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    Clinical Trial Results:
    SAICoDis – Safety of Argatroban Infusion in Conduction Disturbances. A prospective, open, multicenter safety study to investigate conduction disturbances in patients receiving argatroban therapy.

    Summary
    EudraCT number
    		 2016-003521-42
    Trial protocol
    		 DE  
    Global end of trial date
    06 May 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    09 Sep 2023
    First version publication date
    21 Oct 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of a primary end point value - standard deviation at Centre 2.

    Trial information

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    Trial identification
    Sponsor protocol code
    ARG-E08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mitsubishi Tanabe Pharma GmbH
    Sponsor organisation address
    Willstätterstr. 30, Düsseldorf, Germany, 40549
    Public contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd, regulatory@mt-pharma-eu.com
    Scientific contact
    Scientific Medical Adviser, Mitsubishi Tanabe Pharma GmbH, o.grapenthin@mt-pharma-de.com
    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
    12 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the change of QTc interval during argatroban infusion in patients undergoing PCI. To observe whether argatroban had a pharmacological effect on cardiac repolarization it was investigated, if a mean QTc prolongation of more than 10 ms occured between ECG-2, which needed to be performed immediately after cardiac intervention in a status of full anticoagulation with argatroban and ECG-1, the baseline ECG.
    Protection of trial subjects
    The study was conducted in accordance with the 2013 (Fortaleza) revision of the 1964 Declaration of Helsinki, Good Clinical Practice as required by the International Conference on Harmonisation guidelines, applicable regional and local legislation, and standard operating procedures in place at Mitsubishi Tanabe Pharma GmbH, Mitsubishi Tanabe Pharma Europe Ltd. and at the contracted vendor. All participants underwent screening aimed at minimising the likelihood and impact of potential risks of argatroban. In addition, regular safety monitoring during the study period for all participants ensured that any unanticipated effects of study participation were identified promptly and managed appropriately. Risk minimisation measures were also employed during the study as per the risk-benefit assessment for potential anticipated risks. A subject was to be withdrawn if any of the following criteria were met: - Patients have the right to withdraw from the study at any time for any reason. - The investigator also has the right to withdraw patients from the study in the event of intercurrent illness, AEs and treatment failure, administrative reasons or other reasons. -Women of childbearing potential or less than one year after menopause (unless surgically sterile) needed to show a negative pregnancy test at screening.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Apr 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
    Germany: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    24
    From 65 to 84 years
    25
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients were recruited from a patient population who was diagnosed with stable coronary artery disease or unstable angina (troponin negative) undergoing elective PCI or patients in which only angiography was planned. The physician identified suitable patients by pre-screening medical records at the study centre.

    Pre-assignment
    Screening details
    		 Screening assessments were performed from hour -72 to -12. These assessments included written informed consent, demography, height, bodyweight, medical history, past and concomitant treatment, vital signs, verification of inclusion/ exclusion criteria, blood analysis, urine texts, 12-lead ECG. A total of 60 subjects were screened.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Treatment in this clinical trial is open. However, to minimize bias, a central ECG reader (cardiac specialist) was blinded to patient data (patient ID, name, initials and birth date) and the time point on which the ECG was taken. In addition, automatically evaluated and printed ECG data (e.g. QT interval and diagnostic data) was blackened. Finally, each blinded ECG recording was pseudonymised manually by adding a unique number.

    Arms
    Arm title
    		 Overall trial
    Arm description
    		 Patients received an intravenous (i.v.) bolus of 300 μg/kg argatroban administered over a span of 3 to 5 minutes followed by the i.v. infusion of argatroban at 20 μg/kg/min until the end of the procedure. ACT was checked 5 minutes after bolus dose. If ACT remained below the target of 300 s, the patient received an additional i.v. bolus injection of 150 μg/kg and the infusion dose was raised up to 30 μg/kg/min. In cases ACT > 450 s, the infusion was reduced to 15 μg/kg/min and the value was checked again after 5 minutes. As soon as the target ACT (between 300 s and 450 s) was reached, infusion dose remained unchanged during the PCI procedure. Depending on clinical relevancy further ACT assessments were possible.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Argatra® Multidose
    Investigational medicinal product code
    ARG
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Parenteral use
    Dosage and administration details
    Patients received an intravenous (i.v.) bolus of 300 μg/kg argatroban administered over a span of 3 to 5 minutes followed by the i.v. infusion of argatroban at 20 μg/kg/min until the end of the procedure. ACT was checked 5 minutes after bolus dose. If ACT remained below the target of 300 s, the patient received an additional i.v. bolus injection of 150 μg/kg and the infusion dose was raised up to 30 μg/kg/min. In cases ACT > 450 s, the infusion was reduced to 15 μg/kg/min and the value was checked again after 5 minutes. As soon as the target ACT (between 300 s and 450 s) was reached, infusion dose remained unchanged during the PCI procedure. Depending on clinical relevancy further ACT assessments were possible.

    Number of subjects in period 1
    		Overall trial
    Started
    50
    Completed
    49
    Not completed
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All the patients of the enrollment set in whom argatroban was administered (ITT population).

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 50 50
    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)
    		 24 24
        From 65-84 years
    		 25 25
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.50 ± 10.43 -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 39 39
    Stable CAD and/or unstable angina (troponin negative)
    Angina pectoris
    Units: Subjects
        Stable
    		 40 40
        Unstable
    		 9 9
        N/A
    		 1 1
    ECG at screening without changes that impair assessment of QTc interval
    Units: Subjects
        Yes
    		 50 50
        No
    		 0 0
    Ethnicity
    Units: Subjects
        White
    		 49 49
        Black
    		 1 1
    Height, weight, BMI
    BMI (kg/m²; n=50)
    Units: Subjects
        Normal weight (18.5 - < 25 kg/m²)
    		 12 12
        Pre-obesity (25 - < 30 kg/m²)
    		 20 20
        Obesity class I (30 - < 35 kg/m²)
    		 11 11
        Obesity class II (35 - < 40 kg/m²)
    		 5 5
        Obesity class III (>= 40 kg/m²)
    		 2 2
    Pregnancy test
    Patient at least one year after menopause or surgically sterile (n=11).
    Units: Subjects
        Yes
    		 11 11
        N/A
    		 39 39
    Classification for patients with stable Angina pectoris
    n=40 patients
    Units: Subjects
        CCS I
    		 6 6
        CCS II
    		 14 14
        CCS III
    		 20 20
        N/A
    		 10 10
    Maximal stenosis severity pre-PCI
    Units: percent
        arithmetic mean (standard deviation)
    		 72.72 ± 27.65 -
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 175.02 ± 9.69 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 89.86 ± 20.22 -
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 29.22 ± 5.78 -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All the patients of the enrolment set in whom argatroban was administered.

    Subject analysis set title
    ITT population/Subgroup Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Gender Male (subjects from ITT population).

    Subject analysis set title
    ITT population/Subgroup Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Gender Female (subjects from ITT population).

    Subject analysis set title
    ITT population/Centre 01
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Centre 01 (subjects from ITT population).

    Subject analysis set title
    ITT population/Centre 02
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Centre 02 (subjects from ITT population).

    Subject analysis sets values
    		 ITT population ITT population/Subgroup Male ITT population/Subgroup Female ITT population/Centre 01 ITT population/Centre 02
    Number of subjects
    50
    39
    11
    25
    25
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
        Adults (18-64 years)
    24
    21
    3
    10
    14
        From 65-84 years
    25
    18
    7
    14
    11
        85 years and over
    1
    0
    1
    1
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.50 ± 10.43
    63.23 ± 10.51
    69 ± 9.2
    66.28 ± 10.60
    62.72 ± 10.16
    Gender categorical
    Units: Subjects
        Female
    11
    0
    11
    7
    4
        Male
    39
    39
    0
    18
    21
    Stable CAD and/or unstable angina (troponin negative)
    Angina pectoris
    Units: Subjects
        Stable
    40
    33
    7
    19
    21
        Unstable
    9
    6
    3
    6
    3
        N/A
    1
    0
    1
    0
    1
    ECG at screening without changes that impair assessment of QTc interval
    Units: Subjects
        Yes
    50
    39
    11
    25
    25
        No
    0
    0
    0
    0
    0
    Ethnicity
    Units: Subjects
        White
    49
    38
    11
    24
    25
        Black
    1
    1
    0
    1
    0
    Height, weight, BMI
    BMI (kg/m²; n=50)
    Units: Subjects
        Normal weight (18.5 - < 25 kg/m²)
    12
    6
    6
    7
    5
        Pre-obesity (25 - < 30 kg/m²)
    20
    17
    3
    10
    10
        Obesity class I (30 - < 35 kg/m²)
    11
    11
    0
    4
    7
        Obesity class II (35 - < 40 kg/m²)
    5
    5
    0
    2
    3
        Obesity class III (>= 40 kg/m²)
    2
    0
    2
    2
    0
    Pregnancy test
    Patient at least one year after menopause or surgically sterile (n=11).
    Units: Subjects
        Yes
    11
    0
    11
    7
    4
        N/A
    39
    0
    0
    18
    21
    Classification for patients with stable Angina pectoris
    n=40 patients
    Units: Subjects
        CCS I
        CCS II
        CCS III
        N/A
    Maximal stenosis severity pre-PCI
    Units: percent
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    175.02 ± 9.69
    178 ± 8.13
    164.45 ± 7.13
    172.44 ± 8.90
    177.6 ± 9.92
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    89.86 ± 20.22
    93.49 ± 17.45
    77.0 ± 24.75
    93.49 ± 17.31
    92.92 ± 22.70
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Patients received an intravenous (i.v.) bolus of 300 μg/kg argatroban administered over a span of 3 to 5 minutes followed by the i.v. infusion of argatroban at 20 μg/kg/min until the end of the procedure. ACT was checked 5 minutes after bolus dose. If ACT remained below the target of 300 s, the patient received an additional i.v. bolus injection of 150 μg/kg and the infusion dose was raised up to 30 μg/kg/min. In cases ACT > 450 s, the infusion was reduced to 15 μg/kg/min and the value was checked again after 5 minutes. As soon as the target ACT (between 300 s and 450 s) was reached, infusion dose remained unchanged during the PCI procedure. Depending on clinical relevancy further ACT assessments were possible.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All the patients of the enrolment set in whom argatroban was administered.

    Subject analysis set title
    ITT population/Subgroup Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Gender Male (subjects from ITT population).

    Subject analysis set title
    ITT population/Subgroup Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Gender Female (subjects from ITT population).

    Subject analysis set title
    ITT population/Centre 01
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Centre 01 (subjects from ITT population).

    Subject analysis set title
    ITT population/Centre 02
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Centre 02 (subjects from ITT population).

    Primary: Mean difference in QTc interval between ECG-2 and ECG-1

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    End point title
    		 Mean difference in QTc interval between ECG-2 and ECG-1 [1]
    End point description
    It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1. P-values were as follows: ITT population: <0.0866 ITT population/Subgroup Male: <0.0195 ITT population/Subgroup Female: <0.8863 ITT population/Centre 01: <0.7085 ITT population/Centre 02: <0.0076
    End point type
    Primary
    End point timeframe
    ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status).
    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 system does not allow for statistical analysis for single arm studies. P-values are provided in the end point description.
    End point values
    		 ITT population ITT population/Subgroup Male ITT population/Subgroup Female ITT population/Centre 01 ITT population/Centre 02
    Number of subjects analysed
    50
    39
    11
    25
    25
    Units: millisecond(s)
    arithmetic mean (standard deviation)
        Prolongation of QTc >10 ms
    0.94 ± 46.37
    -5.8936 ± 46.4072
    25.1460 ± 39.0616
    15.0046 ± 44.9538
    -13.1343 ± 44.2363
    No statistical analyses for this end point

    Secondary: Proportion of patients with a prolongation of QTc interval to > 500 ms at ECG-2

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    End point title
    		 Proportion of patients with a prolongation of QTc interval to > 500 ms at ECG-2
    End point description
    Number of patients of ITT population exhibiting QTc interval of > 500 ms.
    End point type
    Secondary
    End point timeframe
    ECG-2 immediately after argatroban infusion.
    End point values
    		 Overall trial
    Number of subjects analysed
    50
    Units: number of patients
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the beginning of the study (date of treatment visit) to the study termination (after completion of ECG-3 measurement).
    Adverse event reporting additional description
    All AEs encountered during the clinical study will be reported on the AE page of the CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 50 (6.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Vascular stent thrombosis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 50 (8.00%)
    Investigations
    Electrocardiogram ST segment depression
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Hypertension
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2017
    Protocol change to v1.2: Change of patient recruitment.
    09 Jan 2019
    Protocol change to v1.6: Restart of interrupted study.
    10 Dec 2020
    Protocol change to v2.0: Change from mono-centre to multi-centre study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Jun 2018
    In 2 of 13 treated patients experienced SAEs, one of which was considered "not study drug related", the second one led to the interruption (cause of event: study treatment; related to study medication/SUSAR; outcome: resolving).
    09 Jan 2019

    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
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