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    Clinical Trial Results:
    Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis_ A randomised placebo-controller pilot trial

    Summary
    EudraCT number
    		 2012-000748-81
    Trial protocol
    		 FI  
    Global end of trial date
    01 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2021
    First version publication date
    14 Nov 2021
    Other versions
    Summary report(s)
    		 Main results of the analyses
    Laboratory analyses of MMP8 and MMP9 in individual subjects in different time points and TIMP-1
    Published jouirnal article
    Individual MMP-levels in each group

    Trial information

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    Trial identification
    Sponsor protocol code
    MMP-Doxi-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Helsinki University Hospital
    Sponsor organisation address
    Haartmaninkatu 4, Helsinki, Finland,
    Public contact
    Dr Johanna Hästbacka, University of Helsinki, +358 504286701, johanna.hastbacka@hus.fi
    Scientific contact
    Dr Johanna Hästbacka, University of Helsinki, +358 504286701, johanna.hastbacka@hus.fi
    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
    01 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The feasibility and safety of intravenbous administration of doxycycline in patients with severe sepsis Determining a dosing regimen that achieve sub-antimicrobial plasma concentrations of doxycycline
    Protection of trial subjects
    The patients received routine intensive care treatment and were treated according to written standard operating procedures in the intensive care unit.
    Background therapy
    		 The patients received routine intensive care treatment and were treated according to written standard operating procedures in the intensive care unit.
    Evidence for comparator
    		 Comparator was an equivalent volume of placebo (sodium chloride 0.9%)
    Actual start date of recruitment
    14 May 2012
    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
    Finland: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    17
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Please see Figure 1 and methods in attachment

    Pre-assignment
    Screening details
    		 Please see methods and Fig 1 in attached published article

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor
    Blinding implementation details
    Allocation sheets provided by an external person were saved in a different department in sealed envelopes. A nurse or pharmacist from an unincluded department prepared the study drug and delivered it to the participating department blinded nurse in an opaque syringe labeled with study code.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doxycycline high dose
    Arm description
    		 Doxyxycline 200mg on first and 100mg on second and third study day, intravenously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxycycline hyclate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use, Solution for infusion
    Dosage and administration details
    Intravenously administrated : arm 1: 200mgx1 day 1, 100mgx1 day 2 and 100mgx1 day 3 arm 2 100mg day 1, 50mgx1 day 2 and 50mg x1 day 3 arm 3 placebo NaCl 09% equivalent volume x1 intravenousely on days 1, 2, and 3

    Arm title
    		 Doxyxcycline low dose
    Arm description
    		 Doxycycline 100mg on first , and 50mg on second and third study day , once daily, intravenously
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxycycline hyclate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Solution for infusion , Intravenous use
    Dosage and administration details
    Intravenously administrated : arm 1: 200mgx1 day 1, 100mgx1 day 2 and 100mgx1 day 3 arm 2 100mg day 1, 50mgx1 day 2 and 50mg x1 day 3 arm 3 placebo NaCl 09% equivalent volume x1 intravenousely on days 1, 2, and 3

    Investigational medicinal product name
    Doxycycline hyclate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use, Solution for infusion
    Dosage and administration details
    arm 2 100mg day 1, 50mgx1 day 2 and 50mg x1 day 3

    Arm title
    		 Placebo arm
    Arm description
    		 Sodium chloride 0.9%
    Arm type
    		 Placebo

    Investigational medicinal product name
    Natriumchloride Baxter Viaflo 9mg/ml
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50ml infused once daily for three days

    Number of subjects in period 1
    		Doxycycline high dose Doxyxcycline low dose Placebo arm
    Started
    8
    8
    8
    Completed
    8
    7
    8
    Not completed
    0
    1
    0
         Consent withdrawn by subject
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doxycycline high dose
    Reporting group description
    		 Doxyxycline 200mg on first and 100mg on second and third study day, intravenously

    Reporting group title
    Doxyxcycline low dose
    Reporting group description
    		 Doxycycline 100mg on first , and 50mg on second and third study day , once daily, intravenously

    Reporting group title
    Placebo arm
    Reporting group description
    		 Sodium chloride 0.9%

    Reporting group values
    		 Doxycycline high dose Doxyxcycline low dose Placebo arm Total
    Number of subjects
    		 8 8 8 24
    Age categorical
    All patients were adults, of them 65-84 years of age
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 5 5 6 16
        From 65-84 years
    		 3 3 2 8
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 57 (53 to 65) 58 (52 to 72) 58 (49 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 3 2 7 12
        Male
    		 5 6 1 12
    Subject analysis sets

    Subject analysis set title
    MMP-8-concenbtrations
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Please see attachment file

    Subject analysis set title
    Doxycycline concentrations
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Please see attached file 4

    Subject analysis set title
    Safety and feasibility
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Please see published article, no adverse events were detected during study

    Subject analysis sets values
    		 MMP-8-concenbtrations Doxycycline concentrations Safety and feasibility
    Number of subjects
    23
    23
    24
    Age categorical
    All patients were adults, of them 65-84 years of age
    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)
    4
    5
    6
        From 65-84 years
    3
    3
    2
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    58 (52 to 72)
    57 (53 to 65)
    58 (49 to 70)
    Gender categorical
    Units: Subjects
        Female
    1
    3
    7
        Male
    6
    5
    1

    End points

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    End points reporting groups
    Reporting group title
    Doxycycline high dose
    Reporting group description
    		 Doxyxycline 200mg on first and 100mg on second and third study day, intravenously

    Reporting group title
    Doxyxcycline low dose
    Reporting group description
    		 Doxycycline 100mg on first , and 50mg on second and third study day , once daily, intravenously

    Reporting group title
    Placebo arm
    Reporting group description
    		 Sodium chloride 0.9%

    Subject analysis set title
    MMP-8-concenbtrations
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Please see attachment file

    Subject analysis set title
    Doxycycline concentrations
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Please see attached file 4

    Subject analysis set title
    Safety and feasibility
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Please see published article, no adverse events were detected during study

    Primary: Doxycycline concentrations after dosing

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    End point title
    		 Doxycycline concentrations after dosing [1] [2]
    End point description
    Plasma doxycycline levels
    End point type
    Primary
    End point timeframe
    24 hours from first dosing
    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 statistics are provided in the attached documents
    [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: The statistics are provided in the attached documents
    End point values
    		 Doxycycline high dose Doxyxcycline low dose Doxycycline concentrations
    Number of subjects analysed
    8
    7
    23
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    2.1 (1.6 to 2.7)
    0.72 (0.48 to 1.18)
    0.72 (0 to 2)
    No statistical analyses for this end point

    Primary: MMP 8 levels at 24 hours

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    End point title
    		 MMP 8 levels at 24 hours [3]
    End point description
    End point type
    Primary
    End point timeframe
    24 hours from dosing
    Notes
    [3] - 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 statistics are provided in the attached documents
    End point values
    		 Doxycycline high dose Doxyxcycline low dose Placebo arm MMP-8-concenbtrations
    Number of subjects analysed
    8
    7
    8
    23
    Units: ng/L
        median (inter-quartile range (Q1-Q3))
    75.3 (24.9 to 345.7)
    206.1 (78.5 to 295.6)
    369.3 (71.3 to 488.0)
    125.5 (56.2 to 410.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 28 days from astudy admissio
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    x
    Frequency threshold for reporting non-serious adverse events: 5%
    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: There were no serious adverse events in the study

    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? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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