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

University Hospital Tuebingen

Status and phase: Terminated; Phase 2

Conditions: Acute Ischemic Stroke

Treatments: Other: Standard of care; Drug: Medical oxygen

Study type: Interventional

Funder types: Other

Identifiers

NCT03500939

2017-001355-31 (EudraCT Number)

PROOF

Details and patient eligibility

About

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.

Full description

http://www.proof-trial.eu/

European Union's Horizon 2020 research and innovation programme grant 733379 (2016): Euro 5.8 Mio

Enrollment: 223 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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223 participants in 2 patient groups

Normobaric hyperoxygenation + standard of care

Experimental group

Description:

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.

Treatment:

Drug: Medical oxygen

Other: Standard of care

standard of care alone

Active Comparator group

Description:

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%.

Treatment:

Other: Standard of care