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    Summary
    EudraCT Number:2017-001355-31
    Sponsor's Protocol Code Number:PROOF
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-09-28
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFinland - Fimea
    A.2EudraCT number2017-001355-31
    A.3Full title of the trial
    Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile:
    A Phase II Proof-of-Concept Trial
    Penumbra-Rettung durch normobare Sauerstoff-Gabe bei Patienten mit ischämischem Schlaganfall und Target Mismatch ProFile: eine Phase II Proof-of-Concept Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Inhalation of oxygen at a normal pressure for penumbral rescue (rescue of not yet destroyed brain tissue) in patients with stroke due to a large vessel occlusion ("ischemic stroke")
    A.4.1Sponsor's protocol code numberPROOF
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEberhard-Karls University Tübingen represented by University Hospital Tübingen and its Commercial Director
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEU Commission
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Tübingen
    B.5.2Functional name of contact pointDepartment of Neurology and Stroke
    B.5.3 Address:
    B.5.3.1Street AddressHoppe-Seyler-Str. 3
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number+491724682284
    B.5.5Fax number+4970712925047
    B.5.6E-mailsven.poli@uni-tuebingen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Medical oxygen
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Medicinal gas, compressed
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOXYGEN
    D.3.9.4EV Substance CodeSUB14733MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % (V/V) percent volume/volume
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute ischemic stroke
    E.1.1.1Medical condition in easily understood language
    Acute ischemic stroke
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level PT
    E.1.2Classification code 10061256
    E.1.2Term Ischaemic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level LLT
    E.1.2Classification code 10055221
    E.1.2Term Ischemic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the 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.

    To demonstrate an effect of NBHO on penumbral salvage in ischemic stroke.
    E.2.2Secondary objectives of the trial
    To show clinical efficacy and safety of NBHO adjunct to standard treatment.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    • Exploratory analyses of imaging
    • Exploratory analyses of biochemical biomarkers to develop a blood-based test to monitor efficacy and safety of NBHO treatment
    E.3Principal inclusion criteria
    • Age: ≥ 18 years
    • Acute anterior circulation ischemic stroke due to a Large vessel occlusion (LVO) on CT or MR angiography, i.e. either terminal internal carotid artery (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
    • NIHSS score of ≥ 6 at screening
    • Alberta Stroke Program Early CT score (ASPECTS) of 6-10 on non-contrast CT or 5-10 on diffusion-weighted MRI (DWI-MRI)
    • If recommended by the attending physician, CT or MR perfusion should be performed prior to NBHO
    • NBHO can be initiated within 6 hours of symptom onset (witnessed) or symptom recognition (in case of wake-up or unknown onset stroke), and within 30 minutes after last image of baseline brain Imaging
    • Pre-stroke mRS of 0 to 2
    • 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
    E.4Principal 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 common carotid artery (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)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 common carotid artery (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:
    • Acute or chronic pulmonary disease or respiratory distress that may, in the clinical judgement of the investigator, interfere with the study intervention (e.g. acute pneumonia, COPD flare-up etc.)
    • Prior to enrolment, > 2 L/min oxygen required to maintain peripheral oxygen saturation ≥ 95%
    •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
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the ischemic core growth defined as the difference in ischemic core volume (in mL) from baseline to 24 hours; intention-to-treat analysis
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 24 hours
    E.5.2Secondary end point(s)
    Key secondary efficacy endpoint is the change in National Institutes of Health Stroke Scale (NIHSS) scores from baseline to 24 hours.
    Secondary clinical efficacy endpoints: Survival at visit 6 (V6), and V7; NIHSS score (neurological status) at V2, V4, V5, V6, and V7; modified Rankin Scale (mRS) score, and Barthel Index score at V6 and V7; MoCA at V7 (controlled for Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) at V5), Stroke Impact Scale 16 (SIS-16), EuroQoL Questionnaire (EQ-5D-5L), and Montgomery–Åsberg Depression Rating Scale (MADRS) scores at V7; PaO2 at V3, and V5
    Clinical safety endpoints:all-cause death at V6, and V7; stroke related death at V6, and V7; symptomatic intracranial hemorrhage until V6; vital signs (systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2)) at V1-V7, with body temperature at V1, V5, and V6; 12-lead electrocardiogram (ECG) at V1, and V5; laboratory (blood count, clinical chemistry, coagulation) at V5, and V6; length of ICU stay, hospital stay, and duration of ventilation at V6, and V7; concomitant invasive procedures (e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure) until V7.
    Secondary imaging efficacy endpoints: relative changes in ischemic core volume (in %) from baseline to 24 hours; absolute and relative ischemic core change from baseline to 24 hours using using either NCCT or DWI-MRI (or CT angiography source images and DWI) for ischemic core estimation at baseline 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, independent of imaging modality; penumbral salvage from baseline to 24 hours; TICI (Thrombolysis in Cerebral Infarction perfusion scale grade) in patients who underwent TBY; revascularization on 24-hour follow-up imaging.
    Imaging safety endpoints: new microbleeds on 24-hour follow-up imaging; any intracranial hemorrhage on 24-hour follow-up imaging; peri-interventional occurrence of vasospasms; ischemic lesions in new territories on 24-hour follow-up imaging.
    E.5.2.1Timepoint(s) of evaluation of this end point
    please see timepoints in the description above
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    blinded endpoint assessment (PROBE design)
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    standard treatment
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Czechia
    Finland
    France
    Germany
    Spain
    Switzerland
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months84
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months84
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 228
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 228
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Due to the underlying disease (ischemic stroke), patients will in most cases not be able to give consent personally. However, in case they are able to, they must be informed prior to trial enrolment.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state422
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 422
    F.4.2.2In the whole clinical trial 456
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients are treated according to the local routine. There is only one additional follow-up visit at day 90 after randomization.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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