Imbalance in deaths favoring control arm; deaths not attributed to treatment by the blinded external medical monitor.

The purpose of this study is to compare the safety and efficacy of treating individuals with acute ischemic stroke with normobaric oxygen therapy (NBO, given within 9 hours of symptom onset), to standard medical treatment.

Stroke is the third leading cause of death and the leading cause of disability in the United States. Ischemic stroke is caused by a blockage of blood flow to one or more brain arteries, usually due to a blood clot. As a result there is a reduced supply of oxygen and other nutrients leading to permanent brain damage. Normobaric oxygen therapy (NBO, or high-flow oxygen delivered via a facemask) shows promise as a simple, widely accessible, low-cost therapy that can prevent stroke-related brain damage and extend the time window for administering the clot-busting drug t-PA (tissue plasminogen activator), which is the only acute stroke treatment approved by the Food and Drug Administration.

The primary goal of this trial is to compare the safety and therapeutic efficacy of NBO (started within 9 hours of symptom onset) to standard medical treatment with Room Air. We aim to enroll a total of 240 individuals with acute ischemic stroke less than 9 hours after symptom onset, at the Massachusetts General and Brigham and Women's Hospitals in Boston. Participants will be randomly selected to receive either room air (RA, control) or NBO (active treatment) at flow rates of 30-45L/min administered via a face mask for 8 hours. Neurological function scores and neuroimaging [magnetic resonance imaging (MRI) or computed tomography (CT) scans] will be obtained before, during, and after therapy until 90 days.

This study is part of the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS), which allows researchers to enhance and initiate translational research that ultimately will benefit individuals with stroke.

Inclusion Criteria:

• Age greater than or equal to 18 years.
• Acute ischemic stroke in whom treatment can potentially be started within 9 hours after symptom onset. If the symptom onset time is unknown, the time of onset will be defined as the midpoint between the time when the subject was last seen neurologically intact, and when found to have a neurological deficit.
• National Institutes of Health Stroke Scale (NIHSS) score 4 or greater.

Exclusion Criteria:

• Patients being actively considered for intravenous or intra-arterial thrombolysis will be excluded.
• Patients likely to have acute stroke intervention such as carotid endarterectomy or stent or angioplasty, hemicraniectomy, etc.
• Rapidly improving neurological deficits (transient ischemic attack).
• Known history of severe chronic obstructive pulmonary disease (Forced Expiratory Vital Capacity less than 1.0 or oxygen dependent).
• More than 3 L/min oxygen required to maintain peripheral arterial oxygen saturation above 92%.
• New York Heart Association Class III heart failure.
• Endotracheal intubation prior to enrollment or impending need for artificial ventilation.
• Coma (National Institutes of Health Stroke Scale item 1a score of 3).
• Suspected seizure at or after onset of stroke, or a known active seizure disorder.
• Blood glucose below 50 mg/dL or greater than 250 mg/dL prior to enrollment.
• Concurrent severe non-stroke medical illness requiring admission to a non-neurological intensive care unit
• Expected survival less than 90 days.
• Any condition that might limit neurological assessment or follow-up in the opinion of the investigator.
• Pre-menopausal women with a positive pregnancy blood test performed at admission.
• Inability to obtain consent from the patient or legally authorized representative.
• Active participation in another intervention study (e.g. investigational drug trial).
• Proven alternate etiology for stroke-like symptoms.

AEs were collected until the final visit at 3 months (range, 75-110 days). All deaths until day 110 were included.

Total 24 deaths: 7 RA, 17 NBO. The blinded external medical monitor did not adjudicte any death as "definitely" or "probably" related to therapy. One death in each arm was adjudicated as "possibly" related to therapy; 6 deaths in the Room Air arm and 16 deaths in the NBO arm, were adjudicated as "unlikely or unrelated" to therapy.

Early termination leading to small numbers of subjects analyzed.