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

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

Study Overview

• Status: Recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Intravenous thrombolysis(rt-PA); Procedure: Normobaric Hyperoxia; Procedure: Nasal oxygen

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 1230
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Xunming Ji, MD. PhD; Phone Number: +86010-83199430; Email: jixm@ccmu.edu.cn
• Study Contact Backup: Name: Hetao Bian, MD.PhD; Phone Number: +8618266806812; Email: hetaobian@163.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Xuan Wu Hospital，Capital Medical University
    • Contact: Xunming Ji, MD. PhD; Phone Number: 861013120136877; Email: jixunming@vip.163.com
    • Principal Investigator: Xunming Ji, MD. PhD Xuanwu Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age≥18 years;
2. The time from onset to randomization is within 4.5 hours of onset;
3. The clinical diagnosis is acute ischemic stroke (the criteria followed the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2018);
4. Baseline NIHSS (at the time of randomization) should be ≥5 and ≤25 points;
5. Pre-stroke mRS score≤1 points;
6. Informed consent from the patient or surrogate.

Exclusion Criteria:

1. Intracranial hemorrhage (including parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural/extradural hematoma, etc.);
2. Past history of intracranial hemorrhage;
3. Rapid neurological function improvement, NIHSS score less than 5 points;
4. 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);
5. 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);
6. Intended to proceed endovascular treatment;
7. Pregnant women, or planning to become pregnant during the trial;
8. A history of severe head trauma or stroke within 3 months;
9. A history of intracranial or spinal surgery within 3 months;
10. A history of gastrointestinal or urinary bleeding within 3 weeks;
11. two weeks of major surgery;
12. Arterial puncture was performed at the hemostasis site that was not easily compressed within 1 week;
13. Active visceral bleeding;
14. Intracranial tumors, large intracranial aneurysms;
15. Aortic arch dissection was found;
16. Severe, sustained hypertension (Systolic Blood Pressure >185 mmHg or Diastolic Blood Pressure >110 mmHg);
17. Baseline blood glucose of <50mg/dL (2.78 mmol) or >400mg/dL (22.20 mmol);
18. Oral warfarin anticoagulant with international normalized ratio(INR)>1.7 or prothrombin time(PT)>15 s;
19. Heparin treatment was received within 24 h;
20. Thrombin inhibitors or factor Xa inhibitors were used within 48 h;
21. Propensity for acute bleeding, including platelet counts of less than 100×109/ L or otherwise;
22. Hereditary or acquired bleeding constitution;
23. Onset with seizures;
24. Severe liver and kidney dysfunction;
25. Active and chronic obstructive pulmonary disease or acute respiratory distress syndrome;
26. Patients with anemia or polycythemia vera or other situations that require urgent oxygen inhalation;
27. Patients with upper gastrointestinal bleeding or nausea or vomiting so that they cannot cooperate with the mask to inhale oxygen;
28. Life expectancy < 1 year;
29. Patients who could not complete the 90-day follow-up;
30. Participation in other clinical trials within 3 months prior to screening;
31. Unsuitability or participation in this study as judged by the Investigator may result in subjects being exposed to greater risk.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NBO group; Normobaric Hyperoxia combined with intravenous thrombolysis	Drug: Intravenous thrombolysis(rt-PA); 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.; Procedure: Normobaric Hyperoxia; 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.
Placebo Comparator: Control group; Nasal oxygen combined with intravenous thrombolysis	Drug: Intravenous thrombolysis(rt-PA); 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.; Procedure: Nasal oxygen; 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%.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Utility-weighted modified Rankin scale scores	Utility-weighted modified Rankin scale scores	90±7 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
PaCO2 of arterial blood gas analysis	Safety endpoint	after 4 hours of oxygen therapy
Cerebral infarct volume	The infarct volume of cerebral infarct is evaluated by MRI	24-48hours 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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Ji Xunming,MD,PhD
• Collaborators: The First Affiliated Hospital of Anhui Medical University; Beijing Friendship Hospital; Shandong Provincial Hospital; Beijing Tongren Hospital; The First Affiliated Hospital of Soochow University; The First Affiliated Hospital of Zhengzhou University; Beijing Shijitan Hospital, Capital Medical University; Guizhou Provincial People's Hospital; Second Affiliated Hospital of Nanchang University; The Affiliated Hospital of Xuzhou Medical University; Chengde Central Hospital; The Second Hospital of Anhui Medical University; Liaocheng People's Hospital; Nanyang Central Hospital; Affiliated Hospital of Nantong University; Jiangxi Provincial People's Hopital; Linyi People's Hospital; Tianjin Huanhu Hospital; Changsha Central Hospital; People's Hospital of Beijing Daxing District; Zhumadian Central Hospital; Rizhao People's Hospital; Jiujiang University Affiliated Hospital; Jining First People's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2023
• Primary Completion (Estimated): August 30, 2024
• Study Completion (Estimated): October 30, 2024

Study Registration Dates

• First Submitted: June 7, 2023
• First Submitted That Met QC Criteria: July 20, 2023
• First Posted (Actual): July 28, 2023

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Hyperoxia
• Other Study ID Numbers: OPENS-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No