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    Clinical Trial Results:
    An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy (FAP)

    Summary
    EudraCT number
    2013-004561-13
    Trial protocol
    PT   GB   DE   FR   ES  
    Global end of trial date
    07 Jan 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS420915-CS3
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02175004
    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 Clinical Trial Information, Ionis Pharmaceuticals, Inc., +1 760603-3804, ClinicalTrials@ionisph.com
    Scientific contact
    Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., +1 760603-3804, ClinicalTrials@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 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of extended dosing with ISIS 420915 in subjects with familial amyloid polyneuropathy.
    Protection of trial subjects
    All subjects signed an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 15
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 67
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Brazil: 19
    Worldwide total number of subjects
    135
    EEA total number of subjects
    37
    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)
    72
    From 65 to 84 years
    63
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 135 subjects, of which 50 received placebo, and 85 received inotersen in the previous study ISIS 420915-CS2 (NCT01737398-CS2). Subjects enrolled into this study received inotersen. This study consisted of a 260-week Treatment Period, and 3-month Post-treatment Evaluation Period. Data is reported as per the previous(CS2) study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Previous Placebo-Inotersen 300 mg
    Arm description
    Subjects received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Subjects who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.
    Arm type
    Experimental

    Investigational medicinal product name
    Inotersen
    Investigational medicinal product code
    Other name
    TEGSEDI, IONIS-TTR Rx, ISIS 420915
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Inotersen 300 mg, SC

    Arm title
    Previous Inotersen-Inotersen 300 mg
    Arm description
    Subjects received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Subjects who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
    Arm type
    Experimental

    Investigational medicinal product name
    Inotersen
    Investigational medicinal product code
    Other name
    TEGSEDI, IONIS-TTR Rx, ISIS 420915
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Inotersen 300 mg, SC

    Number of subjects in period 1
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Started
    50
    85
    Completed
    9
    9
    Not completed
    41
    76
         Voluntary Withdrawal
    6
    19
         Investigator Judgment
    1
    4
         Liver Transplant
    1
    -
         Adverse Event or Serious Adverse Event (SAE)
    5
    14
         Treatment With Commercial/Post-study Inotersen
    27
    39
         Disease Progression
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Previous Placebo-Inotersen 300 mg
    Reporting group description
    Subjects received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Subjects who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.

    Reporting group title
    Previous Inotersen-Inotersen 300 mg
    Reporting group description
    Subjects received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Subjects who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.

    Reporting group values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg Total
    Number of subjects
    50 85 135
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.5 ( 14.62 ) 60.3 ( 11.86 ) -
    Gender categorical
    Units: Subjects
        Female
    15 26 41
        Male
    35 59 94
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    6 12 18
        Not Hispanic or Latino
    44 73 117
    Race
    Units: Subjects
        Asian
    3 0 3
        Black
    0 1 1
        White
    44 81 125
        White & Grayish-Brown
    1 0 1
        Other
    2 3 5

    End points

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    End points reporting groups
    Reporting group title
    Previous Placebo-Inotersen 300 mg
    Reporting group description
    Subjects received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Subjects who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.

    Reporting group title
    Previous Inotersen-Inotersen 300 mg
    Reporting group description
    Subjects received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Subjects who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.

    Subject analysis set title
    Previous Placebo-Inotersen 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Subjects who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.

    Subject analysis set title
    Previous Inotersen-Inotersen 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.

    Primary: Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug

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    End point title
    Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug [1]
    End point description
    An adverse event (AE) is any unfavorable 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported. SS included all enrolled subjects who received at least 1 injection of inotersen in CS3.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: percentage of subjects
    number (not applicable)
        TEAEs
    100
    96.5
        Serious TEAEs
    36.0
    54.1
        TEAEs Related to Study Drug
    82.0
    69.4
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Change From Baseline in Vital Signs

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    End point title
    Percentage of Subjects With Change From Baseline in Vital Signs [2]
    End point description
    Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one subject with event are reported. SS included all enrolled subjects who received at least 1 injection of inotersen in CS3. mmHg=millimeters of mercury.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: percentage of subjects
    number (not applicable)
        Systolic Blood Pressure:<90 mmHg
    12.0
    18.8
        Systolic Blood Pressure: >140 mmHg
    32.0
    41.2
        Systolic Blood Pressure: >160 mmHg
    8.0
    20.0
        Diastolic Blood Pressure: <50 mmHg
    6.0
    9.4
        Diastolic Blood Pressure: >90 mmHg
    30.0
    28.2
        Diastolic Blood Pressure: >100 mmHg
    10.0
    7.1
        Heart Rate: <60 beats per minute (bpm)
    30.0
    38.8
        Heart Rate: >100 bpm
    16.0
    9.4
        Temperature (°C): <36.0°C
    46.0
    55.3
        Respiratory Rate (breaths/minute): >20 breaths/min
    24.0
    21.2
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Change From Baseline in Weight

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    End point title
    Percentage of Subjects With Change From Baseline in Weight [3]
    End point description
    As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline. SS included all enrolled subjects who received at least 1 injection of inotersen in CS3. Number of subjects analysed are the number of subjects available for analyses.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Notes
    [3] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    49
    83
    Units: percentage of subjects
    number (not applicable)
        Weight (kg): Decrease of ≥7% From Baseline
    30.0
    47.1
        Weight (kg): Increase of ≥7% From Baseline
    24.0
    11.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Clinically Significant Change From Baseline in Laboratory Test Values

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    End point title
    Percentage of Subjects With Clinically Significant Change From Baseline in Laboratory Test Values [4]
    End point description
    Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one subject with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= <0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10^9/L to 400×10^9/L. CCCL= confirmed creatinine clearance, ULN= upper limit of normal, ALT=alanine aminotransferase. SS included all enrolled subjects who received at least 1 injection of inotersen in CS3. n= number analysed is the number of subjects with data available for analysis for the given category.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Notes
    [4] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: percentage of subjects
    number (not applicable)
        CC CL by CKD-EPI <30 ml/min/1.73m^2 (n=50,83)
    4.0
    4.7
        Confirmed Urine P/C Ratio >5 × ULN (n=50,83)
    8.0
    10.6
        Confirmed ALT ≥3 x ULN (n=50,85)
    4.0
    4.7
        Confirmed Value of Platelets <75 × 10^9/L
    12.0
    12.9
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)

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    End point title
    Percentage of Subjects With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) [5]
    End point description
    Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of subjects with QT interval outside of normal range are reported. SS included all enrolled subjects who received at least 1 injection of inotersen in CS3.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Notes
    [5] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: percentage of subjects
    number (not applicable)
        QTcF >450 ms
    44.0
    43.5
        QTcF >480 ms
    20.0
    23.5
        QTcF >500 ms
    12.0
    16.5
    No statistical analyses for this end point

    Primary: Percentage of Subjects Using Concomitant Medication for Nervous and Cardiovascular System Disorders

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    End point title
    Percentage of Subjects Using Concomitant Medication for Nervous and Cardiovascular System Disorders [6]
    End point description
    A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders. SS included all enrolled subjects who received at least 1 injection of inotersen in CS3.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Notes
    [6] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: percentage of subjects
    number (not applicable)
        Nervous System Disorders
    88.0
    81.2
        Cardiovascular System Disorders
    68.0
    75.3
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes

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    End point title
    Percentage of Subjects With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes [7]
    End point description
    SS included all enrolled subjects who received at least 1 injection of inotersen in CS3.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Notes
    [7] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: percentage of subjects
        number (not applicable)
    0.0
    2.4
    No statistical analyses for this end point

    Primary: Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography

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    End point title
    Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography [8]
    End point description
    SS included all enrolled subjects who received at least 1 injection of inotersen in CS3. Number of subjects analysed are the number of subjects available for analyses at Baseline. n= number analysed is the number of participants with data available for analysis at the given time point. CFB=Change from Baseline.
    End point type
    Primary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    Notes
    [8] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    39
    76
    Units: percentage of subjects
    number (not applicable)
        Subjects With Normal Baseline (n=39,76)
    48.7
    81.6
        Subjects With CFB at Week 78 (n=28,63)
    25.0
    12.7
        Subjects With CFB at Week 156 (n=16,33)
    31.3
    9.1
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156

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    End point title
    Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156
    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 worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Full Analysis Set (FAS) population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=31,66)
    33.11 ( 28.915 )
    10.11 ( 18.204 )
        Change From Baseline at Week 156 (n=21,35)
    37.34 ( 29.030 )
    17.21 ( 27.307 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the mNIS+7 Composite Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [9]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -17.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.12
         upper limit
    -9.56
    Notes
    [9] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change From Baseline in the mNIS+7 Composite Score at Week 156
    Comparison groups
    Previous Inotersen-Inotersen 300 mg v Previous Placebo-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [10]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -20.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.27
         upper limit
    -8.95
    Notes
    [10] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156

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    End point title
    Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156
    End point description
    Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a patients change in heart rate after deep breathing. The maximum score of this component is 3.72 points. The Full Analysis Set (FAS) populations includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=35,72)
    0.23 ( 0.977 )
    0.11 ( 0.761 )
        Change From Baseline at Week 156 (n=22,39)
    0.44 ( 1.099 )
    0.30 ( 0.504 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.638 [11]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    0.2
    Notes
    [11] - P-value=MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Week 156
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.965 [12]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.29
    Notes
    [12] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156

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    End point title
    Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156
    End point description
    The Nerve Conduction tests are quantitative tests that meassure the conduction attributes of preselected nerves. The maximum score of thsis component is 18.6 points. The Full Analysis Set (FAS) population includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=32,68)
    1.86 ( 2.313 )
    0.57 ( 1.361 )
        Change From Baseline at Week 156 (n=21,36)
    2.05 ( 2.351 )
    0.77 ( 1.724 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [13]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.68
         upper limit
    -0.5
    Notes
    [13] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Week 156
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.067 [14]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.38
         upper limit
    0.05
    Notes
    [14] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156

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    End point title
    Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156
    End point description
    The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 40 points. Full Analysis Set (FAS) included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=32,66)
    2.60 ( 8.440 )
    2.45 ( 7.557 )
        Change From Baseline at Week 156 (n=21,35)
    2.90 ( 9.224 )
    3.40 ( 8.774 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.821 [15]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.67
         upper limit
    3.36
    Notes
    [15] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Week 156
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.293 [16]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -2.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.21
         upper limit
    1.9
    Notes
    [16] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156

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    End point title
    Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156
    End point description
    The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The maximum score of this component is 40 points. The Full Analysis Set (FAS) population includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=32,66)
    1.00 ( 6.886 )
    -3.05 ( 8.878 )
        Change From Baseline at Week 156 (n=21,35)
    1.95 ( 6.866 )
    -2.34 ( 8.306 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047 [17]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -2.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.53
         upper limit
    -0.03
    Notes
    [17] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Week 156
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.041 [18]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -3.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    -0.13
    Notes
    [18] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5

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    End point title
    Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5
    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. A positive change from Baseline indicates worsening. FAS included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    9
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    35.78 ( 21.071 )
    18.32 ( 20.970 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    17.75 ( 99999 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the NIS Composite Score at Week 52 of Year 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [19]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -17.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.92
         upper limit
    -8.03
    Notes
    [19] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5

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    End point title
    Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5
    End point description
    Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The maximum score for this component is 40 points. The FAS population includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    9
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    0.0 ( 99999 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change from Baseline in the NIS Component: Cranial Nerves Score Score at Week 52 of Year 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.941 [20]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.17
    Notes
    [20] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5

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    End point title
    Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5
    End point description
    Muscle weakness involves testing 19 movements of muscles. The maximum score of this component is 152 points. The FAS population includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    9
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    23.67 ( 16.712 )
    14.71 ( 19.479 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    13.75 ( 99999 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change from Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011 [21]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -9.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.97
         upper limit
    -2.16
    Notes
    [21] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5

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    End point title
    Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5
    End point description
    The Reflexes Score involves testing 5 reflexes to stimuli. The maximum score of this component is 20 points. The FAS population includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    9
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    4.17 ( 3.553 )
    2.32 ( 1.957 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    4.00 ( 99999 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change from Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.356 [22]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.28
         upper limit
    1.18
    Notes
    [22] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5

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    End point title
    Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5
    End point description
    The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The maximum score of this component is 32 points. The FAS population includes all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    9
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    7.94 ( 5.288 )
    1.29 ( 3.662 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    0.00 ( 99999 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change from Baseline in the NIS Component: Sensory Score at Week 52 of Years 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [23]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -5.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.58
         upper limit
    -2.19
    Notes
    [23] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156

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    End point title
    Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156
    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. A positive change from Baseline indicates worsening in the QoL. The FAS population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=34,71)
    15.22 ( 24.024 )
    3.76 ( 20.832 )
        Change From Baseline at Week 156 (n=22,41)
    14.94 ( 28.944 )
    5.98 ( 22.891 )
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    6.22 ( 18.600 )
    2.36 ( 25.120 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    -1.00 ( 99999 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.026 [24]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -9.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.48
         upper limit
    -1.14
    Notes
    [24] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change From Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 156
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.107 [25]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -7.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.41
         upper limit
    1.62
    Notes
    [25] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Change From Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 52 of Year 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.669 [26]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -2.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.22
         upper limit
    9.77
    Notes
    [26] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

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

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    End point title
    Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score
    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 quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. The FAS population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at Week 52 of Year 4
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    18
    26
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=14,23)
    11.21 ( 11.026 )
    3.61 ( 11.500 )
        Change From Baseline at Week 156 (n=5,11)
    12.60 ( 10.784 )
    -0.55 ( 8.042 )
        Change From Baseline at Week 52 of Year 4 (n=2,4)
    9.50 ( 9.192 )
    3.50 ( 7.047 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change From Baseline in the Norfolk QOL-DN Change From CS2 Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 78
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.097
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.75
         upper limit
    1.15
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change from Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score at Week 156
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.081 [27]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -8.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.88
         upper limit
    1.11
    Notes
    [27] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Change From Baseline in the Norfolk QOL-DN Physical Functioning/Large Fiber Neuropathy Domain Score at Week 52 of Year 4
    Comparison groups
    Previous Placebo-Inotersen 300 mg v Previous Inotersen-Inotersen 300 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.171 [28]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -11.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.89
         upper limit
    5.16
    Notes
    [28] - P-value= MMRM with fixed categorical effects for treatment, time, treatment-by-time interaction, each of 3 randomization stratification factors, fixed covariates for parent study baseline value, baseline-by-time interaction.

    Secondary: Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156

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    End point title
    Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156
    End point description
    BMI=weight (kg)/[height (m)^2]. The mBMI is the BMI multiplied by the serum albumin (g/L). The FAS population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: kg/m^2*g/L
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=35,71)
    -166.27 ( 159.644 )
    -161.52 ( 134.779 )
        Change From Baseline at Week 156 (n=21,39)
    -191.68 ( 130.370 )
    -172.52 ( 131.602 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156

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    End point title
    Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156
    End point description
    BMI=weight (kg)/[height (m)^2]. The FAS population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment f after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=35,71)
    -0.16 ( 2.617 )
    -0.44 ( 1.427 )
        Change From Baseline at Week 156 (n=21,39)
    -0.34 ( 1.908 )
    -0.66 ( 2.220 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Change From Baseline in the Polyneuropathy Disability (PND) Score

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    End point title
    Percentage of Subjects With Change From Baseline in the Polyneuropathy Disability (PND) Score
    End point description
    PND score=defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without need of walking aid; III=one stick or one crutch required for walking; IV=two sticks or two crutches needed. V=wheelchair required or patient confined to bed. Change from Baseline: improved, not changed, worsened, and unknown. Percentage of subjects with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one subjects with event are reported. CFB=change from Baseline. The FAS population included all enrolled subjects who received at least 1 injection of post-baseline efficacy assessment after CS3 Study Day 1. 99999=data not available as no subjects were analysed during that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: percentage of subjects
    number (not applicable)
        CFB at Week 78: Improved (n=36,71)
    5.6
    11.3
        CFB at Week 78: Not Changed (n=36,71)
    69.4
    62.0
        CFB at Week 78: Worsened (n=36,71)
    25.0
    26.8
        CFB at Week 156: Improved (n=21,41)
    4.8
    7.3
        CFB at Week 156: Not Changed (n=21,41)
    52.4
    56.1
        CFB at Week 156: Worsened (n=21,41)
    42.9
    36.6
        CFB at Week 52 of Year 4: Improved (n=9,14)
    11.1
    14.3
        CFB at Week 52 of Year 4: Not Changed (n=9,14)
    33.3
    42.9
        CFB at Week 52 of Year 4: Worsened (n=9,14)
    55.6
    42.9
        CFB at Week 52 of Year 5: Not Changed (n=0,1)
    99999
    100
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set

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    End point title
    Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set
    End point description
    GLS by ECHO is a measure of cardiac systolic function. The Cardiomyopathy-echocardiogram (CM-ECHO) Set included the subset of the 420915-CS2 Randomised Set that had a diagnosis of transthyretin (TTR) cardiomyopathy at study entry of the parent study, but were not in the ECHO Subgroup in the parent study, plus subjects who qualified to subjects in the ECHO Subgroup (whether consented or not). n= Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    30
    59
    Units: percent change
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=18,32)
    0.38 ( 3.178 )
    -0.74 ( 3.120 )
        Change From Baseline at Week 156 (n=9,20)
    1.46 ( 5.313 )
    0.07 ( 4.318 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup

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    End point title
    Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup
    End point description
    GLS by ECHO is a measure of cardiac systolic function. The Cardiomyopathy-echocardiogram (CM-ECHO) Set included the subset of the 420915-CS2 Randomised Set that had a diagnosis of transthyretin (TTR) cardiomyopathy at study entry of the parent study, but were not in the ECHO Subgroup in the parent study, plus subjects who qualified to subjects in the ECHO Subgroup (whether consented or not). n= Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Secondary
    End point timeframe
    Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    19
    36
    Units: percent change
    arithmetic mean (standard deviation)
        Percent Change From Baseline at Week 78 (n=12,18)
    -6.93 ( 20.232 )
    8.99 ( 26.201 )
        Percent Change From Baseline at Week 156 (n=5,12)
    -2.79 ( 24.580 )
    11.46 ( 29.383 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Transthyretin (TTR) Level

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    End point title
    Change From Baseline in Transthyretin (TTR) Level
    End point description
    Measurement of transthyretin protein concentration in serum. The FAS population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: g/L
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=36,72)
    -0.1581 ( 0.05887 )
    -0.1555 ( 0.06751 )
        Change From Baseline at Week 156 (n=25,43)
    -0.1498 ( 0.06366 )
    -0.1692 ( 0.06025 )
    No statistical analyses for this end point

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

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    End point title
    Change From Baseline in Retinol Binding Protein 4 (RBP4) Level
    End point description
    Measurement of RBP4 protein concentration ins serum. The FAS population included all enrolled subjects who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 efficacy assessment after CS3 Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    81
    Units: micrograms per liter (µg/L)
    arithmetic mean (standard deviation)
        Change From Baseline at Week 78 (n=36,72)
    -21073.1 ( 11038.53 )
    -19365.9 ( 10511.83 )
        Change From Baseline at Week 156 (n=25,43)
    -21489.4 ( 10670.52 )
    -22372.3 ( 10372.05 )
        Change From Baseline at Week 52 of Year 4 (n=9,14)
    -28307.1 ( 9539.75 )
    -24893.7 ( 5559.01 )
        Change From Baseline at Week 52 of Year 5 (n=0,1)
    99999 ( 99999 )
    -24444.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Ctrough: Trough Plasma Concentration of ISIS 420915

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    End point title
    Ctrough: Trough Plasma Concentration of ISIS 420915
    End point description
    CS3 Pharmacokinetic (PK) Set included all enrolled subjects who received at least 1 dose of inotersen in CS3 and who had at least 1 evaluable PK sample collected and analysed with reportable result in CS3. n= Number analysed is the number of subjects with data available for analyses at the given time point. 99999=Data was not estimable due to low number of subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, Days 1268, 1359 and 1450 of Year 4, Days 1632, 1723 and 1814 of Year 5
    End point values
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Number of subjects analysed
    50
    85
    Units: nanograms per milliliter (ng/ml)
    geometric mean (geometric coefficient of variation)
        Day 1 (n=49,83)
    99999 ( 99999 )
    34.1 ( 247 )
        Day 43 (n=41,63)
    22.9 ( 97.6 )
    74.0 ( 123 )
        Day 85 (n=37,58)
    28.6 ( 43.6 )
    83.0 ( 138 )
        Day 120 (n=27,31)
    31.5 ( 43.7 )
    81.9 ( 142 )
        Day 176 (n=36,52)
    38.0 ( 52.9 )
    80.0 ( 104 )
        Day 267 (n=24,41)
    47.3 ( 83.4 )
    98.2 ( 183 )
        Day 358 (n=26,48)
    56.2 ( 102 )
    110 ( 130 )
        Day 449 (n=25,37)
    71.1 ( 158 )
    130 ( 218 )
        Day 540 (n=26,39)
    78.7 ( 163 )
    111 ( 219 )
        Day 631 (n=19,28)
    83.8 ( 211 )
    141 ( 187 )
        Day 722 (n=26,32)
    97.6 ( 245 )
    101 ( 127 )
        Day 813 (n=14,28)
    98.0 ( 354 )
    150 ( 273 )
        Day 904 (n=11,27)
    91.4 ( 230 )
    116 ( 148 )
        Day 995 (n=12,15)
    147 ( 809 )
    134 ( 246 )
        Day 1086 (n=13,27)
    131 ( 340 )
    101 ( 159 )
        Day 1268 of Year 4 (n=13,16)
    167 ( 258 )
    102 ( 202 )
        Day 1359 of Year 4 (n=4,10)
    432 ( 307 )
    157 ( 233 )
        Day 1450 of Year 4 (n=4,8)
    55.0 ( 61.1 )
    83.0 ( 111 )
        Day 1632 of Year 5 (n=1,4)
    37.4 ( 99999 )
    75.3 ( 26.9 )
        Day 1723 of Year 5 (n=1,0)
    113 ( 99999 )
    99999 ( 99999 )
        Day 1814 of Year 5 (n=0,1)
    99999 ( 99999 )
    62.1 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
    Adverse event reporting additional description
    SS included all enrolled participants who received at least 1 injection of inotersen in CS3.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Previous Placebo-Inotersen 300 mg
    Reporting group description
    Subjects received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Subjects who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.

    Reporting group title
    Previous Inotersen-Inotersen 300 mg
    Reporting group description
    Subjects received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Subjects who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.

    Serious adverse events
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 50 (36.00%)
    46 / 85 (54.12%)
         number of deaths (all causes)
    2
    15
         number of deaths resulting from adverse events
    2
    15
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Small cell lung cancer
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amyloidosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Ovarian mass
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rib fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spleen contusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 85 (4.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bradycardia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (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
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (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
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 85 (9.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Corneal perforation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous floaters
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (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
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal hypomotility
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Biliary cirrhosis primary
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 85 (4.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacterial toxaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis streptococcal
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Endocarditis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis acute
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    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
    Previous Placebo-Inotersen 300 mg Previous Inotersen-Inotersen 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    80 / 85 (94.12%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 50 (2.00%)
    7 / 85 (8.24%)
         occurrences all number
    1
    18
    Orthostatic hypotension
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 85 (8.24%)
         occurrences all number
    4
    8
    Hypertension
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 85 (5.88%)
         occurrences all number
    1
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 50 (14.00%)
    20 / 85 (23.53%)
         occurrences all number
    10
    26
    Chills
         subjects affected / exposed
    7 / 50 (14.00%)
    16 / 85 (18.82%)
         occurrences all number
    7
    29
    Oedema peripheral
         subjects affected / exposed
    8 / 50 (16.00%)
    14 / 85 (16.47%)
         occurrences all number
    9
    19
    Injection site erythema
         subjects affected / exposed
    4 / 50 (8.00%)
    12 / 85 (14.12%)
         occurrences all number
    17
    13
    Injection site pain
         subjects affected / exposed
    6 / 50 (12.00%)
    12 / 85 (14.12%)
         occurrences all number
    8
    18
    Pyrexia
         subjects affected / exposed
    2 / 50 (4.00%)
    11 / 85 (12.94%)
         occurrences all number
    2
    14
    Asthenia
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 85 (8.24%)
         occurrences all number
    4
    8
    Injection site pruritus
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 85 (8.24%)
         occurrences all number
    3
    7
    Injection site rash
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 85 (5.88%)
         occurrences all number
    5
    6
    Oedema
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 85 (5.88%)
         occurrences all number
    3
    6
    Gait disturbance
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 85 (4.71%)
         occurrences all number
    3
    4
    Injection site bruising
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 85 (4.71%)
         occurrences all number
    4
    4
    Influenza like illness
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 85 (3.53%)
         occurrences all number
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 50 (10.00%)
    10 / 85 (11.76%)
         occurrences all number
    5
    11
    Cough
         subjects affected / exposed
    4 / 50 (8.00%)
    8 / 85 (9.41%)
         occurrences all number
    4
    9
    Epistaxis
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 85 (2.35%)
         occurrences all number
    3
    2
    Pleural effusion
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 85 (5.88%)
         occurrences all number
    1
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 50 (0.00%)
    6 / 85 (7.06%)
         occurrences all number
    0
    6
    Depression
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 85 (3.53%)
         occurrences all number
    3
    3
    Investigations
    Weight decreased
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 85 (8.24%)
         occurrences all number
    4
    7
    Platelet count decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 85 (5.88%)
         occurrences all number
    1
    6
    Glomerular filtration rate decreased
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 85 (4.71%)
         occurrences all number
    7
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 50 (22.00%)
    17 / 85 (20.00%)
         occurrences all number
    17
    25
    Wound
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 85 (1.18%)
         occurrences all number
    4
    1
    Laceration
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 85 (3.53%)
         occurrences all number
    4
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 85 (5.88%)
         occurrences all number
    5
    6
    Nervous system disorders
    Syncope
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 85 (8.24%)
         occurrences all number
    7
    16
    Headache
         subjects affected / exposed
    7 / 50 (14.00%)
    8 / 85 (9.41%)
         occurrences all number
    10
    14
    Dizziness
         subjects affected / exposed
    1 / 50 (2.00%)
    7 / 85 (8.24%)
         occurrences all number
    2
    13
    Hypoaesthesia
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 85 (7.06%)
         occurrences all number
    3
    10
    Paraesthesia
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 85 (7.06%)
         occurrences all number
    4
    7
    Balance disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 85 (5.88%)
         occurrences all number
    1
    6
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    22 / 50 (44.00%)
    14 / 85 (16.47%)
         occurrences all number
    48
    27
    Anaemia
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 85 (9.41%)
         occurrences all number
    5
    10
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 85 (4.71%)
         occurrences all number
    3
    4
    Dry eye
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 85 (3.53%)
         occurrences all number
    3
    3
    Vision blurred
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 85 (5.88%)
         occurrences all number
    0
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 50 (14.00%)
    26 / 85 (30.59%)
         occurrences all number
    11
    38
    Diarrhoea
         subjects affected / exposed
    12 / 50 (24.00%)
    22 / 85 (25.88%)
         occurrences all number
    20
    30
    Vomiting
         subjects affected / exposed
    6 / 50 (12.00%)
    18 / 85 (21.18%)
         occurrences all number
    10
    33
    Constipation
         subjects affected / exposed
    4 / 50 (8.00%)
    12 / 85 (14.12%)
         occurrences all number
    5
    12
    Abdominal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    8 / 85 (9.41%)
         occurrences all number
    1
    9
    Dyspepsia
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 85 (5.88%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 85 (5.88%)
         occurrences all number
    3
    8
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 85 (3.53%)
         occurrences all number
    4
    5
    Urinary retention
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 85 (4.71%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 50 (2.00%)
    10 / 85 (11.76%)
         occurrences all number
    1
    11
    Arthralgia
         subjects affected / exposed
    2 / 50 (4.00%)
    8 / 85 (9.41%)
         occurrences all number
    2
    10
    Back pain
         subjects affected / exposed
    2 / 50 (4.00%)
    7 / 85 (8.24%)
         occurrences all number
    2
    9
    Pain in extremity
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 85 (8.24%)
         occurrences all number
    4
    12
    Muscle atrophy
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 85 (7.06%)
         occurrences all number
    2
    7
    Myalgia
         subjects affected / exposed
    7 / 50 (14.00%)
    5 / 85 (5.88%)
         occurrences all number
    10
    7
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    12 / 50 (24.00%)
    18 / 85 (21.18%)
         occurrences all number
    29
    58
    Nasopharyngitis
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 85 (8.24%)
         occurrences all number
    3
    8
    Bronchitis
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 85 (5.88%)
         occurrences all number
    2
    7
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 85 (7.06%)
         occurrences all number
    2
    8
    Sinusitis
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 85 (5.88%)
         occurrences all number
    2
    6
    Influenza
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 85 (4.71%)
         occurrences all number
    4
    4
    Cellulitis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 85 (0.00%)
         occurrences all number
    3
    0
    Herpes zoster
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 85 (3.53%)
         occurrences all number
    4
    3
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 85 (5.88%)
         occurrences all number
    1
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 85 (5.88%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2015
    The following changes were implemented based on Amendment 1: -Modified renal function monitoring rules and stopping rules to align with CS2. -Modified ocular monitoring and stopping rules to align with CS2. -Added GLS as a secondary efficacy endpoint. -Changed the definition of the analysis sets for ECHO endpoints to align with the definition used in CS2. -Modified the stopping rule for QTc prolongation to allow for clinical interpretation of the changes to the individual subject and the implementation of closer monitoring before permanently discontinuing study drug. -Added 4 additional visits at Weeks 15, 18, 23, and 29 to collect additional safety information. -Added additional urinalysis. -Added albumin-to-creatinine (Alb/C), ratio to urinalysis testing and required back-up retinol and urine samples to be collected.
    10 Aug 2015
    The following changes were implemented based on Amendment 2: -Extended the study duration to 3 years. -Removed language from the platelet stopping rule that mandated permanent treatment discontinuation after 2 dosing rechallenges to allow the Study Medical Monitor and investigator more discretion in determining the suitability of a subject for continued dosing and the need for any modification to treatment schedule or dose.
    07 Mar 2016
    The following changes were implemented based on Amendment 3: -Increased the frequency of safety lab monitoring (hematology and creatinine) to every 2-3 weeks. -Modified the platelet monitoring and stopping rules. -Updated the sample size in order to align with CS2 Amendment 7. -Modified renal monitoring rules. -Allowed use of tafamidis after 18 months at discretion of Study Medical Monitor. -Updated statistical considerations for the efficacy endpoints.
    13 May 2016
    The following changes were implemented based on Amendment 4: -Increased the frequency of platelet monitoring from every 2-3 weeks to every week throughout the treatment period and for a minimum of 6 weeks after the last dose of study drug. -Modified the platelet monitoring rule.
    22 Feb 2017
    The following changes were implemented based on Amendment 5: -Increased the treatment period to 5 years if inotersen is not commercially available at the end of 3 years of treatment. -Updated visit information based on extension to treatment period. -Added alternative reasons for withdrawal, including if inotersen became commercially available or was rejected by the regulatory authority in the local country.

    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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