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History of Changes for Study: NCT03500939
Penumbral Rescue by Normobaric O2 Administration in Patients With Ischemic Stroke and Target Mismatch ProFile (PROOF)
Latest version (submitted March 14, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 April 9, 2018 None (earliest Version on record)
2 April 18, 2018 Arms and Interventions, Outcome Measures and Study Status
3 October 4, 2018 Study Status and Contacts/Locations
4 August 14, 2019 Recruitment Status, Study Status, Contacts/Locations and Oversight
5 April 23, 2020 Contacts/Locations, Study Status and Eligibility
6 November 3, 2020 Study Status
7 April 30, 2021 Study Status
8 March 14, 2022 Study Status
Comparison Format:

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Study NCT03500939
Submitted Date:  April 9, 2018 (v1)

Open or close this module Study Identification
Unique Protocol ID: PROOF
Brief Title: Penumbral Rescue by Normobaric O2 Administration in Patients With Ischemic Stroke and Target Mismatch ProFile (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
Secondary IDs: 2017-001355-31 [EudraCT Number]
Open or close this module Study Status
Record Verification: February 2018
Overall Status: Not yet recruiting
Study Start: June 2018
Primary Completion: March 2021 [Anticipated]
Study Completion: June 2021 [Anticipated]
First Submitted: March 27, 2018
First Submitted that
Met QC Criteria:
April 9, 2018
First Posted: April 18, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
April 9, 2018
Last Update Posted: April 18, 2018 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: University Hospital Tuebingen
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: No
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
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:
Open or close this module Conditions
Conditions: Acute Ischemic Stroke
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Single (Outcomes Assessor)
Allocation: Randomized
Enrollment: 456 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
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
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%.
Standard of care
e.g. thrombectomy, thrombolysis
Open or close this module Outcome Measures
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
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)
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)
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)
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)
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
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 80 Years
Sex: All
Gender Based:
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).
Open or close this module Contacts/Locations
Central Contact Person: Sven Poli, MD MSc FESO
Telephone: +49 7071 290
Email: sven.poli@uni-tuebingen.de
Locations:
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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