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    Clinical Trial Results:
    Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile: A Phase II Proof-of-Concept Trial

    Summary
    EudraCT number
    		 2017-001355-31
    Trial protocol
    		 BE   CZ   FI   ES  
    Global end of trial date
    22 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2023
    First version publication date
    31 Aug 2023
    Other versions
    Summary report(s)
    		 Summary of Clinical Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    PROOF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03500939
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University hospital Tuebingen
    Sponsor organisation address
    Hoppe-Seyler-Straße 3, Tuebingen, Germany,
    Public contact
    Department of Neurology and Stroke, University Hospital Tübingen, +49 1724682284, sven.poli@uni-tuebingen.de
    Scientific contact
    Department of Neurology and Stroke, University Hospital Tübingen, +49 1724682284, sven.poli@uni-tuebingen.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main 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.
    Protection of trial subjects
    The stidy was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    Finland: 24
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 118
    Worldwide total number of subjects
    223
    EEA total number of subjects
    223
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    60
    From 65 to 84 years
    125
    85 years and over
    38

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population for this trial included male and female patients aged 18 to >= 85 with ischemic stroke due to intracranial anterior circulation LVO.

    Pre-assignment
    Screening details
    		 From 17.08.2019 to 13.05.2022 233 of the initially planned 460 patients were enrolled in the PROOF-study. Patients were randomized 1:1.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Clinical trial with blinded outcome assessment (PROBE design).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment group
    Arm description
    		 Normobaric oxygen therapy was started within 6 hours after certain stroke symptom onset (witnessed) or after symptom recognition (in case of wake-up or unknown onset stroke) and within 30 minutes after end of baseline brain imaging and apllied until removal of guide catheter from sheath at the end of endovascular mechanical thromboectomy or for 4 hours if mechnaical thromboectomy was not attempted or stopped prior to manipulation of intracranial anterior circulation large vessel occlusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxygen for medical use
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Inhalation use
    Dosage and administration details
    Oxygen used for medical purposes is a diatmoic gas applied via the natural or an artificial airway in concentrations between 21 % (as in athmosperic air) and 100% depending on he type and severity of the disorder that necessitates oxygen supplementation.

    Arm title
    		 Control group
    Arm description
    		 Control arm: oxygen supplementation if oxygen saturation <= 94% at 2 to 4L/min via nasal cannula according to guidelines of the European Stroke Organsiation, or in case of mechanical thromboectomy-related ventilation, ventilation with an initial inspiratory oxygen fraction of 0,3 to be gradually increased if oxygen saturation <= 94%.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxygen for medical use
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Inhalation use
    Dosage and administration details
    Oxygen used for medical purposes is a diatmoic gas applied via the natural or an artificial airway in concentrations between 21 % (as in athmosperic air) and 100% depending on he type and severity of the disorder that necessitates oxygen supplementation.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Staff that was involved in the emergency treatment of patients was not blinmded. Outcome-raters at the image core laboratory were blinded to the respective tratment as they did not receive any information about randomization and the prior clinical course.
    Number of subjects in period 1
    		Treatment group Control group
    Started
    112
    111
    Completed
    93
    91
    Not completed
    19
    20
         Adverse event, serious fatal
    14
    14
         Consent withdrawn by subject
    1
    -
         Other
    3
    3
         Lost to follow-up
    1
    2
         non compliance /medical reasons
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 Normobaric oxygen therapy was started within 6 hours after certain stroke symptom onset (witnessed) or after symptom recognition (in case of wake-up or unknown onset stroke) and within 30 minutes after end of baseline brain imaging and apllied until removal of guide catheter from sheath at the end of endovascular mechanical thromboectomy or for 4 hours if mechnaical thromboectomy was not attempted or stopped prior to manipulation of intracranial anterior circulation large vessel occlusion.

    Reporting group title
    Control group
    Reporting group description
    		 Control arm: oxygen supplementation if oxygen saturation <= 94% at 2 to 4L/min via nasal cannula according to guidelines of the European Stroke Organsiation, or in case of mechanical thromboectomy-related ventilation, ventilation with an initial inspiratory oxygen fraction of 0,3 to be gradually increased if oxygen saturation <= 94%.

    Reporting group values
    		 Treatment group Control group Total
    Number of subjects
    		 112 111 223
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 30 30 60
        From 65-84 years
    		 64 61 125
        85 years and over
    		 18 20 38
    Age continuous
    Units: years
        median (full range (min-max))
    		 75 (36 to 95) 76 (35 to 93) -
    Gender categorical
    Units: Subjects
        Female
    		 55 55 110
        Male
    		 57 56 113
    Brain Imaging Method
    Units: Subjects
        MRI
    		 11 9 20
        CT
    		 101 102 203
    Side of LVO
    Units: Subjects
        Left
    		 60 58 118
        Right
    		 52 53 105
    LVO location
    Units: Subjects
        carotid-T
    		 19 13 32
        proximal M12-segment
    		 40 41 81
        distal M1-segment
    		 27 28 55
        M2/M3 segments
    		 26 29 55
    time window until randomization
    Units: Subjects
        known, <6h
    		 95 86 181
        unknown/wake up/>=6h
    		 17 25 42
    NIH Stroke Scale Score
    Units: Subjects
        5 and less
    		 0 1 1
        6-10
    		 33 31 64
        11-20
    		 63 66 129
        21 and more
    		 16 13 29
    Tandem stenosis
    Units: Subjects
        yes
    		 18 13 31
        no
    		 94 98 192

    End points

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    End points reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 Normobaric oxygen therapy was started within 6 hours after certain stroke symptom onset (witnessed) or after symptom recognition (in case of wake-up or unknown onset stroke) and within 30 minutes after end of baseline brain imaging and apllied until removal of guide catheter from sheath at the end of endovascular mechanical thromboectomy or for 4 hours if mechnaical thromboectomy was not attempted or stopped prior to manipulation of intracranial anterior circulation large vessel occlusion.

    Reporting group title
    Control group
    Reporting group description
    		 Control arm: oxygen supplementation if oxygen saturation <= 94% at 2 to 4L/min via nasal cannula according to guidelines of the European Stroke Organsiation, or in case of mechanical thromboectomy-related ventilation, ventilation with an initial inspiratory oxygen fraction of 0,3 to be gradually increased if oxygen saturation <= 94%.

    Primary: Core Volume

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    End point title
    		 Core Volume [1]
    End point description
    Primary efficacy of normobaric oxygen therapy is determined by ischemic core growth in the normobaric oxygen therapy and control arms. ischemic core growth is defined as the change in vore volume (mL) from baseline (determined on diffsuion-weighted MRI, CT perfusion or cT angiography source images) to 24 hours (diffusion-weighted MRI).
    End point type
    Primary
    End point timeframe
    24h
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See the attached Clinical Trial Report.
    End point values
    		 Treatment group Control group
    Number of subjects analysed
    112
    111
    Units: mL
        number (not applicable)
    105
    109
    No statistical analyses for this end point

    Secondary: Change in NIHSS

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    End point title
    		 Change in NIHSS [2]
    End point description
    Key secondary outcome was the change in NIHSS from baseline to 24hurs. Further secondary efficacy outcomes include the mRS at 90days, arterial oxygen pressure mechanical thromboectomy (or at 90 minutes), relative percent change in ischemic core volume from baseline to 24 hours and Barthel Index, Montreal Cognitive Assessment, Montgomery-Asberg Depression Rating Scale and the patient reported outcomes Stroke Impact Scale-16 and EuroQoL-5 Dimensions-5 Levels at 90 days.
    End point type
    Secondary
    End point timeframe
    24h
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: See the attached Clinical Trial Report.
    End point values
    		 Control group
    Number of subjects analysed
    111
    Units: n.n.
        number (not applicable)
    111
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    90 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4.0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: For the safety evaluation see the attached Clinical Trial Report

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2018
    1)Protocol V1.1 Submitted via international step of VHP on 30.05.2018 to address the requested modifications from the participating competent authorities to obtain the approval after the first submission. The protocol was later approved in a national step by Belgium, Czech Republic, Finland, Germany and Spain
    12 Apr 2019
    2) Protocol V1.2 Submitted via international step of VHP on 12.04.2019 to combine the requested modifications from the participating competent authorities and Ethics Committees e.g integration of a risk-benefit analysis. The protocol was later approved in a national step by Belgium, Czech Republic, Finland, Germany and Spain
    15 Dec 2019
    3) Protocol V1.3 Submitted via international step of VHP on 15.12.2019 to simplify inclusion criteria to boost patient recruitment e.g. the extension of the therapeutic time window from 3 to 6 hours and the omitting of the upper age limit of previously 80 years, allowing enrollment of more distal M2/3 segment occlu-sions, and tandem‐stenoses. The protocol was later approved in a national step by Belgium, Czech Republic, Finland, Germany and Spain. The protocol was submitted outside the VHP procedure to French competent authorities and ethics committee. France requested some clarification in the wording of the protocol, which did not have any impact on the study conduct and design, so that a French specific protocol was created and approved.
    01 Dec 2020
    4) Temporary hold of patient recruitment The patient recruitment was temporarily suspended due to safety concerns (number of observed intracranial hemorrhages) after the data and safety monitoring board held their first meeting. The temporary hold was reported nationally to the competent authorities and ethics committees via a substantial amendment.
    22 Mar 2021
    5) Protocol V1.4 Submitted via international step of VHP on 22.03.2021. The protocol was modified following the recommendations from the DSMB and taking the updated current international acute ischemic stroke guidelines into account. Besides, the risk-benefit section was updated, the biomarker study simplified and the French modifications integrated. The protocol was later approved in a national step by the competent authorities and Ethic committees in Belgium, Czech Republic, Finland, France, Germany and Spain, so that new patients could be enrolled.
    13 May 2022
    6) Early study termination due to futility result of pre-specified interim analysis After the first 160 patients were enrolled and treated an pre-specified interim analysis was done carried out while the patient enrollment continued. The trial protocol foresees stopping the trial for futility if the direction of the effect for the primary endpoint favours the control arm. The data and safety monitoring board recommended to stop the patient recruitment, because there were no indications that the normobaric oxygen therapy is advantageous. At that point 223 of the initially planned 460 patients were enrolled in the PROOF study from 17.08.2019 (FPI) – 13.05.2022 (LPI)).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Dec 2020
    temporary interruption till may 2021
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No reported limitations and caveats.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37515459
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