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Acute Ischemic StrokePhase 2PROOFNCT03500939

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

A Phase 2 study testing Medical oxygen in people with Acute Ischemic Stroke, run by University Hospital Tuebingen at 22 sites in 5 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Acute Ischemic Stroke
What is being tested?
Medical oxygen
Could I receive a placebo?
No, everyone receives an active treatment
How many people
223 participants
Where
22 sitesin 5 countries
Study dates
1 Aug 2019to 22 Aug 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 10Show fewer
  • 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.

Who cannot join

  • 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
Show all 24Show fewer
  • 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

Trial locations and contacts

22 sites in 5 countries.

22 sites in 5 countries

Germany9 sites

  • Universitätsklinikum Essen

    Essen

  • Universitätsklinikum Gießen

    Giessen

  • Universitätsklinikum Eppendorf

    Hamburg

  • Universitätsklinikum Heidelberg

    Heidelberg

  • Universitätsklinikum Schleswig-Holstein

    Kiel

  • Ludwig-Maximilians-Universität München

    München

  • St. Lukas Klinik

    Solingen

  • University Hospital Tuebingen

    Tübingen, 72076

  • Universitätsklinikum Ulm

    Ulm

Other trials in Germany

France5 sites

  • CHU de Grenoble

    Grendelbruch

  • CHU de Nancy

    Nancy

  • CHU de Nice

    Nice

  • Centre Hospitalier Saint Anne de Paris

    Paris

  • Fondation Ophtalmologique Adolphe de Rothschild

    Paris

Other trials in France

Belgium4 sites

  • UZ Gent

    Ghent

  • AZ Groeninge Kortrijk

    Kortrijk

  • KU Leuven

    Leuven

  • CHU de Liège

    Liernu

Other trials in Belgium

Spain3 sites

  • Fundacio Hospital Universitari Vall D'Hebron

    Barcelona

  • Hospital Universitari de Bellvitge

    Barcelona

  • HCU Valladolid

    Valladolid

Other trials in Spain

Finland1 site

  • Helsinki University Hospital

    Helsinki

Other trials in Finland

About this study

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

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.

Read the detailed description

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

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

Being tested
Medical oxygen, Standard of care
Medical subject headings
Ischemic Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Medical oxygenDrug

    inhalation of 100% oxygen at high flow via a sealed non-rebreather face-mask with reservoir

  • Standard of careOther

    e.g. thrombectomy, thrombolysis

Study groups in NCT03500939
Study groupRoleWhat they receive
Normobaric hyperoxygenation + standard of careExperimentalNormobaric 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.
Receives: Drug: Medical oxygen; Other: Standard of care
standard of care aloneActive comparatorstandard 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%.
Receives: Other: Standard of care

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: from baseline to 24 (22 to 36) hours

Secondary outcomes (29)

  1. 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

    Measured: from baseline to 24 ± 6 hours

  2. survival

    secondary clinical efficacy endpoint; survival to be assessed at visit 6 (V6, day 5), and V7 (day 90)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  3. 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)

    Measured: 20 ± 10 minutes, 4 hours ± 15 minutes, 24 ± 6 hours, 5 ± 2 days, 90 ± 10 days after randomization

  4. 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)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  5. Barthel Index (BI)

    secondary clinical efficacy endpoint; BI to be assessed at visit 6 (V6, day 5), and V7 (day 90)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  6. Montreal Cognitive Assessment (MoCA)

    secondary clinical efficacy endpoint; MoCA to be assessed at visit 7 (day 90)

    Measured: 90 ± 10 days after randomization

  7. 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)

    Measured: 90 ± 10 days after randomization

  8. EuroQoL Questionnaire (EQ-5D-5L)

    secondary clinical efficacy endpoint; EQ-5D-5L to be assessed at visit 7 (day 90)

    Measured: 90 ± 10 days after randomization

  9. 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)

    Measured: 90 ± 10 days after randomization

  10. 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)

    Measured: 90 ± 30 minutes, 24 ± 6 hours after randomization

  11. 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)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  12. 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)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  13. duration of ventilation

    secondary clinical efficacy endpoint; duration of ventilation to be assessed at visit 6 (V6, day 5), and V7 (day 90)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  14. all-cause death

    clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  15. stroke related death

    clinical safety endpoint; to be assessed at visit 6 (V6, day 5), and V7 (day 90)

    Measured: 5 ± 2 days, 90 ± 10 days after randomization

  16. symptomatic intracranial hemorrhage

    clinical safety endpoint; per ECASS III definition and per Heidelberg bleeding classification

    Measured: 5 ± 2 days after randomization or discharge

  17. vital signs

    clinical safety endpoint; systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2)

    Measured: 90 ± 10 days after randomization

  18. 12-lead electrocardiogram (ECG)

    clinical safety endpoint

    Measured: 24 ± 6 hours after randomization

  19. safety laboratory

    clinical safety endpoint; blood count, clinical chemistry, coagulation

    Measured: 5 ± 2 days after randomization or discharge

  20. concomitant invasive procedures

    clinical safety endpoint; e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure

    Measured: 90 ± 10 days after randomization

  21. relative changes in ischemic core volume (in %) from baseline to 24 hours

    secondary imaging efficacy endpoint

    Measured: from baseline to 24 (22 to 36) hours

  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

    secondary imaging efficacy endpoint; independent of imaging modality

    Measured: from baseline to 24 (22 to 36) hours

  23. penumbral salvage from baseline to 24 hours

    secondary imaging efficacy endpoint

    Measured: from baseline to 24 (22 to 36) hours

  24. TICI (Thrombolysis in Cerebral Infarction perfusion scale grade)

    secondary imaging efficacy endpoint; in patients who underwent mechanical thrombectomy (TBY)

    Measured: 4 hours ± 15 minutes

  25. revascularization on 24-hour follow-up imaging

    secondary imaging efficacy endpoint

    Measured: 24 (22 to 36) hours

  26. 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

    Measured: 24 (22 to 36) hours

  27. any intracranial hemorrhage on 24-hour follow-up imaging

    imaging safety endpoints

    Measured: 24 (22 to 36) hours

  28. peri-interventional occurrence of vasospasms

    imaging safety endpoints; in patients who underwent mechanical thrombectomy (TBY)

    Measured: 4 hours ± 15 minutes

  29. ischemic lesions in new territories on 24-hour follow-up imaging

    imaging safety endpoints

    Measured: 24 (22 to 36) hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Apr 2018
  2. Study start1 Aug 2019
  3. Primary completion16 May 2022
  4. Study completion22 Aug 2022

Why it stopped: Futility

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
223 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03500939
Sponsor's protocol ID
PROOF
Other IDs
2017-001355-31, 2017
Acronym
PROOF
Status last verified
Sep 2022
First submitted
27 Mar 2018
Last updated
23 Sep 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Poli S, Mbroh J, Baron JC, Singhal AB, Strbian D, Molina C, Lemmens R, Turc G, Mikulik R, Michel P, Tatlisumak T, Audebert HJ, Dichgans M, Veltkamp R, Husing J, Graessner H, Fiehler J, Montaner J, Adeyemi AK, Althaus K, Arenillas JF, Bender B, Benedikt F, Broocks G, Burghaus I, Cardona P, Deb-Chatterji M, Cvikova M, Defreyne L, De Herdt V, Detante O, Ernemann U, Flottmann F, Garcia Guillamon L, Glauch M, Gomez-Exposito A, Gory B, Sylvie Grand S, Harsany M, Hauser TK, Heck O, Hemelsoet D, Hennersdorf F, Hoppe J, Kalmbach P, Kellert L, Kohrmann M, Kowarik M, Lara-Rodriguez B, Legris L, Lindig T, Luntz S, Lusk J, Mac Grory B, Manger A, Martinez-Majander N, Mengel A, Meyne J, Muller S, Mundiyanapurath S, Naggara O, Nedeltchev K, Nguyen TN, Nilsson MA, Obadia M, Poli K, Purrucker JC, Raty S, Richard S, Richter H, Schilte C, Schlemm E, Stohr L, Stolte B, Sykora M, Thomalla G, Tomppo L, van Horn N, Zeller J, Ziemann U, Zuern CS, Hartig F, Tuennerhoff J; PROOF investigators. Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial. Int J Stroke. 2024 Jan;19(1):120-126. doi: 10.1177/17474930231185275. Epub 2023 Aug 18.

    PubMed 37515459

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Medical oxygen in people with Acute Ischemic Stroke, run by University Hospital Tuebingen at 22 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 23 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 22 sites in Germany, France, Belgium, Spain, Finland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Futility). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

ischemic core growth from baseline to 24 hours (time frame: from baseline to 24 (22 to 36) hours). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03500939, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Sep 2022.

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