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    Clinical Trial Results:
    A Randomized, Double-blind, Double-dummy, Multicenter, Adaptive Design, Dose Escalation (Part 1) and Dose-Response (Part 2) Study to Evaluate the Safety and Efficacy of Intravenous JNJ-64179375 Versus Oral Apixaban in Subjects Undergoing Elective Total Knee Replacement Surgery

    Summary
    EudraCT number
    2016-004550-15
    Trial protocol
    BE   ES   PL   LV   LT   BG   GR   PT   IT  
    Global end of trial date
    05 Nov 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    64179375THR2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03251482
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    05 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective for Part 1 was to assess in men and women undergoing primary unilateral total knee replacement (TKR) surgery the safety and tolerability of JNJ-64179375 for each dose level for dose escalation within Part 1 and any bleeding events (the composite of major, clinically relevant nonmajor [CRNM], and minimal bleeding events) for the selection of doses for Part 2 and for Part 2 was to assess in men and women undergoing primary unilateral total knee replacement (TKR) surgery the efficacy dose-response of JNJ-64179375 for the prevention of total venous thromboembolism (VTE) (proximal and/or distal deep vein thrombosis (DVT) [asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic], nonfatal pulmonary embolism [PE], or any death).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included the monitoring of all non-serious and serious adverse events (AEs), (including AEs of special interest: suspected symptomatic efficacy (thrombotic) events, bleeding events, infusion reactions, hypersensitivity reactions, and wound or joint complications), clinical laboratory tests (ie, hematology, clinical chemistry, urinalysis), vital signs measurements (blood pressure, pulse/heart rate, temperature), and physical examinations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Turkey: 23
    Country: Number of subjects enrolled
    Ukraine: 38
    Country: Number of subjects enrolled
    United States: 56
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Japan: 12
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Lithuania: 12
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Poland: 60
    Country: Number of subjects enrolled
    Russian Federation: 14
    Worldwide total number of subjects
    305
    EEA total number of subjects
    128
    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)
    128
    From 65 to 84 years
    173
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 360 subjects were screened. Of those, 308 subjects were randomized: 245 subjects to JNJ-64179375 intravenous (IV) doses and 63 subjects to the apixaban dose. The safety analysis set included 305 of the 308 subjects (99.0%) who were treated with study drug.

    Pre-assignment
    Screening details
    The study was planned to be conducted in 2 parts: Part 1 (Dose- Escalation) and Part 2 (Dose-Response). After completion of Part 1, the sponsor made the decision to not move forward with Part 2 as there was sufficient data to make a determination of efficacy in Part 1. Part 2 was not conducted, hence endpoints for Part 2 are not reported.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo
    Arm description
    Subjects received a single intravenous (IV) infusion of JNJ-64179375 0.3 milligrams per kilogram (mg/kg) on Day 1 and matching apixaban placebo tablets orally twice daily (BID) for 10 to 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    JNJ-64179375 0.3 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single IV infusion of JNJ-64179375 0.3 mg/kg on Day 1.

    Investigational medicinal product name
    Apixaban Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching apixaban placebo tablets BID for 10 to 14 days.

    Arm title
    JNJ-64179375 0.6 mg/kg and Apixaban Placebo
    Arm description
    Subjects received a single IV infusion of JNJ-64179375 0.6 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    JNJ-64179375 0.6 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single IV infusion of JNJ-64179375 0.6 mg/kg on Day 1.

    Investigational medicinal product name
    Apixaban Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching apixaban placebo tablets BID for 10 to 14 days.

    Arm title
    JNJ-64179375 1.2 mg/kg and Apixaban Placebo
    Arm description
    Subjects received a single IV infusion of JNJ-64179375 1.2 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    JNJ-6417937 1.2 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single IV infusion of JNJ-64179375 1.2 mg/kg on Day 1.

    Investigational medicinal product name
    Apixaban Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching apixaban placebo tablets BID for 10 to 14 days.

    Arm title
    JNJ-64179375 1.8 mg/kg and Apixaban Placebo
    Arm description
    Subjects received a single IV infusion of JNJ-64179375 1.8 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Apixaban Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching apixaban placebo tablets BID for 10 to 14 days.

    Investigational medicinal product name
    JNJ-64179375 1.8 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single IV infusion of JNJ-64179375 1.8 mg/kg on Day 1.

    Arm title
    Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Arm description
    Subjects received a single IV infusion of matching JNJ-64179375 placebo on Day 1 and apixaban 2.5 mg tablet orally BID for 10 to 14 days.
    Arm type
    Active comparator

    Investigational medicinal product name
    JNJ-64179375 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single IV infusion of matching JNJ-64179375 placebo on Day 1.

    Investigational medicinal product name
    Apixaban 2.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an oral dose of apixaban 2.5 mg tablets BID for 10 to 14 days.

    Number of subjects in period 1
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Started
    38
    40
    42
    122
    63
    Completed
    38
    40
    42
    122
    63

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single intravenous (IV) infusion of JNJ-64179375 0.3 milligrams per kilogram (mg/kg) on Day 1 and matching apixaban placebo tablets orally twice daily (BID) for 10 to 14 days.

    Reporting group title
    JNJ-64179375 0.6 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 0.6 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    JNJ-64179375 1.2 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 1.2 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    JNJ-64179375 1.8 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 1.8 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Reporting group description
    Subjects received a single IV infusion of matching JNJ-64179375 placebo on Day 1 and apixaban 2.5 mg tablet orally BID for 10 to 14 days.

    Reporting group values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV Total
    Number of subjects
    38 40 42 122 63 305
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0
        Adults (18-64 years)
    16 20 13 49 30 128
        From 65 to 84 years
    22 19 29 70 33 173
        85 years and over
    0 1 0 3 0 4
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    66.2 ± 7.53 65.8 ± 8.14 66.9 ± 6.41 67.2 ± 8.84 65.1 ± 7.01 -
    Title for Gender
    Units: subjects
        Female
    21 25 35 99 42 222
        Male
    17 15 7 23 21 83

    End points

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    End points reporting groups
    Reporting group title
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single intravenous (IV) infusion of JNJ-64179375 0.3 milligrams per kilogram (mg/kg) on Day 1 and matching apixaban placebo tablets orally twice daily (BID) for 10 to 14 days.

    Reporting group title
    JNJ-64179375 0.6 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 0.6 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    JNJ-64179375 1.2 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 1.2 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    JNJ-64179375 1.8 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 1.8 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Reporting group description
    Subjects received a single IV infusion of matching JNJ-64179375 placebo on Day 1 and apixaban 2.5 mg tablet orally BID for 10 to 14 days.

    Primary: Number of Subjects with Treatment-emergent Bleeding Events (Clinical Events Committee [CEC]-adjudicated)

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    End point title
    Number of Subjects with Treatment-emergent Bleeding Events (Clinical Events Committee [CEC]-adjudicated) [1]
    End point description
    Number of subjects with treatment-emergent bleeding events (adjudicated by CEC) were reported. Bleeding event (BE) was defined as the composite of major, clinically relevant nonmajor (CRNM), and minimal bleeding events assessed through the Day 10 to 14. Safety Analysis Set (SAS) included all randomized subjects who received at least 1 dose (partial or complete) of active study drug (JNJ-64179375 or apixaban).
    End point type
    Primary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    38
    40
    42
    122
    63
    Units: Subjects
    2
    0
    5
    1
    4
    No statistical analyses for this end point

    Primary: Number of Subjects With Total Venous Thromboembolism (VTE) (CEC-adjudicated)

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    End point title
    Number of Subjects With Total Venous Thromboembolism (VTE) (CEC-adjudicated) [2]
    End point description
    Number of subjects with total VTE were reported. Total VTE was defined as the composite of CEC-adjudicated proximal and/or distal deep vein thrombosis (DVT) (asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic), nonfatal pulmonary embolism (PE), or any death assessed through the Day 10 to 14 visit. Modified Intent-to-treat (mITT) analysis set included all randomized subjects with an evaluable venography assessment or a confirmed symptomatic VTE event or any death. 1 subject had an asymptomatic distal clot in the non-operated leg which is not counted in the Total VTE and 2 subjects had symptomatic proximal clots at the Day 10 to 14 venography and are counted in both the asymptomatic proximal and symptomatic proximal groups.
    End point type
    Primary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    Notes
    [2] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
    10
    9
    9
    31
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Composite of Major and CRNM Bleeding Events (CEC-adjudicated)

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    End point title
    Number of Subjects With Composite of Major and CRNM Bleeding Events (CEC-adjudicated)
    End point description
    Number of subjects with composite of major and CRNM bleeding events were reported. Major Bleeding: Fatal bleeding; Bleeding that is symptomatic and occurs in critical area/organ and/or; Extrasurgical site bleeding causing fall in Hb level of 20 g/L or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; Surgical site bleeding that requires second intervention open, arthroscopic, endovascular, or hemarthrosis resulting in prolonged hospitalization or a deep wound infection and/or; Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria for BE to be defined as major BE and meets at least 1 of following: Epistaxis, Gastrointestinal bleed, Hematuria, Bruising/ecchymosis, Hemoptysis, Hematoma. Population included safety analysis set.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    38
    40
    42
    122
    63
    Units: Subjects
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Major Bleeding Events (CEC-adjudicated)

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    End point title
    Number of Subjects With Major Bleeding Events (CEC-adjudicated)
    End point description
    Number of subjects with major bleeding events (CEC-adjudicated) were reported. Major bleeding: fatal bleeding or bleeding that is symptomatic and occurs in a critical area or organ in a non-operated joint, or intramuscular with compartment syndrome, assessed in consultation with surgeon, and/or extra-surgical site bleeding causing a fall in hemoglobin (Hb) level of 20 grams per liter (g/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells, with temporal association within 24-48 hours to bleeding or surgical site bleeding that requires a second intervention open, arthroscopic, endovascular, or a hemarthrosis of sufficient size as to interfere with rehabilitation by delaying mobilization or delayed wound healing, resulting in prolonged hospitalization or a deep wound infection or Surgical site bleeding that is unexpected and prolonged or sufficiently large to cause hemodynamic instability, as assessed by surgeon. Population included safety analysis set.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    38
    40
    42
    122
    63
    Units: Subjects
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Relevant non-major (CRNM) Bleeding Events (CEC-adjudicated)

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    End point title
    Number of Subjects With Clinically Relevant non-major (CRNM) Bleeding Events (CEC-adjudicated)
    End point description
    Number of subjects with CRNM bleeding events (adjudicated by CEC) were reported. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria for BE to be defined as major BE and meets at least 1 of following: Epistaxis, Gastrointestinal bleed, Hematuria, Bruising/ecchymosis, Hemoptysis, Hematoma. Safety analysis set included all randomized participants who received at least 1 dose (partial or complete) of active study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    38
    40
    42
    122
    63
    Units: Subjects
    1
    0
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Major Bleeding or CRNM Bleeding Events (CEC-adjudicated)

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    End point title
    Number of Subjects With Major Bleeding or CRNM Bleeding Events (CEC-adjudicated)
    End point description
    Number of subjects with major bleeding or CRNM bleeding events (adjudicated by CEC) were reported. Major Bleeding: Fatal bleeding; Bleeding that is symptomatic and occurs in critical area/organ and/or; Extrasurgical site bleeding causing fall in Hb level of 20 g/L or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; Surgical site bleeding that requires second intervention open, arthroscopic, endovascular, or hemarthrosis resulting in prolonged hospitalization or a deep wound infection and/or; Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria for bleeding events to be defined as major bleeding event and meets at least 1 of following: Epistaxis, Gastrointestinal bleed, Hematuria, Bruising/ecchymosis, Hemoptysis, Hematoma. SAS was analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 and 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    38
    40
    42
    122
    63
    Units: Subjects
    1
    0
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Minimal Bleeding Events (CEC-adjudicated)

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    End point title
    Number of Subjects With Minimal Bleeding Events (CEC-adjudicated)
    End point description
    Number of subjects with minimal bleeding events (adjudicated by CEC) were reported. Minimal bleeding event was defined as any bleeding event not met major or CRNM criteria. Safety analysis set included all randomized subjects who received at least 1 dose (partial or complete) of active study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    38
    40
    42
    122
    63
    Units: Subjects
    2
    0
    4
    0
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Major VTE (CEC-adjudicated)

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    End point title
    Number of Subjects With Major VTE (CEC-adjudicated)
    End point description
    Number of subjects with major VTE (adjudicated by CEC) were reported. Major VTE was defined as a composite of proximal DVT (asymptomatic confirmed by venography or objectively confirmed symptomatic), nonfatal PE, or any death. mITT analysis set included all randomized subjects with an evaluable venography assessment or a confirmed symptomatic VTE event or any death. 2 subjects had symptomatic proximal clots at the Day 10 to 14 venography and are counted in both the asymptomatic proximal and symptomatic proximal groups.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
    2
    2
    1
    7
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)

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    End point title
    Number of Subjects With Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)
    End point description
    Number of subjects with proximal DVT (adjudicated by CEC) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic. mITT analysis set included all randomized subjects with an evaluable venography assessment or a confirmed symptomatic VTE event or any death. 2 subjects had symptomatic proximal clots at the Day 10 to 14 venography and are counted in both the asymptomatic proximal and symptomatic proximal groups.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
        Asymptomatic
    1
    2
    0
    3
    0
        Symptomatic
    0
    0
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)

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    End point title
    Number of Subjects With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)
    End point description
    Number of subjects with nonfatal PE (adjudicated by CEC) were reported. mITT analysis set included all randomized subjects with an evaluable venography assessment or a confirmed symptomatic VTE event, or any death.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Death (CEC-adjudicated)

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    End point title
    Number of Subjects With Death (CEC-adjudicated)
    End point description
    Number of subjects with death (adjudicated by CEC) were reported. mITT analysis set included all randomized subjects with an evaluable venography assessment or a confirmed symptomatic VTE event, or any death.
    End point type
    Secondary
    End point timeframe
    Up to 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Proximal and Distal DVT (CEC-adjudicated)

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    End point title
    Number of Subjects With Proximal and Distal DVT (CEC-adjudicated)
    End point description
    Number of subjects with proximal and distal DVT (adjudicated by CEC) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic. mITT analysis set included all randomized subjects with an evaluable venography assessment or a confirmed symptomatic VTE event, or any death. 2 subjects had symptomatic proximal clots at the Day 10 to 14 venography and are counted in both the asymptomatic proximal and symptomatic proximal groups.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
        Asymptomatic
    1
    0
    1
    4
    0
        Symptomatic
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Distal DVT (CEC-adjudicated)

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    End point title
    Number of Subjects With Distal DVT (CEC-adjudicated)
    End point description
    Number of subjects with distal DVT (adjudicated by CEC) were reported. mITT analysis set included all randomized participants with an evaluable venography assessment or a confirmed symptomatic VTE event, or any death.
    End point type
    Secondary
    End point timeframe
    Up to Day 10 to 14 (visit observation period)
    End point values
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Number of subjects analysed
    30
    33
    30
    97
    49
    Units: Subjects
        Asymptomatic
    8
    7
    8
    24
    6
        Symptomatic
    0
    0
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 18 weeks
    Adverse event reporting additional description
    Safety Analysis set included all randomized subjects who received at least 1 dose (partial or complete) of active study drug (JNJ-64179375 or apixaban).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single intravenous (IV) infusion of JNJ-64179375 0.3 milligrams per kilogram (mg/kg) on Day 1 and matching apixaban placebo tablets orally twice daily (BID) for 10 to 14 days.

    Reporting group title
    JNJ-64179375 0.6 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 0.6 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    JNJ-64179375 1.2 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 1.2 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    JNJ-64179375 1.8 mg/kg and Apixaban Placebo
    Reporting group description
    Subjects received a single IV infusion of JNJ-64179375 1.8 mg/kg on Day 1 and matching apixaban placebo tablets orally BID for 10 to 14 days.

    Reporting group title
    Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Reporting group description
    Subjects received a single IV infusion of matching JNJ-64179375 placebo on Day 1 and apixaban 2.5 mg tablet orally BID for 10 to 14 days.

    Serious adverse events
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 40 (5.00%)
    4 / 42 (9.52%)
    13 / 122 (10.66%)
    5 / 63 (7.94%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Bloody Discharge
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    6 / 122 (4.92%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Thrombotic Syndrome
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Complication
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer Stage 0, with Cancer in Situ
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Unstable
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired Healing
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Contracture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Primary Hyperaldosteronism
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Herpes Zoster
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    JNJ-64179375 0.3 mg/kg and Apixaban Placebo JNJ-64179375 0.6 mg/kg and Apixaban Placebo JNJ-64179375 1.2 mg/kg and Apixaban Placebo JNJ-64179375 1.8 mg/kg and Apixaban Placebo Apixaban 2.5 mg and JNJ-64179375 Placebo IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 38 (50.00%)
    17 / 40 (42.50%)
    26 / 42 (61.90%)
    37 / 122 (30.33%)
    20 / 63 (31.75%)
    Vascular disorders
    Bloody Discharge
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    2 / 122 (1.64%)
    3 / 63 (4.76%)
         occurrences all number
    2
    1
    0
    2
    3
    Haematoma
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    4 / 122 (3.28%)
    2 / 63 (3.17%)
         occurrences all number
    1
    1
    0
    4
    2
    Hypotension
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    2
    0
    1
    Peripheral Venous Disease
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    3 / 122 (2.46%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Thrombophlebitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    General disorders and administration site conditions
    Catheter Site Haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Fat Necrosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Feeling Hot
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hyperthermia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    2 / 42 (4.76%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Impaired Healing
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Injection Site Irritation
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    2 / 122 (1.64%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Peripheral Swelling
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    8 / 122 (6.56%)
    1 / 63 (1.59%)
         occurrences all number
    9
    0
    0
    10
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    1
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    3 / 42 (7.14%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    5
    0
    1
    Patella Fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Post Procedural Haematoma
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Post Procedural Swelling
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Procedural Haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Procedural Pain
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    4 / 122 (3.28%)
    2 / 63 (3.17%)
         occurrences all number
    0
    0
    1
    4
    2
    Tendon Rupture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Wound Haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    3 / 42 (7.14%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Investigations
    Blood Glucose Increased
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Blood Thyroid Stimulating Hormone Increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood Triglycerides Increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Body Temperature Increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cardiovascular Evaluation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gamma-Glutamyltransferase Decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Platelet Count Increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    1
    Pulmonary Embolism
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    0
    0
    1
    Nervous system disorders
    Dizziness Exertional
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    1
    0
    0
    0
    1
    Dizziness Postural
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    3 / 122 (2.46%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    3
    2
    Neuralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eye disorders
    Conjunctival Haemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    1
    Gastrointestinal disorders
    Aphthous Ulcer
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    2 / 63 (3.17%)
         occurrences all number
    2
    0
    0
    1
    3
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 40 (5.00%)
    0 / 42 (0.00%)
    2 / 122 (1.64%)
    1 / 63 (1.59%)
         occurrences all number
    2
    2
    0
    2
    1
    Food Poisoning
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 40 (7.50%)
    5 / 42 (11.90%)
    3 / 122 (2.46%)
    0 / 63 (0.00%)
         occurrences all number
    1
    3
    5
    3
    0
    Stomatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    2 / 42 (4.76%)
    3 / 122 (2.46%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    2
    3
    0
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Decubitus Ulcer
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dermatitis Contact
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dry Skin
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Pruritus Generalised
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 40 (5.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Rash Pruritic
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    5 / 42 (11.90%)
    3 / 122 (2.46%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    5
    3
    0
    Arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    2 / 122 (1.64%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Haemarthrosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    1 / 122 (0.82%)
    1 / 63 (1.59%)
         occurrences all number
    1
    0
    0
    1
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain in Extremity
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    2 / 122 (1.64%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    2
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    1 / 122 (0.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 40 (0.00%)
    3 / 42 (7.14%)
    1 / 122 (0.82%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    6
    1
    1
    Wound Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 122 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0

    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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