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    Clinical Trial Results:
    Direct thrombin inhibitors versus low molecular weight heparins as thromboprophylaxis in Staphylococcus aureus bacteraemia. A prospective randomized controlled academic single-centre feasibility study

    Summary
    EudraCT number
    		 2012-004863-29
    Trial protocol
    		 BE  
    Global end of trial date
    08 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Feb 2021
    First version publication date
    28 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1M
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Peter Verhamme, university hospitals Leuven (Gasthuisberg), +32 16341463,
    Scientific contact
    Peter Verhamme, university hospitals Leuven (Gasthuisberg), +32 16341463,
    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 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Feasibility and safety of direct thrombin inhibitors (dabigatran or argatroban) versus LMWH (clexane) in patients with staphylococcus aureus bacteraemia. Effect on coagulation parameters.
    Protection of trial subjects
    0
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 94
    Worldwide total number of subjects
    94
    EEA total number of subjects
    94
    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)
    42
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients aged 18 years and older with blood cultures growing S. aureus and with symptoms or signs of infection, for whom prophylaxis of venous thromboembolism was indicated, were eligible for the study. Between March 2013 and July 2016, 303 patients were eligible.

    Pre-assignment
    Screening details
    		 Regarding feasibility, 209 of the 303 patients were excluded from the trial. The main reasons for exclusion were kidney or liver failure, planned surgery, recent bleeding, thrombocytopenia and contraindications related to study drug administration. The remaining 94 patients were randomized 1:1.

    Period 1
    Period 1 title
    Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Due to different routes of administration of dabigatran, argatroban and LMWH, the study physician and data collection team, nor the patient were blinded for the intervention during the trial. The technicians who performed laboratory analyses, the investigators who performed and interpreted the medical imaging and the investigators performing bleeding severity adjudication were blinded to treatment group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Direct thrombin inhibitor
    Arm description
    		 Dabigatran or argatroban
    Arm type
    		 Experimental

    Investigational medicinal product name
    dabigatran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    110 mg BID

    Investigational medicinal product name
    argatroban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    argatroban according to aPTT 1.5-2ULN

    Arm title
    		 Enoxaparin
    Arm description
    		 enoxaparin 40 mg OD SC
    Arm type
    		 Active comparator

    Investigational medicinal product name
    enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    enoxaparin 40 mg

    Number of subjects in period 1
    		Direct thrombin inhibitor Enoxaparin
    Started
    47
    47
    Completed
    47
    47

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Direct thrombin inhibitor
    Reporting group description
    		 Dabigatran or argatroban

    Reporting group title
    Enoxaparin
    Reporting group description
    		 enoxaparin 40 mg OD SC

    Reporting group values
    		 Direct thrombin inhibitor Enoxaparin Total
    Number of subjects
    		 47 47 94
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age of all patients included in the full analysis set
    Units: years
        median (standard deviation)
    		 64 ( 15 ) 63 ( 18 ) -
    Gender categorical
    Gender of all patients included in the full-analysis set
    Units: Subjects
        Female
    		 7 20 27
        Male
    		 40 27 67

    End points

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    End points reporting groups
    Reporting group title
    Direct thrombin inhibitor
    Reporting group description
    		 Dabigatran or argatroban

    Reporting group title
    Enoxaparin
    Reporting group description
    		 enoxaparin 40 mg OD SC

    Primary: Bleeding

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    End point title
    		 Bleeding
    End point description
    Bleeding
    End point type
    Primary
    End point timeframe
    During study drug treatment and until 3 days after the end of the study period
    End point values
    		 Direct thrombin inhibitor Enoxaparin
    Number of subjects analysed
    47
    47
    Units: whole
        Major bleeding
    1
    1
        Clinically relevant non major bleeding
    4
    4
        Gastro intestinal tract
    2
    0
        Respiratory tract
    2
    0
        Urogenital tract
    0
    2
        post intervention
    0
    2
        Minor bleeding
    4
    6
    Statistical analysis title
    		 intention to treat
    Statistical analysis description
    The study was not powered to detect significant differences in the Clinical outcomes due to the small study population. Statistical analysis was done in an intention to treat model (retaining all participants in their originally assigned group), as well as per protocol (defined as patients that received at least 80% of sheduled doses of DTI from randomization to day 4, compared with control patients). We uses GraphPad Prism and utilzed appropriate tests to compare variables between groups.
    Comparison groups
    Direct thrombin inhibitor v Enoxaparin
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.45
    Method
    		 GraphPad Prism
    Confidence interval
    Notes
    [1] - An intention to treat model. A preliminary power calculation was based on a differential evolution of D dimers in DTI treated versus control patients. We hypothesized that DTIs would result in a more rapid resolution of coagulation activation in S Aureus bacteraemia. With an estimated D dimer decline of 1.000 ng/mL in the DTI group versus 500 ng/mL in the control group, a sample size 2X50 patients has 80% power to detect such difference.

    Secondary: hospital stay

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    End point title
    		 hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    whole study
    End point values
    		 Direct thrombin inhibitor Enoxaparin
    Number of subjects analysed
    47
    47
    Units: whole
    19
    16
    Statistical analysis title
    		 intention to treat
    Statistical analysis description
    The study was not powered to detect significant differences in the Clinical outcomes due to the small study population. Statistical analysis was done in an intention to treat model (retaining all participants in their originally assigned group), as well as per protocol (defined as patients that received at least 80% of sheduled doses of DTI from randomization to day 4, compared with control patients). We uses GraphPad Prism and utilzed appropriate tests to compare variables between groups.
    Comparison groups
    Direct thrombin inhibitor v Enoxaparin
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.27
    Method
    		 GraphPad Prism
    Confidence interval
    Notes
    [2] - An intention to treat model. A preliminary power calculation was based on a differential evolution of D dimers in DTI treated versus control patients. We hypothesized that DTIs would result in a more rapid resolution of coagulation activation in S Aureus bacteraemia. With an estimated D dimer decline of 1.000 ng/mL in the DTI group versus 500 ng/mL in the control group, a sample size 2X50 patients has 80% power to detect such difference.

    Secondary: 90 day mortality

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    End point title
    		 90 day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    whole study
    End point values
    		 Direct thrombin inhibitor Enoxaparin
    Number of subjects analysed
    47
    47
    Units: whole
    10
    9
    Statistical analysis title
    		 intention to treat
    Statistical analysis description
    The study was not powered to detect significant differences in the Clinical outcomes due to the small study population. Statistical analysis was done in an intention to treat model (retaining all participants in their originally assigned group), as well as per protocol (defined as patients that received at least 80% of sheduled doses of DTI from randomization to day 4, compared with control patients). We uses GraphPad Prism and utilzed appropriate tests to compare variables between groups.
    Comparison groups
    Direct thrombin inhibitor v Enoxaparin
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 > 0.99
    Method
    		 GraphPad Prism
    Confidence interval
    Notes
    [3] - An intention to treat model. A preliminary power calculation was based on a differential evolution of D dimers in DTI treated versus control patients. We hypothesized that DTIs would result in a more rapid resolution of coagulation activation in S Aureus bacteraemia. With an estimated D dimer decline of 1.000 ng/mL in the DTI group versus 500 ng/mL in the control group, a sample size 2X50 patients has 80% power to detect such difference.

    Secondary: Thrombosis

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    End point title
    		 Thrombosis
    End point description
    Total Thrombosis
    End point type
    Secondary
    End point timeframe
    whole study
    End point values
    		 Direct thrombin inhibitor Enoxaparin
    Number of subjects analysed
    47
    47
    Units: whole
        Arterial thromboembolism
    1
    1
        Superficial venous thrombophlebitis
    4
    5
        Deep vein thrombosis
    2
    1
    Statistical analysis title
    		 intention to treat
    Statistical analysis description
    The study was not powered to detect significant differences in the Clinical outcomes due to the small study population. Statistical analysis was done in an intention to treat model (retaining all participants in their originally assigned group), as well as per protocol (defined as patients that received at least 80% of sheduled doses of DTI from randomization to day 4, compared with control patients). We uses GraphPad Prism and utilzed appropriate tests to compare variables between groups.
    Comparison groups
    Direct thrombin inhibitor v Enoxaparin
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 > 0.99
    Method
    		 GraphPad Prism
    Confidence interval
    Notes
    [4] - An intention to treat model. A preliminary power calculation was based on a differential evolution of D dimers in DTI treated versus control patients. We hypothesized that DTIs would result in a more rapid resolution of coagulation activation in S Aureus bacteraemia. With an estimated D dimer decline of 1.000 ng/mL in the DTI group versus 500 ng/mL in the control group, a sample size 2X50 patients has 80% power to detect such difference.

    Other pre-specified: Defervescence

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    End point title
    		 Defervescence
    End point description
    End point type
    Other pre-specified
    End point timeframe
    whole study
    End point values
    		 Direct thrombin inhibitor Enoxaparin
    Number of subjects analysed
    47
    47
    Units: whole
    26
    12
    Statistical analysis title
    		 intention to treat
    Statistical analysis description
    The study was not powered to detect significant differences in the Clinical outcomes due to the small study population. Statistical analysis was done in an intention to treat model (retaining all participants in their originally assigned group), as well as per protocol (defined as patients that received at least 80% of sheduled doses of DTI from randomization to day 4, compared with control patients). We uses GraphPad Prism and utilzed appropriate tests to compare variables between groups.
    Comparison groups
    Direct thrombin inhibitor v Enoxaparin
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.3
    Method
    		 GraphPad Prism
    Confidence interval
    Notes
    [5] - An intention to treat model. A preliminary power calculation was based on a differential evolution of D dimers in DTI treated versus control patients. We hypothesized that DTIs would result in a more rapid resolution of coagulation activation in S Aureus bacteraemia. With an estimated D dimer decline of 1.000 ng/mL in the DTI group versus 500 ng/mL in the control group, a sample size 2X50 patients has 80% power to detect such difference.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 months after inclusion
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ISTH major bleeding
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Direct thrombin inhibitor
    Reporting group description
    		 -

    Reporting group title
    Enoxaparin
    Reporting group description
    		 -

    Serious adverse events
    		 Direct thrombin inhibitor Enoxaparin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         number of deaths (all causes)
    10
    9
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Direct thrombin inhibitor Enoxaparin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 47 (14.89%)
    8 / 47 (17.02%)
    Infections and infestations
    relapse infection
    Additional description: Relapse of S. Aureus bacteraemia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    metastatic infection
    Additional description: Metastatic infection on PET/CT. Not all patients received planned PET/CT: DTI Group: 30 patients received PET/CT (2/30) Control group: 27 patients received PET/CT (6/27)
         subjects affected / exposed
    2 / 47 (4.26%)
    6 / 47 (12.77%)
         occurrences all number
    2
    6
    infective endocarditis
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    3
    2

    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.
    The feasibility of the broad application of DTI in septic patients is limited by their anticoagulant action, hence explaining the large proportion of excluded patients (with bleeding risk) and the non-negligible number of bleeding events.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29614521
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