PROOF: "Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile: A Phase II Proof-of-Concept Trial"

Study Objective:

The main objective of the PROOF trial is to investigate efficacy and safety of normobaric hyperoxygenation (NBHO) as a neuroprotective treatment in patients with acute ischemic stroke due to large vessel occlusion likely to receive endovascular mechanical thrombectomy (TBY) in a randomized controlled clinical phase IIb trial.

The experimental arm will be : normobaric hyperoxygenation + standard of care while the active comparator arm will be standard of care alone.

Participation conditions:

Inclusion criteria:

• Age: male patients: 18 to 80 years, female patients: 50 to 80 years
• Clinical signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke
• LVO on CT angiography or MR angiography consistent with clinical signs and symptoms, i.e. either the terminal ICA with involvement of the M1-segment of the MCA/carotid-T, the proximal M1-segment, or the distal M1-segments (distal to perforating branches)
• NIHSS score of ≥ 6 at screening
• NIHSS item 1a (level of consciousness) of 0 or 1
• Alberta Stroke Program Early CT score (ASPECTS) of 7-10 on non-contrast CT or 6-10 on diffusion-weighted MRI (DWI-MRI)
• CT perfusion (preferably whole-brain, minimal coverage ≥ 75 mm) or MR perfusion imaging performed prior to NBHO
• NBHO can be initiated within 3 hours of certain stroke symptom onset (witnessed or last seen well) and within 20 minutes after end of baseline brain imaging
• Pre-stroke mRS of 0 or 1
• Due to the emergency situation in which patients are enrolled and the presumed safety of the IMP as applied in the PROOF trial, their own written informed consent is not obtained prior to study inclusion but has to be gained as soon as possible. Patients who are able to give consent will be informed about trial participation orally and may consent to or decline participation. Patients unable to give consent will be enrolled through a deferred consent procedure

Exclusion criteria

Neurological:

• Rapid improvement in neurological status to an NIHSS < 6 or evidence of vessel recanalization prior to randomization
• Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment
• Acute neurological symptoms related to other pathology than ischemic stroke
• Evidence of intracranial hemorrhage (except of cerebral microbleeds), intracranial tumor (except small meningioma), and/or intracranial arteriovenous malformation as confirmed by baseline brain imaging
• Intracranial aneurysm or prior stent implantation in the vascular territory (upstream and downstream) affected by qualifying LVO
• TBY procedure initiated (groin puncture) prior to randomization
• Previously known or CT angiographic / MR angiographic visualization of ipsilateral high-grade stenosis, complete cervical carotid occlusion, or flow-limiting carotid dissection
• Suspected aortic dissection or cerebral vasculitis based on medical history or CT angiography / MR angiography
• Clinical or imaging evidence of acute bilateral stroke or stroke in other vascular territories than qualifying LVO (except of clinically silent micro-DWI lesions in patients who received MR-based acute brain imaging)
• Significant mass effect with midline shift as confirmed by brain imaging
• Any co-existing neurological (especially neuromuscular) disorder

Respiratory:

• Known history of chronic pulmonary disease (e.g. COPD, pulmonary fibrosis) or any condition leading to hypoxic respiratory drive (e.g. neuromuscular disease)
• Prior to enrolment, > 2 L/min oxygen required to maintain peripheral oxygen saturation ≥ 95% or acute respiratory distress that may, in the clinical judgment of the investigator, interfere with the study intervention
• Endotracheal intubation at time of screening or anticipated intubation for other reasons than TBY procedure

Other:

• Clinical suspicion of acute myocardial infarction (e.g. pressure or tightness in the chest, pain in the chest, back, jaw, and other areas of the upper body that lasts more than a few minutes or that goes away and comes back, shortness of breath)
• Baseline blood glucose of < 50 mg/dL (2.78 mmol) or > 400 mg/dL (22.20 mmol)
• Body temperature ≥ 38.0°C at screening
• Presumed septic embolus, or suspicion of bacterial endocarditis
• History of severe allergy (more than rash) to contrast medium
• Current treatment with nitrofurantoin or amiodaron, paraquat poisoning, or history of treatment with bleomycin
• Women of childbearing age, i.e. < 50 years as defined by World Health Organization
• Any co-existing or terminal disease with anticipated life expectancy of less than 6 months
• Any pre-existing condition that may, in the clinical judgment of the investigator, not allow safe participation in the study (e.g. substance abuse, co-existing disease) or would complicate assessment of outcomes (e.g. dementia, psychiatric disease) or would confound the neurological or functional evaluations (e.g. dementia)
• Participation in another interventional (drug or device) study within the last four weeks
• Prior participation in the PROOF trial (no subject will be allowed to enroll in this trial more than once).

Coordinating PI:

Sven Poli MD, University Hospital Tübingen, Germany

Participating centers in Belgium:

UZ Leuven, UZ Gent, AZ St Jan Brugge, AZ Groeninge Kortrijk