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

Phase 2TerminatedNCT03500939

University Hospital Tuebingen223 enrolled

Overview

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.

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

223

Conditions

Acute Ischemic Stroke

Interventions

Medical oxygenDRUG

inhalation of 100% oxygen at high flow via a sealed non-rebreather face-mask with reservoir

Standard of careOTHER

e.g. thrombectomy, thrombolysis

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (22)

UZ Gent

Ghent, Belgium

AZ Groeninge Kortrijk

Kortrijk, Belgium

Outcomes

Primary Outcomes

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

Time frame: from baseline to 24 (22 to 36) hours

Secondary Outcomes

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

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Data from ClinicalTrials.gov

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KU Leuven

Leuven, Belgium

CHU de Liège

Liernu, Belgium

Helsinki University Hospital

Helsinki, Finland

CHU de Grenoble

Grendelbruch, France

CHU de Nancy

Nancy, France

CHU de Nice

Nice, France

Centre Hospitalier Saint Anne de Paris

Paris, France

Fondation Ophtalmologique Adolphe de Rothschild

Paris, France

...and 12 more locations

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 5 ± 2 days, 90 ± 10 days after randomization

symptomatic intracranial hemorrhage

clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification

Time frame: 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)

Time frame: 90 ± 10 days after randomization

12-lead electrocardiogram (ECG)

clinical safety endpoint

Time frame: 24 ± 6 hours after randomization

safety laboratory

clinical safety endpoint; blood count, clinical chemistry, coagulation

Time frame: 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

Time frame: 90 ± 10 days after randomization

relative changes in ischemic core volume (in %) from baseline to 24 hours

secondary imaging efficacy endpoint

Time frame: 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

Time frame: from baseline to 24 (22 to 36) hours

penumbral salvage from baseline to 24 hours

secondary imaging efficacy endpoint

Time frame: 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)

Time frame: 4 hours ± 15 minutes

revascularization on 24-hour follow-up imaging

secondary imaging efficacy endpoint

Time frame: 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

Time frame: 24 (22 to 36) hours

any intracranial hemorrhage on 24-hour follow-up imaging

imaging safety endpoints

Time frame: 24 (22 to 36) hours

peri-interventional occurrence of vasospasms

imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY)

Time frame: 4 hours ± 15 minutes

ischemic lesions in new territories on 24-hour follow-up imaging

imaging safety endpoints

Time frame: 24 (22 to 36) hours