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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of Bempedoic Acid (ETC-1002) 180 mg/day as Add-on to Ezetimibe Therapy in Patients with Elevated LDL-C on Low Dose or Less than Low Dose Statins

    Summary
    EudraCT number
    		 2016-004084-39
    Trial protocol
    		 HU   GB   DE   CZ  
    Global end of trial date
    11 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2019
    First version publication date
    20 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1002-048
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03001076
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Esperion Therapeutics Inc.
    Sponsor organisation address
    Bldg. I: 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan, United States, 48108
    Public contact
    Director of Clinical Operations, Esperion Therapeutics, 00 1 7348873903, clinicaltrials@esperion.com
    Scientific contact
    Director of Clinical Operations, Esperion Therapeutics, 00 1 7348873903, clinicaltrials@esperion.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
    22 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the 12-week efficacy of bempedoic acid 180 mg/day versus placebo in decreasing low-density lipoprotein cholesterol (LDL-C) when added to ezetimibe therapy in participants with elevated LDL-C.
    Protection of trial subjects
    The trial was designed, conducted, and monitored in accordance with sponsor procedures, which comply with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.
    Background therapy
    		 All participants received study supplied ezetimibe 10 mg/day as background therapy throughout the study. Participants on low or very low-dose statin at screening could continue statin therapy throughout the study provided that the dose was stable (≥4 weeks) and well tolerated. Low dose statin therapy was defined as an average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg. Very low-dose statin therapy was defined as an average daily dose of rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin <20 mg, pravastatin <40 mg, fluvastatin <40 mg, or pitavastatin <2 mg. Participants were instructed to continue taking their lipid-modifying therapy (LMT) throughout the study. PCSK9 inhibitors were not allowed during the study period. Other LMTs were to remain stable for at least 4 weeks prior to screening; fibrates (with the exception of gemfibrozil which was exclusionary in participants aking a statin) were to remain stable for at least 6 weeks prior to screening.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Nov 2016
    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
    Canada: 17
    Country: Number of subjects enrolled
    United States: 203
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Czech Republic: 22
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Hungary: 7
    Worldwide total number of subjects
    269
    EEA total number of subjects
    49
    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)
    122
    From 65 to 84 years
    143
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Out of the 269 participants who were randomized to the double-blind treatment period, 181 participants were randomized to bempedoic acid and 88 participants to placebo. One participant in the placebo group was randomized but never started treatment.

    Pre-assignment
    Screening details
    		 The study consisted of an approximate 1-week screening period, a 4-week single-blind placebo and ezetimibe run-in period, and a 12-week double-blind treatment period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Sponsor, all clinical site personnel (investigator, pharmacist, etc.), and other vendor personnel were blinded to the treatment group for each participant. Participants were also blinded to the treatment they received. Bempedoic acid and placebo had identical physical appearance and packaging. Blinding of treatment was maintained for all participants unless, in the opinion of the investigator, the safety of the participant was at risk.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 4 weeks prior to the 12-week treatment period. During the treatment period, participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ezetimibe 10 mg capsule, once-daily by mouth for 4 weeks during the run-in period and 12 weeks during the treatment period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo tablet, once-daily by mouth for 4 weeks during the run-in period and 12 weeks during the treatment period.

    Arm title
    		 Bempedoic Acid
    Arm description
    		 Participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 4 weeks prior to the 12-week treatment period. During the treatment period, participants received bempedoic acid 180 mg tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo tablet, once-daily by mouth, with or without food for 4 weeks during the run-in period.

    Investigational medicinal product name
    Bempedoic acid
    Investigational medicinal product code
    ETC-1002
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received bempedoic acid 180 mg tablet, once-daily by mouth, with or without food for 12 weeks during the treatment period.

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ezetimibe 10 mg capsule, once-daily by mouth for 4 weeks during the run-in period and 12 weeks during the treatment period.

    Number of subjects in period 1
    		Placebo Bempedoic Acid
    Started
    88
    181
    Completed
    81
    176
    Not completed
    7
    5
         Adverse event, non-fatal
    3
    3
         Unknown
    1
    -
         Sponsor decision
    1
    -
         Lost to follow-up
    -
    2
         Withdrawal by patient
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 4 weeks prior to the 12-week treatment period. During the treatment period, participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 12 weeks.

    Reporting group title
    Bempedoic Acid
    Reporting group description
    		 Participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 4 weeks prior to the 12-week treatment period. During the treatment period, participants received bempedoic acid 180 mg tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 12 weeks.

    Reporting group values
    		 Placebo Bempedoic Acid Total
    Number of subjects
    		 88 181 269
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ± 11.32 63.8 ± 10.77 -
    Gender categorical
    Units: Subjects
        Female
    		 56 109 165
        Male
    		 32 72 104
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 3 4
        Native Hawaiian or Other Pacific Islander
    		 0 2 2
        Black or African American
    		 10 11 21
        White
    		 75 165 240
        More than one race
    		 2 0 2
        Unknown or Not Reported
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 23 43 66
        Not Hispanic or Latino
    		 65 138 203
        Unknown or Not Reported
    		 0 0 0
    LDL-C category
    Units: Subjects
        <130 mg/dL
    		 56 99 155
        ≥130 to <160 mg/dL
    		 24 53 77
        ≥160 mg/dL
    		 8 29 37
    Concomitant lipid-modifying therapy medications
    Concomitant medications were defined as medications that started prior to, on or after the first dose of double-blind IMP and started no later than 30 days following end of double-blind IMP, and ended on or after the date of first dose of double-blind IMP or were ongoing at the end of the study. Other LMT included fish oil, eicosapentaenoic acid ethyl ester, omega-3 fatty acids, salmon oil, and sitosterol. Participants received ezetimibe 10 mg/day as background therapy throughout the study. Participants who took at least one concomitant LMT have been reported.
    Units: Subjects
        Statins
    		 25 59 84
        Fibrates
    		 3 7 10
        Nicotinic acid and derivatives
    		 4 3 7
        Bile acid sequestrants
    		 1 1 2
        Other lipid-modifying therapies
    		 8 19 27
        No concomitant lipid-modifying therapies
    		 47 92 139
    Concomitant illness: Cardiac disorder
    Concomitant illness was defined as the present condition that started prior to the date of randomization and was ongoing at the time of randomization.
    Units: Subjects
        Participants with cardiac disorder
    		 22 49 71
        Participants without cardiac disorder
    		 66 132 198
    History of diabetes
    Units: Subjects
        Participants with history of diabetes
    		 17 35 52
        Participants without history of diabetes
    		 71 146 217
    History of hypertension
    Units: Subjects
        Participants with history of hypertension
    		 51 111 162
        Participants without history of hypertension
    		 37 70 107
    Estimated glomerular filtration rate (eGFR) category
    milliliter per minutes per 1.73 square meter (mL/min/1.73m2)
    Units: Subjects
        ≥90 mL/min/1.73m2
    		 17 45 62
        60 to <90 mL/min/1.73m2
    		 57 110 167
        <60 mL/min/1.73m2
    		 14 26 40
    Low-density lipoprotein cholesterol (LDL-C)
    Baseline was defined as the mean of the last two non-missing values on or prior to Day 1.
    Units: milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    		 123.02 ± 27.197 129.77 ± 30.871 -
    Non-high-density lipoprotein cholesterol (non-HDL-C)
    Baseline was defined as the mean of the last two non-missing values on or prior to Day 1.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 151.55 ± 32.734 162.41 ± 35.413 -
    Total cholesterol (TC)
    Baseline was defined as the mean of the last two non-missing values on or prior to Day 1.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 208.62 ± 35.712 218.24 ± 35.883 -
    Apolipoprotein B (apoB)
    Baseline was defined as the last non-missing value on or prior to Day 1.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 115.8 ± 23.47 123.3 ± 26.48 -
    High-sensitivity C-reactive protein (hsCRP)
    Baseline was defined as the last non-missing value on or prior to Day 1.
    Units: mg/dL
        median (full range (min-max))
    		 2.260 (0.13 to 14.37) 2.205 (0.22 to 39.20) -
    Triglycerides (TGs)
    Baseline was defined as the mean of the last two non-missing values on or prior to Day 1.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 143.39 ± 61.932 166.93 ± 75.683 -
    High-density lipoprotein cholesterol (HDL-C)
    Baseline was defined as the mean of the last two non-missing values on or prior to Day 1.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 57.07 ± 21.319 55.84 ± 16.326 -
    Systolic blood pressure
    Units: millimeter of mercury (mmHg)
        arithmetic mean (standard deviation)
    		 126.0 ± 13.50 127.3 ± 13.34 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 77.0 ± 7.56 76.4 ± 8.46 -
    Body mass index (BMI)
    Units: kilograms per square meter (kg/m2)
        arithmetic mean (standard deviation)
    		 30.45 ± 5.787 29.52 ± 4.740 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 4 weeks prior to the 12-week treatment period. During the treatment period, participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 12 weeks.

    Reporting group title
    Bempedoic Acid
    Reporting group description
    		 Participants received placebo tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 4 weeks prior to the 12-week treatment period. During the treatment period, participants received bempedoic acid 180 mg tablet, once-daily by mouth and ezetimibe 10 mg capsules, once-daily by mouth for 12 weeks.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS), also known as the intention-to-treat set was defined as all randomized participants. Participants in the FAS were included in their randomized treatment group, regardless of their actual treatment.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set (SAS) was defined as all randomized participants who received at least 1 dose of study medication.

    Primary: Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C)

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    End point title
    		 Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: ([LDL-C value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100. Bempedoic Acid = BA.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [1]
    181 [2]
    Units: percent change
    least squares mean (standard error)
        Week 12 (n= 82, 175)
    4.99 ± 2.299
    -23.46 ± 1.945
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. Least square (LS) mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. The missing parameter at Week 12 was imputed using a multiple imputation method taking into account adherence to treatment.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -28.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.376
         upper limit
    		 -22.531
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.022

    Secondary: Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (non-HDL-C)

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    End point title
    		 Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (non-HDL-C)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for non-HDL-C. Baseline was defined as the mean of the non-HDL-C values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: ([non-HDL-C value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [3]
    181 [4]
    Units: percent change
    least squares mean (standard error)
        Week 12 (n= 82, 175)
    5.19 ± 2.202
    -18.38 ± 1.668
    Notes
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. The missing parameter at Week 12 was imputed using a multiple imputation method taking into account adherence to treatment.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -23.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.005
         upper limit
    		 -18.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.777

    Secondary: Percent Change From Baseline to Week 12 in Total Cholesterol (TC)

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    End point title
    		 Percent Change From Baseline to Week 12 in Total Cholesterol (TC)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for TC. Baseline was defined as the mean of the TC values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: ([TC value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [5]
    181 [6]
    Units: Percent change
    least squares mean (standard error)
        Week 12 (n= 82, 176)
    2.88 ± 1.553
    -15.11 ± 1.282
    Notes
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. The missing parameter at Week 12 was imputed using a multiple imputation method taking into account adherence to treatment.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -17.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.94
         upper limit
    		 -14.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.018

    Secondary: Percent Change From Baseline to Week 12 in Apolipoprotein B (apoB)

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    End point title
    		 Percent Change From Baseline to Week 12 in Apolipoprotein B (apoB)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for apoB. Baseline was defined as the last non-missing value on or prior to Day 1. Percent change from baseline was calculated as: [(apoB value at Week 12 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [7]
    181 [8]
    Units: Percent change
    least squares mean (standard error)
        Week 12 (n= 81, 174)
    4.74 ± 1.786
    -14.58 ± 1.497
    Notes
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. The missing parameter at Week 12 was imputed using a multiple imputation method taking into account adherence to treatment.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -19.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.908
         upper limit
    		 -14.732
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.341

    Secondary: Percent Change From Baseline to Week 12 in High-sensitivity C-reactive protein (hsCRP)

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    End point title
    		 Percent Change From Baseline to Week 12 in High-sensitivity C-reactive protein (hsCRP)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for hsCRP. Baseline was defined as the last non-missing value on or prior to Day 1. Percent change from baseline was calculated as: [(hsCRP value at Week 12 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [9]
    181 [10]
    Units: Percent change
    median (inter-quartile range (Q1-Q3))
        Week 12 (n= 81, 175)
    2.088 (-99999 to 81.367)
    -32.521 (-99999 to 66.270)
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    		 Location shift
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. The location shift and 95% CI was based on Hodges-Lehman estimation. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon Two Sample Test
    Parameter type
    		 Location shift
    Point estimate
    -31.045
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.761
         upper limit
    		 -17.401

    Secondary: Percent Change From Baseline to Week 12 in Triglycerides (TGs)

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    End point title
    		 Percent Change From Baseline to Week 12 in Triglycerides (TGs)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for TGs. Baseline was defined as the mean of the TGs values from the last two non-missing values on or prior to D 1. Percent change from baseline was calculated as: [(TGs value at Week 12 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [11]
    181 [12]
    Units: Percent change
    least squares mean (standard error)
        Week 12 (n= 82, 176)
    9.23 ± 4.218
    4.70 ± 3.068
    Notes
    [11] - FAS
    [12] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -4.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.877
         upper limit
    		 5.812
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.24

    Secondary: Percent Change From Baseline to Week 12 in High-density lipoprotein cholesterol (HDL-C)

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    End point title
    		 Percent Change From Baseline to Week 12 in High-density lipoprotein cholesterol (HDL-C)
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for HDL-C. Baseline was defined as the mean of the HDL-C values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: [(HDL-C value at Week 12 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [13]
    181 [14]
    Units: percent change
    least squares mean (standard error)
        Week 12 (n= 82, 175)
    -1.38 ± 1.389
    -7.27 ± 1.214
    Notes
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -5.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.528
         upper limit
    		 -2.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.845

    Secondary: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
    End point description
    TEAEs, defined as an adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and prior to the last dose of double-blind study drug + 30 days, were collected and reported.
    End point type
    Secondary
    End point timeframe
    Up to approximately 16 weeks
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    87 [15]
    181 [16]
    Units: percentage of participants
    number (not applicable)
        TEAEs
    44.8
    48.6
        Non-serious TEAEs
    20.7
    25.4
        Serious TEAEs
    3.4
    2.8
        Deaths
    0
    0
    Notes
    [15] - SAS
    [16] - SAS
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline to Weeks 4 and 8 in LDL-C

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    End point title
    		 Percent Change From Baseline to Weeks 4 and 8 in LDL-C
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: [(LDL-C value at Week 4 or 8 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Other pre-specified
    End point timeframe
    Week 4 and Week 8
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [17]
    181 [18]
    Units: Percent change
    least squares mean (standard error)
        Week 4 (n= 85, 180)
    3.05 ± 1.442
    -28.04 ± 1.704
        Week 8 (n= 82, 173)
    3.61 ± 1.773
    -25.51 ± 1.773
    Notes
    [17] - FAS
    [18] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 4
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -31.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.498
         upper limit
    		 -26.682
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.238
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 8
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -29.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.074
         upper limit
    		 -24.168
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.513

    Other pre-specified: Percent Change From Baseline to Weeks 4 and 8 in Non-HDL-C

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    End point title
    		 Percent Change From Baseline to Weeks 4 and 8 in Non-HDL-C
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for Non-HDL-C. Baseline was defined as the mean of the Non-HDL-C values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: [(Non-HDL-C value at Week 4 or 8 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Other pre-specified
    End point timeframe
    Week 4 and Week 8
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [19]
    181 [20]
    Units: Percent change
    least squares mean (standard error)
        Week 4 (n= 85, 180)
    3.08 ± 1.362
    -22.17 ± 1.457
        Week 8 (n= 82, 173)
    3.71 ± 1.660
    -20.04 ± 1.531
    Notes
    [19] - FAS
    [20] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 4
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -25.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.204
         upper limit
    		 -21.308
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.004
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 8
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -23.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.219
         upper limit
    		 -19.276
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.268

    Other pre-specified: Percent Change From Baseline to Weeks 4 and 8 in TC

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    End point title
    		 Percent Change From Baseline to Weeks 4 and 8 in TC
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for TC. Baseline was defined as the mean of the TC values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: [(TC value at Week 4 or 8 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Other pre-specified
    End point timeframe
    Week 4 and Week 8
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [21]
    181 [22]
    Units: Percent change
    least squares mean (standard error)
        Week 4 (n= 85, 180)
    2.08 ± 1.000
    -18.33 ± 1.129
        Week 8 (n= 82, 173)
    1.82 ± 1.110
    -16.63 ± 1.215
    Notes
    [21] - FAS
    [22] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 4
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -20.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.39
         upper limit
    		 -17.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.513
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 8
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -18.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.71
         upper limit
    		 -15.206
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.651

    Other pre-specified: Percent Change From Baseline to Weeks 4 and 8 in TGs

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    End point title
    		 Percent Change From Baseline to Weeks 4 and 8 in TGs
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for TGs. Baseline was defined as the mean of the TGs values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: [(TGs value at Week 4 or 8 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Other pre-specified
    End point timeframe
    Week 4 and Week 8
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [23]
    181 [24]
    Units: Percent change
    least squares mean (standard error)
        Week 4 (n= 85, 180)
    6.00 ± 4.273
    5.20 ± 2.536
        Week 8 (n= 82, 173)
    7.68 ± 4.246
    7.60 ± 2.849
    Notes
    [23] - FAS
    [24] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 4
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.873
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.663
         upper limit
    		 9.059
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.99
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 8
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.988
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.215
         upper limit
    		 10.055
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.131

    Other pre-specified: Percent Change From Baseline to Weeks 4 and 8 in HDL-C

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    End point title
    		 Percent Change From Baseline to Weeks 4 and 8 in HDL-C
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for HDL-C. Baseline was defined as the mean of the HDL-C values from the last two non-missing values on or prior to Day 1. Percent change from baseline was calculated as: [(HDL-C value at Week 4 or 8 minus Baseline value) divided by (Baseline Value)] multiplied by 100.
    End point type
    Other pre-specified
    End point timeframe
    Week 4 and Week 8
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [25]
    181 [26]
    Units: Percent change
    least squares mean (standard error)
        Week 4 (n= 85, 180)
    0.85 ± 1.204
    -7.73 ± 1.081
        Week 8 (n= 82, 173)
    -1.33 ± 1.272
    -7.75 ± 1.144
    Notes
    [25] - FAS
    [26] - FAS
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 4
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -8.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.778
         upper limit
    		 -5.394
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.619
    Statistical analysis title
    		 Difference [BA - placebo] in LS mean at Week 8
    Statistical analysis description
    The analysis compared the percent change from baseline between treatment groups using a two-sided test at the 0.05 level of significance and a confidence interval of 95%. LS mean, 95% CI, and P-value was based on an ANCOVA model with percent change from baseline as the dependent variable, treatment as a fixed effects and baseline as a covariate. Observed data was used for the analysis, no imputation for the missing data was performed.
    Comparison groups
    Placebo v Bempedoic Acid
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean
    Point estimate
    -6.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.798
         upper limit
    		 -3.049
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.712

    Other pre-specified: Absolute Change From Baseline to Weeks 4, 8, and 12 in LDL-C

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    End point title
    		 Absolute Change From Baseline to Weeks 4, 8, and 12 in LDL-C
    End point description
    Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analysed for LDL-C. Baseline was defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1. Absolute change from baseline was calculated as: LDL-C value at Week 4, 8, or 12 minus Baseline value.
    End point type
    Other pre-specified
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    		 Placebo Bempedoic Acid
    Number of subjects analysed
    88 [27]
    181 [28]
    Units: milligrams per deciliter (mg/dL)
    geometric mean (standard deviation)
        Change from Baseline at Week 4 (n= 85, 180)
    3.6 ± 15.65
    -37.4 ± 30.90
        Change from Baseline at Week 8 (n= 82, 173)
    3.9 ± 19.22
    -34.5 ± 32.29
        Change from Baseline at Week 12 (n= 82, 175)
    5.3 ± 23.96
    -32.9 ± 34.14
    Notes
    [27] - FAS
    [28] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 16 weeks
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs), defined as an adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and prior to the last dose of double-blind study drug + 30 days, were collected and reported. The analysis was performed using the Safety Analysis Set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Bempedoic Acid
    Reporting group description
    		 Participants received bempedoic acid 180 mg tablet, once-daily by mouth and ezetimibe 10 mg capsule, once-daily by mouth for 12 weeks during the treatment period.

    Serious adverse events
    		 Placebo Bempedoic Acid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 87 (3.45%)
    5 / 181 (2.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Poisoning deliberate
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         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
    Osteoarthritis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Bempedoic Acid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 87 (20.69%)
    46 / 181 (25.41%)
    Investigations
    Blood uric acid increase
         subjects affected / exposed
    2 / 87 (2.30%)
    14 / 181 (7.73%)
         occurrences all number
    2
    14
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 87 (0.00%)
    4 / 181 (2.21%)
         occurrences all number
    0
    4
    Liver function test increased
         subjects affected / exposed
    0 / 87 (0.00%)
    7 / 181 (3.87%)
         occurrences all number
    0
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 87 (3.45%)
    8 / 181 (4.42%)
         occurrences all number
    3
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 181 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 87 (0.00%)
    5 / 181 (2.76%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 87 (3.45%)
    6 / 181 (3.31%)
         occurrences all number
    4
    6
    Myalgia
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 181 (1.66%)
         occurrences all number
    4
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 87 (1.15%)
    4 / 181 (2.21%)
         occurrences all number
    1
    4
    Sinusitis
         subjects affected / exposed
    0 / 87 (0.00%)
    5 / 181 (2.76%)
         occurrences all number
    0
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 87 (5.75%)
    5 / 181 (2.76%)
         occurrences all number
    5
    7
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 181 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 87 (2.30%)
    2 / 181 (1.10%)
         occurrences all number
    2
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2017
    Protocol Amendment 2, dated 10 February 2017, included the following key changes: • Changed protocol title to more accurately reflect the study population based on guidance from the Food and Drug Administration (FDA) • Updated the bempedoic acid mechanism of action • Revised various inclusion criterion and exclusion criterion • Excluded use of cholesteryl ester transfer protein inhibitor (CETP) inhibitors • Changed exclusion time period for mipomersen to 6 months • Removed the allowance to rescreen if low-density lipoprotein cholesterol (LDL-C) criteria at screening visit 1 (S1) were not met • Extended screening an additional 4 weeks if needed to adjust background therapy • Removed collection of pharmacokinetic (PK) at Day 0; specified collection of PK samples prior to Investigational medicinal product (IMP) dosing • Added requirement to Visit S3 (Week -1) that LDL-C ≥70 milligrams per deciliter (mg/dL) • Added chemistry panel and creatine kinase (CK) to Visit S3 (Week -1) given inclusion of ezetimibe naive participants • Removed optional genetic sampling • Removed instructions to reserve samples • Corrected windowing of allowable and prohibited medications to be consistent between entry criteria and protocol body • Removed lipids other than LDL-C as a specified tertiary endpoint • Removed manufacturing contact details (provided in pharmacy manual) • Added text on the administration of study-supplied ezetimibe, including assessment of relationship of adverse events (AEs) to both IMP and ezetimibe • Changed monitoring of CK for asymptomatic participants per FDA request • Revised safety endpoints • Revised statistical sections to clarify level of significance, standard deviation, methods for imputation of missing data, and application of analysis of covariance (ANCOVA) model for primary and secondary endpoints • Made administrative changes made throughout protocol where required to correct inconsistencies, add clarification, or correct errors

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29910030
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