Acute Ischemic Stroke
Conditions
Brief summary
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
http://www.proof-trial.eu/ European Union's Horizon 2020 research and innovation programme grant 733379 (2016): Euro 5.8 Mio
Interventions
DRUGMedical oxygen
inhalation of 100% oxygen at high flow via a sealed non-rebreather face-mask with reservoir
OTHERStandard of care
e.g. thrombectomy, thrombolysis
Sponsors
Coordination Centre for Clinical trials (KKS), 69120 Heidelberg, Germany
European Clinical Research Infrastructure Network (ECRIN), 10559 Berlin, Germany
CORE IMAGING LABORATORY: Eppdata GmbH, 22529 Hamburg, Germany
CORE BIOMARKER LABORATORY: Fundatio Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
University Hospital Tuebingen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ischemic core growth from baseline to 24 hours | from baseline to 24 (22 to 36) hours | difference in ischemic core volume (in mL) from baseline to 24 hours; intention-to-treat (ITT) analysis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| survival | 5 ± 2 days, 90 ± 10 days after randomization | secondary clinical efficacy endpoint; survival to be assessed at visit 6 (V6, day 5), and V7 (day 90) |
| National Institutes of Health Stroke Scale score (NIHSS) | 20 ± 10 minutes, 4 hours ± 15 minutes, 24 ± 6 hours, 5 ± 2 days, 90 ± 10 days after randomization | 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) |
| modified Rankin Scale score (mRS) | 5 ± 2 days, 90 ± 10 days after randomization | 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) |
| Barthel Index (BI) | 5 ± 2 days, 90 ± 10 days after randomization | secondary clinical efficacy endpoint; BI to be assessed at visit 6 (V6, day 5), and V7 (day 90) |
| all-cause death | 5 ± 2 days, 90 ± 10 days after randomization | clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90) |
| Montreal Cognitive Assessment (MoCA) | 90 ± 10 days after randomization | secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90) |
| Stroke Impact Scale 16 (SIS-16) | 90 ± 10 days after randomization | 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) |
| EuroQoL Questionnaire (EQ-5D-5L) | 90 ± 10 days after randomization | secondary clinical efficacy endpoint; EQ-5D-5L to be assessed at visit 7 (day 90) |
| Montgomery-Åsberg Depression Rating Scale (MADRS) | 90 ± 10 days after randomization | 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) |
| partial pressure of oxygen in the arterial blood (PaO2) | 90 ± 30 minutes, 24 ± 6 hours after randomization | secondary clinical efficacy endpoint; PaO2 to be assessed at visit 3 (90 minutes after start of study treatment), and V5 (24 hours) |
| length of ICU stay | 5 ± 2 days, 90 ± 10 days after randomization | 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) |
| length of hospital stay | 5 ± 2 days, 90 ± 10 days after randomization | secondary clinical efficacy endpoint; length of hospital stay to be assessed at visit 6 (V6, day 5), and V7 (day 90) |
| duration of ventilation | 5 ± 2 days, 90 ± 10 days after randomization | secondary clinical efficacy endpoint; duration of ventilation to be assessed at visit 6 (V6, day 5), and V7 (day 90) |
| stroke related death | 5 ± 2 days, 90 ± 10 days after randomization | clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90) |
| change in National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 hours | from baseline to 24 ± 6 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 |
| vital signs | 90 ± 10 days after randomization | clinical safety endpoint; systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2) |
| 12-lead electrocardiogram (ECG) | 24 ± 6 hours after randomization | clinical safety endpoint |
| safety laboratory | 5 ± 2 days after randomization or discharge | clinical safety endpoint; blood count, clinical chemistry, coagulation |
| concomitant invasive procedures | 90 ± 10 days after randomization | clinical safety endpoint; e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure |
| relative changes in ischemic core volume (in %) from baseline to 24 hours | from baseline to 24 (22 to 36) hours | secondary imaging efficacy endpoint |
| 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 | from baseline to 24 (22 to 36) hours | secondary imaging efficacy endpoint; independent of imaging modality |
| penumbral salvage from baseline to 24 hours | from baseline to 24 (22 to 36) hours | secondary imaging efficacy endpoint |
| TICI (Thrombolysis in Cerebral Infarction perfusion scale grade) | 4 hours ± 15 minutes | secondary imaging efficacy endpoint; in patients who underwent mechanical thrombectomy (TBY) |
| revascularization on 24-hour follow-up imaging | 24 (22 to 36) hours | secondary imaging efficacy endpoint |
| new microbleeds on 24-hour follow-up MRI (vs. baseline T2*weighted MRI) | 24 (22 to 36) hours | imaging safety endpoints; only possible in patients who had MRI at baseline as well as at 24 hours |
| any intracranial hemorrhage on 24-hour follow-up imaging | 24 (22 to 36) hours | imaging safety endpoints |
| peri-interventional occurrence of vasospasms | 4 hours ± 15 minutes | imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY) |
| ischemic lesions in new territories on 24-hour follow-up imaging | 24 (22 to 36) hours | imaging safety endpoints |
| symptomatic intracranial hemorrhage | 5 ± 2 days after randomization or discharge | clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification |
Countries
Belgium, Finland, France, Germany, Spain
Outcome results
None listed