Penumbral Rescue by Normobaric O2 Administration in Patients With Ischemic Stroke and Target Mismatch ProFile

Study Overview
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Brief Summary
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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.

Detailed Description
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http://www.proof-trial.eu/ European Union's Horizon 2020 research and innovation programme grant 733379 (2016): Euro 5.8 Mio

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

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: Medical oxygen
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age: >= 18 years Acute anterior circulation ischemic stroke due to an LVO on CT or MR angiography, i.e. either terminal ICA with M1/carotid-T, proximal M1, distal M1 (distal to perforating branches), or M2/3 segment(s) If TBY is likely to be conducted* (*However, neither TBY nor IVT are a prerequisite for inclusion; patients not receiving TBY or IVT or both can be enrolled. Clinical treatment decisions should not delay study enrollment). NIHSS score of ≥ 6 at screening ASPECTS of 7-10 on NCCT or 6-10 on DWI-MRI CT or MR perfusion (whole-brain or minimal coverage ≥ 75 mm) prior to NBHO NBHO can be initiated within 6 hours of symptom onset (witnessed or last seen well) and within 30 minutes after last image of baseline brain imaging Pre-stroke mRS of 0 or 1 Breastfeeding women must stop breastfeeding after randomization 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: TBY procedure initiated (groin puncture) prior to randomization Rapid major improvement in neurological status prior to randomization Any condition which precludes obtaining an accurate baseline NIHSS or outcome assessment (e.g. seizures, dementia, psychiatric or neuromuscular disease) Intracranial hemorrhage (except of cerebral microbleeds), intracranial tumor (except small meningioma), and/or intracranial arteriovenous malformation Intracranial aneurysm or prior stent implantation in the vascular territory (upstream and downstream) affected by qualifying LVO Suspected complete CCA occlusion, aortic dissection, cerebral vasculitis, septic embolism, or bacterial endocarditis Acute bilateral stroke or stroke in multiple vascular territories (except of clinically silent micro-lesions) Respiratory: Known history of chronic pulmonary disease (e.g. COPD, pulmonary fibrosis, alveolitis or pneumonitis) Prior to enrolment, > 2 L/min oxygen required to maintain peripheral oxygen saturation ≥ 95% Acute respiratory distress that may, in the clinical judgment of the investigator, interfere with the study intervention Acute pneumonia, alveolitis or pneumonitis of viral, bacterial, fungal or any other etiology Other: Clinical suspicion of acute myocardial infarction (e.g. acute chest pain) Baseline blood glucose of < 50 mg/dL (2.78 mmol) or > 400 mg/dL (22.20 mmol) Body temperature ≥ 38.0°C at screening History of severe allergy (more than rash) to contrast medium Current treatment with nitrofurantoin or amiodaron, paraquat poisoning, or history of treatment with bleomycin Pregnancy at screening, to be excluded (β-HCG in serum or urine) in all women ≤ 55 years except if surgically sterile; in women >55 years pregnancy must be excluded only in case of increased probability e.g. due to in-vitro fertilization Any co-existing or terminal disease (except qualifying stroke) 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. alcohol or substance abuse, co-existing disease) Participation in another interventional (drug or device) study within the last four weeks Prior participation in the PROOF trial

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: Normobaric hyperoxygenation + standard of care<br>Normobaric hyperoxygenation (NBHO), i.e. inhalation of 100% oxygen at high flow (≥ 40 L/min) via a sealed non-rebreather face-mask with reservoir, or in case of intubation/ventilation for (study-independent) TBY, ventilation with an inspiratory oxygen fraction (FiO2) of 1.0. NBHO is started within 3 hours of stroke symptom onset (witnessed or last seen well) and within 20 minutes after end of baseline brain imaging and applied until the end of TBY procedure (defined by removal of guide catheter from sheath) or, in case TBY is not attempted, 4 hours after start of study treatment. | Drug: Medical oxygen<br>* inhalation of 100% oxygen at high flow via a sealed non-rebreather face-mask with reservoir<br>Other: Standard of care<br>* e.g. thrombectomy, thrombolysis<br>|
| Active Comparator: standard of care alone<br>standard of care alone; oxygen supplementation if SpO2 ≤ 94% at 2 to 4 L/min via nasal cannula according to guidelines of the European Stroke Organisation (ESO), or in case of TBY-related intubation/ventilation, ventilation with an initial FiO2 of 0.3 to be gradually increased if SpO2 ≤ 94%. | Other: Standard of care<br>* e.g. thrombectomy, thrombolysis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ischemic core growth from baseline to 24 hours | difference in ischemic core volume (in mL) from baseline to 24 hours; intention-to-treat (ITT) analysis | from baseline to 24 (22 to 36) hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 hours | key secondary endpoint; the NIHSS is a stroke severity score that is composed of 11 items; range from 0 to 41, higher values indicate more severe deficits | from baseline to 24 ± 6 hours | 
| survival | secondary clinical efficacy endpoint; survival to be assessed at visit 6 (V6, day 5), and V7 (day 90) | 5 ± 2 days, 90 ± 10 days after randomization | 
| National Institutes of Health Stroke Scale score (NIHSS) | secondary clinical efficacy endpoint; NIHSS to be assessed at visit 2 (V2, 20 minutes), V4 (end of study treatment), V5 (24 hours), V6 (day 5), and V7 (day 90); the NIHSS is a stroke severity score composed of 11 items (range from 0 to 41, higher values indicate more severe deficits) | 20 ± 10 minutes, 4 hours ± 15 minutes, 24 ± 6 hours, 5 ± 2 days, 90 ± 10 days after randomization | 
| modified Rankin Scale score (mRS) | secondary clinical efficacy endpoint; mRS to be assessed at visit 6 (V6, day 5), and V7 (day 90); the mRs is an ordinal disability score of 7 categories (0 = no symptoms to 5 = severe disability, and 6 = death) | 5 ± 2 days, 90 ± 10 days after randomization | 
| Barthel Index (BI) | secondary clinical efficacy endpoint; BI to be assessed at visit 6 (V6, day 5), and V7 (day 90) | 5 ± 2 days, 90 ± 10 days after randomization | 
| Montreal Cognitive Assessment (MoCA) | secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90) | 90 ± 10 days after randomization | 
| Stroke Impact Scale 16 (SIS-16) | secondary clinical efficacy endpoint; SIS-16 to be assessed at visit 7 (day 90); the SIS-16 is a 16-item physical dimension instrument for measuring the physical aspects of stroke recovery (items are rated on a 1 to 5 scale; 5 = not difficult at all, 1 = could not do at all) | 90 ± 10 days after randomization | 
| EuroQoL Questionnaire (EQ-5D-5L) | secondary clinical efficacy endpoint; EQ-5D-5L to be assessed at visit 7 (day 90) | 90 ± 10 days after randomization | 
| Montgomery-Åsberg Depression Rating Scale (MADRS) | secondary clinical efficacy endpoint; MADRS to be assessed at visit 7 (day 90); the MADRS is a 10-item depression rating test that uses a 0 to 6 severity scale (higher scores indicate increasing depressive symptoms) | 90 ± 10 days after randomization | 
| partial pressure of oxygen in the arterial blood (PaO2) | secondary clinical efficacy endpoint; PaO2 to be assessed at visit 3 (90 minutes after start of study treatment), and V5 (24 hours) | 90 ± 30 minutes, 24 ± 6 hours after randomization | 
| length of ICU stay | secondary clinical efficacy endpoint; length of ICU stay to be assessed at visit 6 (V6, day 5), and V7 (day 90); ICU is defined as a ward with capacity for mechanical ventilation and/or continuous monitoring of vital parameters (including stroke units) | 5 ± 2 days, 90 ± 10 days after randomization | 
| length of hospital stay | secondary clinical efficacy endpoint; length of hospital stay to be assessed at visit 6 (V6, day 5), and V7 (day 90) | 5 ± 2 days, 90 ± 10 days after randomization | 
| duration of ventilation | secondary clinical efficacy endpoint; duration of ventilation to be assessed at visit 6 (V6, day 5), and V7 (day 90) | 5 ± 2 days, 90 ± 10 days after randomization | 
| all-cause death | clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90) | 5 ± 2 days, 90 ± 10 days after randomization | 
| stroke related death | clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90) | 5 ± 2 days, 90 ± 10 days after randomization | 
| symptomatic intracranial hemorrhage | clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification | 5 ± 2 days after randomization or discharge | 
| vital signs | clinical safety endpoint; systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2) | 90 ± 10 days after randomization | 
| 12-lead electrocardiogram (ECG) | clinical safety endpoint | 24 ± 6 hours after randomization | 
| safety laboratory | clinical safety endpoint; blood count, clinical chemistry, coagulation | 5 ± 2 days after randomization or discharge | 
| concomitant invasive procedures | clinical safety endpoint; e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure | 90 ± 10 days after randomization | 
| relative changes in ischemic core volume (in %) from baseline to 24 hours | secondary imaging efficacy endpoint | from baseline to 24 (22 to 36) hours | 
| absolute and relative ischemic core change from baseline to 24 hours using cerebral blood flow (CBF) < 30% for ischemic core estimation at baseline in all patients | secondary imaging efficacy endpoint; independent of imaging modality | from baseline to 24 (22 to 36) hours | 
| penumbral salvage from baseline to 24 hours | secondary imaging efficacy endpoint | from baseline to 24 (22 to 36) hours | 
| TICI (Thrombolysis in Cerebral Infarction perfusion scale grade) | secondary imaging efficacy endpoint; in patients who underwent mechanical thrombectomy (TBY) | 4 hours ± 15 minutes | 
| revascularization on 24-hour follow-up imaging | secondary imaging efficacy endpoint | 24 (22 to 36) hours | 
| new microbleeds on 24-hour follow-up MRI (vs. baseline T2*weighted MRI) | imaging safety endpoints; only possible in patients who had MRI at baseline as well as at 24 hours | 24 (22 to 36) hours | 
| any intracranial hemorrhage on 24-hour follow-up imaging | imaging safety endpoints | 24 (22 to 36) hours | 
| peri-interventional occurrence of vasospasms | imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY) | 4 hours ± 15 minutes | 
| ischemic lesions in new territories on 24-hour follow-up imaging | imaging safety endpoints | 24 (22 to 36) hours |