Endovascular Treatment, Neuroprotection, Normobaric Hyperoxia, Stroke, Acute
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGOxygen (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 1.0 during the 4-hour intervention period. If clinically necessary for participant safety, FiO₂ may be gradually reduced; whenever clinically feasible, FiO₂ should be maintained at 0.8 or greater. All FiO₂ adjustments and their reasons will be documented. After completion of the 4-hour intervention, normobaric hyperoxia will be discontinued. Supplemental oxygen may subsequently be provided as clinically indicated to maintain peripheral oxygen saturation above 94%.
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 intubated participants, mechanical ventilation will be provided with FiO₂ initially set at 0.30. Peripheral oxygen saturation will be continuously monitored, and oxygen flow or FiO₂ may be increased as clinically necessary to maintain SpO₂ above 94%. After 4 hours, the sham intervention will be discontinued unless supplemental oxygen is clinically required.
PROCEDUREEndovascular 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.
Sponsors
Weifang Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years or older. 2. 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. 3. Pre-stroke modified Rankin Scale (mRS) score of 0 or 1. 4. Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6 or greater on baseline non-contrast computed tomography or diffusion-weighted magnetic resonance imaging. 5. Eligible for endovascular therapy according to current guideline-recommended clinical practice and the judgment of the treating stroke team and neurointerventional team. 6. 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. 7. 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. 8. Baseline level of consciousness score on item 1a of the NIHSS is 0 or 1. 9. Written informed consent has been obtained from the participant or the participant's legally authorized representative.
Exclusion criteria
* General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Distribution of Modified Rankin Scale Scores at 90 Days | 90 days after randomization, with an allowable visit window of ±14 days | The modified Rankin Scale is a 7-level ordinal scale assessing global disability after stroke, ranging from 0 (no symptoms) to 6 (death). The distribution of scores across all seven categories will be compared between the treatment groups using an ordinal shift analysis and reported as an adjusted common odds ratio with a 95% confidence interval. A common odds ratio greater than 1 will indicate a shift toward better functional outcomes in the NBO group. |
| All-Cause Mortality at 90 Days | Within 90 days after randomization | The proportion of participants who die from any cause within 90 days after randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Independence at 90 Days | 90 days after randomization, with an allowable visit window of ±14 days | The proportion of participants with a modified Rankin Scale score of 0 to 2. A score of 0 to 2 indicates functional independence. |
| Excellent Functional Outcome at 90 Days | 90 days after randomization, with an allowable visit window of ±14 days | The proportion of participants with a modified Rankin Scale score of 0 to 1. |
| Modified Rankin Scale Score of 0 to 3 at 90 Days | 90 days after randomization, with an allowable visit window of ±14 days | The proportion of participants with a modified Rankin Scale score of 0 to 3 |
| Barthel Index Score at 90 Days | 90 days after randomization, with an allowable visit window of ±14 days | The Barthel Index assesses independence in activities of daily living. The total score ranges from 0 to 100, with higher scores indicating greater functional independence. |
| EuroQol five dimensions questionnaire at 90 Days | 90 days after randomization, with an allowable visit window of ±14 days | The score ranges from 0 to 100, with 100 indicating optimal health |
| National Institutes of Health Stroke Scale Score | 24 hours and 7 days after randomization | Neurological impairment will be assessed using the National Institutes of Health Stroke Scale. The total score ranges from 0 to 42, with higher scores indicating greater neurological impairment. Scores at each time point will be analyzed separately. |
| Early Neurological Improvement at 24 Hours | 24 hours after randomization | The proportion of participants with early neurological improvement, defined as a reduction of at least 30% in the National Institutes of Health Stroke Scale score from baseline to 24 hours after randomization. |
| Length of Index Hospital Stay | From index hospital admission to hospital discharge, anticipated within 30 days | The total number of days from admission for the index stroke to discharge from the hospital. |
| Infarct Volume at 24 to 48 Hours | 24 to 48 hours after randomization | Final cerebral infarct volume, measured in milliliters using diffusion-weighted magnetic resonance imaging and assessed by the blinded imaging core laboratory. |
| Infarct Core Growth Ratio | Baseline and 24 to 48 hours after randomization | The infarct core growth ratio will be calculated as the infarct volume measured on diffusion-weighted magnetic resonance imaging at 24 to 48 hours divided by the baseline ischemic core volume. A higher ratio indicates greater infarct growth. |
| Successful Reperfusion at the End of Endovascular Therapy | Immediately after completion of endovascular therapy | The proportion of participants achieving successful reperfusion, defined as an expanded Treatment in Cerebral Ischemia grade of 2b, 2c, or 3, as assessed by the blinded imaging core laboratory. |
| Symptomatic Intracranial Hemorrhage | Within 24 to 48 hours after randomization | The proportion of participants with symptomatic intracranial hemorrhage according to the ECASS III definition, defined as imaging-confirmed intracranial hemorrhage associated with an increase of at least 4 points in the National Institutes of Health Stroke Scale score. |
| Any Intracranial Hemorrhage Within 24 Hours | Within 24 hours after randomization | The proportion of participants with any intracranial hemorrhage detected by follow-up computed tomography or magnetic resonance imaging, regardless of neurological deterioration. |
| Early Neurological Deterioration | Within 24 to 48 hours after randomization | The proportion of participants with early neurological deterioration, defined as an increase of at least 4 points in the National Institutes of Health Stroke Scale score compared with baseline. |
| Stroke-Related Mortality at 90 Days | Within 90 days after randomization | The proportion of participants who die from the index stroke or its direct neurological complications within 90 days after randomization. The cause of death will be adjudicated by an independent clinical event committee masked to treatment assignment. |
| Incidence of Adverse Events | Within 7 days after randomization | he proportion of participants experiencing at least one adverse event during the first 7 days after randomization. Prespecified events include oxygen-related adverse events, pulmonary infection, deep-vein thrombosis, procedural complications, vessel reocclusion, and other clinically significant events. |
| Incidence of Serious Adverse Events | Within 7 days after randomization | The proportion of participants experiencing at least one serious adverse event according to the protocol-defined seriousness criteria. |
Contacts
CONTACTWeili Li, MD
Outcome results
None listed