Clinical trial NCT03500939: Penumbral Rescue by Normobaric O2 Administration in Patients With Ischemic Stroke and Target Mismatch ProFile
Official title: Penumbral Rescue by Normobaric O=O Administration in Patients With Ischemic Stroke and Target Mismatch ProFile: A Phase II Proof-of-Concept Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Ischemic Stroke
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: Coordination Centre for Clinical trials (KKS), 69120 Heidelberg, Germany
name: European Clinical Research Infrastructure Network (ECRIN), 10559 Berlin, Germany
name: CORE IMAGING LABORATORY: Eppdata GmbH, 22529 Hamburg, Germany
name: CORE BIOMARKER LABORATORY: Fundatio Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
First posted: 2018-04-18
Enrollment: 223
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility 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

Primary outcomes:
measure: ischemic core growth from baseline to 24 hours
timeFrame: from baseline to 24 (22 to 36) hours
Secondary outcomes:
measure: change in National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 hours
timeFrame: from baseline to 24 ± 6 hours
measure: survival
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: National Institutes of Health Stroke Scale score (NIHSS)
timeFrame: 20 ± 10 minutes, 4 hours ± 15 minutes, 24 ± 6 hours, 5 ± 2 days, 90 ± 10 days after randomization
measure: modified Rankin Scale score (mRS)
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: Barthel Index (BI)
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: 90 ± 10 days after randomization
measure: Stroke Impact Scale 16 (SIS-16)
timeFrame: 90 ± 10 days after randomization
measure: EuroQoL Questionnaire (EQ-5D-5L)
timeFrame: 90 ± 10 days after randomization
measure: Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: 90 ± 10 days after randomization
measure: partial pressure of oxygen in the arterial blood (PaO2)
timeFrame: 90 ± 30 minutes, 24 ± 6 hours after randomization
measure: length of ICU stay
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: length of hospital stay
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: duration of ventilation
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: all-cause death
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: stroke related death
timeFrame: 5 ± 2 days, 90 ± 10 days after randomization
measure: symptomatic intracranial hemorrhage
timeFrame: 5 ± 2 days after randomization or discharge
measure: vital signs
timeFrame: 90 ± 10 days after randomization
measure: 12-lead electrocardiogram (ECG)
timeFrame: 24 ± 6 hours after randomization
measure: safety laboratory
timeFrame: 5 ± 2 days after randomization or discharge
measure: concomitant invasive procedures
timeFrame: 90 ± 10 days after randomization
measure: relative changes in ischemic core volume (in %) from baseline to 24 hours
timeFrame: from baseline to 24 (22 to 36) hours
measure: 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
timeFrame: from baseline to 24 (22 to 36) hours
measure: penumbral salvage from baseline to 24 hours
timeFrame: from baseline to 24 (22 to 36) hours
measure: TICI (Thrombolysis in Cerebral Infarction perfusion scale grade)
timeFrame: 4 hours ± 15 minutes
measure: revascularization on 24-hour follow-up imaging
timeFrame: 24 (22 to 36) hours
measure: new microbleeds on 24-hour follow-up MRI (vs. baseline T2*weighted MRI)
timeFrame: 24 (22 to 36) hours
measure: any intracranial hemorrhage on 24-hour follow-up imaging
timeFrame: 24 (22 to 36) hours
measure: peri-interventional occurrence of vasospasms
timeFrame: 4 hours ± 15 minutes
measure: ischemic lesions in new territories on 24-hour follow-up imaging
timeFrame: 24 (22 to 36) hours
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk
city: Leuven
country: Belgium
facility: KU Leuven
city: Liernu
country: Belgium
facility: CHU de Liège
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Grendelbruch
country: France
facility: CHU de Grenoble
city: Nancy
country: France
facility: CHU de Nancy
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Centre Hospitalier Saint Anne de Paris
city: Paris
country: France
facility: Fondation Ophtalmologique Adolphe de Rothschild
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen
city: Hamburg
country: Germany
facility: Universitätsklinikum Eppendorf
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: München
country: Germany
facility: Ludwig-Maximilians-Universität München
city: Solingen
country: Germany
facility: St. Lukas Klinik
city: Tuebingen
country: Germany
facility: University Hospital Tuebingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Barcelona
country: Spain
facility: Fundacio Hospital Universitari Vall D'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Valladolid
country: Spain
facility: HCU Valladolid
Study officials:
affiliation: University Hospital Tübingen
name: Sven Poli, MD
role: PRINCIPAL_INVESTIGATOR
References: