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    Clinical Trial Results:
    Open label clinical study to evaluate the safety and efficacy of ProvayBlueTM (methylene blue injection USP) for the treatment of acquired methemoglobinemia

    Summary
    EudraCT number
    		 2017-000290-37
    Trial protocol
    		 FR   GB  
    Global end of trial date
    09 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jul 2022
    First version publication date
    21 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PVP-2016003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03395223
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Provepharm SAS
    Sponsor organisation address
    22 rue Marc Donadille, Marseille, France, 13013
    Public contact
    Clinical Trials Information, Provepharm SAS, +33 491086930,
    Scientific contact
    Clinical Trials Information, Provepharm SAS, +33 491086930,
    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
    09 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to confirm that ProvayBlue is efficacious in patients with acquired methemoglobinemia.
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Oct 2017
    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
    France: 6
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    31
    EEA total number of subjects
    6
    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)
    29
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Pediatric or adult patients (males and females of all ages) diagnosed with acquired methemoglobinemia and receiving treatment with ProvayBlue per the treating physician’s diagnosis and hospital/urgent care/acute care facility’s standard care. Acquired methemoglobinemia was defined as a level of metHb >30% or ≤30% with associated clinical symptoms.

    Pre-assignment
    Screening details
    		 Subjects who presented in a hospital/urgent care setting with acquired methemoglobinemia, defined as a metHb level of 30% or higher and/or symptoms referable to reduced oxygen-carrying capacity and resulting respiratory distress, alteration in mental status, sleepiness, cyanosis, dizziness, etc.

    Pre-assignment period milestones
    Number of subjects started
    		 31
    Number of subjects completed
    		 31

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Period
    Arm description
    		 Pediatric or adult patients (males and females of all ages) diagnosed with acquired methemoglobinemia and receiving treatment with ProvayBlue per the treating physician’s diagnosis and hospital/urgent care/acute care facility’s standard care. Acquired methemoglobinemia was defined as a level of metHb >30% or ≤30% with associated clinical symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ProvayBlue (Methylthioninium Chloride Proveblue)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered ProvayBlue IV over 5 to 30 minutes, usually at a dose of 1 mg/kg, and, if the metHb level remained above 30% or clinical symptoms persisted, a repeat dose of up to 1 mg/kg was to be administered 1 hour after the first dose

    Number of subjects in period 1
    		Overall Period
    Started
    31
    Completed
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 29 29
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 13 13

    End points

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    End points reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 Pediatric or adult patients (males and females of all ages) diagnosed with acquired methemoglobinemia and receiving treatment with ProvayBlue per the treating physician’s diagnosis and hospital/urgent care/acute care facility’s standard care. Acquired methemoglobinemia was defined as a level of metHb >30% or ≤30% with associated clinical symptoms.

    Primary: Efficacy endpoints: changes from baseline in metHb levels

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    End point title
    		 Efficacy endpoints: changes from baseline in metHb levels [1]
    End point description
    The primary efficacy endpoint was the number (%) of subjects with ≥50% reduction in metHb based on the first available posttreatment assessment when the first posttreatment measurement was taken within 2 hours of completion of first infusion.
    End point type
    Primary
    End point timeframe
    Before and after ProvayBlue infusion
    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: The results are presented as a series of individual patient narratives with limited statistical analysis, befitting the observational nature of most of the data. Test Hypothesis and P Value Justification is not applicable since no inferential statistics are provided for this study.
    End point values
    		 Overall Period
    Number of subjects analysed
    9 [2]
    Units: Number of subjects with 50% reduction
    8
    Notes
    [2] - 9 subjects had MethHb level assessed withinb 2 hours of the end of the first ProvayBlue treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Prevalence and nature of TEAEs, defined as all adverse events (AEs) with an onset date after the first dose of ProvayBlue infusion and within 10 days of the last dose of ProvayBlue infusion
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    		 All 31 enrolled subjects received at least 1 ProvayBlue infusion and were included in the Safety Analysis Set.

    Serious adverse events
    		 Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 31 (9.68%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure-like phenomena
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Methemoglobinemia
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 31 (25.81%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Myoclonus
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Gastrointestinal disorders
    diarrhea
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypokalemia
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    31 Aug 2020
    A total of 31 subjects were enrolled into the study. The study was early closed owing to the rarity of the clinical presentation of interest.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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