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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Cemdisiran in Adult Patients with IgA Nephropathy

    Summary
    EudraCT number
    		 2018-002716-27
    Trial protocol
    		 GB   SE   ES  
    Global end of trial date
    27 Jun 2023

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-CC5-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03841448
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alnylam Pharmaceuticals Inc.
    Sponsor organisation address
    675 W Kendall St, Cambridge, United States, 02142
    Public contact
    Clinical Trial Information Line, Alnylam Pharmaceuticals Inc, +1 8772569526, clinicaltrials@alnylam.com
    Scientific contact
    Clinical Trial Information Line, Alnylam Pharmaceuticals Inc, +1 877ALNYLAM, clinicaltrials@alnylam.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
    27 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the effect of cemdisiran on proteinuria in adults with immunoglobulin A nephropathy (IgAN), who excrete >1 gram (gm) of protein per day despite standard of care, which includes treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). These participants are at high risk for progression of kidney disease, which can result in end-stage renal failure.
    Protection of trial subjects
    This study was conducted in accordance with the protocol, all applicable regulatory requirements, and the guidelines of Good Clinical Practice (GCP). Compliance with GCP provides public assurance that the rights, safety, and well-being of study patients are protected consistent with the principles that have their origin in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2019
    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
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Taiwan: 1
    Worldwide total number of subjects
    31
    EEA total number of subjects
    10
    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)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in the study at 19 investigative centers in Canada, France, Malaysia, Philippines, Singapore, Spain, Sweden, Taiwan, and the United Kingdom from 30 Sept 2019 to 27 June 2023.

    Pre-assignment
    Screening details
    		 A total of 31 participants were enrolled in this study to receive cemdisiran or placebo. This study has two parts: Double Blind Treatment (DBT) Period and Open-Label Extension (OLE) Period.

    Period 1
    Period 1 title
    Double Blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject
    Blinding implementation details
    During the DB Treatment Period participants were randomized in a 2:1 ratio to receive 600 mg of SC cemdisiran or SC placebo every 4 weeks in combination with standard of care. Modified Intent-to-treat (mITT) Analysis Set included all participants who received any amount of study drug and had at least one post baseline 24-hour urine protein/creatinine ratio (UPCR) assessment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBT Period: Placebo
    Arm description
    		 Participants received cemdisiran matching placebo, subcutaneous (SC) injection, once every 4 weeks (Q4W) in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Subcutaneous use
    Dosage and administration details
    Placebo was administered by SC injection.

    Arm title
    		 DBT Period: Cemdisiran
    Arm description
    		 Participants received cemdisiran, 600 milligrams (mg), SC injection, Q4W in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cemdisiran
    Investigational medicinal product code
    Other name
    ALN-CC5
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Subcutaneous use
    Dosage and administration details
    Cemdisiran 600 mg was administered by SC injection.

    Number of subjects in period 1
    		DBT Period: Placebo DBT Period: Cemdisiran
    Started
    9
    22
    Modified ITT (mITT) Analysis Set
    9
    22
    Completed
    8
    21
    Not completed
    1
    1
         Death
    1
    1
    Period 2
    Period 2 title
    Open-Label Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Participants who were randomized to receive placebo and cemdisiran the DBT period started receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBT Period: Placebo to OLE Period: Cemdisiran
    Arm description
    		 Participants who were randomized to receive cemdisiran matching placebo in the DBT period started receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Subcutaneous use
    Dosage and administration details
    Placebo was administered by SC injection.

    Investigational medicinal product name
    Cemdisiran
    Investigational medicinal product code
    Other name
    ALN-CC5
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Subcutaneous use
    Dosage and administration details
    Cemdisiran 600 mg was administered by SC injection.

    Arm title
    		 DBT Period: Cemdisiran to OLE Period: Cemdisiran
    Arm description
    		 Participants who were randomized to receive cemdisiran in the DBT period continued receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cemdisiran
    Investigational medicinal product code
    Other name
    ALN-CC5
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use, Injection
    Dosage and administration details
    Cemdisiran 600 mg was administered by SC injection.

    Number of subjects in period 2 [1]
    		DBT Period: Placebo to OLE Period: Cemdisiran DBT Period: Cemdisiran to OLE Period: Cemdisiran
    Started
    8
    20
    Completed
    0
    0
    Not completed
    8
    20
         Physician decision
    1
    3
         Adverse event, non-fatal
    1
    2
         Death
    -
    1
         Other Reason not Specified
    2
    5
         Study Terminated by Sponsor
    4
    9
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One participant in the DBT Period: Cemdisiran to OLE Period: Cemdisiran arm completed the DB Treatment Period but did not start the OLE Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DBT Period: Placebo
    Reporting group description
    		 Participants received cemdisiran matching placebo, subcutaneous (SC) injection, once every 4 weeks (Q4W) in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.

    Reporting group title
    DBT Period: Cemdisiran
    Reporting group description
    		 Participants received cemdisiran, 600 milligrams (mg), SC injection, Q4W in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.

    Reporting group values
    		 DBT Period: Placebo DBT Period: Cemdisiran Total
    Number of subjects
    		 9 22 31
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 22 31
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.6 ( 10.4 ) 40.5 ( 10.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 9 15
        Male
    		 3 13 16
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 3 4
        Not Hispanic or Latino
    		 7 18 25
        Unknown or Not Reported
    		 1 1 2
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 4 12 16
        White
    		 4 8 12
        Other
    		 0 1 1
        Not reported
    		 1 1 2
    Urine Protein to Creatinine Ratio (UPCR)
    Units: g/g
        arithmetic mean (standard deviation)
    		 1.972 ( 0.815 ) 1.554 ( 1.032 ) -

    End points

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    End points reporting groups
    Reporting group title
    DBT Period: Placebo
    Reporting group description
    		 Participants received cemdisiran matching placebo, subcutaneous (SC) injection, once every 4 weeks (Q4W) in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.

    Reporting group title
    DBT Period: Cemdisiran
    Reporting group description
    		 Participants received cemdisiran, 600 milligrams (mg), SC injection, Q4W in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.
    Reporting group title
    DBT Period: Placebo to OLE Period: Cemdisiran
    Reporting group description
    		 Participants who were randomized to receive cemdisiran matching placebo in the DBT period started receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.

    Reporting group title
    DBT Period: Cemdisiran to OLE Period: Cemdisiran
    Reporting group description
    		 Participants who were randomized to receive cemdisiran in the DBT period continued receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.

    Subject analysis set title
    DBT Period: Cemdisiran to OLE Period: Cemdisiran
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were randomized to receive cemdisiran in the DBT period continued receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period. The data reported for this group is for the DBT and OLE Periods inclusively, in which all participants were receiving treatment with cemdisiran.

    Subject analysis set title
    All Cemdisiran
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who received at least one dose of cemdisiran, including participants who received cemdisiran during the DB Period and participants who first received placebo during the DB Period and switched to cemdisiran during the OLE Period.

    Primary: Percent Change From Baseline in UPCR as Measured in 24-hour Urine at Week 32

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    End point title
    		 Percent Change From Baseline in UPCR as Measured in 24-hour Urine at Week 32
    End point description
    UPCR is a way of assessing the amount of protein in the urine. The primary analysis for UPCR was performed using Mixed-Effect Model Repeated Measures (MMRM) approach. Geometric mean (GM)ratios were obtained by exponentially back-transforming the arithmetic mean of change in log-transformed 24h UPCR. Standard error of the mean (SEM) was calculated as exponential (mean of change in log-transformed data) * (standard error of change in log-transformed data). Adjusted GM ratio to baseline and 90% confidence interval (CIs) were calculated by exponentially back-transforming the model-based least square (LS) mean and the corresponding 90% CI.
    End point type
    Primary
    End point timeframe
    Baseline to Week 32
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran
    Number of subjects analysed
    9 [1]
    22 [2]
    Units: percent change
        geometric mean (standard error)
    1.095 ( 0.258 )
    0.686 ( 0.098 )
    Notes
    [1] - mITT Analysis Set
    [2] - mITT Analysis Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: Placebo-adjusted GM percent change, 90% CIs were calculated by exponentially back-transforming the model based LS mean difference (cemdisiran - placebo) and the corresponding 90% CI then subtracting by 1.
    Comparison groups
    DBT Period: Placebo v DBT Period: Cemdisiran
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1032
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Placebo-adjusted GM Percent Change
    Point estimate
    -37.367
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -60.951
         upper limit
    		 0.46

    Secondary: Percent Change From Baseline in 24-hour Proteinuria at Week 32

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    End point title
    		 Percent Change From Baseline in 24-hour Proteinuria at Week 32
    End point description
    Proteinuria is high levels of protein in the urine. 24-hour proteinuria assessment included 24-hour urine collections to assess total protein excretion per 24 hours. Analysis was performed using the MMRM model. GM ratios were obtained by exponentially back-transforming the arithmetic mean of change in log-transformed 24h urine protein (UP). SEM was calculated as exp (mean of change in log-transformed data) *(standard error of change in log-transformed data). Adjusted GM ratio to baseline and 90% CIs are calculated by exponentially back-transforming the model-based LS Means and the corresponding 90% CI.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 32
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran
    Number of subjects analysed
    9 [3]
    22 [4]
    Units: percent change
        geometric mean (standard error)
    1.051 ( 0.266 )
    0.671 ( 0.104 )
    Notes
    [3] - mITT Analysis Set
    [4] - mITT Analysis Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: Placebo-adjusted GM percent change, 90% CIs were calculated by exponentially back-transforming the model based LS mean difference (cemdisiran - placebo) and the corresponding 90% CI then subtracting by 1.
    Comparison groups
    DBT Period: Placebo v DBT Period: Cemdisiran
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1432
    Method
    		 MMRM
    Parameter type
    		 Placebo-adjusted GM Percent Change
    Point estimate
    -36.167
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -61.552
         upper limit
    		 5.978

    Secondary: Percentage of Participants With Partial Clinical Remission at Week 32

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    End point title
    		 Percentage of Participants With Partial Clinical Remission at Week 32
    End point description
    Partial clinical remission was defined as having UP <1.0 g/24-hours.
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran
    Number of subjects analysed
    9 [5]
    22 [6]
    Units: percentage of participants
        number (not applicable)
    0
    22.7
    Notes
    [5] - mITT Analysis Set
    [6] - mITT Analysis Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: Odds ratio was estimated with logit method using a correction of 0.5 in every cell of the 2x2 table that contains a zero.
    Comparison groups
    DBT Period: Placebo v DBT Period: Cemdisiran
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1177 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 21.27
    Notes
    [7] - p-value was based on Cochran-Mantel-Haenszel test stratified by baseline 24-hour UP (≥1.0 g and <2 g/day versus ≥2.0 g/day).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Estimation Comments: Difference in proportions (cemdisiran - placebo) (90% CI) was based on the Wilson score method with continuity correction.
    Comparison groups
    DBT Period: Placebo v DBT Period: Cemdisiran
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    0.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.42

    Secondary: Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32

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    End point title
    		 Percentage of Participants With >50% Reduction in 24-hour Proteinuria at Week 32
    End point description
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran
    Number of subjects analysed
    9 [8]
    22 [9]
    Units: percentage of participants
        number (not applicable)
    0
    22.7
    Notes
    [8] - mITT Analysis Set
    [9] - mITT Analysis Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: Odds ratio was estimated with logit method using a correction of 0.5 in every cell of the 2x2 table that contains a zero.
    Comparison groups
    DBT Period: Placebo v DBT Period: Cemdisiran
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1533 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 20.34
    Notes
    [10] - p-value was based on Cochran-Mantel-Haenszel test stratified by baseline 24-hour UP (≥1.0 g and <2 g/day versus ≥2.0 g/day).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Estimation Comments: Difference in proportions (cemdisiran - placebo) (90% CI) was based on the Wilson score method with continuity correction.
    Comparison groups
    DBT Period: Placebo v DBT Period: Cemdisiran
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    0.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.42

    Secondary: Change From Baseline in UPCR as Measured in a Spot Urine at Week 32

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    End point title
    		 Change From Baseline in UPCR as Measured in a Spot Urine at Week 32
    End point description
    UPCR was calculated by dividing the level of protein in a spot urine test by the creatinine level. Analysis was performed using MMRM model. GM ratios were obtained by exponentially back-transforming the arithmetic mean of change in log-transformed spot UPCR. SEM was calculated as exp (mean of change in log-transformed data) *(standard error of change in log-transformed data). Adjusted GM ratio to baseline and 90% CIs are calculated by exponentially back-transforming the model-based LS Means and the corresponding 90% CI.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 32
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran
    Number of subjects analysed
    9 [11]
    22 [12]
    Units: g/g
        geometric mean (standard error)
    1.344 ( 0.139 )
    0.729 ( 0.109 )
    Notes
    [11] - mITT Analysis Set
    [12] - mITT Analysis Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: Placebo-adjusted GM percent change, 90% CIs were calculated by exponentially back-transforming the model based LS means difference (cemdisiran - placebo) and the corresponding 90% CI then subtracting by 1.
    Comparison groups
    DBT Period: Cemdisiran v DBT Period: Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021
    Method
    		 MMRM
    Parameter type
    		 Placebo-adjusted GM Percent Change
    Point estimate
    -45.771
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -60.093
         upper limit
    		 -26.309

    Secondary: Number of Participants With Change From Baseline in Hematuria at Week 32

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    End point title
    		 Number of Participants With Change From Baseline in Hematuria at Week 32
    End point description
    Hematuria is the presence of blood in the urine. Hematuria from spot urine collections was evaluated to assess the effect of cemdisiran on disease course in participants. The degree of hematuria was assessed by microscopic examination of the spun urine sediment (red blood cell (RBC)/ high power field [hpf]) and by urine dipstick.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 32
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran
    Number of subjects analysed
    8 [13]
    20 [14]
    Units: Count of Participants
        Post-Baseline Category: Negative
    0
    4
        Post-Baseline Category: Small
    2
    11
        Post-Baseline Category: Moderate
    2
    4
        Post-Baseline Category: Large
    4
    1
    Notes
    [13] - mITT Analysis Set participants with data available for analysis.
    [14] - mITT Analysis Set participants with data available for analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 240 weeks
    End point values
    		 DBT Period: Placebo DBT Period: Cemdisiran DBT Period: Placebo to OLE Period: Cemdisiran DBT Period: Cemdisiran to OLE Period: Cemdisiran All Cemdisiran
    Number of subjects analysed
    9 [15]
    22 [16]
    8 [17]
    22 [18]
    30 [19]
    Units: Count of Participants
    8
    19
    8
    22
    30
    Notes
    [15] - mITT Analysis Set
    [16] - mITT Analysis Set
    [17] - All Cemdisiran Treated Set
    [18] - All Cemdisiran Treated Set
    [19] - All Cemdisiran Treated Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DBT Period: from the first dose of study drug up to 88 weeks. OLE Period: from Week 32 up to 240 weeks. All Cemdisiran: from the first dose of study drug up to 240 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    DBT Period: Placebo
    Reporting group description
    		 Participants received cemdisiran matching placebo, SC injection, Q4W in combination with standard of care up to a maximum of 38 weeks in the DBT period.

    Reporting group title
    DBT Period: Cemdisiran
    Reporting group description
    		 Participants received cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 38 weeks in the DBT period.

    Reporting group title
    DBT Period: Placebo + OLE Period: Cemdisiran
    Reporting group description
    		 Participants who were randomized to receive cemdisiran matching placebo in the DBT period started receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.

    Reporting group title
    DBT Period: Cemdisiran + OLE Period: Cemdisiran
    Reporting group description
    		 Participants who were randomized to receive cemdisiran in the DBT period continued receiving cemdisiran, 600 mg, SC injection, Q4W in combination with standard of care treatment up to a maximum of 88 weeks in the OLE treatment period.

    Reporting group title
    All Cemdisiran
    Reporting group description
    		 All participants who received at least one dose of cemdisiran, including participants who received cemdisiran during the DB Period and participants who first received placebo during the DB Period and switched to cemdisiran during the OLE Period.

    Serious adverse events
    		 DBT Period: Placebo DBT Period: Cemdisiran DBT Period: Placebo + OLE Period: Cemdisiran DBT Period: Cemdisiran + OLE Period: Cemdisiran All Cemdisiran
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    3 / 8 (37.50%)
    2 / 22 (9.09%)
    5 / 30 (16.67%)
         number of deaths (all causes)
    1
    1
    0
    1
    1
         number of deaths resulting from adverse events
    0
    1
    0
    1
    1
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    End stage renal disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Helicobacter gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 DBT Period: Placebo DBT Period: Cemdisiran DBT Period: Placebo + OLE Period: Cemdisiran DBT Period: Cemdisiran + OLE Period: Cemdisiran All Cemdisiran
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    19 / 22 (86.36%)
    8 / 8 (100.00%)
    22 / 22 (100.00%)
    30 / 30 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    2 / 8 (25.00%)
    1 / 22 (4.55%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    2
    3
    5
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    General disorders and administration site conditions
    Dyspepsia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Feeling cold
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    2
    21
    Injection site bruising
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Injection site reaction
         subjects affected / exposed
    2 / 9 (22.22%)
    9 / 22 (40.91%)
    5 / 8 (62.50%)
    9 / 22 (40.91%)
    14 / 30 (46.67%)
         occurrences all number
    7
    25
    31
    52
    83
    Injection site recall reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    3 / 8 (37.50%)
    2 / 22 (9.09%)
    5 / 30 (16.67%)
         occurrences all number
    0
    2
    3
    3
    6
    Malaise
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 22 (13.64%)
    1 / 8 (12.50%)
    3 / 22 (13.64%)
    4 / 30 (13.33%)
         occurrences all number
    1
    5
    1
    6
    7
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 22 (4.55%)
    2 / 8 (25.00%)
    3 / 22 (13.64%)
    5 / 30 (16.67%)
         occurrences all number
    1
    1
    2
    5
    7
    Suprapubic pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Swelling face
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Vaccination site reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Milk allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Haematospermia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Menorrhagia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Testicular pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Vaginal discharge
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    2 / 8 (25.00%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    3
    0
    3
    3
    Productive cough
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    0
    2
    2
    Sneezing
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    1 / 8 (12.50%)
    2 / 22 (9.09%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    1
    2
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    1 / 8 (12.50%)
    2 / 22 (9.09%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    1
    2
    3
    Blood pressure increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Gamma-glutamyltransferase abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Liver function test increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Urine sodium increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    1
    2
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Ligament sprain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Muscle contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin laceration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    0
    2
    2
    Migraine
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nephrogenic anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Splenomegaly
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Deafness unilateral
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Keratosis obturans
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    0
    4
    4
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    2 / 8 (25.00%)
    1 / 22 (4.55%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    2
    1
    3
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Drug eruption
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    2
    2
    Rash
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    1 / 8 (12.50%)
    3 / 22 (13.64%)
    4 / 30 (13.33%)
         occurrences all number
    0
    2
    1
    3
    4
    Rash erythematous
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    3 / 22 (13.64%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    0
    3
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Renal impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    1
    2
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    2
    0
    2
    Back pain
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    1
    1
    1
    Joint stiffness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Limb discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    1
    2
    Muscle twitching
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 22 (9.09%)
    5 / 8 (62.50%)
    9 / 22 (40.91%)
    14 / 30 (46.67%)
         occurrences all number
    0
    2
    5
    10
    15
    Conjunctivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Cystitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Eyelid infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Helicobacter infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    0
    2
    0
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    2
    2
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Superinfection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    4 / 22 (18.18%)
    4 / 30 (13.33%)
         occurrences all number
    0
    0
    0
    9
    9
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    2
    2
    Viral infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 22 (0.00%)
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Gout
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 22 (4.55%)
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Hyperphosphataemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    2 / 8 (25.00%)
    0 / 22 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    0
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 22 (0.00%)
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2018
    Amendment 1: The main purpose of this protocol amendment was to incorporate changes requested by a Health Authority.
    20 Sep 2019
    Amendment 2: The primary purpose for this protocol amendment was to incorporate changes previously made to a regional protocol amendment into the global protocol.
    27 Apr 2020
    Amendment 3: The purpose of this protocol amendment was to incorporate Urgent Safety Measures (USMs) that were communicated to investigators in a Dear Investigator Letter (DIL) dated 06 April 2020.
    19 Jan 2021
    Amendment 4: The primary purpose for this protocol amendment was to extend the open-label extension (OLE) period by an additional 2 years.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Jun 2023
    The study was terminated early having identified clinically meaningful magnitude of proteinuria reduction due to cemdisiran (study goal). Participants completed DBT period and were in OLE period. Sponsor had no concerns with safety and integrity of participants
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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