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    Clinical Trial Results:
    A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL TO EVALUATE THE EFFECT OF 300 MG OF INCLISIRAN SODIUM GIVEN AS SUBCUTANEOUS INJECTIONS IN SUBJECTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HeFH) AND ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C)

    Summary
    EudraCT number
    		 2017-002472-30
    Trial protocol
    		 GB   ES   CZ   SE   DK  
    Global end of trial date
    27 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Sep 2020
    First version publication date
    11 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MDCO-PCS-17-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03397121
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Medicines Company
    Sponsor organisation address
    8 Sylvan Way, Parsippany, United States, NJ 07054
    Public contact
    Global Health Science Center, The Medicines Company, +1 9732906000, medical.information@themedco.com
    Scientific contact
    Global Health Science Center, The Medicines Company, +1 9732906000, medical.information@themedco.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 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the effect of inclisiran treatment on: •LDL-C levels at Day 510 •Time adjusted percent change in LDL-C levels from baseline between Day 90 and Day 540 levels
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 All subjects participating must be on and maintain maximally tolerated statin therapy and/or other LDL-C lowering therapies such as ezetimibe in addition to receiving inclisiran or placebo.
    Evidence for comparator
    		 Use of placebo is consistent with other investigational lipid lowering therapy Phase III designs, including the statins and the monoclonal antibody PCSK9 inhibitors. All subjects participating must be on and maintain maximally tolerated statin therapy and/or other LDL-C lowering therapies such as ezetimibe in addition to receiving inclisiran or placebo. The use of placebo in this type of study is consistent with EU guidance on clinical investigation of medicinal products in the treatment of lipid disorders (EMA/CHMP/748108/2013, Rev. 3).
    Actual start date of recruitment
    01 Nov 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 38
    Country: Number of subjects enrolled
    Spain: 84
    Country: Number of subjects enrolled
    Sweden: 34
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Denmark: 49
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    South Africa: 177
    Country: Number of subjects enrolled
    United States: 65
    Worldwide total number of subjects
    482
    EEA total number of subjects
    217
    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)
    374
    From 65 to 84 years
    108
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Not applicable

    Pre-assignment
    Screening details
    		 Screening occurred prior to randomization and consisted of confirming eligibility and collecting Baseline assessments. Subjects enrolled must have fasting triglyceride <4.52 mmol/L (<400 mg/dL) and serum LDL-C ≥2.6 mmol/L (≥100 mg/dL) at screening.

    Pre-assignment period milestones
    Number of subjects started
    		 482
    Number of subjects completed
    		 482

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inclisiran
    Arm description
    		 Inclisiran sodium 300 milligrams
    Arm type
    		 Experimental

    Investigational medicinal product name
    Inclisiran
    Investigational medicinal product code
    ALN-60212
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months. Inclisiran: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

    Number of subjects in period 1
    		Inclisiran Placebo
    Started
    242
    240
    Completed
    235
    231
    Not completed
    7
    9
         Initiation of protocol-prohibited PCSK9 inhibitor
    -
    1
         Consent withdrawn by subject
    -
    4
         death
    1
    1
         Not specified
    5
    1
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inclisiran
    Reporting group description
    		 Inclisiran sodium 300 milligrams

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Inclisiran Placebo Total
    Number of subjects
    		 242 240 482
    Age categorical
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 189 185 374
        Adults (65 - 74 years)
    		 45 48 93
        Adults (75+ years)
    		 8 7 15
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ( 12.48 ) 55.0 ( 12.48 ) -
    Gender categorical
    Gender
    Units: Subjects
        Female
    		 130 125 255
        Male
    		 112 115 227
    Subject analysis sets

    Subject analysis set title
    Inclisiran
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months. Inclisiran: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

    Subject analysis sets values
    		 Inclisiran Placebo
    Number of subjects
    242
    240
    Age categorical
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    189
    185
        Adults (65 - 74 years)
    45
    48
        Adults (75+ years)
    8
    7
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Gender
    Units: Subjects
        Female
    130
    125
        Male
    112
    115

    End points

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    End points reporting groups
    Reporting group title
    Inclisiran
    Reporting group description
    		 Inclisiran sodium 300 milligrams

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    Inclisiran
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months. Inclisiran: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

    Primary: Percentage Change In LDL-C From Baseline To Day 510

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    End point title
    		 Percentage Change In LDL-C From Baseline To Day 510
    End point description
    % change in LDL-C to Day 510
    End point type
    Primary
    End point timeframe
    Baseline to Day 510
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -41.15 (-44.52 to -37.77)
    8.37 (3.96 to 12.77)
    -41.15 (-44.52 to -37.77)
    8.37 (3.96 to 12.77)
    Statistical analysis title
    		 Percentage Change In LDL-C From Baseline - Day 510
    Statistical analysis description
    Difference in the percentage change in LDL-C from baseline to Day 510 between inclisiran and placebo arms
    Comparison groups
    Inclisiran v Placebo v Inclisiran v Placebo
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -49.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.04
         upper limit
    		 -43.99

    Primary: Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540

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    End point title
    		 Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540
    End point description
    Time adjusted change in LDL-C
    End point type
    Primary
    End point timeframe
    Baseline, Day 90 to Day 540
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -38.08 (-41.03 to -35.14)
    6.22 (3.26 to 9.17)
    -38.08 (-41.03 to -35.14)
    6.22 (3.26 to 9.17)
    Statistical analysis title
    		 Percentage Change In LDL-C From Day 90 to Day 540
    Statistical analysis description
    Difference in time-adjusted percentage change in LDL-C Levels From Baseline After Day 90 and up to Day 540 between inclisiran and placebo arms
    Comparison groups
    Inclisiran v Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -44.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.48
         upper limit
    		 -40.12

    Secondary: Absolute Change in LDL-C From Baseline to Day 510

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    End point title
    		 Absolute Change in LDL-C From Baseline to Day 510
    End point description
    Absolute change in LDL-C
    End point type
    Secondary
    End point timeframe
    Baseline to Day 510
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -58.95 (-64.75 to -53.15)
    9.94 (4.10 to 15.78)
    -58.95 (-64.75 to -53.15)
    9.94 (4.10 to 15.78)
    Statistical analysis title
    		 Absolute Change in LDL-C From Baseline To Day 510
    Statistical analysis description
    Difference in Absolute Change in LDL-C From Baseline To Day 510 between inclisiran and placebo arms
    Comparison groups
    Inclisiran v Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -68.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.11
         upper limit
    		 -60.67

    Secondary: Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

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    End point title
    		 Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540
    End point description
    Time-adjusted absolute change in LDL-C
    End point type
    Secondary
    End point timeframe
    From Baseline After Day 90 and up to Day 540
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -56.58 (-60.98 to -52.17)
    6.17 (1.72 to 10.62)
    -56.58 (-60.98 to -52.17)
    6.17 (1.72 to 10.62)
    Statistical analysis title
    		 Absolute Change in Time-adjusted Change in LDL-C
    Statistical analysis description
    Difference in the change in time-adjusted LDL-C after Day 90 and up to Day 540, between inclisiran and placebo groups
    Comparison groups
    Inclisiran v Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -62.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69.01
         upper limit
    		 -56.48

    Secondary: Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

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    End point title
    		 Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510
    End point description
    Change in PCSK9
    End point type
    Secondary
    End point timeframe
    Baseline to Day 510
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: percentage change
        least squares mean (confidence interval 95%)
    -60.68 (-64.40 to -56.96)
    17.66 (13.91 to 21.42)
    -60.68 (-64.40 to -56.96)
    17.66 (13.91 to 21.42)
    Statistical analysis title
    		 Percentage change in PCSK9 from Baseline - Day 510
    Statistical analysis description
    Difference in percentage change in PCSK9 from baseline to Day 510, between inclisiran and placebo arms
    Comparison groups
    Inclisiran v Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -78.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.65
         upper limit
    		 -73.04

    Secondary: Percentage Change in Total Cholesterol From Baseline to Day 510

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    End point title
    		 Percentage Change in Total Cholesterol From Baseline to Day 510
    End point description
    Change in total cholesterol
    End point type
    Secondary
    End point timeframe
    Baseline to Day 510
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -25.11 (-27.83 to -22.39)
    6.66 (3.96 to 9.36)
    -25.11 (-27.83 to -22.39)
    6.66 (3.96 to 9.36)
    Statistical analysis title
    		 Percentage change in Total Cholesterol
    Statistical analysis description
    Difference in the percentage change in total cholesterol from baseline to Day 510, between inclisiran and placebo arms
    Comparison groups
    Inclisiran v Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -31.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.59
         upper limit
    		 -27.94

    Secondary: Percentage Change in Apolipoprotein B (ApoB) From Baseline To Day 510

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    End point title
    		 Percentage Change in Apolipoprotein B (ApoB) From Baseline To Day 510
    End point description
    Change in ApoB
    End point type
    Secondary
    End point timeframe
    Baseline To Day 510
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -33.14 (-35.91 to -30.36)
    2.93 (0.14 to 5.71)
    -33.14 (-35.91 to -30.36)
    2.93 (0.14 to 5.71)
    Statistical analysis title
    		 Percentage change in Apo B form Baseline - Day 510
    Statistical analysis description
    Difference in the percentage change in Apolipoprotein B (ApoB) from baseline to Day 510
    Comparison groups
    Inclisiran v Placebo
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -36.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.99
         upper limit
    		 -32.14

    Secondary: Percentage Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510

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    End point title
    		 Percentage Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510
    End point description
    Change in non-HDL-C
    End point type
    Secondary
    End point timeframe
    Baseline To Day 510
    End point values
    		 Inclisiran Placebo Inclisiran Placebo
    Number of subjects analysed
    242
    240
    242
    240
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -34.93 (-38.46 to -31.40)
    7.43 (3.93 to 10.92)
    -34.93 (-38.46 to -31.40)
    7.43 (3.93 to 10.92)
    Statistical analysis title
    		 Percentage Change in Non-HDL-C: baseline - Day 510
    Statistical analysis description
    Difference in the percentage change in Non-HDL-C from baseline to Day 510, between inclisiran and placebo arms
    Comparison groups
    Placebo v Inclisiran
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -42.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.32
         upper limit
    		 -37.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 0 to Day 510
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Inclisiran
    Reporting group description
    		 Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months. Inclisiran: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

    Serious adverse events
    		 Inclisiran Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 241 (7.47%)
    33 / 240 (13.75%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hernia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device loosening
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Soft tissue injury
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 241 (0.83%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 241 (0.41%)
    4 / 240 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 241 (0.41%)
    3 / 240 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Sensory disturbance
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 241 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective tenosynovitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelitis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tick-borne fever
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Inclisiran Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 241 (39.83%)
    67 / 240 (27.92%)
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    22 / 241 (9.13%)
    0 / 240 (0.00%)
         occurrences all number
    37
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 241 (7.05%)
    10 / 240 (4.17%)
         occurrences all number
    19
    11
    Infections and infestations
    Influenza
         subjects affected / exposed
    13 / 241 (5.39%)
    21 / 240 (8.75%)
         occurrences all number
    15
    24
    Nasopharyngitis
         subjects affected / exposed
    28 / 241 (11.62%)
    20 / 240 (8.33%)
         occurrences all number
    36
    21
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 241 (6.64%)
    16 / 240 (6.67%)
         occurrences all number
    19
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2017
    Global Amendment #1 Clarifications have been made to the various sections of the protocol synopsis and main body in order to address comments received from an FDA review of the study. These clarification are related to exclusion criterion #3, site training requirements and statistics. Changes made to the Synopsis section to include an update to exclusion criterion #3 and the Statistical Methods – Key Secondary Endpoints Analysis. Changes made to the Protocol Main Body include: Section 4.3-Exclusion Criteria, Section 10.3.2.1-Intent-to-Treat (ITT) Population, Section 10.3.2.2-Modified Intent-to-Treat (mITT) Population, Section 10.3.4-Missing Data Handling, Section 10.4.3-Efficacy Analysis, 10.4.3.1.1-Sensitivity Analysis for Primary Efficacy Endpoints and 10.4.3.2-Secondary Efficacy Endpoint. Changes made to the Appendices included the addition of a new Appendix C, Genetic Informed Consent, which shifted the numbering of subsequent appendices.
    08 Jan 2018
    Global Amendment #2 Clarifications made to the protocol main body were included in order to address comments received from the FDA. Changes were made to the following sections: Section 4.4-Withdrawal criteria, Section 6.1-Table 2 Schedule of Assessments (including footnote 7) and Section 7.1.3-Vital Signs.
    30 Aug 2018
    Global Amendment #3 Changes were made to the Procedures in Case of Emergency section of the protocol to replace Pharmaceutical Product Development, LLC with The Medicines Company. Changes were made to the following sections to remove the month, year and/or edition associated with the Investigator’s Brochure as investigative sites should always refer to the latest edition: Section 1.3 Known and Potential Risks and Benefits Section 16 References
    31 Jan 2019
    Global Amendment # 4 Changes have been made to the following sections: - Synopsis, Section 3.1, Section 4.1, Section 6.4, Section 10 to account for actual number of randomized subjects. - Synopsis, Section 2.1, Section 3.3, Section 3.4, Section 7.2.1, Section 10.4.3.1 to account for refinement in the description of time adjusted analyses of LDL-C. - Section 6.1. Table 2. Section 6.4, Section 6.6, Section 6.8, Section 7.1.8.8 to clarify the plan to test for ADA. - Section 6.1. Table 2, Schedule of Assessments to align with Health Authority feedback for wider visit windows. - Section 10.3.2.2., Section 10.4.1., Section 10.4.3 to add to account for the addition of a new analysis set (Full Analysis Set). - Section 10.3.3. Analysis Windows and Baseline to clarify that analysis windows will be defined to maximize the amount of data that are included in the analysis models and that full details will be provided in the Statistical Analysis Plan. - Synopsis, Section 10.3.4, Section 10.4.3.1, Section 10.4.3.1.1. Missing Data Handling to align approach to missing data handling with Health Authority feedback and that details are provided in the Statistical Analysis Plan. - Section 10.4.4.2. Laboratory Tests to add analyses for clinically significant laboratory parameters.

    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.
    Not applicable.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32197277
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