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    Clinical Trial Results:
    A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy

    Summary
    EudraCT number
    		 2012-001831-30
    Trial protocol
    		 GB   PT   DE   IT   ES   BG  
    Global end of trial date
    07 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jul 2019
    First version publication date
    24 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS420915-CS2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01737398
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, 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
    07 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of ISIS 420915 as compared to placebo, given for 65 weeks, as measured by the change from baseline in the modified neuropathy impairment score +7 (mNIS+7) and in the norfolk quality of life-diabetic neuropathy (Norfolk QOL-DN) questionnaire total score, in subjects with familial amyloid polyneuropathy (FAP).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Portugal: 24
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 82
    Country: Number of subjects enrolled
    Brazil: 22
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    New Zealand: 1
    Worldwide total number of subjects
    172
    EEA total number of subjects
    60
    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)
    98
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects randomized: 113 inotersen and 60 placebo; received study treatment: 112 inotersen and 60 placebo. One subject in the inotersen group was ineligible, but was randomized in error. This study consisted of a 65-week Treatment Period, 1-week End of Treatment (EOT) Period, and a 6-month Post-treatment Evaluation Period.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inotersen
    Arm description
    		 Subjects received 3 subcutaneous (SC) doses of 300 milligrams (mg) inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Inotersen
    Investigational medicinal product code
    Other name
    ISIS 420915
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Inotersen administered as subcutaneous (SC) injection, 300 mg in Week 1 followed by once-weekly SC injection for 64 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
    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
    Placebo administered as SC injection in Week 1 followed by once-weekly SC injection for 64 weeks.

    Number of subjects in period 1
    		Inotersen Placebo
    Started
    112
    60
    Completed
    87
    52
    Not completed
    25
    8
         Consent withdrawn by subject
    2
    3
         Stopping Rule Met
    2
    1
         Liver Transplant
    1
    -
         Sponsor Decision
    2
    -
         Adverse Event or Serious Adverse Event (SAE)
    16
    1
         Disease Progression
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inotersen
    Reporting group description
    		 Subjects received 3 subcutaneous (SC) doses of 300 milligrams (mg) inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.

    Reporting group values
    		 Inotersen Placebo Total
    Number of subjects
    		 112 60 172
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.0 ( 12.53 ) 59.5 ( 14.05 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 19 54
        Male
    		 77 41 118
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 17 7 24
        Not Hispanic or Latino
    		 95 53 148
    Race
    Units: Subjects
        Asian
    		 1 3 4
        Black
    		 3 1 4
        White
    		 105 53 158
        White & Grayish-Brown
    		 0 1 1
        Other
    		 3 2 5
    Subjects diagnosed with Familial Amyloid Cardiomyopathy
    Units: Subjects
        Yes
    		 45 22 67
        No
    		 67 38 105

    End points

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    End points reporting groups
    Reporting group title
    Inotersen
    Reporting group description
    		 Subjects received 3 subcutaneous (SC) doses of 300 milligrams (mg) inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.

    Subject analysis set title
    Inotersen 300 mg IM Positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive immunogenicity (IM) status.

    Subject analysis set title
    Inotersen 300 mg IM Negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative IM status.

    Primary: Change From Baseline in the Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66

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    End point title
    		 Change From Baseline in the Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
    End point description
    The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 composite score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates lower function. The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Primary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    85
    52
    Units: score on a Scale
        arithmetic mean (standard deviation)
    4.16 ( 15.672 )
    23.89 ( 24.190 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Inotersen v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [1]
    Method
    		 MMRM
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -19.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.43
         upper limit
    		 -13.03
    Notes
    [1] - P-value was calculated using mixed effects model with repeated measures (MMRM).

    Primary: Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66

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    End point title
    		 Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
    End point description
    The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher Norfolk QoL-DN score indicates poorer QoL. The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Primary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    84
    52
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.08 ( 18.967 )
    10.77 ( 21.134 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Inotersen v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 MMRM
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -11.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.29
         upper limit
    		 -5.06

    Secondary: Change From Baseline in the Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66

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    End point title
    		 Change From Baseline in the Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66
    End point description
    The Norfolk QoL-DN symptoms score is a sub-score of the total Norfolk QoL-DN questionnaire. The Norfolk QoL-DN symptoms domain score has a range of 0-32, and a higher Norfolk QoL-DN score indicates poorer QoL. This endpoint only measured subjects with Stage 1 hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in full analysis set. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    55
    33
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.40 ( 4.763 )
    1.18 ( 5.270 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66

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    End point title
    		 Change From Baseline in the Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66
    End point description
    The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer QoL. This endpoints only measured subjects who had Stage 2 hATTR-PN in full analysis set. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    29
    19
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.05 ( 11.924 )
    8.74 ( 9.689 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Modified Body Mass Index (mBMI) at Week 65

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    End point title
    		 Change From Baseline in Modified Body Mass Index (mBMI) at Week 65
    End point description
    The mBMI is the BMI multiplied by the serum albumin g/L. The full analysis set included all randomized subject who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 65
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    82
    49
    Units: kilogram(kg)/metre(m)^2*gram(g)/litre(L)
        arithmetic mean (standard deviation)
    -73.32 ( 96.311 )
    -85.21 ( 91.259 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In Body Mass Index (BMI) at Week 65

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    End point title
    		 Change From Baseline In Body Mass Index (BMI) at Week 65
    End point description
    The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 65
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    82
    49
    Units: kg/m^2
        arithmetic mean (standard deviation)
    -0.24 ( 1.521 )
    -0.87 ( 1.202 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66

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    End point title
    		 Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66
    End point description
    The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    85
    52
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.47 ( 10.329 )
    17.29 ( 16.986 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Modified +7 at Week 66

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    End point title
    		 Change From Baseline in Modified +7 at Week 66
    End point description
    The Modified +7 score is a version of the NIS score that is a measure of neurologic impairment. The Modified +7 Score has a range of -22.32 to 102.32 and a higher NIS score indicates lower function. The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    85
    52
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.31 ( 11.134 )
    6.60 ( 12.770 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in NIS+7 at Week 66

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    End point title
    		 Change From Baseline in NIS+7 at Week 66
    End point description
    The NIS+7 score is a version of the NIS score that is a measure of neurologic impairment. The NIS+7 Score has a range of -26.04 to 270.04 and a higher NIS score indicates lower function. The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    85
    52
    Units: score on a scale
        arithmetic mean (standard deviation)
    5.10 ( 10.709 )
    19.00 ( 16.824 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set

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    End point title
    		 Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set
    End point description
    GLS by ECHO is a measure of cardiac systolic function. The CM-ECHO set included the subset of the randomized set who had a diagnosis of transthyretin (TTR) cardiomyopathy at study entry but are not in the ECHO subgroup, plus subjects who qualified to participate in the ECHO subgroup (whether consented or not). Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 65
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    50
    25
    Units: percent change
        arithmetic mean (standard deviation)
    0.69 ( 3.134 )
    0.46 ( 2.702 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup

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    End point title
    		 Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup
    End point description
    GLS by ECHO is a measure of cardiac systolic function. The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 65
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    30
    16
    Units: percent change
        arithmetic mean (standard deviation)
    0.25 ( 3.163 )
    1.05 ( 2.745 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Transthyretin (TTR) Level at Week 65

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    End point title
    		 Change From Baseline in Transthyretin (TTR) Level at Week 65
    End point description
    The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 65
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    84
    51
    Units: g/L
        arithmetic mean (standard deviation)
    -0.1570 ( 0.0619 )
    -0.0146 ( 0.0402 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65

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    End point title
    		 Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65
    End point description
    The full analysis set included all randomized subjects who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 65
    End point values
    		 Inotersen Placebo
    Number of subjects analysed
    83
    51
    Units: microgram (ug)/L
        arithmetic mean (standard deviation)
    -21725.9 ( 9884.04 )
    -1768.7 ( 8027.78 )
    No statistical analyses for this end point

    Secondary: Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65

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    End point title
    		 Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65
    End point description
    The pharmacokinetic (PK) Set was defined as all randomized subjects who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analysed with a reportable result. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Week 65
    End point values
    		 Inotersen 300 mg IM Positive Inotersen 300 mg IM Negative
    Number of subjects analysed
    3
    5
    Units: micrograms per millilitre (ug/mL)
        arithmetic mean (standard deviation)
    11.1 ( 4.80 )
    6.76 ( 1.88 )
    No statistical analyses for this end point

    Secondary: Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65

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    End point title
    		 Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65
    End point description
    The PK Set was defined as all randomized subjects who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analysed with a reportable result. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Week 65
    End point values
    		 Inotersen 300 mg IM Positive Inotersen 300 mg IM Negative
    Number of subjects analysed
    3
    5
    Units: hour (hr)
        arithmetic mean (standard deviation)
    3.48 ( 0.684 )
    4.14 ( 1.11 )
    No statistical analyses for this end point

    Secondary: Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65

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    End point title
    		 Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65
    End point description
    The PK Set was defined as all randomized subjects who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analysed with a reportable result. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Week 65
    End point values
    		 Inotersen 300 mg IM Positive Inotersen 300 mg IM Negative
    Number of subjects analysed
    3
    5
    Units: microgram hours (ug*hr) per/mL
        arithmetic mean (standard deviation)
    92.4 ( 77.3 )
    93.1 ( 30.7 )
    No statistical analyses for this end point

    Secondary: Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65

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    End point title
    		 Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65
    End point description
    The PK Set was defined as all randomized subjects who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analysed with a reportable result. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Week 65
    End point values
    		 Inotersen 300 mg IM Positive Inotersen 300 mg IM Negative
    Number of subjects analysed
    3
    4
    Units: ug*hr/mL
        arithmetic mean (standard deviation)
    103 ( 88.2 )
    98.9 ( 33.5 )
    No statistical analyses for this end point

    Secondary: Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65

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    End point title
    		 Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65
    End point description
    The PK Set was defined as all randomized subjects who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analysed with a reportable result. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Week 65
    End point values
    		 Inotersen 300 mg IM Positive Inotersen 300 mg IM Negative
    Number of subjects analysed
    3
    5
    Units: L/hr
        arithmetic mean (standard deviation)
    6.14 ( 5.92 )
    3.57 ( 1.32 )
    No statistical analyses for this end point

    Secondary: Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65

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    End point title
    		 Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65
    End point description
    The PK Set was defined as all randomized subjects who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analysed with a reportable result. Subjects analysed is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Week 65
    End point values
    		 Inotersen 300 mg IM Positive Inotersen 300 mg IM Negative
    Number of subjects analysed
    3
    4
    Units: L/hr
        arithmetic mean (standard deviation)
    5.46 ( 5.13 )
    3.33 ( 1.21 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 1 to Week 91
    Adverse event reporting additional description
    Adverse events that first occurred or worsened after the first dose of study drug (inotersen or placebo), including serious adverse events, were summarized for each treatment group. Analysis is based on data collected while study treatment was administered and during follow-up until the day of the subject's last contact date within the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Inotersen
    Reporting group description
    		 Subjects received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.

    Serious adverse events
    		 Inotersen Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 112 (32.14%)
    13 / 60 (21.67%)
         number of deaths (all causes)
    5
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiopathy
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    4 / 112 (3.57%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dementia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mesenteric arterial occlusion
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 112 (1.79%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 112 (2.68%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Inotersen Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    110 / 112 (98.21%)
    60 / 60 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 60 (3.33%)
         occurrences all number
    8
    4
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    35 / 112 (31.25%)
    0 / 60 (0.00%)
         occurrences all number
    117
    0
    Injection site pain
         subjects affected / exposed
    23 / 112 (20.54%)
    4 / 60 (6.67%)
         occurrences all number
    47
    7
    Fatigue
         subjects affected / exposed
    28 / 112 (25.00%)
    12 / 60 (20.00%)
         occurrences all number
    43
    14
    Chills
         subjects affected / exposed
    20 / 112 (17.86%)
    2 / 60 (3.33%)
         occurrences all number
    40
    3
    Pyrexia
         subjects affected / exposed
    22 / 112 (19.64%)
    5 / 60 (8.33%)
         occurrences all number
    32
    6
    Oedema peripheral
         subjects affected / exposed
    21 / 112 (18.75%)
    6 / 60 (10.00%)
         occurrences all number
    23
    6
    Asthenia
         subjects affected / exposed
    14 / 112 (12.50%)
    8 / 60 (13.33%)
         occurrences all number
    17
    11
    Injection site pruritus
         subjects affected / exposed
    13 / 112 (11.61%)
    0 / 60 (0.00%)
         occurrences all number
    16
    0
    Influenza like illness
         subjects affected / exposed
    9 / 112 (8.04%)
    2 / 60 (3.33%)
         occurrences all number
    10
    2
    Injection site bruising
         subjects affected / exposed
    8 / 112 (7.14%)
    2 / 60 (3.33%)
         occurrences all number
    8
    2
    Peripheral swelling
         subjects affected / exposed
    7 / 112 (6.25%)
    0 / 60 (0.00%)
         occurrences all number
    7
    0
    Injection site reaction
         subjects affected / exposed
    6 / 112 (5.36%)
    0 / 60 (0.00%)
         occurrences all number
    7
    0
    Gait disturbance
         subjects affected / exposed
    6 / 112 (5.36%)
    5 / 60 (8.33%)
         occurrences all number
    6
    5
    Injection site swelling
         subjects affected / exposed
    6 / 112 (5.36%)
    0 / 60 (0.00%)
         occurrences all number
    6
    0
    Pain
         subjects affected / exposed
    2 / 112 (1.79%)
    5 / 60 (8.33%)
         occurrences all number
    2
    6
    Oedema
         subjects affected / exposed
    1 / 112 (0.89%)
    3 / 60 (5.00%)
         occurrences all number
    1
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 112 (0.89%)
    4 / 60 (6.67%)
         occurrences all number
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    10 / 112 (8.93%)
    2 / 60 (3.33%)
         occurrences all number
    13
    2
    Cough
         subjects affected / exposed
    10 / 112 (8.93%)
    8 / 60 (13.33%)
         occurrences all number
    11
    8
    Oropharyngeal pain
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 60 (3.33%)
         occurrences all number
    6
    2
    Dyspnoea exertional
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 60 (5.00%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    7 / 112 (6.25%)
    4 / 60 (6.67%)
         occurrences all number
    7
    5
    Insomnia
         subjects affected / exposed
    6 / 112 (5.36%)
    3 / 60 (5.00%)
         occurrences all number
    6
    3
    Anxiety
         subjects affected / exposed
    1 / 112 (0.89%)
    4 / 60 (6.67%)
         occurrences all number
    1
    5
    Investigations
    Platelet count decreased
         subjects affected / exposed
    12 / 112 (10.71%)
    0 / 60 (0.00%)
         occurrences all number
    14
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 60 (3.33%)
         occurrences all number
    7
    2
    Weight decreased
         subjects affected / exposed
    4 / 112 (3.57%)
    5 / 60 (8.33%)
         occurrences all number
    5
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    19 / 112 (16.96%)
    13 / 60 (21.67%)
         occurrences all number
    26
    16
    Contusion
         subjects affected / exposed
    9 / 112 (8.04%)
    1 / 60 (1.67%)
         occurrences all number
    11
    1
    Thermal burn
         subjects affected / exposed
    6 / 112 (5.36%)
    6 / 60 (10.00%)
         occurrences all number
    6
    6
    Ligament sprain
         subjects affected / exposed
    1 / 112 (0.89%)
    3 / 60 (5.00%)
         occurrences all number
    2
    5
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 112 (5.36%)
    1 / 60 (1.67%)
         occurrences all number
    6
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 112 (23.21%)
    7 / 60 (11.67%)
         occurrences all number
    34
    10
    Paraesthesia
         subjects affected / exposed
    11 / 112 (9.82%)
    2 / 60 (3.33%)
         occurrences all number
    21
    3
    Dizziness
         subjects affected / exposed
    14 / 112 (12.50%)
    7 / 60 (11.67%)
         occurrences all number
    17
    7
    Syncope
         subjects affected / exposed
    9 / 112 (8.04%)
    2 / 60 (3.33%)
         occurrences all number
    16
    2
    Hypoaesthesia
         subjects affected / exposed
    10 / 112 (8.93%)
    6 / 60 (10.00%)
         occurrences all number
    11
    7
    Presyncope
         subjects affected / exposed
    6 / 112 (5.36%)
    0 / 60 (0.00%)
         occurrences all number
    10
    0
    Neuralgia
         subjects affected / exposed
    3 / 112 (2.68%)
    8 / 60 (13.33%)
         occurrences all number
    3
    8
    Neuropathy peripheral
         subjects affected / exposed
    2 / 112 (1.79%)
    4 / 60 (6.67%)
         occurrences all number
    3
    5
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    14 / 112 (12.50%)
    1 / 60 (1.67%)
         occurrences all number
    19
    2
    Anaemia
         subjects affected / exposed
    15 / 112 (13.39%)
    2 / 60 (3.33%)
         occurrences all number
    16
    2
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 60 (5.00%)
         occurrences all number
    3
    3
    Blepharitis
         subjects affected / exposed
    2 / 112 (1.79%)
    4 / 60 (6.67%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    35 / 112 (31.25%)
    7 / 60 (11.67%)
         occurrences all number
    44
    9
    Diarrhoea
         subjects affected / exposed
    27 / 112 (24.11%)
    12 / 60 (20.00%)
         occurrences all number
    29
    16
    Vomiting
         subjects affected / exposed
    17 / 112 (15.18%)
    2 / 60 (3.33%)
         occurrences all number
    21
    2
    Constipation
         subjects affected / exposed
    15 / 112 (13.39%)
    6 / 60 (10.00%)
         occurrences all number
    16
    7
    Abdominal pain
         subjects affected / exposed
    6 / 112 (5.36%)
    4 / 60 (6.67%)
         occurrences all number
    6
    5
    Dry mouth
         subjects affected / exposed
    6 / 112 (5.36%)
    1 / 60 (1.67%)
         occurrences all number
    6
    1
    Dysphagia
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 60 (5.00%)
         occurrences all number
    2
    3
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    5 / 112 (4.46%)
    4 / 60 (6.67%)
         occurrences all number
    7
    4
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    7 / 112 (6.25%)
    2 / 60 (3.33%)
         occurrences all number
    9
    3
    Haematuria
         subjects affected / exposed
    5 / 112 (4.46%)
    5 / 60 (8.33%)
         occurrences all number
    5
    7
    Dysuria
         subjects affected / exposed
    2 / 112 (1.79%)
    4 / 60 (6.67%)
         occurrences all number
    2
    4
    Urinary retention
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 60 (5.00%)
         occurrences all number
    2
    3
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    17 / 112 (15.18%)
    6 / 60 (10.00%)
         occurrences all number
    25
    7
    Arthralgia
         subjects affected / exposed
    13 / 112 (11.61%)
    5 / 60 (8.33%)
         occurrences all number
    20
    9
    Muscle spasms
         subjects affected / exposed
    11 / 112 (9.82%)
    4 / 60 (6.67%)
         occurrences all number
    13
    5
    Pain in extremity
         subjects affected / exposed
    10 / 112 (8.93%)
    8 / 60 (13.33%)
         occurrences all number
    12
    11
    Muscular weakness
         subjects affected / exposed
    11 / 112 (9.82%)
    6 / 60 (10.00%)
         occurrences all number
    11
    7
    Back pain
         subjects affected / exposed
    10 / 112 (8.93%)
    5 / 60 (8.33%)
         occurrences all number
    11
    5
    Musculoskeletal pain
         subjects affected / exposed
    6 / 112 (5.36%)
    1 / 60 (1.67%)
         occurrences all number
    6
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    21 / 112 (18.75%)
    11 / 60 (18.33%)
         occurrences all number
    46
    13
    Nasopharyngitis
         subjects affected / exposed
    9 / 112 (8.04%)
    6 / 60 (10.00%)
         occurrences all number
    9
    7
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 112 (6.25%)
    3 / 60 (5.00%)
         occurrences all number
    8
    4
    Influenza
         subjects affected / exposed
    4 / 112 (3.57%)
    3 / 60 (5.00%)
         occurrences all number
    4
    3
    Rhinitis
         subjects affected / exposed
    0 / 112 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 112 (9.82%)
    0 / 60 (0.00%)
         occurrences all number
    14
    0

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

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