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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 17, 2018
Last Update Posted : August 19, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital Tuebingen

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.

Condition or disease Intervention/treatment Phase
Acute Ischemic Stroke Drug: Medical oxygen Other: Standard of care Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 456 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
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
Estimated Study Start Date : August 2019
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : June 2021

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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)

  3. 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)

  4. 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)

  5. 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)

  6. Montreal Cognitive Assessment (MoCA) [ Time Frame: 90 ± 10 days after randomization ]
    secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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)

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. symptomatic intracranial hemorrhage [ Time Frame: 5 ± 2 days after randomization or discharge ]
    clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification

  17. 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)

  18. 12-lead electrocardiogram (ECG) [ Time Frame: 24 ± 6 hours after randomization ]
    clinical safety endpoint

  19. safety laboratory [ Time Frame: 5 ± 2 days after randomization or discharge ]
    clinical safety endpoint; blood count, clinical chemistry, coagulation

  20. 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

  21. 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

  22. 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

  23. penumbral salvage from baseline to 24 hours [ Time Frame: from baseline to 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint

  24. 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)

  25. revascularization on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    secondary imaging efficacy endpoint

  26. 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

  27. any intracranial hemorrhage on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints

  28. peri-interventional occurrence of vasospasms [ Time Frame: 4 hours ± 15 minutes ]
    imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY)

  29. ischemic lesions in new territories on 24-hour follow-up imaging [ Time Frame: 24 (22 to 36) hours ]
    imaging safety endpoints



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Age: male patients: 18 to 80 years, female patients: 50 to 80 years
  • Clinical signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke
  • LVO on CT angiography or MR angiography consistent with clinical signs and symptoms, i.e. either the terminal ICA with involvement of the M1-segment of the MCA/carotid-T, the proximal M1-segment, or the distal M1-segments (distal to perforating branches)
  • NIHSS score of ≥ 6 at screening
  • NIHSS item 1a (level of consciousness) of 0 or 1
  • Alberta Stroke Program Early CT score (ASPECTS) of 7-10 on non-contrast CT or 6-10 on diffusion-weighted MRI (DWI-MRI)
  • CT perfusion (preferably whole-brain, minimal coverage ≥ 75 mm) or MR perfusion imaging performed prior to NBHO
  • NBHO can be initiated within 3 hours of certain stroke symptom onset (witnessed or last seen well) and within 20 minutes after end of baseline brain imaging
  • Pre-stroke mRS of 0 or 1
  • Due to the emergency situation in which patients are enrolled and the presumed safety of the IMP as applied in the PROOF trial (see Section 4.3 Risk-benefit Assessment), their 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 (see Section 14.5 Subject Information and Informed Consent)

Exclusion Criteria

Neurological:

  • Rapid improvement in neurological status to an NIHSS < 6 or evidence of vessel recanalization prior to randomization
  • Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment
  • Acute neurological symptoms related to other pathology than ischemic stroke
  • Evidence of intracranial hemorrhage (except of cerebral microbleeds), intracranial tumor (except small meningioma), and/or intracranial arteriovenous malformation as confirmed by baseline brain imaging
  • Intracranial aneurysm or prior stent implantation in the vascular territory (upstream and downstream) affected by qualifying LVO
  • TBY procedure initiated (groin puncture) prior to randomization
  • Previously known or CT angiographic / MR angiographic visualization of ipsilateral high-grade stenosis, complete cervical carotid occlusion, or flow-limiting carotid dissection
  • Suspected aortic dissection or cerebral vasculitis based on medical history or CT angiography / MR angiography
  • Clinical or imaging evidence of acute bilateral stroke or stroke in other vascular territories than qualifying LVO (except of clinically silent micro-DWI lesions in patients who received MR-based acute brain imaging)
  • Significant mass effect with midline shift as confirmed by brain imaging
  • Any co-existing neurological (especially neuromuscular) disorder

Respiratory:

  • Known history of chronic pulmonary disease (e.g. COPD, pulmonary fibrosis) or any condition leading to hypoxic respiratory drive (e.g. neuromuscular disease)
  • Prior to enrolment, > 2 L/min oxygen required to maintain peripheral oxygen saturation ≥ 95% or acute respiratory distress that may, in the clinical judgment of the investigator, interfere with the study intervention
  • Endotracheal intubation at time of screening or anticipated intubation for other reasons than TBY procedure

Other:

  • Clinical suspicion of acute myocardial infarction (e.g. pressure or tightness in the chest, pain in the chest, back, jaw, and other areas of the upper body that lasts more than a few minutes or that goes away and comes back, shortness of breath)
  • Baseline blood glucose of < 50 mg/dL (2.78 mmol) or > 400 mg/dL (22.20 mmol)
  • Body temperature ≥ 38.0°C at screening
  • Presumed septic embolus, or suspicion of bacterial endocarditis
  • History of severe allergy (more than rash) to contrast medium
  • Current treatment with nitrofurantoin or amiodaron, paraquat poisoning, or history of treatment with bleomycin
  • Women of childbearing age, i.e. < 50 years as defined by World Health Organization
  • Any co-existing or terminal disease 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. substance abuse, co-existing disease) or would complicate assessment of outcomes (e.g. dementia, psychiatric disease) or would confound the neurological or functional evaluations (e.g. dementia)
  • Participation in another interventional (drug or device) study within the last four weeks
  • Prior participation in the PROOF trial (no subject will be allowed to enroll in this trial more than once).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03500939


Contacts
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Contact: Sven Poli, MD MSc FESO FAHA +49 7071 290 sven.poli@uni-tuebingen.de
Contact: Monika Glauch +49 7071 290 monika.glauch@med.uni-tuebingen.de

Locations
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Germany
University Hospital Tuebingen Recruiting
Tuebingen, Germany, 72076
Contact: Sven Poli, MD MSc    +497071290 ext 83269    sven.poli@uni-tuebingen.de   
Contact: Julia Zeller, MBA    +497071290 ext 68293    julia.zeller@med.uni-tuebingen.de   
Sponsors and Collaborators
University Hospital Tuebingen

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Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT03500939     History of Changes
Other Study ID Numbers: PROOF
2017-001355-31 ( EudraCT Number )
First Posted: April 17, 2018    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Stroke
Cerebral Infarction
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia