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

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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Medical oxygen; Other: Standard of care

Detailed Description

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

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

• Study Type: Interventional
• Enrollment (Actual): 223
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium
    • UZ Gent
  • Kortrijk, Belgium
    • AZ Groeninge Kortrijk
  • Leuven, Belgium
    • KU Leuven
  • Liernu, Belgium
    • CHU de Liege
• Finland
  • Helsinki, Finland
    • Helsinki University Hospital
• France
  • Grendelbruch, France
    • Chu de Grenoble
  • Nancy, France
    • Chu de Nancy
  • Nice, France
    • CHU de Nice
  • Paris, France
    • Centre Hospitalier Saint Anne de Paris
  • Paris, France
    • Fondation Ophtalmologique Adolphe de Rothschild
• Germany
  • Essen, Germany
    • Universitätsklinikum Essen
  • Gießen, Germany
    • Universitätsklinikum Gießen
  • Hamburg, Germany
    • Universitätsklinikum Eppendorf
  • Heidelberg, Germany
    • Universitätsklinikum Heidelberg
  • Kiel, Germany
    • Universitätsklinikum Schleswig-Holstein
  • München, Germany
    • Ludwig-Maximilians-Universität München
  • Solingen, Germany
    • St. Lukas Klinik
  • Tuebingen, Germany, 72076
    • University Hospital Tuebingen
  • Ulm, Germany
    • Universitatsklinikum Ulm
• Spain
  • Barcelona, Spain
    • Fundacio Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Hospital Universitari de Bellvitge
  • Valladolid, Spain
    • HCU Valladolid

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normobaric hyperoxygenation + standard of care; 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; inhalation of 100% oxygen at high flow via a sealed non-rebreather face-mask with reservoir; Other: Standard of care; e.g. thrombectomy, thrombolysis
Active Comparator: standard of care alone; 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; e.g. thrombectomy, thrombolysis

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: 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
• Investigators: Principal Investigator: Sven Poli, MD, University Hospital Tübingen

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Actual): May 16, 2022
• Study Completion (Actual): August 22, 2022

Study Registration Dates

• First Submitted: March 27, 2018
• First Submitted That Met QC Criteria: April 9, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): September 23, 2022
• Last Update Submitted That Met QC Criteria: September 21, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction
• Other Study ID Numbers: PROOF; 2017-001355-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No