Normobaric Hyperoxia Combined With Intravenous Thrombolysis for Acute Ischemic Stroke (OPENS-3)

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of Normobaric Hyperoxia combined with intravenous thrombolysis for acute ischemic stroke.

Detailed Description
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In this study, cases of acute ischemic stroke who undergo intravenous thrombolysis within 4.5 hours from onset are included. The Normobaric Hyperoxia(NBO) group receive basic intravenous thrombolysis and given 100% oxygen inhalation at a ventilation rate of 10L/ min using a sealed non-ventilating oxygen storage mask and keep giving oxygen for 4 hours. The control group receive basic intravenous thrombolysis and given oxygen inhalation at a ventilation rate of 1L/min using nasal cannula and keep giving oxygen for 4 hours. The investigators aimed to determine the efficacy and safety of Normobaric Hyperoxia combined with intravenous thrombolysis for acute ischemic stroke.

Official Title
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Normobaric Hyperoxia Combined With Intravenous Thrombolysis for Acute Ischemic Stroke (OPENS-3)

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Procedure: Normobaric Hyperoxia
* Procedure: Nasal oxygen
* Drug: Intravenous thrombolysis(rt-PA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥18 years; The time from onset to randomization is within 4.5 hours of onset; The clinical diagnosis is acute ischemic stroke (the criteria followed the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2018); Baseline NIHSS (at the time of randomization) should be ≥5 and ≤25 points; Pre-stroke mRS score≤1 points; Informed consent from the patient or surrogate. Exclusion Criteria: Intracranial hemorrhage (including parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural/extradural hematoma, etc.); Past history of intracranial hemorrhage; Rapid neurological function improvement, NIHSS score less than 5 points; Presence of proximal arterial occlusion on computed tomographic angiography(CTA)/magnetic resonance angiography(MRA) (e.g., intracranial internal carotid artery(ICA), middle cerebral artery(MCA)-M1, and vertebrobasilar arteries); Massive anterior cerebral infarction identified by CT or MRI (ASPECT < 6 or lesions larger than one third of the territory of the middle cerebral artery); Intended to proceed endovascular treatment; Pregnant women, or planning to become pregnant during the trial; A history of severe head trauma or stroke within 3 months; A history of intracranial or spinal surgery within 3 months; A history of gastrointestinal or urinary bleeding within 3 weeks; two weeks of major surgery; Arterial puncture was performed at the hemostasis site that was not easily compressed within 1 week; Active visceral bleeding; Intracranial tumors, large intracranial aneurysms; Aortic arch dissection was found; Severe, sustained hypertension (Systolic Blood Pressure >185 mmHg or Diastolic Blood Pressure >110 mmHg); Baseline blood glucose of <50mg/dL (2.78 mmol) or >400mg/dL (22.20 mmol); Oral warfarin anticoagulant with international normalized ratio(INR)>1.7 or prothrombin time(PT)>15 s; Heparin treatment was received within 24 h; Thrombin inhibitors or factor Xa inhibitors were used within 48 h; Propensity for acute bleeding, including platelet counts of less than 100×109/ L or otherwise; Hereditary or acquired bleeding constitution; Onset with seizures; Severe liver and kidney dysfunction; Active and chronic obstructive pulmonary disease or acute respiratory distress syndrome; Patients with anemia or polycythemia vera or other situations that require urgent oxygen inhalation; Patients with upper gastrointestinal bleeding or nausea or vomiting so that they cannot cooperate with the mask to inhale oxygen; Life expectancy < 1 year; Patients who could not complete the 90-day follow-up; Participation in other clinical trials within 3 months prior to screening; Unsuitability or participation in this study as judged by the Investigator may result in subjects being exposed to greater risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NBO group<br>Normobaric Hyperoxia combined with intravenous thrombolysis | Procedure: Normobaric Hyperoxia<br>* Within 4.5 hours after stroke onset, patients were randomized into the NBO group and immediately given 100% oxygen inhalation (no more than 30 minutes after randomization) at a ventilation rate of 10L/ min using a sealed non-ventilating oxygen storage mask and keep giving oxygen for 4 hours. If the patient needs to be intubated with a ventilator to maintain ventilation, the FiO2 should be set to 1.0.<br>Drug: Intravenous thrombolysis(rt-PA)<br>* 10% dose of rt-PA (0.9 mg/kg) is given as bolus and the rest given as an infusion over the remaining 1 hour. Maximum dose 90mg.<br>|
| Placebo Comparator: Control group<br>Nasal oxygen combined with intravenous thrombolysis | Procedure: Nasal oxygen<br>* For nasal oxygen group, patients were immediately given oxygen inhalation (no more than 30 minutes after randomization) at a ventilation rate of 1L/min using nasal cannula and keep giving oxygen for 4 hours. If the patient needs to be intubated with a ventilator to maintain, the FiO2 should be set to 0.3 and gradualy incerased if spO2≤94%.<br>Drug: Intravenous thrombolysis(rt-PA)<br>* 10% dose of rt-PA (0.9 mg/kg) is given as bolus and the rest given as an infusion over the remaining 1 hour. Maximum dose 90mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Excellent functional outcome | Proportion of subjects with modified Rankin Scale(mRS) 0-1 at 90±7 days after randomization;mRS score ranges from 0 to 5, and the higher score means a worse outcome | 90±7 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral infarct volume | The infarct volume of cerebral infarct is evaluated by MRI | 24-48hours after randomization | 
| modified rankin scale (mRS) score | Ordinal distribution of mRS at 90±7 days after randomization;mRS score ranges from 0 to 5, and the higher score means a worse outcome | 90±7 days after randomization | 
| Good functional outcome | Proportion of subjects with modified rankin scale (mRS) 0-2 at 90±7 days after randomization;mRS score ranges from 0 to 5, and the higher score means a worse outcome | 90 ± 7 days after randomization | 
| Proportion of subjects with modified rankin scale (mRS) 0-3 | Proportion of subjects with mRS 0-3 at 90±7 days after randomization;mRS score ranges from 0 to 5, and the higher score means a worse outcome | 90 ± 7 days after randomization | 
| Scores assessed by National Institutes of Health Stroke Scale(NIHSS) | Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits | 4 ± 2 hours, 24 ± 6 hours, 72 ± 24 hours, 7 ± 2 days after randomization | 
| The proportion of neurological function improvement | ≥ 4 point reduction in National Institutes of Health Stroke Scale (NIHSS) score from baseline at 24 ± 6 hours after randomization;NIHSS score ranges from 0 to 42, and higher scores mean a worse outcome | 24 ± 6 hours after randomization | 
| Proportion of subjects with modified rankin scale (mRS) 0-1 | Proportion of subjects with mRS 0-1 at 30±7 days after randomization;mRS score ranges from 0 to 5, and the higher score means a worse outcome | 30 ± 7 days after randomization | 
| Barthel Index (BI) | The BI is an ordinal disability score of 10 categories (range from 0 to 100, higher values indicate better prognosis) | 30 ± 7 days,90 ± 7 days after randomization | 
| EuroQol five dimensions questionnaire（EQ-5D） | The score ranges from 0 to 100, with higher scores indicating optimal health | baseline before randomization,7 ± 2 days,30 ± 7 days,90 ± 7 days after randomization | 
| Days of hospitalization | Length of stay in hospital | 30 ± 7 days after randomization | 
| Stroke-related mortality | Safety endpoint; the proportion of stroke related deaths in each group | 90 ± 7 days after randomization | 
| All-cause mortality | Safety endpoint; the proportion of all patients who died in each group | 90 ± 7 days after randomization | 
| Symptomatic intracranial hemorrhage | Proportion of subjects with symptomatic intracranial hemorrhage at 24 ± 6 hours after randomization (defined by ECASSII and ECASS III) | 24 ± 6 hours after randomization | 
| Asymptomatic intracranial hemorrhage | The incidence of asymptomatic intracranial hemorrhage at 24 ± 6 hours after randomization | 24 ± 6 hours after randomization | 
| PH2 intracranial hemorrhage | The incidence of PH2 intracranial hemorrhage at 24 ± 6 hours after randomization (according to SITS standards) | 24 ± 6 hours after randomization | 
| Any intracranial hemorrhage | The incidence of any intracranial hemorrhage at 24 ± 6 hours after randomization | 24 ± 6 hours after randomization | 
| Systematic bleeding | The incidence of systematic bleeding at 24 ± 6 hours after randomization | 24 ± 6 hours after randomization | 
| Early neurological deterioration | Safety endpoint; defined as ≥4 point increase in National Institutes of Health Stroke Scale (NIHSS) score from baseline;NIHSS score ranges from 0 to 42, and higher scores mean a worse outcome | 24 ± 6 hours after randomization | 
| Oxygen-related adverse events | Safety endpoint; the proportion of oxygen-related adverse events in each group, including severe lung infection, pneumothorax, atelectasis, respiratory failure, acute respiratory distress syndrome, and cardiopulmonary arrest | 90 ± 7 days after randomization | 
| Adverse events/serious adverse events | Safety endpoint; the proportion of adverse events/serious adverse events in each group | 24 ± 12 hours, 7 ± 2 days, 90± 7 days after randomization | 
| PaO2 of arterial blood gas analysis | Safety endpoint | after 4 hours of oxygen therapy | 
| PaCO2 of arterial blood gas analysis | Safety endpoint | after 4 hours of oxygen therapy | 
| Potential of hydrogen(PH) of arterial blood gas analysis | Safety endpoint | after 4 hours of oxygen therapy | 
| Concentration of Lactic acid of arterial blood gas analysis | Safety endpoint | after 4 hours of oxygen therapy | 
| Systolic and diastolic blood pressure | Safety endpoint; vital signs | 24 ± 6 hours after randomization | 
| Heart rate | Safety endpoint; vital signs | 24 ± 6 hours after randomization | 
| Respiratory rate | Safety endpoint; vital signs | 24 ± 6 hours after randomization | 
| Oxygen saturation | Safety endpoint; vital signs | 24 ± 6 hours after randomization | 
| Unit costs | Unit costs will be attached to resource use, patient-reported and from hospital records after randomization, to obtain a cost per patient over the period of follow-up | 7 ± 2 days, 30 ± 7 days,90 ± 7 days after randomization |