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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03500939
Recruitment Status : Terminated (Futility)
First Posted : April 18, 2018
Last Update Posted : September 23, 2022
Sponsor:
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
Information provided by (Responsible Party):
University Hospital Tuebingen

Study Description
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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

Detailed Description:

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

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

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 223 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
Actual Study Start Date : August 1, 2019
Actual Primary Completion Date : May 16, 2022
Actual Study Completion Date : August 22, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ischemic Stroke

Arms and Interventions
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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


Outcome Measures
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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


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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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


Locations
Show Show 22 study locations
Sponsors and Collaborators
University Hospital Tuebingen
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
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Principal Investigator: Sven Poli, MD University Hospital Tübingen
More Information
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Additional Information:

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Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT03500939    
Other Study ID Numbers: PROOF
2017-001355-31 ( EudraCT Number )
First Posted: April 18, 2018    Key Record Dates
Last Update Posted: September 23, 2022
Last Verified: September 2022

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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
Ischemic 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
Infarction
Necrosis