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    Clinical Trial Results:
    A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

    Summary
    EudraCT number
    2019-001698-10
    Trial protocol
    GB   PT   DE   ES   IT   SE   GR   FR   CY   NL  
    Global end of trial date
    12 Jul 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jul 2024
    First version publication date
    29 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ION-682884-CS3
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04136184
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, 92010
    Public contact
    Global Regulatory Affairs, Ionis Pharmaceuticals, Inc., 1 760603-2346, globalregulatoryaffairs@ionis.com
    Scientific contact
    Global Regulatory Affairs, Ionis Pharmaceuticals, Inc., 1 760603-2346, globalregulatoryaffairs@ionis.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
    12 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of eplontersen as compared to the historical control of the placebo cohort in the NEURO-TTR trial (NCT01737398/2012-001831-30), in subjects with hereditary transthyretin-mediated amyloidosis polyneuropathy (hATTR-PN).
    Protection of trial subjects
    All subjects in this study were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Dec 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Cyprus: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Portugal: 28
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Türkiye: 7
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 40
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Taiwan: 23
    Worldwide total number of subjects
    168
    EEA total number of subjects
    57
    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)
    116
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 46 investigative sites in 15 countries (Argentina, Australia, Brazil, Canada, Cyprus, France, Germany, Italy, New Zealand, Portugal, Spain, Sweden, Taiwan, Turkey, and the United States) from 11 December 2019 to 12 July 2023.

    Pre-assignment
    Screening details
    Subjects with a diagnosis of hATTR-PN were randomized in a 6:1 ratio to receive eplontersen (ION-682884) or inotersen respectively. The eplontersen arm of this study was compared to the placebo-cohort group from ISIS 420915-CS2 (NEURO-TTR) study (NCT01737398/ 2012-001831-30), which was used as an external control for efficacy analysis.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Eplontersen
    Arm description
    Subjects received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.
    Arm type
    Experimental

    Investigational medicinal product name
    Eplontersen
    Investigational medicinal product code
    Other name
    ION-682884, AKCEA-TTR-LRx, IONIS-TTR-LRx
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    45 mg eplontersen, Q4W administered by SC route

    Arm title
    Inotersen
    Arm description
    Subjects received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, subjects received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.
    Arm type
    Active comparator

    Investigational medicinal product name
    Inotersen
    Investigational medicinal product code
    Other name
    Tegsedi®
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    300 mg inotersen, administered once weekly by SC route.

    Number of subjects in period 1
    Eplontersen Inotersen
    Started
    144
    24
    Completed
    22
    1
    Not completed
    122
    23
         Lost to Follow Up
    3
    -
         Voluntary Withdrawal (including enrolled OLE)
    119
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eplontersen
    Reporting group description
    Subjects received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.

    Reporting group title
    Inotersen
    Reporting group description
    Subjects received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, subjects received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.

    Reporting group values
    Eplontersen Inotersen Total
    Number of subjects
    144 24 24
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.0 ± 15.0 51.1 ± 14.38 -
    Gender categorical
    Units: Subjects
        Male
    100 16 116
        Female
    44 8 52
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    22 5 27
        Not Hispanic or Latino
    120 18 138
        Unknown or Not Reported
    2 1 3
    Race
    Units: Subjects
        American Indian or Alaskan Native
    0 0 0
        Asian
    22 2 24
        Black or African American
    5 0 5
        Native Hawaiian or Other Pacific Islander
    0 0 0
        White
    112 19 131
        Other
    3 2 5
        Multiple
    1 0 1
        Unknown or Not Reported
    1 1 2
    Serum Transthyretin (TTR) Concentration
    Units: grams per litre (g/L)
        arithmetic mean (standard deviation)
    0.23 ± 0.075 0.22 ± 0.069 -
    Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Total Score
    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 score indicates poorer quality of life. Number analsyed is the number of subjects with data available for analysis
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0 ± 0 40.05 ± 21.488 -
    Modified Neuropathy Impairment Score Plus 7 (mNIS+7) Composite Score
    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 consists of 2 composite scores: the NIS composite score (maximum of 244 points) and the modified +7 composite score (maximum of 102.32 points). The mNIS+7 composite total score has a range of -22.32 to 346.32, and a higher score indicates lower function.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    81.28 ± 43.401 65.06 ± 33.515 -
    Subject analysis sets

    Subject analysis set title
    External Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.

    Subject analysis set title
    Eplontersen
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.

    Subject analysis sets values
    External Placebo Eplontersen
    Number of subjects
    60
    137
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    Gender categorical
    Units: Subjects
        Male
    0
        Female
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0
    0
        Not Hispanic or Latino
    0
    0
        Unknown or Not Reported
    Race
    Units: Subjects
        American Indian or Alaskan Native
    0
    0
        Asian
    0
    0
        Black or African American
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
        White
    0
    0
        Other
    0
    0
        Multiple
    0
    0
        Unknown or Not Reported
    Serum Transthyretin (TTR) Concentration
    Units: grams per litre (g/L)
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Total Score
    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 score indicates poorer quality of life. Number analsyed is the number of subjects with data available for analysis
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0 ± 0
    44.09 ± 26.590
    Modified Neuropathy Impairment Score Plus 7 (mNIS+7) Composite Score
    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 consists of 2 composite scores: the NIS composite score (maximum of 244 points) and the modified +7 composite score (maximum of 102.32 points). The mNIS+7 composite total score has a range of -22.32 to 346.32, and a higher score indicates lower function.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0

    End points

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    End points reporting groups
    Reporting group title
    Eplontersen
    Reporting group description
    Subjects received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.

    Reporting group title
    Inotersen
    Reporting group description
    Subjects received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, subjects received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.

    Subject analysis set title
    External Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.

    Subject analysis set title
    Eplontersen
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.

    Primary: Change from Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66

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    End point title
    Change from Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66 [1]
    End point description
    mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score =lower function. FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed = number of subjects with data available for analysis. Least square (LS) mean and standard error (SE) were analyzed using MMRM.
    End point type
    Primary
    End point timeframe
    Baseline, Week 66
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    128
    52
    Units: scores on a scale
        least squares mean (standard error)
    25.0557 ± 2.3874
    25.0557 ± 2.3874
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 1E-8
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -24.7593
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -30.9552
         upper limit
    -18.5635

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

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    End point title
    Change from Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 [2]
    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 138, and a higher score indicates poorer quality of life. FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed is the number of subjects with data available for analysis. LS mean and SE were analyzed using MMRM.
    End point type
    Primary
    End point timeframe
    Baseline, Week 66
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    128
    52
    Units: scores on a scale
        least squares mean (standard error)
    -5.4964 ± 2.2976
    14.2388 ± 2.3488
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 1E-8
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -19.7352
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.6301
         upper limit
    -13.8403

    Primary: Percent Change from Baseline in Serum TTR Concentration at Week 65

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    End point title
    Percent Change from Baseline in Serum TTR Concentration at Week 65 [3]
    End point description
    FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen and had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug and had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score.
    End point type
    Primary
    End point timeframe
    Baseline, Week 66
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    135
    51
    Units: percentage
        least squares mean (standard error)
    -81.65 ± 1.605
    -11.24 ± 1.910
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 1E-8
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -70.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -75.17
         upper limit
    -65.66

    Primary: Percent Change from Baseline in Serum TTR Concentration at Week 35

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    End point title
    Percent Change from Baseline in Serum TTR Concentration at Week 35 [4]
    End point description
    FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen and had a baseline and at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug & had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score.
    End point type
    Primary
    End point timeframe
    Baseline, Week 35
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    139
    57
    Units: percentage
        least squares mean (standard error)
    -81.14 ± 1.674
    -14.49 ± 1.966
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 1E-8
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -66.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -71.59
         upper limit
    -61.71

    Primary: Change from Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35

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    End point title
    Change from Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35 [5]
    End point description
    mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicates lower function. FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed = number of subjects with data available for analysis. LS mean and SE were analyzed using MMRM.
    End point type
    Primary
    End point timeframe
    Baseline, Week 35
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    138
    55
    Units: scores on a scale
        least squares mean (standard error)
    0.6795 ± 1.9073
    10.0337 ± 1.8544
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00012203
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -9.3542
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.8691
         upper limit
    -4.8394

    Secondary: Change from Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66

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    End point title
    Change from Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 [6]
    End point description
    NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal & urinary incontinence), & autonomic (non-GI/non-urinary incontinence)]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 35, Week 66
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    141
    57
    Units: scores on a scale
    least squares mean (standard error)
        At Week 35
    0.79 ± 0.867
    4.73 ± 0.870
        At Week 66
    -0.03 ± 0.955
    8.18 ± 0.962
    Statistical analysis title
    Week 66: External Placebo vs Eplontersen
    Statistical analysis description
    Week 66
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1E-8
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -8.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.65
         upper limit
    -5.76
    Statistical analysis title
    Week 35: External Placebo vs Eplontersen
    Statistical analysis description
    Week 35
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00052447
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -3.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.08
         upper limit
    -1.8

    Secondary: Change from Baseline in Norfolk QOL-DN at Week 35

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    End point title
    Change from Baseline in Norfolk QOL-DN at Week 35 [7]
    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 138, and a higher score indicates poorer quality of life. FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed is the number of subjects with data available for analysis. LS mean and SE were analyzed using MMRM.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 35
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    130
    57
    Units: scores on a scale
        least squares mean (standard error)
    -3.6306 ± 2.0678
    8.1896 ± 2.0730
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00001873
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -11.8202
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.8927
         upper limit
    -6.7477

    Secondary: Change from baseline in Polyneuropathy Disability (PND) Score at Week 65

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    End point title
    Change from baseline in Polyneuropathy Disability (PND) Score at Week 65 [8]
    End point description
    PND = 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or subject confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 & IV as 5. Lower scores = greater ambulatory function. FAS = all randomized subjects received at least 1 injection of ION-682884 or inotersen & who have a baseline and at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized subjects who received at least 1 injection of study drug and who had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed is the number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 35
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    134
    51
    Units: scores on a scale
        least squares mean (standard error)
    0.1 ± 0.07
    0.3 ± 0.07
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02407897
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0

    Secondary: Change from Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65

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    End point title
    Change from Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65 [9]
    End point description
    SF-36 comprises 36 items that yield 8 subscales & 2 summary measures (PCS & Mental component summary [MCS]). Multi-item subscales (35 items): physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items & mental health=5 items. 8 subscales are scored from 0-100. Higher scores=better health. 8 subscales are aggregated into a PCS score (0-100). Higher scores=better health. FAS = all randomized subjects who received at least 1 injection of ION-682884/inotersen & have a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS=all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed is the number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 65
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    136
    50
    Units: scores on a scale
        least squares mean (standard error)
    0.851 ± 0.7913
    -4.455 ± 0.8338
    Statistical analysis title
    External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00000558
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    5.305
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.195
         upper limit
    7.416

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

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    End point title
    Change from Baseline in Modified Body Mass Index (mBMI) at Week 65 [10]
    End point description
    mBMI is defined as body mass index in kilograms per square meter (kg/m^2) multiplied by serum albumin in grams per liter (g/L). FAS was defined as all randomized subjects who received at least 1 injection of ION-682884/inotersen & have a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS was defined as all randomized subjects who received at least 1 injection of study drug & had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. Number analysed is the number of subjects with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 65
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to report data for External Placebo and Eplontersen arms only.
    End point values
    Eplontersen External Placebo
    Number of subjects analysed
    130
    49
    Units: kilogram(kg)/metre(m)^2*gram(g)/litre(L)
        least squares mean (standard error)
    -8.0655 ± 10.3786
    -90.7645 ± 10.9465
    Statistical analysis title
    Baseline External Placebo vs Eplontersen
    Comparison groups
    Eplontersen v External Placebo
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 2E-7
    Method
    MMRM
    Parameter type
    Difference in LS Mean
    Point estimate
    82.6991
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    54.6431
         upper limit
    110.7551

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 1 to Week 85
    Adverse event reporting additional description
    Safety Set (SS) included all participants who were randomized and received at least 1 injection of eplontersen or inotersen.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Eplontersen
    Reporting group description
    Subjects received eplontersen, 45 mg, SC, Q4W up to Week 81.

    Reporting group title
    Eplontersen 45mg Week 37 - Week 85
    Reporting group description
    Subjects received 45 mg of eplontersen by SC route once every 4 weeks SC from Week 37 to Week 81.

    Reporting group title
    Inotersen (Prior to Switch)
    Reporting group description
    Subjects received 300 mg of inotersen by SC route once weekly from Week 1 through Week 34.

    Serious adverse events
    Eplontersen Eplontersen 45mg Week 37 - Week 85 Inotersen (Prior to Switch)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 144 (18.75%)
    3 / 20 (15.00%)
    3 / 24 (12.50%)
         number of deaths (all causes)
    4
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium test positive
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns third degree
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 144 (0.69%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 144 (3.47%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephroangiosclerosis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Eplontersen Eplontersen 45mg Week 37 - Week 85 Inotersen (Prior to Switch)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 144 (90.97%)
    18 / 20 (90.00%)
    24 / 24 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 144 (3.47%)
    2 / 20 (10.00%)
    0 / 24 (0.00%)
         occurrences all number
    5
    2
    0
    Orthostatic hypotension
         subjects affected / exposed
    6 / 144 (4.17%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    7
    0
    0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    2 / 144 (1.39%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    Chills
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    1
    0
    7
    Pain
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    1
    0
    2
    Injection site swelling
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 20 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    0
    5
    Injection site bruising
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    3
    0
    18
    Asthenia
         subjects affected / exposed
    4 / 144 (2.78%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    0
    Pyrexia
         subjects affected / exposed
    4 / 144 (2.78%)
    0 / 20 (0.00%)
    7 / 24 (29.17%)
         occurrences all number
    5
    0
    11
    Injection site pruritus
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    5
    0
    1
    Injection site pain
         subjects affected / exposed
    5 / 144 (3.47%)
    0 / 20 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    8
    0
    5
    Fatigue
         subjects affected / exposed
    8 / 144 (5.56%)
    2 / 20 (10.00%)
    6 / 24 (25.00%)
         occurrences all number
    9
    5
    9
    Oedema peripheral
         subjects affected / exposed
    13 / 144 (9.03%)
    2 / 20 (10.00%)
    0 / 24 (0.00%)
         occurrences all number
    14
    2
    0
    Injection site erythema
         subjects affected / exposed
    5 / 144 (3.47%)
    0 / 20 (0.00%)
    8 / 24 (33.33%)
         occurrences all number
    7
    0
    42
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    13 / 144 (9.03%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    19
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 144 (5.56%)
    0 / 20 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    8
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 144 (2.78%)
    2 / 20 (10.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    2
    0
    Depression
         subjects affected / exposed
    5 / 144 (3.47%)
    2 / 20 (10.00%)
    0 / 24 (0.00%)
         occurrences all number
    5
    2
    0
    Insomnia
         subjects affected / exposed
    6 / 144 (4.17%)
    1 / 20 (5.00%)
    1 / 24 (4.17%)
         occurrences all number
    6
    1
    1
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    0
    2
    Glomerular filtration rate Decreased
         subjects affected / exposed
    3 / 144 (2.08%)
    2 / 20 (10.00%)
    4 / 24 (16.67%)
         occurrences all number
    3
    3
    5
    Weight decreased
         subjects affected / exposed
    4 / 144 (2.78%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    1
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    9 / 144 (6.25%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    9
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 144 (3.47%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    9
    0
    2
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    6 / 144 (4.17%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    8
    1
    0
    Fall
         subjects affected / exposed
    10 / 144 (6.94%)
    2 / 20 (10.00%)
    2 / 24 (8.33%)
         occurrences all number
    13
    4
    2
    Contusion
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    3
    0
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 144 (7.64%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    12
    1
    0
    Neuralgia
         subjects affected / exposed
    5 / 144 (3.47%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    7
    1
    0
    Paraesthesia
         subjects affected / exposed
    4 / 144 (2.78%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    6
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 144 (0.69%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    0
    Syncope
         subjects affected / exposed
    5 / 144 (3.47%)
    0 / 20 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    0
    Headache
         subjects affected / exposed
    9 / 144 (6.25%)
    1 / 20 (5.00%)
    5 / 24 (20.83%)
         occurrences all number
    10
    1
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 144 (4.86%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    8
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    2
    0
    4
    Eye disorders
    Vision blurred
         subjects affected / exposed
    8 / 144 (5.56%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    11
    0
    2
    Cataract
         subjects affected / exposed
    8 / 144 (5.56%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    8
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    28 / 144 (19.44%)
    1 / 20 (5.00%)
    1 / 24 (4.17%)
         occurrences all number
    33
    1
    1
    Vomiting
         subjects affected / exposed
    11 / 144 (7.64%)
    1 / 20 (5.00%)
    4 / 24 (16.67%)
         occurrences all number
    13
    1
    4
    Nausea
         subjects affected / exposed
    14 / 144 (9.72%)
    0 / 20 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    19
    0
    6
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    6 / 144 (4.17%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    6
    0
    2
    Rash
         subjects affected / exposed
    7 / 144 (4.86%)
    1 / 20 (5.00%)
    2 / 24 (8.33%)
         occurrences all number
    9
    1
    2
    Renal and urinary disorders
    Albuminuria
         subjects affected / exposed
    2 / 144 (1.39%)
    2 / 20 (10.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    0
    Urinary retention
         subjects affected / exposed
    6 / 144 (4.17%)
    1 / 20 (5.00%)
    0 / 24 (0.00%)
         occurrences all number
    7
    1
    0
    Proteinuria
         subjects affected / exposed
    12 / 144 (8.33%)
    1 / 20 (5.00%)
    1 / 24 (4.17%)
         occurrences all number
    14
    1
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    7 / 144 (4.86%)
    0 / 20 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    10
    0
    10
    Pain in extremity
         subjects affected / exposed
    9 / 144 (6.25%)
    1 / 20 (5.00%)
    3 / 24 (12.50%)
         occurrences all number
    11
    1
    7
    Back pain
         subjects affected / exposed
    11 / 144 (7.64%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    12
    0
    1
    Arthralgia
         subjects affected / exposed
    10 / 144 (6.94%)
    1 / 20 (5.00%)
    4 / 24 (16.67%)
         occurrences all number
    12
    1
    6
    Muscle spasms
         subjects affected / exposed
    6 / 144 (4.17%)
    2 / 20 (10.00%)
    1 / 24 (4.17%)
         occurrences all number
    13
    2
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    26 / 144 (18.06%)
    4 / 20 (20.00%)
    2 / 24 (8.33%)
         occurrences all number
    50
    11
    4
    COVID-19
         subjects affected / exposed
    47 / 144 (32.64%)
    5 / 20 (25.00%)
    1 / 24 (4.17%)
         occurrences all number
    49
    5
    1
    Sinusitis
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 20 (5.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    Influenza
         subjects affected / exposed
    7 / 144 (4.86%)
    1 / 20 (5.00%)
    1 / 24 (4.17%)
         occurrences all number
    8
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 144 (6.25%)
    0 / 20 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    11
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    9 / 144 (6.25%)
    0 / 20 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    12
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 20 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    1
    0
    6
    Vitamin A deficiency
         subjects affected / exposed
    17 / 144 (11.81%)
    2 / 20 (10.00%)
    1 / 24 (4.17%)
         occurrences all number
    17
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2019
    The main purpose of this amendment is to remove the collection of a whole blood sample (Section 6.1.3 Treatment Period) for whole genome sequencing.
    18 Sep 2019
    1. Additional exploratory efficacy assessments were added (5-Level EQ-5D [EQ-5D-5L] and Composite Autonomic Symptom Score-31 [COMPASS-31]). 2. Protocol was harmonised with the historical inotersen NEURO-TTR trial to support data comparison between the 2 trials better also with the Phase 3 ION-682884-CS2 ATTR .nd
    29 Jan 2020
    1. Two clinical outcome assessments were added to collect additional patient-reported outcomes data to assess the efficacy of ION-682884; 2. The international normalized ratio (INR) was added to the confirmatory tests in case of elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) (or 2 × Baseline value if the Baseline value was > ULN); 3. 3. Adjustments to the schedule of sample collection for coagulation was done and collection of samples for additional biomarkers were added.
    10 Dec 2020
    In response to the COVID-19 pandemic, and in accordance with regulatory guidance worldwide, the main purpose of the protocol addendum was to enhance trial safety by minimizing patient and site personnel exposure to potentially SARS-CoV-2-infected individuals. Below measures were adopted: 1. Selected visits and procedures were conducted remotely (as “virtual visits”), 2. Selected time windows for certain visits and procedures had lengthened to provide increased scheduling flexibility. 3. The option for remote consent was added. 4. Additionally, the requirement for periodic ophthalmology assessments throughout the study was removed and selected eligibility criteria have been clarified.
    12 Aug 2021
    The purpose of this amendment was to update the frequency of safety monitoring of platelet count, eGFR and UPCR, per endorsement by the independent data and safety monitoring board (DSMB) and feedback from the US Food and Drug Administration (FDA) review division.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/37768671
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