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

Acute Ischemic Stroke Clinical Trial

— PROOF  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03500939
• Other study ID #: PROOF
• Secondary ID: 2017-001355-31
• Status: Terminated
• Phase: Phase 2
• Start date: August 1, 2019
• Est. completion date: August 22, 2022

Study information

• Verified date: September 2022
• Source: University Hospital Tuebingen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 223
• Est. completion date: August 22, 2022
• Est. primary completion date: May 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (ß-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

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Cerebral Infarction
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

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

Locations

Country	Name	City	State
Belgium	UZ Gent	Gent
Belgium	AZ Groeninge Kortrijk	Kortrijk
Belgium	KU Leuven	Leuven
Belgium	CHU de Liège	Liernu
Finland	Helsinki University Hospital	Helsinki
France	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
Germany	Universitätsklinikum Essen	Essen
Germany	Universitätsklinikum Gießen	Gießen
Germany	Universitätsklinikum Eppendorf	Hamburg
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Ludwig-Maximilians-Universität München	München
Germany	St. Lukas Klinik	Solingen
Germany	University Hospital Tuebingen	Tuebingen
Germany	Universitätsklinikum Ulm	Ulm
Spain	Fundacio Hospital Universitari Vall D'Hebron	Barcelona
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	HCU Valladolid	Valladolid

Sponsors (5)

Lead Sponsor	Collaborator
University Hospital Tuebingen	Coordination Centre for Clinical trials (KKS), 69120 Heidelberg, Germany, CORE BIOMARKER LABORATORY: Fundatio Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain, CORE IMAGING LABORATORY: Eppdata GmbH, 22529 Hamburg, Germany, European Clinical Research Infrastructure Network (ECRIN), 10559 Berlin, Germany

Countries where clinical trial is conducted

Belgium,  Finland,  France,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Montreal Cognitive Assessment (MoCA)	secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90)	90 ± 10 days after randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	symptomatic intracranial hemorrhage	clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification	5 ± 2 days after randomization or discharge
Secondary	vital signs	clinical safety endpoint; systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2)	90 ± 10 days after randomization
Secondary	12-lead electrocardiogram (ECG)	clinical safety endpoint	24 ± 6 hours after randomization
Secondary	safety laboratory	clinical safety endpoint; blood count, clinical chemistry, coagulation	5 ± 2 days after randomization or discharge
Secondary	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
Secondary	relative changes in ischemic core volume (in %) from baseline to 24 hours	secondary imaging efficacy endpoint	from baseline to 24 (22 to 36) hours
Secondary	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
Secondary	penumbral salvage from baseline to 24 hours	secondary imaging efficacy endpoint	from baseline to 24 (22 to 36) hours
Secondary	TICI (Thrombolysis in Cerebral Infarction perfusion scale grade)	secondary imaging efficacy endpoint; in patients who underwent mechanical thrombectomy (TBY)	4 hours ± 15 minutes
Secondary	revascularization on 24-hour follow-up imaging	secondary imaging efficacy endpoint	24 (22 to 36) hours
Secondary	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
Secondary	any intracranial hemorrhage on 24-hour follow-up imaging	imaging safety endpoints	24 (22 to 36) hours
Secondary	peri-interventional occurrence of vasospasms	imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY)	4 hours ± 15 minutes
Secondary	ischemic lesions in new territories on 24-hour follow-up imaging	imaging safety endpoints	24 (22 to 36) hours

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