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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of Factor XI), Administered Subcutaneously to Patients with End-Stage Renal Disease on Hemodialysis

    Summary
    EudraCT number
    		 2017-002165-21
    Trial protocol
    		 ES   CZ   AT   NL   BG   BE   GR   LV  
    Global end of trial date
    10 Jul 2019

    Results information
    Results version number
    		 v1
    This version publication date
    26 Jul 2020
    First version publication date
    26 Jul 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 416858-CS5
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03358030
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, CA , United States, 92010
    Public contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.com
    Scientific contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.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
    10 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the trial was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ISIS 416858 (200, 250, and 300 milligrams (mg) once weekly) compared to placebo as assessed by factor XI (FXI) activity reduction in End-Stage Renal Disease on Hemodialysis (ESRD) subjects on hemodialysis.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form. Subjects were encouraged to complete the early termination study procedures and observations at the time of withdrawal.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Bulgaria: 22
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    Greece: 33
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Russian Federation: 71
    Worldwide total number of subjects
    213
    EEA total number of subjects
    130
    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)
    127
    From 65 to 84 years
    84
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 10 countries (Latvia, Netherlands, Spain, Austria, Belgium, Bulgaria, Czech Republic, Greece, Canada and Russian Federation) from 26 December 2017 to 10 July 2019.

    Pre-assignment
    Screening details
    		 A total of 213 subjects were enrolled and randomised in the study. Out of 213, 3 subjects did not receive the study drug and were not considered a part of the starting population.

    Pre-assignment period milestones
    Number of subjects started
    		 213
    Number of subjects completed
    		 210

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not receive study treatment: 3
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo subcutaneously, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Arm title
    		 Cohort A: ISIS 416858, 200 mg
    Arm description
    		 Subjects received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 416858
    Investigational medicinal product code
    Other name
    IONIS-FXIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS 416858, 200 mg, subcutaneously, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Arm title
    		 Cohort B: ISIS 416858, 250 mg
    Arm description
    		 Subjects received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 416858
    Investigational medicinal product code
    Other name
    IONIS-FXIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS 416858, 250 mg, subcutaneously, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Arm title
    		 Cohort C: ISIS 416858, 300 mg
    Arm description
    		 Subjects received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 416858
    Investigational medicinal product code
    Other name
    IONIS-FXIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS 416858, 300 mg, subcutaneously, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Number of subjects in period 1 [1]
    		Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Started
    53
    53
    54
    50
    Safety Population
    53
    53
    54
    50
    Per Protocol Population
    49 [2]
    45 [3]
    43 [4]
    35 [5]
    Completed
    50
    52
    46
    48
    Not completed
    3
    1
    8
    2
         Unspecified
    -
    -
    1
    -
         Adverse Event or SAE
    2
    -
    6
    1
         Voluntary withdrawal
    1
    1
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 213 subjects were enrolled and randomised in the study. Out of 213, 3 subjects did not receive the study drug and were not considered a part of the starting population.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 213 subjects were enrolled and randomised in the study. Out of 213, 3 subjects did not receive the study drug and were not considered a part of the starting population.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 213 subjects were enrolled and randomised in the study. Out of 213, 3 subjects did not receive the study drug and were not considered a part of the starting population.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 213 subjects were enrolled and randomised in the study. Out of 213, 3 subjects did not receive the study drug and were not considered a part of the starting population.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 213 subjects were enrolled and randomised in the study. Out of 213, 3 subjects did not receive the study drug and were not considered a part of the starting population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort A: ISIS 416858, 200 mg
    Reporting group description
    		 Subjects received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort B: ISIS 416858, 250 mg
    Reporting group description
    		 Subjects received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort C: ISIS 416858, 300 mg
    Reporting group description
    		 Subjects received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group values
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg Total
    Number of subjects
    		 53 53 54 50 210
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61 ± 13 61 ± 14 63 ± 12 58 ± 14 -
    Gender categorical
    Units: Subjects
        Female
    		 19 23 19 20 81
        Male
    		 34 30 35 30 129
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 6 5 12
        Not Hispanic or Latino
    		 52 53 48 45 198
    Race
    Units: Subjects
        White
    		 52 51 50 49 202
        Black
    		 0 0 3 0 3
        Asian
    		 1 1 0 1 3
        Other Race
    		 0 1 0 0 1
        Multiple Race
    		 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort A: ISIS 416858, 200 mg
    Reporting group description
    		 Subjects received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort B: ISIS 416858, 250 mg
    Reporting group description
    		 Subjects received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort C: ISIS 416858, 300 mg
    Reporting group description
    		 Subjects received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Primary: Number of Subjects With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)

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    End point title
    		 Number of Subjects With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB) [1]
    End point description
    MB was defined as one of the following: Fatal bleeding; symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or intramuscular with compartment syndrome, clinically overt bleeding leading to transfusion of greater than or equal to (>=) 2 units of packed red blood cells or whole blood or a fall in hemoglobin of 20 grams per litre (g/L) (1.24 millimoles per litre [mmol/L]) or more within 24 hours. CRNMB was defined as overt bleeding not meeting the criteria for MB but that resulted, in either medical examination, intervention, or had clinical consequences for a subject. Safety population included all randomised subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Day 260
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for the combination of MB and CRNMB.
    End point values
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Number of subjects analysed
    53
    53
    54
    50
    Units: subjects
    3
    2
    3
    3
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline (PCFB) in Activated Partial Thromboplastin Time (aPTT)

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    End point title
    		 Percent Change From Baseline (PCFB) in Activated Partial Thromboplastin Time (aPTT)
    End point description
    PP population: All subjects, randomised without missing more than 2 doses during first 12 weeks or more than 5 doses over 26-week Treatment Period (TP) and not have any major protocol violations that would have affected interpretation/integrity of study results. Number analysed ("n") is the number of subjects with data available for analyses at the given time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day 1) up to Day 260
    End point values
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Number of subjects analysed
    49
    45
    43
    35
    Units: percent change
    arithmetic mean (standard deviation)
        Baseline (n= 49, 45, 43, 35)
    30.1 ± 6.3
    28.0 ± 5.9
    30.1 ± 7.0
    30.1 ± 5.1
        PCFB at Day 5 (n= 48, 44, 43, 35)
    -2.8 ± 23.1
    9.3 ± 41.5
    -2.8 ± 19.2
    0.7 ± 18.2
        PCFB at Day 12 (n= 47, 43, 42, 34)
    1.4 ± 33.5
    9.4 ± 25.9
    0.8 ± 21.9
    3.6 ± 19.5
        PCFB at Day 15 (n= 49, 45, 42, 35)
    3.8 ± 47.7
    7.5 ± 29.0
    12.5 ± 39.8
    12.5 ± 38.4
        PCFB at Day 22 (n= 48, 44, 43, 35)
    -0.6 ± 25.6
    11.4 ± 38.1
    8.4 ± 30.4
    16.6 ± 32.0
        PCFB at Day 29 (n= 47, 45, 42, 35)
    -1.9 ± 23.8
    11.0 ± 28.4
    11.4 ± 30.7
    18.8 ± 46.6
        PCFB at Day 36 (n= 47, 45, 42, 35)
    -3.1 ± 17.8
    7.1 ± 18.2
    13.2 ± 35.5
    16.9 ± 21.0
        PCFB at Day 50 (n= 49, 44, 43, 33)
    6.8 ± 46.9
    24.1 ± 53.4
    27.5 ± 42.4
    24.3 ± 34.3
        PCFB at Day 64 (n= 48, 44, 42,35)
    6.0 ± 36.1
    20.3 ± 25.8
    29.9 ± 75.6
    40.5 ± 53.7
        PCFB at Day 78 (n= 46, 45, 42, 35)
    6.6 ± 49.5
    27.9 ± 49.2
    27.9 ± 38.6
    42.9 ± 47.8
        PCFB at Day 92 (n= 47, 45, 42, 34)
    9.5 ± 58.8
    19.1 ± 27.1
    52.5 ± 83.1
    42.1 ± 57.2
        PCFB at Day 106 (n= 49, 45, 42, 34)
    10.9 ± 70.7
    38.9 ± 71.7
    28.5 ± 46.1
    44.8 ± 60.7
        PCFB at Day 120 (n= 45, 44, 42, 35)
    2.6 ± 26.6
    28.5 ± 43.1
    22.5 ± 33.1
    41.4 ± 49.4
        PCFB at Day 134 (n= 49, 43, 43, 34)
    -6.2 ± 16.0
    42.9 ± 86.6
    29.5 ± 49.8
    50.1 ± 98.1
        PCFB at Day 148 (n= 47, 45, 43, 34)
    1.0 ± 25.8
    26.1 ± 28.7
    34.0 ± 53.5
    38.7 ± 61.5
        PCFB at Day 162 (n= 49, 44, 41, 33)
    -1.6 ± 17.1
    27.6 ± 30.1
    31.6 ± 39.3
    33.3 ± 34.9
        PCFB at Day 176 (n= 47, 45, 42, 33)
    3.7 ± 31.6
    28.8 ± 35.0
    36.3 ± 79.0
    32.3 ± 34.6
        PCFB at Day 190 (n= 44, 44, 42, 32)
    -3.6 ± 12.5
    38.3 ± 92.9
    20.5 ± 31.6
    23.5 ± 20.2
        PCFB at Day 204 (n= 46, 44, 41, 33)
    -0.4 ± 27.9
    17.4 ± 39.3
    13.3 ± 27.1
    16.9 ± 32.1
        PCFB at Day 218 (n= 47, 44, 41, 34)
    -0.7 ± 26.4
    13.1 ± 25.8
    7.0 ± 24.6
    13.2 ± 30.3
        PCFB at Day 232 (n= 47, 43, 41, 33)
    -0.7 ± 41.8
    8.6 ± 24.0
    16.8 ± 44.0
    3.1 ± 14.8
        PCFB at Day 246 (n= 46, 42, 38, 34)
    -0.0 ± 44.2
    10.0 ± 26.9
    3.5 ± 25.2
    3.6 ± 20.6
        PCFB at Day 260 (n= 46, 41, 40, 34)
    2.3 ± 50.7
    16.1 ± 54.4
    -2.9 ± 21.6
    3.6 ± 30.1
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Factor XI (FXI) Activity

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    End point title
    		 Percent Change From Baseline in Factor XI (FXI) Activity
    End point description
    PP population: All subjects, randomised without missing more than 2 doses during first 12 weeks or more than 5 doses over 26-week TP and not have any major protocol violations that would have affected interpretation/integrity of study results. "n" is the number of subjects with data available for analyses at the given time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day 1) up to Day 260
    End point values
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Number of subjects analysed
    49
    45
    43
    35
    Units: percent change
    arithmetic mean (standard deviation)
        Baseline (n= 49, 45, 43, 35)
    0.99 ± 0.19
    1.00 ± 0.21
    1.05 ± 0.24
    1.03 ± 0.17
        PCFB at Day 5 (n= 48, 45, 43, 35)
    -0.6 ± 14.4
    2.5 ± 24.6
    -0.0 ± 14.8
    -2.5 ± 18.3
        PCFB at Day 12 (n= 47, 43, 42, 34)
    -1.9 ± 13.7
    -3.0 ± 17.3
    -8.8 ± 18.7
    -14.1 ± 16.1
        PCFB at Day 15 (n= 49, 45, 42, 35)
    -0.6 ± 15.1
    -7.1 ± 16.2
    -14.0 ± 21.3
    -18.8 ± 17.3
        PCFB at Day 22 (n= 49, 44, 43, 35)
    -3.7 ± 18.2
    -17.2 ± 16.2
    -22.7 ± 19.5
    -27.6 ± 19.3
        PCFB at Day 29 (n= 47, 45, 42, 35)
    -3.3 ± 18.3
    -21.4 ± 16.9
    -31.5 ± 23.4
    -37.9 ± 18.5
        PCFB at Day 36 (n= 48, 45, 41, 35)
    -6.0 ± 18.1
    -26.3 ± 18.4
    -37.3 ± 22.0
    -42.8 ± 17.9
        PCFB at Day 50 (n= 49, 45, 43, 34)
    -3.2 ± 19.7
    -37.9 ± 22.2
    -48.1 ± 24.1
    -55.7 ± 20.6
        PCFB at Day 64 (n= 48, 44, 42,34)
    -4.5 ± 20.2
    -41.8 ± 20.1
    -55.1 ± 24.0
    -61.7 ± 20.3
        PCFB at Day 78 (n= 46, 45, 42, 35)
    -8.1 ± 19.6
    -44.6 ± 20.9
    -56.4 ± 23.9
    -64.2 ± 19.5
        PCFB at Day 92 (n= 46, 45, 43, 35)
    -6.2 ± 16.0
    -45.0 ± 21.6
    -60.2 ± 21.8
    -66.0 ± 19.0
        PCFB at Day 106 (n= 49, 45, 43, 35)
    -6.6 ± 19.2
    -49.4 ± 20.4
    -58.1 ± 22.2
    -67.8 ± 18.4
        PCFB at Day 120 (n= 46, 44, 43, 35)
    -0.8 ± 23.0
    -47.8 ± 20.3
    -57.2 ± 28.1
    -66.9 ± 17.6
        PCFB at Day 134 (n= 49, 45, 43, 35)
    -1.3 ± 18.1
    -50.0 ± 19.1
    -57.0 ± 28.0
    -67.7 ± 19.7
        PCFB at Day 148 (n= 49, 45, 43, 35)
    -4.3 ± 23.6
    -50.4 ± 17.5
    -59.2 ± 24.0
    -65.5 ± 20.0
        PCFB at Day 162 (n= 49, 45, 43, 35)
    -3.1 ± 22.8
    -48.9 ± 21.5
    -60.0 ± 23.4
    -64.1 ± 24.5
        PCFB at Day 176 (n= 48, 45, 42, 34)
    -4.1 ± 23.6
    -49.9 ± 24.8
    -61.1 ± 21.2
    -64.3 ± 17.4
        PCFB at Day 190 (n= 44, 44, 42, 35)
    -2.7 ± 17.8
    -45.4 ± 28.9
    -55.2 ± 22.2
    -60.9 ± 19.6
        PCFB at Day 204 (n= 47, 45, 41, 34)
    -1.8 ± 25.0
    -36.9 ± 28.7
    -48.2 ± 24.3
    -52.2 ± 22.1
        PCFB at Day 218 (n= 48, 45, 42, 35)
    -5.6 ± 17.8
    -29.3 ± 20.7
    -37.4 ± 22.8
    -41.8 ± 24.2
        PCFB at Day 232 (n= 47, 45, 41, 34)
    -0.7 ± 18.6
    -19.5 ± 24.7
    -28.0 ± 21.2
    -29.6 ± 25.2
        PCFB at Day 246 (n= 46, 44, 37, 35)
    -2.6 ± 21.0
    -13.6 ± 27.6
    -20.7 ± 18.4
    -22.3 ± 24.0
        PCFB at Day 260 (n= 46, 43, 40, 35)
    -3.8 ± 21.3
    -11.1 ± 25.0
    -15.3 ± 19.5
    -16.0 ± 22.1
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Laboratory Abnormalities – Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST)

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    End point title
    		 Number of Subjects With Laboratory Abnormalities – Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST)
    End point description
    Subjects were assessed based on pre-defined criteria in protocol for abnormality in ALT and AST values: Confirmed ALT (serum glutamic pyruvic transaminase [SGPT]); greater than (>) 3*Upper limit of normal range (ULN), >5*ULN and confirmed AST (serum glutamic-oxaloacetic transaminase [SGOT]); >3*ULN and >5*ULN. A confirmed value was based on a consecutive lab value within 7 days of the initial value. If that value was in the same or worse category the initial value was confirmed. If the consecutive value was in a better category then the initial value was confirmed using the consecutive value category. If there were multiple results on the same day, no matter from the same lab vendor or different lab vendors, then the worst value was used in the analysis. Abnormality in laboratory parameter was based on investigator’s discretion. Safety population included all randomised subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Up to Day 260
    End point values
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Number of subjects analysed
    53
    53
    54
    50
    Units: subjects
        ALT: >3*ULN, Confirmed
    0
    0
    1
    0
        ALT: >5*ULN, Confirmed
    0
    0
    1
    0
        AST: >3*ULN, Confirmed
    0
    0
    1
    0
        AST: >5*ULN, Confirmed
    0
    0
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Factor XI (FXI) Antigen Levels

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    End point title
    		 Percent Change From Baseline in Factor XI (FXI) Antigen Levels
    End point description
    PP population: All subjects, randomised without missing more than 2 doses during first 12 weeks or more than 5 doses over 26-week TP and not have any major protocol violations that would have affected interpretation/integrity of study results. "n" is the number of subjects with data available for analyses at the given time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day 1) up to Day 260
    End point values
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Number of subjects analysed
    49
    45
    43
    35
    Units: percent change
    arithmetic mean (standard deviation)
        Baseline (n= 49, 45, 43, 35)
    1.09 ± 0.23
    1.13 ± 0.26
    1.20 ± 0.31
    1.17 ± 0.26
        PCFB at Day 260 (n= 46, 43, 40, 35)
    11.3 ± 27.0
    -3.4 ± 17.5
    -10.1 ± 21.8
    -13.9 ± 22.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 260
    Adverse event reporting additional description
    Safety population included all randomised subjects who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort A: ISIS 416858, 200 mg
    Reporting group description
    		 Subjects received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort B: ISIS 416858, 250 mg
    Reporting group description
    		 Subjects received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Reporting group title
    Cohort C: ISIS 416858, 300 mg
    Reporting group description
    		 Subjects received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

    Serious adverse events
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 53 (18.87%)
    6 / 53 (11.32%)
    20 / 54 (37.04%)
    13 / 50 (26.00%)
         number of deaths (all causes)
    3
    0
    5
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 54 (3.70%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    2 / 54 (3.70%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial bypass thrombosis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula maturation failure
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft thrombosis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 54 (3.70%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic intracranial hypertension
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    4 / 54 (7.41%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Cohort A: ISIS 416858, 200 mg Cohort B: ISIS 416858, 250 mg Cohort C: ISIS 416858, 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 53 (47.17%)
    27 / 53 (50.94%)
    35 / 54 (64.81%)
    39 / 50 (78.00%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    4 / 54 (7.41%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    7
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 53 (5.66%)
    2 / 54 (3.70%)
    1 / 50 (2.00%)
         occurrences all number
    0
    4
    2
    1
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 53 (5.66%)
    4 / 54 (7.41%)
    6 / 50 (12.00%)
         occurrences all number
    3
    3
    7
    7
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 53 (3.77%)
    3 / 54 (5.56%)
    5 / 50 (10.00%)
         occurrences all number
    0
    2
    7
    5
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    3 / 54 (5.56%)
    1 / 50 (2.00%)
         occurrences all number
    1
    2
    5
    1
    Procedural hypotension
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    5 / 54 (9.26%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    5
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 53 (3.77%)
    1 / 54 (1.85%)
    1 / 50 (2.00%)
         occurrences all number
    3
    2
    1
    1
    Hypotension
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 53 (7.55%)
    3 / 54 (5.56%)
    2 / 50 (4.00%)
         occurrences all number
    1
    5
    3
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 53 (5.66%)
    2 / 54 (3.70%)
    5 / 50 (10.00%)
         occurrences all number
    5
    3
    2
    8
    General disorders and administration site conditions
    Injection site haematoma
         subjects affected / exposed
    2 / 53 (3.77%)
    12 / 53 (22.64%)
    8 / 54 (14.81%)
    9 / 50 (18.00%)
         occurrences all number
    2
    24
    47
    26
    Injection site erythema
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 53 (11.32%)
    6 / 54 (11.11%)
    14 / 50 (28.00%)
         occurrences all number
    1
    23
    12
    39
    Injection site pruritus
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 53 (9.43%)
    6 / 54 (11.11%)
    11 / 50 (22.00%)
         occurrences all number
    4
    11
    13
    16
    Injection site pain
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 53 (7.55%)
    7 / 54 (12.96%)
    6 / 50 (12.00%)
         occurrences all number
    2
    4
    10
    9
    Injection site bruising
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    3 / 54 (5.56%)
    4 / 50 (8.00%)
         occurrences all number
    1
    7
    7
    10
    Pyrexia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    1
    5
    Injection site discolouration
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    2 / 54 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    0
    9
    3
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 53 (7.55%)
    6 / 54 (11.11%)
    7 / 50 (14.00%)
         occurrences all number
    0
    7
    7
    9
    Anaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    5 / 54 (9.26%)
    2 / 50 (4.00%)
         occurrences all number
    1
    1
    5
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 53 (3.77%)
    4 / 54 (7.41%)
    1 / 50 (2.00%)
         occurrences all number
    6
    2
    4
    1
    Vomiting
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 53 (7.55%)
    2 / 54 (3.70%)
    0 / 50 (0.00%)
         occurrences all number
    6
    6
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 53 (7.55%)
    0 / 54 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    5
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 53 (3.77%)
    3 / 54 (5.56%)
    1 / 50 (2.00%)
         occurrences all number
    3
    2
    4
    1
    Epistaxis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    2 / 54 (3.70%)
    5 / 50 (10.00%)
         occurrences all number
    1
    2
    3
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 53 (3.77%)
    0 / 54 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    3
    2
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 53 (7.55%)
    2 / 54 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    5
    2
    5
    Back pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    4 / 54 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    5
    3
    Pain in extremity
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    3 / 54 (5.56%)
    1 / 50 (2.00%)
         occurrences all number
    4
    2
    5
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 53 (3.77%)
    1 / 54 (1.85%)
    3 / 50 (6.00%)
         occurrences all number
    5
    3
    2
    3
    Respiratory tract infection
         subjects affected / exposed
    6 / 53 (11.32%)
    1 / 53 (1.89%)
    2 / 54 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    7
    1
    4
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2018
    The following changes were made in Amendment 1: 1. Clarified that subjects were encouraged to complete the entire treatment and post-treatment evaluation periods, even if study drug had been discontinued. 2. Added to exclusion criterion #3 to include FXI activity < 0.3 Units per millilitre (U/mL) at screening. 3. For subjects in the optional platelet function sub study, allowed aspirin or nonsteroidal anti-inflammatory drug (NSAID) use. 4. Extended the screening period for signing of the informed consent from 28 to 49 days. 5. Provided additional clarification on the expected completion of dialysis and study drug administration. 6. Clarified that subjects were also stratified based on their participation in either or both sub studies (PK and/or platelet sub study) as applicable.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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