knowledge of oxygen settings will not be masked. The independent clinical event committee and imaging core laboratory will remain masked.

The primary efficacy outcome is the distribution of modified Rankin Scale scores at 90 days, analyzed using an ordinal shift approach. Key secondary outcomes include functional independence at 90 days, early neurological improvement at 24 hours, NIHSS score at 7 days, infarct volume at 24 to 48 hours, and EQ-5D-5L score at 90 days. Key safety outcomes include symptomatic intracranial hemorrhage, any intracranial hemorrhage, and all-cause mortality at 90 days.

The primary analysis will be performed in the intention-to-treat population. The study will evaluate whether periprocedural NBO combined with EVT improves 90-day functional outcomes without increasing clinically important safety risks.

Вмешательства

• Препарат Oxygen (Normobaric Hyperoxia)
  Normobaric hyperoxia will be initiated as soon as possible and within 30 minutes after randomization and will continue for 4 hours. For participants who are not intubated, 100% medical oxygen will be delivered through a non-rebreather mask at a flow rate of 10 L/min. For participants requiring endotracheal intubation for airway protection, procedural sedation, or general anesthesia, normobaric hyperoxia will be delivered through mechanical ventilation, with FiO₂ initially set and targeted at 1.
• Препарат Sham Normobaric Hyperoxia
  Sham normobaric hyperoxia will be initiated within 30 minutes after randomization and continued for 4 hours. Non-intubated participants will wear the same mask model as the experimental group. The respiratory indicator and the green membrane covering the opposite side valve will be removed, allowing ambient air to enter through both open lateral ports. Medical oxygen will be delivered at a nominal flow rate of 1 L/min; the intervention is not intended to produce normobaric hyperoxia. For intuba
• Процедура Endovascular Therapy
  Endovascular therapy will be performed as soon as possible in accordance with current guideline-recommended practice for acute ischemic stroke. The selection of thrombectomy devices, procedural techniques, and anesthesia methods will be determined by the treating neurointerventionalist. All participants will also receive guideline-recommended standard medical treatment and secondary stroke prevention.

Первичные конечные точки

• Distribution of Modified Rankin Scale Scores at 90 Days [Срок оценки: 90 days after randomization, with an allowable visit window of ±14 days]
• All-Cause Mortality at 90 Days [Срок оценки: Within 90 days after randomization]

Вторичные конечные точки (12)

• Functional Independence at 90 Days [Срок оценки: 90 days after randomization, with an allowable visit window of ±14 days]
• Excellent Functional Outcome at 90 Days [Срок оценки: 90 days after randomization, with an allowable visit window of ±14 days]
• Modified Rankin Scale Score of 0 to 3 at 90 Days [Срок оценки: 90 days after randomization, with an allowable visit window of ±14 days]
• Barthel Index Score at 90 Days [Срок оценки: 90 days after randomization, with an allowable visit window of ±14 days]
• EuroQol five dimensions questionnaire at 90 Days [Срок оценки: 90 days after randomization, with an allowable visit window of ±14 days]
• National Institutes of Health Stroke Scale Score [Срок оценки: 24 hours and 7 days after randomization]
• Early Neurological Improvement at 24 Hours [Срок оценки: 24 hours after randomization]
• Length of Index Hospital Stay [Срок оценки: From index hospital admission to hospital discharge, anticipated within 30 days]
• Infarct Volume at 24 to 48 Hours [Срок оценки: 24 to 48 hours after randomization]
• Infarct Core Growth Ratio [Срок оценки: Baseline and 24 to 48 hours after randomization]
• Successful Reperfusion at the End of Endovascular Therapy [Срок оценки: Immediately after completion of endovascular therapy]
• Symptomatic Intracranial Hemorrhage [Срок оценки: Within 24 to 48 hours after randomization]

Критерии участия

Критерии включения

• Age 18 years or older.
• Clinical signs and symptoms consistent with acute anterior-circulation ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 10 or greater at the time of randomization.
• Pre-stroke modified Rankin Scale (mRS) score of 0 or 1.
• Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6 or greater on baseline non-contrast computed tomography or diffusion-weighted magnetic resonance imaging.
• Eligible for endovascular therapy according to current guideline-recommended clinical practice and the judgment of the treating stroke team and neurointerventional team.
• Randomization can be completed between 6 and 24 hours after the time the participant was last known well. Randomization and initiation of the study intervention must not cause an avoidable delay in endovascular therapy.
• Pre-procedural computed tomography angiography or magnetic resonance angiography confirms large-vessel occlusion consistent with the participant's neurological deficits, involving one of the following: internal carotid artery or M1 segment of the middle cerebral artery.
• Baseline level of consciousness score on item 1a of the NIHSS is 0 or 1.
• Written informed consent has been obtained from the participant or the participant's legally authorized representative.

Критерии исключения

• General Exclusion Criteria

• NIHSS score of less than 10 at the time of randomization; substantial neurological improvement such that the participant is no longer considered eligible for endovascular therapy; or imaging-confirmed spontaneous recanalization with no remaining treatable target-vessel occlusion.
• Seizure at stroke onset when the current neurological deficits are considered primarily attributable to a postictal state, or when a reliable baseline NIHSS assessment cannot be obtained.
• Active clinically significant bleeding or a bleeding diathesis that, in the judgment of the investigator or treating clinical team, makes endovascular therapy or participation in the study unsafe.
• Platelet count below 100 × 10⁹/L.
• Clinically significant coagulation abnormality, anticoagulant exposure, or coagulation-factor deficiency that, according to the local standard of care at the participating center, makes the participant ineligible for endovascular therapy.
• Severe or end-stage cardiac, hepatic, or renal dysfunction that is expected to substantially affect 90-day survival, functional outcome assessment, or the safety of study participation.
• Persistent baseline blood glucose below 50 mg/dL (2.78 mmol/L) or above 400 mg/dL (22.20 mmol/L) after appropriate initial evaluation or correction.
• Persistent systolic blood pressure above 185 mmHg or diastolic blood pressure above 110 mmHg despite appropriate antihypertensive treatment.
• Life expectancy of less than 90 days because of a pre-existing disease or other underlying medical condition.
• Known pregnancy.
• Any of the following clinically significant respiratory diseases or conditions that, in the investigator's judgment, may make high-concentration oxygen therapy unsafe or interfere with reliable administration of the study intervention:chronic obstructive pulmonary disease; acute pulmonary infection; acute respiratory distress syndrome;clinically significant pleural effusion;chronic hypercapnic respiratory failure; another respiratory condition that may affect the safety of high-concentration oxygen therapy or the administration of the mask-based intervention.
• Any of the following conditions before randomization: requirement for supplemental oxygen at a flow rate greater than 3 L/min to maintain peripheral oxygen saturation above 94%;requirement for noninvasive ventilatory support because of respiratory failure; or requirement for invasive mechanical ventilation because of respiratory failure.
• Persistent clinically significant vital-sign instability after initial treatment, including but not limited to: heart rate of 50 beats per minute or lower or 120 beats per minute or higher; peripheral oxygen saturation of 90% or lower;respiratory rate of 10 breaths per minute or lower or 30 breaths per minute or higher; or other unstable vital signs considered by the investigator to potentially compromise participant safety.
• Active vomiting, a high risk of aspiration, or inability to tolerate the study mask, except for participants who require clinically indicated endotracheal intubation and mechanical ventilation.
• Active gastrointestinal bleeding.
• History of a severe adverse reaction to iodinated contrast media that cannot be adequately managed with premedication, an alternative contrast strategy, or other appropriate clinical measures and therefore precludes endovascular therapy.
• Current participation in another interventional clinical trial that may interfere with the study intervention, safety assessment, or evaluation of study outcomes.
• Any other disease, condition, or circumstance that, in the investigator's judgment, makes the participant unsuitable for the study or may interfere with study treatment, participant safety, or outcome assessment. The specific reason must be documented.
• Imaging Exclusion Criteria

• Evidence of intracranial hemorrhage on baseline computed tomography or magnetic resonance imaging, including but not limited to intraparenchymal hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, or epidural hemorrhage.
• Failure to meet the prespecified perfusion-mismatch imaging criteria, including an ischemic core volume of 70 mL or greater.
• Pre-randomization computed tomography angiography or magnetic resonance angiography demonstrates abnormal vascular anatomy or excessive vascular tortuosity such that, in the judgment of the treating neurointerventionalist, the target vessel cannot be safely accessed with endovascular devices or endovascular therapy is technically infeasible.
• Based on the medical history, computed tomography angiography, magnetic resonance angiography, or other imaging findings, any of the following is suspected to be the primary cause of the index stroke and is considered to make endovascular therapy inappropriate or unsafe: cerebral vasculitis; aortic dissection; cervical arterial dissection; or intracranial arterial dissection.
• Intracranial vascular occlusions involving multiple independent vascular territories, bilateral anterior-circulation infarction, or simultaneous anterior- and posterior-circulation infarction.

A tandem lesion consisting of cervical internal carotid artery occlusion together with an intracranial large-vessel occlusion in the same vascular territory will not be automatically excluded if the treating neurointerventionalist considers endovascular therapy appropriate.

• Confirmed moyamoya disease or moyamoya syndrome.
• Substantial cerebral edema, mass effect, or midline shift on baseline computed tomography or magnetic resonance imaging.
• Intracranial neoplasm that may affect the 90-day functional outcome, increase the risk of hemorrhage, or interfere with study assessment. A small, asymptomatic meningioma may be permitted at the investigator's discretion.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07717216 · OPENS-EXTEND

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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