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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Clinical Trial Results:
    A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or New Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

    Summary
    EudraCT number
    		 2017-005029-19
    Trial protocol
    		 CZ   DE   ES   SE   HU   NO   FI   BE   GB   AT   DK   GR   IT  
    Global end of trial date
    31 Mar 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 May 2023
    First version publication date
    17 Apr 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CV010-031
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03766581
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    13 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this clinical study is to estimate the dose-response relationship of milvexian in participants with ischemic stroke or transient ischemic attack (TIA) treated with aspirin and clopidogrel.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 2019
    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
    Argentina: 23
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    Belgium: 55
    Country: Number of subjects enrolled
    Brazil: 41
    Country: Number of subjects enrolled
    Canada: 126
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    Denmark: 43
    Country: Number of subjects enrolled
    Finland: 33
    Country: Number of subjects enrolled
    France: 104
    Country: Number of subjects enrolled
    Germany: 100
    Country: Number of subjects enrolled
    Greece: 211
    Country: Number of subjects enrolled
    Hungary: 221
    Country: Number of subjects enrolled
    Israel: 64
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    Japan: 295
    Country: Number of subjects enrolled
    Korea, Republic of: 91
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 160
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Spain: 342
    Country: Number of subjects enrolled
    Sweden: 27
    Country: Number of subjects enrolled
    Switzerland: 25
    Country: Number of subjects enrolled
    United Kingdom: 39
    Country: Number of subjects enrolled
    United States: 212
    Worldwide total number of subjects
    2366
    EEA total number of subjects
    1387
    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)
    720
    From 65 to 84 years
    1481
    85 years and over
    165

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 2366 participants were randomized and 2334 treated. 1 participant was randomized to Milvexian 200 mg BID, but received Milvexian 25 mg QD.

    Period 1
    Period 1 title
    Randomization
    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
    		 Placebo
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 25 mg QD
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 25 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 50 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 100 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 200 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 50 mg QD
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 100 mg QD
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Number of subjects in period 1
    		Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Started
    691
    328
    318
    328
    310
    351
    22
    18
    Completed
    682
    324
    313
    325
    306
    345
    22
    17
    Not completed
    9
    4
    5
    3
    4
    6
    0
    1
         Participant withdrew consent
    1
    -
    1
    2
    1
    1
    -
    -
         Participant no longer meets study criteria
    5
    3
    4
    -
    2
    3
    -
    1
         Other reasons
    2
    1
    -
    1
    -
    -
    -
    -
         Participant request to discontinue study treatment
    1
    -
    -
    -
    1
    2
    -
    -
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 25 mg QD
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 25 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 50 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 100 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 200 mg BID
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 50 mg QD
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Arm title
    		 Milvexian 100 mg QD
    Arm description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Milvexian
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Number of subjects in period 2
    		Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Started
    682
    325
    313
    325
    306
    344
    22
    17
    Completed
    529
    260
    242
    251
    230
    240
    15
    14
    Not completed
    153
    65
    71
    74
    76
    104
    7
    3
         Participant request to discontinue treatment
    34
    6
    10
    10
    14
    15
    -
    1
         Adverse event, serious fatal
    1
    -
    -
    -
    -
    -
    -
    -
         Participant withdrew consent
    11
    4
    5
    5
    4
    4
    -
    -
         Poor/Non compliance
    2
    2
    1
    1
    1
    1
    -
    -
         Adverse event, non-fatal
    82
    44
    47
    46
    50
    77
    5
    2
         Participant no longer meets study criteria
    9
    1
    5
    4
    4
    4
    2
    -
         Other reasons
    13
    8
    3
    7
    3
    3
    -
    -
         Lost to follow-up
    1
    -
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 200 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD Total
    Number of subjects
    		 691 328 318 328 310 351 22 18 2366
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 208 90 97 108 92 106 10 9 720
        From 65-84 years
    		 441 208 193 201 198 221 11 8 1481
        85 years and over
    		 42 30 28 19 20 24 1 1 165
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.1 ( 10.58 ) 70.9 ( 10.66 ) 70.1 ( 11.34 ) 69.3 ( 10.69 ) 69.7 ( 10.59 ) 69.5 ( 11.11 ) 65.7 ( 10.64 ) 65.4 ( 11.65 ) -
    Sex: Female, Male
    Units:
        Female
    		 254 109 118 121 112 128 7 10 859
        Male
    		 437 219 200 207 198 223 15 8 1507
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 4 2 1 2 1 1 1 22
        Not Hispanic or Latino
    		 62 20 22 23 29 27 7 7 197
        Unknown or Not Reported
    		 619 304 294 304 279 323 14 10 2147
    Race/Ethnicity, Customized
    Race
    Units: Subjects
        White
    		 549 257 246 260 251 288 18 15 1884
        Black or African American
    		 15 5 6 8 3 5 3 3 48
        Asian
    		 35 12 21 13 11 17 0 0 109
        Native Hawaiian or Other Pacific Islander
    		 0 1 1 0 0 0 0 0 2
        Asian Indian
    		 2 1 2 1 0 0 0 0 6
        Chinese
    		 0 0 0 0 1 0 0 0 1
        Japanese
    		 84 46 40 41 39 40 0 0 290
        Malay
    		 1 0 0 0 0 0 0 0 1
        Asian Other
    		 0 0 0 1 0 0 0 0 1
        Other
    		 5 6 2 4 5 1 1 0 24

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 200 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.
    Reporting group title
    Placebo
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 200 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Primary: Percent of Participants with Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90

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    End point title
    		 Percent of Participants with Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 [1]
    End point description
    Model based assessment estimate for composite event is a customized statistical analysis called MCP-MOD (Multiple Comparison Procedures, MODel) estimation, which is used to check for dose-response relationship. 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
    End point type
    Primary
    End point timeframe
    From randomization to up to 90 days after randomization
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID
    Number of subjects analysed
    625
    308
    287
    306
    277
    317
    Units: Percentage of participants
        number (confidence interval 95%)
    16.8 (14.2 to 19.4)
    16.7 (14.4 to 19.0)
    16.6 (14.5 to 18.7)
    15.6 (13.6 to 17.9)
    15.4 (13.0 to 18.0)
    15.3 (12.3 to 20.4)
    Statistical analysis title
    		 Milvexian 25 mg QD over Placebo
    Statistical analysis description
    Multiple Comparison Procedures, MODel (MCP-MOD). 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
    Comparison groups
    Placebo v Milvexian 25 mg QD
    Number of subjects included in analysis
    933
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 MCP-MOD
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.1
    Statistical analysis title
    		 Milvexian 200 mg BID over Placebo
    Statistical analysis description
    Multiple Comparison Procedures, MODel (MCP-MOD). 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
    Comparison groups
    Placebo v Milvexian 200 mg BID
    Number of subjects included in analysis
    942
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 MCP-MOD
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.31
    Statistical analysis title
    		 Milvexian 100 mg BID over Placebo
    Statistical analysis description
    Multiple Comparison Procedures, MODel (MCP-MOD). 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
    Comparison groups
    Placebo v Milvexian 100 mg BID
    Number of subjects included in analysis
    902
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 MCP-MOD
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.18
    Statistical analysis title
    		 Milvexian 25 mg BID over Placebo
    Statistical analysis description
    Multiple Comparison Procedures, MODel (MCP-MOD). 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
    Comparison groups
    Placebo v Milvexian 25 mg BID
    Number of subjects included in analysis
    912
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 MCP-MOD
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.15
    Statistical analysis title
    		 Milvexian 50 mg BID over Placebo
    Statistical analysis description
    Multiple Comparison Procedures, MODel (MCP-MOD). 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
    Comparison groups
    Placebo v Milvexian 50 mg BID
    Number of subjects included in analysis
    931
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 MCP-MOD
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.16

    Secondary: Percent of Participants with Major Bleeding According to BARC Type 3 and 5

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    End point title
    		 Percent of Participants with Major Bleeding According to BARC Type 3 and 5
    End point description
    Percent of participants with major bleeding based on the Bleeding Academic Research Consortium (BARC) Types 3 and 5 definitions. BARC bleeding types: 3a = Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL transfusion with overt bleeding 3b = Overt bleeding plus hemoglobin drop ≥5 g/dL; cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents 3c = Intracranial hemorrhage, 5a = Probable fatal bleeding 5b = Definite fatal bleeding
    End point type
    Secondary
    End point timeframe
    From first dose to up to 107 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Percentage of participants
        number (confidence interval 95%)
    0.6 (0.2 to 1.5)
    0.6 (0.1 to 2.2)
    0.6 (0.1 to 2.3)
    1.5 (0.5 to 3.6)
    1.6 (0.5 to 3.8)
    1.5 (0.5 to 3.4)
    0 (0 to 15.4)
    0 (0 to 19.5)
    No statistical analyses for this end point

    Secondary: Percent of Participants with Bleeding Based on BARC Types 1-5

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    End point title
    		 Percent of Participants with Bleeding Based on BARC Types 1-5
    End point description
    Percent of participants with bleeding based on Bleeding Academic Research Consortium (BARC) Type 1 to 5. BARC bleeding types: 0=No bleeding. 1=Not actionable bleeding. 2=Overt, actionable sign of hemorrhage requiring nonsurgical, medical intervention by a health-care professional, leading to hospitalization or increased level of care, or prompting evaluation. 3a=Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL. 3b=Overt bleeding plus hemoglobin drop ≥5 g/dL; cardiac tamponade; bleeding requiring surgical intervention; bleeding requiring IV vasoactive agents. 3c=Intracranial hemorrhage; intraocular bleed compromising vision. 4=CABG-related bleeding, perioperative intracranial bleeding within 48 hours, reoperation after closure of sternotomy to control bleeding, transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period, chest tube output more than or equal to 2L within a 24-hour period. 5a=Probable fatal bleeding. 5b=Definite fatal bleeding.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 107 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
        TYPE 1
    41
    26
    16
    28
    25
    22
    5
    2
        TYPE 2
    9
    7
    9
    7
    10
    8
    1
    1
        TYPE 3A
    2
    1
    1
    1
    2
    3
    0
    0
        TYPE 3B
    0
    1
    1
    1
    3
    1
    0
    0
        TYPE 3C
    2
    0
    0
    3
    0
    1
    0
    0
        TYPE 4
    0
    0
    0
    0
    0
    0
    0
    0
        TYPE 5A
    0
    0
    0
    0
    0
    0
    0
    0
        TYPE 5B
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Bleeding Based on ISTH-Defined Criteria

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    End point title
    		 Number of Participants with Bleeding Based on ISTH-Defined Criteria
    End point description
    Number of participants with bleeding based on International Society on Thrombosis and Hemostasis (ISTH). ISTH Bleeding Types: 1) Fatal bleeding and/or 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome and/or 3) Bleeding causing a fall in hemoglobin level of ≥2 g/dL, or leading to transfusion of ≥2 units of whole blood or red cells.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 107 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
        Major
    4
    2
    2
    5
    6
    5
    0
    0
        Clinically Relevant Non-Major (CRNM)
    7
    8
    9
    7
    8
    8
    1
    1
        Major or CRNM
    11
    10
    11
    12
    14
    13
    1
    1
        Minor Bleed
    43
    25
    16
    28
    26
    22
    5
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with Bleeding Based on PLATO-Defined Criteria

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    End point title
    		 Number of Participants with Bleeding Based on PLATO-Defined Criteria
    End point description
    Number of participants with bleeding based on Platelet Inhibition and Patient Outcomes (PLATO) defined criteria. PLATO bleeding definitions: 1. Major Life-threatening: Fatal, Intracranial, Intrapericardial with cardiac tamponade, Resulting in hypovolemic shock or severe hypotension that requires pressors or surgery, Clinically overt or apparent bleeding associated with decrease in hemoglobin >5 g/dL, Requiring transfusion of ≥4 U whole blood or packed red blood cells (PRBCs) 2. Other Major: Significantly disabling (eg, intraocular with permanent vision loss), Associated drop in hemoglobin of 3 to 5 g/dL, Requiring transfusion of 2 to 3 U whole blood or PRBCs 3. Any Major: Any one of the above criteria 4. Minor: Bleeding that does not meet criteria for PLATO Major bleeding, and requiring medical intervention
    End point type
    Secondary
    End point timeframe
    From first dose to up to 107 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
        MAJOR LIFE-THREATENING
    2
    1
    1
    4
    3
    2
    0
    0
        OTHER MAJOR BLEEDING
    2
    1
    1
    1
    2
    3
    0
    0
        ANY MAJOR
    4
    2
    2
    5
    5
    5
    0
    0
        MINOR
    7
    6
    7
    7
    9
    9
    0
    1
        MINIMAL
    43
    27
    18
    28
    26
    21
    6
    2
    No statistical analyses for this end point

    Secondary: Percent of Participants with Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90

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    End point title
    		 Percent of Participants with Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90
    End point description
    Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90.
    End point type
    Secondary
    End point timeframe
    From randomization to up to 90 days after randomization
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    625
    308
    287
    306
    277
    317
    21
    16
    Units: Percentage of participants
        number (not applicable)
    16.6
    16.2
    18.5
    14.1
    14.8
    16.4
    19.0
    18.8
    No statistical analyses for this end point

    Secondary: National Institutes of Health Stroke Scale (NIHSS)

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    End point title
    		 National Institutes of Health Stroke Scale (NIHSS)
    End point description
    The NIHSS is an 11-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent’s ability to answer questions and perform activities. The score for each ability is a number between 0 and 4, 0 being normal functioning and 4 being completely impaired. The patient's NIHSS score is calculated by adding the number for each element of the scale; 42 is the highest score possible. In the NIHSS, the higher the score, the more impaired a stroke participant is. 99999 = Not Available
    End point type
    Secondary
    End point timeframe
    At baseline, on Days 21 and 90, and at the time of a new stroke event
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    684
    324
    311
    326
    305
    348
    22
    17
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.6 ( 1.87 )
    1.7 ( 1.68 )
    1.6 ( 1.73 )
    1.6 ( 1.79 )
    1.8 ( 1.81 )
    1.6 ( 1.79 )
    1.1 ( 1.44 )
    2.0 ( 1.70 )
        Day 21
    0.9 ( 2.11 )
    0.8 ( 1.35 )
    0.8 ( 1.43 )
    0.8 ( 1.58 )
    0.8 ( 1.48 )
    0.9 ( 1.88 )
    0.8 ( 1.90 )
    0.9 ( 1.39 )
        Day 90
    0.5 ( 1.40 )
    0.6 ( 1.06 )
    0.6 ( 1.51 )
    0.6 ( 1.14 )
    0.6 ( 1.32 )
    0.6 ( 1.29 )
    0.3 ( 0.72 )
    0.6 ( 1.45 )
        First recurrent stroke
    6.2 ( 5.01 )
    4.6 ( 6.79 )
    5.4 ( 3.17 )
    4.6 ( 4.30 )
    7.1 ( 4.68 )
    4.4 ( 4.60 )
    5.3 ( 3.06 )
    1.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Composite of Percent of Participants with New Ischemic Stroke, MI and All Cause Death

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    End point title
    		 Composite of Percent of Participants with New Ischemic Stroke, MI and All Cause Death
    End point description
    Composite of percent of participants of new ischemic stroke, (Myocardial Infarction) MI and all cause death.
    End point type
    Secondary
    End point timeframe
    From randomization to up to 90 days after randomization
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    691
    328
    318
    328
    310
    351
    22
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    6.1 (4.3 to 7.9)
    5.2 (2.8 to 7.6)
    4.7 (2.4 to 7.0)
    4.9 (2.5 to 7.2)
    5.2 (2.7 to 7.6)
    9.4 (6.3 to 12.5)
    18.2 (2.1 to 34.3)
    5.6 (0 to 16.1)
    No statistical analyses for this end point

    Secondary: Modified Rankin Scale (mRS)

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    End point title
    		 Modified Rankin Scale (mRS)
    End point description
    The Modified Rankin Score (mRS) is a 6-point disability scale with possible scores ranging from 0 to 6. 0 = No symptoms at all 1 = No significant disability despite symptoms; able to carry out all usual duties and activities 2 = Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 = Moderate disability; requiring some help, but able to walk without assistance 4 = Moderately severe disability; unable to walk and attend to bodily needs without assistance 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6 = Dead 99999 = Not Available
    End point type
    Secondary
    End point timeframe
    At baseline, on Days 21 and 90, and at the time of a new stroke event
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    688
    326
    314
    328
    309
    349
    22
    17
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    0.5 ( 0.87 )
    0.6 ( 0.95 )
    0.6 ( 0.96 )
    0.5 ( 0.86 )
    0.5 ( 0.89 )
    0.6 ( 0.95 )
    0.2 ( 0.53 )
    0.7 ( 0.99 )
        Day 21
    1.0 ( 1.18 )
    1.0 ( 1.13 )
    0.9 ( 1.15 )
    0.9 ( 1.15 )
    1.0 ( 1.17 )
    0.9 ( 1.19 )
    0.9 ( 1.27 )
    1.3 ( 1.14 )
        Day 90
    0.7 ( 1.04 )
    0.8 ( 1.04 )
    0.8 ( 1.07 )
    0.7 ( 1.01 )
    0.7 ( 1.01 )
    0.8 ( 1.05 )
    0.6 ( 1.05 )
    1.0 ( 1.11 )
        First recurrent stroke
    3.0 ( 1.60 )
    2.7 ( 1.03 )
    2.6 ( 1.35 )
    2.3 ( 1.62 )
    2.9 ( 1.64 )
    1.8 ( 1.72 )
    2.0 ( 0.00 )
    1.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Montreal Cognitive Assessment (MoCA)

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    End point title
    		 Montreal Cognitive Assessment (MoCA)
    End point description
    The Montreal Cognitive Assessment (MoCA) is a survey with a summed score. MoCA score ranges between a lowest score of 0 to a highest score of 30. A score of: - ≥26 points: indicates normal cognitive function - 18–25 points: Mild cognitive impairment - 10–17 points: Moderate cognitive impairment - fewer than 10 points: Severe cognitive impairment 99999 = Not Available
    End point type
    Secondary
    End point timeframe
    At baseline, on Days 21 and 90, and at the time of a new stroke event
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    541
    257
    235
    257
    235
    276
    17
    14
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    22.3 ( 5.06 )
    21.6 ( 5.59 )
    22.0 ( 5.18 )
    22.5 ( 4.82 )
    22.4 ( 5.04 )
    22.1 ( 5.31 )
    24.4 ( 3.84 )
    22.0 ( 4.59 )
        Day 21
    24.0 ( 4.77 )
    23.9 ( 5.01 )
    24.0 ( 4.70 )
    24.3 ( 4.57 )
    23.6 ( 4.48 )
    24.0 ( 4.96 )
    26.4 ( 2.61 )
    24.1 ( 4.70 )
        Day 90
    24.6 ( 4.54 )
    24.0 ( 4.69 )
    24.2 ( 4.80 )
    24.4 ( 4.48 )
    24.5 ( 4.36 )
    24.2 ( 5.05 )
    25.0 ( 4.72 )
    26.4 ( 1.69 )
        First recurrent stroke
    23.2 ( 6.63 )
    17.3 ( 6.11 )
    25.3 ( 2.31 )
    19.0 ( 8.49 )
    3.0 ( 99999 )
    23.1 ( 7.08 )
    11.0 ( 99999 )
    22.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Digit Symbol Substitution Test (DSST)

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    End point title
    		 Digit Symbol Substitution Test (DSST)
    End point description
    The Descriptive Summary of the Digit Symbol Substitution Test (DSST) is a scale item, with a lowest score of 0 and highest total score of 135. Higher score indicates better cognitive functioning. 99999 = Not Available
    End point type
    Secondary
    End point timeframe
    At baseline, on Days 21 and 90, and at the time of a new stroke event
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    493
    238
    209
    234
    220
    257
    17
    14
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    34.9 ( 22.36 )
    31.2 ( 18.87 )
    32.9 ( 22.89 )
    37.2 ( 25.67 )
    33.7 ( 21.89 )
    31.7 ( 19.15 )
    47.1 ( 29.34 )
    29.2 ( 18.16 )
        Day 21
    41.2 ( 22.14 )
    38.9 ( 19.27 )
    40.2 ( 21.60 )
    45.1 ( 25.77 )
    41.2 ( 22.87 )
    39.1 ( 21.35 )
    54.6 ( 32.73 )
    37.1 ( 20.13 )
        Day 90
    42.8 ( 21.18 )
    41.7 ( 21.66 )
    41.3 ( 20.29 )
    45.2 ( 21.86 )
    45.5 ( 23.44 )
    41.4 ( 21.97 )
    47.5 ( 27.48 )
    40.7 ( 17.46 )
        First recurrent stroke
    36.3 ( 13.56 )
    28.0 ( 20.95 )
    42.0 ( 4.36 )
    40.5 ( 2.12 )
    23.0 ( 99999 )
    27.5 ( 16.96 )
    9.0 ( 99999 )
    47.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Vital Sign Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Vital Sign Abnormalities
    End point description
    Number of participants with clinically significant vital sign abnormalities. Vital signs included heart rate and diastolic and systolic blood pressure.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 90 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    AE: include all non-serious adverse events with onset on or after first dose date and within 2 days after the last dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose to 2 days after last dose of study therapy (up to approximately 107 days)
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
    399
    190
    186
    192
    193
    211
    11
    13
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Physical Examination Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Physical Examination Abnormalities
    End point description
    Number of participants with clinically significant physical examination abnormalities.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 90 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Electrocardiogram (ECG) Abnormalities
    End point description
    Number of participants with clinically significant ECG abnormalities.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 90 days after first dose
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    682
    325
    313
    325
    306
    344
    22
    17
    Units: Participants
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Laboratory Abnormalities - Liver

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    End point title
    		 Number of Participants with Clinically Significant Laboratory Abnormalities - Liver
    End point description
    The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Results reported in International System of Units (SI)
    End point type
    Secondary
    End point timeframe
    From first dose to up to approximately 38 months
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    642
    303
    280
    306
    281
    324
    21
    16
    Units: Participants
        ALT > 3x ULN
    4
    2
    0
    2
    3
    3
    0
    0
        ALT > 5x ULN
    1
    0
    0
    0
    2
    2
    0
    0
        ALT > 10x ULN
    1
    0
    0
    0
    1
    1
    0
    0
        ALT > 20x ULN
    0
    0
    0
    0
    1
    0
    0
    0
        AST > 3x ULN
    6
    5
    1
    4
    3
    3
    1
    0
        AST > 5x ULN
    3
    2
    1
    0
    2
    1
    1
    0
        AST > 10x ULN
    1
    0
    0
    0
    1
    0
    0
    0
        AST > 20x ULN
    0
    0
    0
    0
    1
    0
    0
    0
        ALP > 2x ULN
    4
    5
    1
    6
    4
    2
    0
    0
        Total Bilirubin > 1.5x ULN
    10
    6
    2
    7
    5
    2
    0
    0
        Total Bilirubin > 2x ULN
    3
    1
    1
    2
    2
    1
    0
    0
        ALT/AST elevation >3xULN w/ total bili >2xULN
    0
    0
    0
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Factor XI Clotting Activity

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    End point title
    		 Percent Change from Baseline in Factor XI Clotting Activity
    End point description
    Percent change from baseline in factor XI clotting activity via exposure response.
    End point type
    Secondary
    End point timeframe
    Baseline and day 90
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    503
    251
    223
    228
    216
    236
    15
    13
    Units: Seconds
        arithmetic mean (standard error)
    4.48 ( 3.455 )
    -8.88 ( 1.280 )
    -1767 ( 1.900 )
    -37.20 ( 1.655 )
    -61.52 ( 1.869 )
    -70.25 ( 3.043 )
    3.86 ( 13.754 )
    -44.27 ( 6.501 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in aPTT Activity

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    End point title
    		 Percent Change from Baseline in aPTT Activity
    End point description
    Percent change from baseline in activated partial thromboplastin time (aPTT) activity via exposure response.
    End point type
    Secondary
    End point timeframe
    Baseline and day 90
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    503
    251
    226
    241
    214
    232
    14
    14
    Units: Seconds
        arithmetic mean (standard error)
    2.47 ( 0.768 )
    38.72 ( 2.264 )
    58.30 ( 3.195 )
    97.32 ( 3.601 )
    140.76 ( 5.154 )
    193.64 ( 7.041 )
    48.48 ( 11.243 )
    118.06 ( 13.840 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter - Estimated Clearance (CL)

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    End point title
    		 Pharmacokinetic Parameter - Estimated Clearance (CL) [2]
    End point description
    Pharmacokinetic Parameter - Estimated Clearance (CL). CL is derived from plasma concentration versus time data. PK parameters were generated using a Population Pharmacokinetics (PPK) model. Summary statistics for these individual predicted PK parameters and exposures were stratified by dose. The PPK model analysis was based on combined PK data collected on days 1, 21, and 90.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 90 days after first dose
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID
    Number of subjects analysed
    323
    307
    323
    303
    341
    Units: L/h
        geometric mean (geometric coefficient of variation)
    8.15 ( 34 )
    8.01 ( 34.3 )
    7.54 ( 32.8 )
    7.08 ( 31.3 )
    7.43 ( 32.9 )
    No statistical analyses for this end point

    Secondary: Volume of DWI-Positive Infarct (s) on the DWI Sequence

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    End point title
    		 Volume of DWI-Positive Infarct (s) on the DWI Sequence
    End point description
    Total Volume of diffusion-weighted imaging MRI (DWI)-Positive Infarct (s) on the DWI Sequence.
    End point type
    Secondary
    End point timeframe
    From randomization to up to 90 days after randomization
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    516
    242
    241
    256
    237
    278
    16
    12
    Units: mL
        arithmetic mean (standard deviation)
    4.6 ( 7.7 )
    6.0 ( 13.2 )
    4.2 ( 9.4 )
    6.3 ( 14.0 )
    4.3 ( 7.4 )
    6.1 ( 10.1 )
    3.8 ( 5.5 )
    10.6 ( 8.5 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter - Volume of the Central Compartment (VC)

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    End point title
    		 Pharmacokinetic Parameter - Volume of the Central Compartment (VC) [3]
    End point description
    Pharmacokinetic Parameter - Volume of the Central Compartment (VC). VC is derived from plasma concentration versus time data. PK parameters were generated using a Population Pharmacokinetics (PPK) model. Summary statistics for these individual predicted PK parameters and exposures were stratified by dose. The PPK model analysis was based on combined PK data collected on days 1, 21, and 90.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 90 days after first dose
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID
    Number of subjects analysed
    323
    307
    323
    303
    341
    Units: Liter
        geometric mean (geometric coefficient of variation)
    34.9 ( 152 )
    31.4 ( 138 )
    30.9 ( 145 )
    28.9 ( 149 )
    31.6 ( 181 )
    No statistical analyses for this end point

    Secondary: Number of DWI-Positive Infarct (s) on the DWI Sequence

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    End point title
    		 Number of DWI-Positive Infarct (s) on the DWI Sequence
    End point description
    Number of diffusion-weighted imaging MRI (DWI)-Positive Infarct (s) on the DWI Sequence.
    End point type
    Secondary
    End point timeframe
    From randomization to up to 90 days after randomization
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    516
    242
    241
    256
    237
    278
    16
    12
    Units: DWI-Positive Infarct(s)
        arithmetic mean (standard deviation)
    4.5 ( 5.7 )
    4.6 ( 7.0 )
    4.6 ( 5.8 )
    3.7 ( 4.1 )
    4.3 ( 5.2 )
    4.2 ( 5.1 )
    1.6 ( 1.1 )
    4.2 ( 4.3 )
    No statistical analyses for this end point

    Other pre-specified: Percent of Participants with Ischemic Stroke Events

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    End point title
    		 Percent of Participants with Ischemic Stroke Events
    End point description
    Secondary analysis of symptomatic ischemic stroke events. Clinical events are included up to day 90. Wald 95% CI within group. Undetermined stroke is included.
    End point type
    Other pre-specified
    End point timeframe
    From randomization to up to 90 days after randomization
    End point values
    		 Placebo Milvexian 25 mg QD Milvexian 25 mg BID Milvexian 50 mg BID Milvexian 100 mg BID Milvexian 200 mg BID Milvexian 50 mg QD Milvexian 100 mg QD
    Number of subjects analysed
    691
    328
    318
    328
    310
    351
    22
    18
    Units: Percentage of participants
    number (confidence interval 95%)
        Ischemic stroke
    5.5 (3.8 to 7.2)
    4.6 (2.3 to 6.8)
    3.8 (1.7 to 5.9)
    4.0 (1.9 to 6.1)
    3.5 (1.5 to 5.6)
    7.7 (4.9 to 10.5)
    13.6 (0.0 to 28.0)
    5.6 (0.0 to 16.1)
        Undetermined stroke
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Milvexian 25 mg QD over Placebo
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 25 mg QD
    Number of subjects included in analysis
    1019
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.49
    Statistical analysis title
    		 Milvexian 25 mg BID over Placebo
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 25 mg BID
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.3
    Statistical analysis title
    		 Milvexian 50 mg BID over Placebo
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 50 mg BID
    Number of subjects included in analysis
    1019
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.33
    Statistical analysis title
    		 Milvexian 100 mg BID over Placebo
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 100 mg BID
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.25
    Statistical analysis title
    		 Milvexian 200 mg BID
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 200 mg BID
    Number of subjects included in analysis
    1042
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 2.25
    Statistical analysis title
    		 Milvexian 50 mg QD over Placebo
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 50 mg QD
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 7.42
    Statistical analysis title
    		 Milvexian 100 mg QD over Placebo
    Statistical analysis description
    Wald Confidence Limits. 95% CIs for RR are constructed using Wald Confidence Limits.
    Comparison groups
    Placebo v Milvexian 100 mg QD
    Number of subjects included in analysis
    709
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wald Confidence Limits
    Parameter type
    		 Relative Risk (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 6.96

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs were assessed from first dose to 7 days after last dose of study therapy (up to approximately 112 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg QD
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 50 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 25 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 100 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Reporting group title
    Milvexian 200 mg BID
    Reporting group description
    		 Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally.

    Serious adverse events
    		 Placebo Milvexian 25 mg QD Milvexian 50 mg QD Milvexian 100 mg QD Milvexian 50 mg BID Milvexian 25 mg BID Milvexian 100 mg BID Milvexian 200 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    94 / 682 (13.78%)
    37 / 325 (11.38%)
    5 / 22 (22.73%)
    3 / 17 (17.65%)
    41 / 325 (12.62%)
    39 / 313 (12.46%)
    42 / 306 (13.73%)
    54 / 344 (15.70%)
         number of deaths (all causes)
    5
    4
    0
    0
    3
    3
    5
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 1
    0 / 0
    0 / 0
    Sinonasal papilloma
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Post procedural stroke
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Reactive gastropathy
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 682 (0.29%)
    0 / 325 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 682 (0.59%)
    3 / 325 (0.92%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    3 / 306 (0.98%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 682 (0.15%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 682 (0.29%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    2 / 313 (0.64%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    2 / 306 (0.65%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodal rhythm
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basilar artery occlusion
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Carotid artery thrombosis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    4 / 682 (0.59%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Brain stem stroke
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basilar migraine
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Basilar artery stenosis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    4 / 682 (0.59%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    1 / 306 (0.33%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral venous thrombosis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    2 / 325 (0.62%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    21 / 682 (3.08%)
    9 / 325 (2.77%)
    3 / 22 (13.64%)
    1 / 17 (5.88%)
    10 / 325 (3.08%)
    6 / 313 (1.92%)
    7 / 306 (2.29%)
    11 / 344 (3.20%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 9
    0 / 3
    0 / 1
    0 / 10
    0 / 6
    0 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    3 / 682 (0.44%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    2 / 325 (0.62%)
    3 / 313 (0.96%)
    1 / 306 (0.33%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudostroke
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sedation complication
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    5 / 682 (0.73%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    4 / 313 (1.28%)
    1 / 306 (0.33%)
    8 / 344 (2.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 4
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 682 (0.29%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    8 / 682 (1.17%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    4 / 313 (1.28%)
    4 / 306 (1.31%)
    4 / 344 (1.16%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral artery dissection
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    2 / 313 (0.64%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 682 (0.15%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis haemorrhagic
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 682 (0.29%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis fulminant
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 682 (0.29%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    2 / 313 (0.64%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 682 (0.44%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    4 / 344 (1.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    5 / 682 (0.73%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    2 / 313 (0.64%)
    0 / 306 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal perforated
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    3 / 682 (0.44%)
    0 / 325 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    2 / 306 (0.65%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Wound infection pseudomonas
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 682 (0.15%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    5 / 344 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Milvexian 25 mg QD Milvexian 50 mg QD Milvexian 100 mg QD Milvexian 50 mg BID Milvexian 25 mg BID Milvexian 100 mg BID Milvexian 200 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    178 / 682 (26.10%)
    81 / 325 (24.92%)
    6 / 22 (27.27%)
    11 / 17 (64.71%)
    92 / 325 (28.31%)
    83 / 313 (26.52%)
    82 / 306 (26.80%)
    90 / 344 (26.16%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    56 / 682 (8.21%)
    21 / 325 (6.46%)
    0 / 22 (0.00%)
    2 / 17 (11.76%)
    24 / 325 (7.38%)
    23 / 313 (7.35%)
    20 / 306 (6.54%)
    19 / 344 (5.52%)
         occurrences all number
    60
    21
    0
    3
    24
    23
    20
    19
    Hypotension
         subjects affected / exposed
    5 / 682 (0.73%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    4 / 325 (1.23%)
    2 / 313 (0.64%)
    1 / 306 (0.33%)
    3 / 344 (0.87%)
         occurrences all number
    5
    2
    0
    1
    4
    2
    1
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 682 (0.88%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    2 / 17 (11.76%)
    1 / 325 (0.31%)
    3 / 313 (0.96%)
    2 / 306 (0.65%)
    4 / 344 (1.16%)
         occurrences all number
    6
    2
    0
    2
    1
    4
    2
    4
    Feeling cold
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 682 (0.15%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    2 / 325 (0.62%)
    1 / 313 (0.32%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences all number
    1
    2
    0
    2
    2
    1
    1
    0
    Thirst
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 682 (0.00%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    2 / 313 (0.64%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    10 / 682 (1.47%)
    2 / 325 (0.62%)
    2 / 22 (9.09%)
    0 / 17 (0.00%)
    5 / 325 (1.54%)
    4 / 313 (1.28%)
    4 / 306 (1.31%)
    6 / 344 (1.74%)
         occurrences all number
    12
    4
    5
    0
    5
    4
    5
    6
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    2 / 313 (0.64%)
    0 / 306 (0.00%)
    1 / 344 (0.29%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    0
    1
    Anxiety
         subjects affected / exposed
    5 / 682 (0.73%)
    3 / 325 (0.92%)
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    3 / 325 (0.92%)
    6 / 313 (1.92%)
    5 / 306 (1.63%)
    3 / 344 (0.87%)
         occurrences all number
    5
    3
    1
    1
    3
    6
    5
    3
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    1 / 682 (0.15%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    3 / 313 (0.96%)
    1 / 306 (0.33%)
    1 / 344 (0.29%)
         occurrences all number
    1
    2
    0
    1
    1
    3
    1
    1
    Road traffic accident
         subjects affected / exposed
    0 / 682 (0.00%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 682 (1.03%)
    4 / 325 (1.23%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    7 / 325 (2.15%)
    4 / 313 (1.28%)
    5 / 306 (1.63%)
    2 / 344 (0.58%)
         occurrences all number
    7
    4
    0
    1
    7
    4
    5
    2
    Headache
         subjects affected / exposed
    23 / 682 (3.37%)
    16 / 325 (4.92%)
    3 / 22 (13.64%)
    1 / 17 (5.88%)
    14 / 325 (4.31%)
    12 / 313 (3.83%)
    12 / 306 (3.92%)
    9 / 344 (2.62%)
         occurrences all number
    24
    16
    3
    1
    14
    13
    13
    10
    Tremor
         subjects affected / exposed
    3 / 682 (0.44%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    1 / 313 (0.32%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    1
    1
    0
    Paraesthesia
         subjects affected / exposed
    3 / 682 (0.44%)
    0 / 325 (0.00%)
    1 / 22 (4.55%)
    2 / 17 (11.76%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    1 / 344 (0.29%)
         occurrences all number
    3
    0
    1
    2
    0
    0
    1
    2
    Syncope
         subjects affected / exposed
    1 / 682 (0.15%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    3 / 325 (0.92%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    1
    1
    0
    1
    3
    0
    0
    0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 682 (0.15%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    2 / 313 (0.64%)
    1 / 306 (0.33%)
    0 / 344 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    2
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Increased tendency to bruise
         subjects affected / exposed
    2 / 682 (0.29%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    0
    0
    Anaemia
         subjects affected / exposed
    4 / 682 (0.59%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    2 / 17 (11.76%)
    2 / 325 (0.62%)
    2 / 313 (0.64%)
    5 / 306 (1.63%)
    8 / 344 (2.33%)
         occurrences all number
    4
    1
    0
    2
    2
    2
    5
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 682 (0.73%)
    3 / 325 (0.92%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    2 / 306 (0.65%)
    1 / 344 (0.29%)
         occurrences all number
    5
    3
    0
    1
    1
    0
    2
    1
    Constipation
         subjects affected / exposed
    44 / 682 (6.45%)
    22 / 325 (6.77%)
    0 / 22 (0.00%)
    3 / 17 (17.65%)
    20 / 325 (6.15%)
    17 / 313 (5.43%)
    20 / 306 (6.54%)
    24 / 344 (6.98%)
         occurrences all number
    46
    22
    0
    3
    23
    17
    20
    24
    Flatulence
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    2 / 325 (0.62%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    3 / 682 (0.44%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    1 / 344 (0.29%)
         occurrences all number
    8
    0
    0
    1
    1
    0
    1
    1
    Nausea
         subjects affected / exposed
    14 / 682 (2.05%)
    11 / 325 (3.38%)
    1 / 22 (4.55%)
    2 / 17 (11.76%)
    6 / 325 (1.85%)
    6 / 313 (1.92%)
    11 / 306 (3.59%)
    5 / 344 (1.45%)
         occurrences all number
    15
    12
    1
    2
    7
    6
    13
    5
    Rectal haemorrhage
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    2 / 22 (9.09%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    1 / 306 (0.33%)
    2 / 344 (0.58%)
         occurrences all number
    1
    0
    2
    1
    1
    0
    1
    2
    Vomiting
         subjects affected / exposed
    7 / 682 (1.03%)
    7 / 325 (2.15%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    3 / 325 (0.92%)
    2 / 313 (0.64%)
    3 / 306 (0.98%)
    3 / 344 (0.87%)
         occurrences all number
    7
    7
    0
    1
    3
    2
    3
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 682 (0.29%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    2 / 17 (11.76%)
    1 / 325 (0.31%)
    1 / 313 (0.32%)
    1 / 306 (0.33%)
    9 / 344 (2.62%)
         occurrences all number
    2
    0
    0
    2
    1
    1
    1
    9
    Pollakiuria
         subjects affected / exposed
    2 / 682 (0.29%)
    1 / 325 (0.31%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    2 / 306 (0.65%)
    1 / 344 (0.29%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    2
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    17 / 682 (2.49%)
    8 / 325 (2.46%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    6 / 325 (1.85%)
    9 / 313 (2.88%)
    11 / 306 (3.59%)
    12 / 344 (3.49%)
         occurrences all number
    19
    9
    0
    1
    6
    10
    11
    13
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 325 (0.00%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    2 / 344 (0.58%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 682 (0.15%)
    0 / 325 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 325 (0.31%)
    0 / 313 (0.00%)
    0 / 306 (0.00%)
    0 / 344 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 682 (0.29%)
    2 / 325 (0.62%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    2 / 325 (0.62%)
    0 / 313 (0.00%)
    3 / 306 (0.98%)
    3 / 344 (0.87%)
         occurrences all number
    2
    2
    0
    1
    2
    0
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2019
    Removed 3 QD doses groups (lowest 25 mg QD dose is maintained); keeping all BID doses. Title of the protocol was changed to reflect the new design.
    09 Oct 2020
    Updated the milestone requirement for DMC review to decide on inclusion of the 200-mg BID dose arm.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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