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    Clinical Trial Results:
    A Randomized, Double Blind, Placebo-Controlled, Dose Titration, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 494372 Administered Subcutaneously to Patients with High Lipoprotein(a)

    Summary
    EudraCT number
    		 2014-000701-13
    Trial protocol
    		 DE   GB   DK   NL  
    Global end of trial date
    18 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS494372-CS3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02160899
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, CA 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
    18 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective this study is to characterize the safety and tolerability of ISIS-APO(a)Rx in individual subjects at escalating doses of 100, 200, and 300 mg/week; and to characterize the efficacy of ISIS-APO(a)Rx in lowering Lp(a) using a dose titration study design.
    Protection of trial subjects
    Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Netherlands: 30
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Germany: 11
    Worldwide total number of subjects
    64
    EEA total number of subjects
    54
    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)
    55
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 51 subjects were enrolled in Cohort A and 13 subjects were enrolled in Cohort B.

    Pre-assignment
    Screening details
    		 A total of 86 subjects were screened for the study and 64 subjects were randomized into Cohort A and Cohort B and received study treatment. Two subjects in Cohort B did not complete the study treatment but completed the post-treatment follow-up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: Placebo
    Arm description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
    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 (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Arm title
    		 Cohort A: ISIS-APO(a)Rx < 2000 mg
    Arm description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS-APO(a)Rx
    Investigational medicinal product code
    Other name
    ISIS 494372
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Arm title
    		 Cohort A: ISIS-APO(a)Rx >= 2000 mg
    Arm description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS-APO(a)Rx
    Investigational medicinal product code
    Other name
    ISIS 494372
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Arm title
    		 Cohort B: Placebo
    Arm description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
    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 (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Arm title
    		 Cohort B: ISIS-APO(a)Rx < 2000 mg
    Arm description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS-APO(a)Rx
    Investigational medicinal product code
    Other name
    ISIS 494372
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Arm title
    		 Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Arm description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS-APO(a)Rx
    Investigational medicinal product code
    Other name
    ISIS 494372
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Number of subjects in period 1
    		Cohort A: Placebo Cohort A: ISIS-APO(a)Rx < 2000 mg Cohort A: ISIS-APO(a)Rx >= 2000 mg Cohort B: Placebo Cohort B: ISIS-APO(a)Rx < 2000 mg Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Started
    26
    4
    21
    3
    2
    8
    Completed
    26
    3
    21
    2
    0
    8
    Not completed
    0
    1
    0
    1
    2
    0
         Adverse Event or Serious Adverse Event
    -
    1
    -
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: Placebo
    Reporting group description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Reporting group title
    Cohort A: ISIS-APO(a)Rx < 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort A: ISIS-APO(a)Rx >= 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort B: Placebo
    Reporting group description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Reporting group title
    Cohort B: ISIS-APO(a)Rx < 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group values
    		 Cohort A: Placebo Cohort A: ISIS-APO(a)Rx < 2000 mg Cohort A: ISIS-APO(a)Rx >= 2000 mg Cohort B: Placebo Cohort B: ISIS-APO(a)Rx < 2000 mg Cohort B: ISIS-APO(a)Rx >= 2000 mg Total
    Number of subjects
    		 26 4 21 3 2 8 64
    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)
    		 54 ( 10 ) 50 ( 9 ) 56 ( 6 ) 62 ( 8 ) 45 ( 11 ) 61 ( 8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 2 12 3 2 6 31
        Male
    		 20 2 9 0 0 2 33

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: Placebo
    Reporting group description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Reporting group title
    Cohort A: ISIS-APO(a)Rx < 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort A: ISIS-APO(a)Rx >= 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort B: Placebo
    Reporting group description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Reporting group title
    Cohort B: ISIS-APO(a)Rx < 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Subject analysis set title
    Cohort A: Placebo (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol Set (PPS) included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set included the subset of the Safety Set with at least 1 post-baseline Lp(a) measurement.

    Subject analysis set title
    Cohort A: ISIS-APO(a)Rx < 2000 mg (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set included the subset of the Safety Set with at least 1 post-baseline Lp(a) measurement.

    Subject analysis set title
    Cohort A: ISIS-APO(a)Rx >= 2000 mg (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set included the subset of the Safety Set with at least 1 post-baseline Lp(a) measurement.

    Subject analysis set title
    Cohort B: Placebo (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set included the subset of the Safety Set with at least 1 post-baseline Lp(a) measurement.

    Subject analysis set title
    Cohort B: ISIS-APO(a)Rx >= 2000 mg (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set included the subset of the Safety Set with at least 1 post-baseline Lp(a) measurement.

    Primary: Number of Subjects With at Least One Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Subjects With at Least One Treatment-emergent Adverse Event (TEAE) [1]
    End point description
    An adverse event is any unfavourable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. The Safety Set included all randomised subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to approximately 32 weeks
    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 planned for this primary endpoint.
    End point values
    		 Cohort A: Placebo Cohort A: ISIS-APO(a)Rx < 2000 mg Cohort A: ISIS-APO(a)Rx >= 2000 mg Cohort B: Placebo Cohort B: ISIS-APO(a)Rx < 2000 mg Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Number of subjects analysed
    26
    4
    21
    3
    2
    8
    Units: percentage of subjects
        number (not applicable)
    23
    4
    21
    2
    2
    8
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99

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    End point title
    		 Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99
    End point description
    The Per-Protocol Set included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set included the subset of the Safety Set with at least 1 post-baseline Lp(a) measurement. Day 85/Day 99 result is defined as the result at Day 85 or Day 99.
    End point type
    Primary
    End point timeframe
    Day 85/Day 99
    End point values
    		 Cohort A: Placebo (PPS) Cohort A: ISIS-APO(a)Rx < 2000 mg (PPS) Cohort A: ISIS-APO(a)Rx >= 2000 mg (PPS) Cohort B: Placebo (PPS) Cohort B: ISIS-APO(a)Rx >= 2000 mg (PPS)
    Number of subjects analysed
    26
    3
    21
    2
    8
    Units: percent change
        arithmetic mean (standard deviation)
    -3.7 ( 13.7 )
    -44.5 ( 13.1 )
    -70.0 ( 19.6 )
    -5.6 ( 3.9 )
    -71.6 ( 13.0 )
    Statistical analysis title
    		 Cohort A:Placebo v Cohort A: ISIS-APO(a)Rx < 2000
    Comparison groups
    Cohort A: Placebo (PPS) v Cohort A: ISIS-APO(a)Rx < 2000 mg (PPS)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Cohort A:Placebo v Cohort A: ISIS-APO(a)Rx >= 200
    Comparison groups
    Cohort A: Placebo (PPS) v Cohort A: ISIS-APO(a)Rx >= 2000 mg (PPS)
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Cohort B:Placebo v Cohort B: ISIS-APO(a)Rx >= 200
    Comparison groups
    Cohort B: Placebo (PPS) v Cohort B: ISIS-APO(a)Rx >= 2000 mg (PPS)
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 32 weeks
    Adverse event reporting additional description
    The Safety Set included all randomised subjects who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort A: Placebo
    Reporting group description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Reporting group title
    Cohort A: ISIS-APO(a)Rx < 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort A: ISIS-APO(a)Rx >= 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort B: Placebo
    Reporting group description
    		 Subjects received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

    Reporting group title
    Cohort B: ISIS-APO(a)Rx < 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Reporting group title
    Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Reporting group description
    		 Subjects received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.

    Serious adverse events
    		 Cohort A: Placebo Cohort A: ISIS-APO(a)Rx < 2000 mg Cohort A: ISIS-APO(a)Rx >= 2000 mg Cohort B: Placebo Cohort B: ISIS-APO(a)Rx < 2000 mg Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 4 (50.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Myocardial infarction
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A: Placebo Cohort A: ISIS-APO(a)Rx < 2000 mg Cohort A: ISIS-APO(a)Rx >= 2000 mg Cohort B: Placebo Cohort B: ISIS-APO(a)Rx < 2000 mg Cohort B: ISIS-APO(a)Rx >= 2000 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 26 (88.46%)
    3 / 4 (75.00%)
    21 / 21 (100.00%)
    2 / 3 (66.67%)
    2 / 2 (100.00%)
    8 / 8 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Pallor
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 4 (75.00%)
    16 / 21 (76.19%)
    0 / 3 (0.00%)
    2 / 2 (100.00%)
    6 / 8 (75.00%)
         occurrences all number
    0
    23
    103
    0
    8
    48
    Injection site pain
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 4 (25.00%)
    12 / 21 (57.14%)
    0 / 3 (0.00%)
    2 / 2 (100.00%)
    2 / 8 (25.00%)
         occurrences all number
    7
    7
    71
    0
    7
    14
    Injection site induration
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 4 (75.00%)
    8 / 21 (38.10%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    0
    13
    20
    0
    0
    26
    Injection site swelling
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    10 / 21 (47.62%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    2
    45
    0
    2
    19
    Injection site warmth
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    0
    9
    0
    1
    10
    Injection site pruritus
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 4 (50.00%)
    8 / 21 (38.10%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    5
    23
    0
    0
    16
    Injection site reaction
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    7 / 21 (33.33%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    11
    0
    1
    2
    Chills
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 4 (50.00%)
    3 / 21 (14.29%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    4
    2
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 26 (11.54%)
    2 / 4 (50.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    11
    9
    7
    0
    0
    4
    Injection site discolouration
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    5 / 21 (23.81%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    14
    0
    0
    5
    Malaise
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 4 (0.00%)
    4 / 21 (19.05%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    3
    0
    12
    0
    0
    10
    Injection site haematoma
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    8
    0
    0
    2
    Injection site urticaria
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    12
    0
    0
    2
    Asthenia
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    1
    0
    0
    1
    Hyperthermia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Injection site hyperaesthesia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    0
    8
    0
    0
    11
    Injection site oedema
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    12
    0
    0
    12
    Oedema peripheral
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    3
    0
    0
    4
    Pyrexia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    1
    1
    1
    0
    3
    Pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Injection site bruising
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Injection site haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injection site pallor
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injection site paraesthesia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 4 (0.00%)
    3 / 21 (14.29%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    3
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    1
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Mood swings
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urine analysis abnormal
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    4
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 26 (23.08%)
    1 / 4 (25.00%)
    10 / 21 (47.62%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    1 / 8 (12.50%)
         occurrences all number
    10
    1
    12
    0
    2
    1
    Dizziness
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 4 (0.00%)
    4 / 21 (19.05%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    4
    0
    5
    0
    0
    4
    Disturbance in attention
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Tension headache
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 4 (25.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    1
    4
    0
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    3
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    5
    0
    0
    1
    Cheilitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    0
    0
    4
    Hyperhidrosis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Erythema annulare
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 4 (25.00%)
    4 / 21 (19.05%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    5
    0
    0
    2
    Myalgia
         subjects affected / exposed
    6 / 26 (23.08%)
    2 / 4 (50.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    7
    4
    11
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    4 / 26 (15.38%)
    2 / 4 (50.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    7
    3
    2
    0
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Joint stiffness
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    3
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 26 (34.62%)
    0 / 4 (0.00%)
    8 / 21 (38.10%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    11
    0
    10
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    4
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Bacteriuria
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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