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

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ClinicalTrials.gov Identifier: NCT03500939
Recruitment Status : Recruiting
First Posted : April 18, 2018
Last Update Posted : May 3, 2021
Sponsor:
Information provided by (Responsible Party):
University Hospital Tuebingen

Tracking Information
First Submitted Date  ICMJE March 27, 2018
First Posted Date  ICMJE April 18, 2018
Last Update Posted Date May 3, 2021
Actual Study Start Date  ICMJE August 1, 2019
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
ischemic core growth from baseline to 24 hours [ Time Frame: from baseline to 24 (22 to 36) hours ]
difference in ischemic core volume (in mL) from baseline to 24 hours; intention-to-treat (ITT) analysis
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2018)
  • change in National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 hours [ Time Frame: from baseline to 24 ± 6 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
  • survival [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; survival to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • National Institutes of Health Stroke Scale score (NIHSS) [ Time Frame: 20 ± 10 minutes, 4 hours ± 15 minutes, 24 ± 6 hours, 5 ± 2 days, 90 ± 10 days after randomization ]
    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)
  • modified Rankin Scale score (mRS) [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    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)
  • Barthel Index (BI) [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; BI to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • Montreal Cognitive Assessment (MoCA) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90)
  • Stroke Impact Scale 16 (SIS-16) [ Time Frame: 90 ± 10 days after randomization ]
    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)
  • EuroQoL Questionnaire (EQ-5D-5L) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; EQ-5D-5L to be assessed at visit 7 (day 90)
  • Montgomery-Åsberg Depression Rating Scale (MADRS) [ Time Frame: 90 ± 10 days after randomization ]
    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)
  • partial pressure of oxygen in the arterial blood (PaO2) [ Time Frame: 90 ± 30 minutes, 24 ± 6 hours after randomization ]
    secondary clinical efficacy endpoint; PaO2 to be assessed at visit 3 (90 minutes after start of study treatment), and V5 (24 hours)
  • length of ICU stay [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    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)
  • length of hospital stay [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; length of hospital stay to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • duration of ventilation [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; duration of ventilation to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • all-cause death [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • stroke related death [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • symptomatic intracranial hemorrhage [ Time Frame: 5 ± 2 days after randomization or discharge ]
    clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification
  • vital signs [ Time Frame: 90 ± 10 days after randomization ]
    clinical safety endpoint; systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2)
  • 12-lead electrocardiogram (ECG) [ Time Frame: 24 ± 6 hours after randomization ]
    clinical safety endpoint
  • safety laboratory [ Time Frame: 5 ± 2 days after randomization or discharge ]
    clinical safety endpoint; blood count, clinical chemistry, coagulation
  • concomitant invasive procedures [ Time Frame: 90 ± 10 days after randomization ]
    clinical safety endpoint; e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure
  • relative changes in ischemic core volume (in %) from baseline to 24 hours [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint
  • 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 [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint; independent of imaging modality
  • penumbral salvage from baseline to 24 hours [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint
  • TICI (Thrombolysis in Cerebral Infarction perfusion scale grade) [ Time Frame: 4 hours ± 15 minutes ]
    secondary imaging efficacy endpoint; in patients who underwent mechanical thrombectomy (TBY)
  • revascularization on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint
  • new microbleeds on 24-hour follow-up MRI (vs. baseline T2*weighted MRI) [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints; only possible in patients who had MRI at baseline as well as at 24 hours
  • any intracranial hemorrhage on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints
  • peri-interventional occurrence of vasospasms [ Time Frame: 4 hours ± 15 minutes ]
    imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY)
  • ischemic lesions in new territories on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • change in National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 hours [ Time Frame: from baseline to 24 ± 6 hours ]
    key secondary endpoint
  • survival [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; survival to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • National Institutes of Health Stroke Scale score (NIHSS) [ Time Frame: 20 ± 10 minutes, 4 hours ± 15 minutes, 24 ± 6 hours, 5 ± 2 days, 90 ± 10 days after randomization ]
    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)
  • modified Rankin Scale score (mRS) [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; mRS to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • Barthel Index (BI) [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; BI to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • Montreal Cognitive Assessment (MoCA) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90)
  • Stroke Impact Scale 16 (SIS-16) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; SIS-16 to be assessed at visit 7 (day 90)
  • EuroQoL Questionnaire (EQ-5D-5L) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; EQ-5D-5L to be assessed at visit 7 (day 90)
  • Montgomery-Åsberg Depression Rating Scale (MADRS) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; MADRS to be assessed at visit 7 (day 90)
  • partial pressure of oxygen in the arterial blood (PaO2) [ Time Frame: 90 ± 30 minutes, 24 ± 6 hours after randomization ]
    secondary clinical efficacy endpoint; PaO2 to be assessed at visit 3 (90 minutes after start of study treatment), and V5 (24 hours)
  • length of ICU stay [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    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)
  • length of hospital stay [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; length of hospital stay to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • duration of ventilation [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; duration of ventilation to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • all-cause death [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • stroke related death [ Time Frame: 5 ± 2 days, 90 ± 10 days after randomization ]
    clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90)
  • symptomatic intracranial hemorrhage [ Time Frame: 5 ± 2 days after randomization or discharge ]
    clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification
  • vital signs [ Time Frame: 90 ± 10 days after randomization ]
    clinical safety endpoint; systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2)
  • 12-lead electrocardiogram (ECG) [ Time Frame: 24 ± 6 hours after randomization ]
    clinical safety endpoint
  • safety laboratory [ Time Frame: 5 ± 2 days after randomization or discharge ]
    clinical safety endpoint; blood count, clinical chemistry, coagulation
  • concomitant invasive procedures [ Time Frame: 90 ± 10 days after randomization ]
    clinical safety endpoint; e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure
  • relative changes in ischemic core volume (in %) from baseline to 24 hours [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint
  • 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 [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint; independent of imaging modality
  • penumbral salvage from baseline to 24 hours [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint
  • TICI (Thrombolysis in Cerebral Infarction perfusion scale grade) [ Time Frame: 4 hours ± 15 minutes ]
    secondary imaging efficacy endpoint; in patients who underwent mechanical thrombectomy (TBY)
  • revascularization on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint
  • new microbleeds on 24-hour follow-up MRI (vs. baseline T2*weighted MRI) [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints; only possible in patients who had MRI at baseline as well as at 24 hours
  • any intracranial hemorrhage on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints
  • peri-interventional occurrence of vasospasms [ Time Frame: 4 hours ± 15 minutes ]
    imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY)
  • ischemic lesions in new territories on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Penumbral Rescue by Normobaric O2 Administration in Patients With Ischemic Stroke and Target Mismatch ProFile
Official Title  ICMJE Penumbral Rescue by Normobaric O=O Administration in Patients With Ischemic Stroke and Target Mismatch ProFile: A Phase II Proof-of-Concept Trial
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 Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Acute Ischemic Stroke
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Medical oxygen
    • Other: Standard of care
  • 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%.
    Intervention: Other: Standard of care
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2018)
456
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sven Poli, MD +49 7071 290 sven.poli@uni-tuebingen.de
Contact: Monika Glauch +49 7071 2972308 monika.glauch@med.uni-tuebingen.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03500939
Other Study ID Numbers  ICMJE PROOF
2017-001355-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Hospital Tuebingen
Study Sponsor  ICMJE University Hospital Tuebingen
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University Hospital Tuebingen
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP