Evaluation of Long-Term Efficacy of Bempedoic Acid (ETC-1002) in Patients With Hyperlipidemia at High Cardiovascular Risk (CLEAR Wisdom)

• ClinicalTrials.gov Identifier: NCT02991118
• Recruitment Status: Completed
• First Posted: December 13, 2016
• Results First Posted: April 27, 2020
• Last Update Posted: April 27, 2020
• Sponsor: Esperion Therapeutics, Inc.
• Information provided by (Responsible Party): Esperion Therapeutics, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Hypercholesterolemia; Atherosclerotic Cardiovascular Disease
• Interventions: Drug: bempedoic acid; Drug: placebo
• Enrollment: 779

Participant Flow

Recruitment Details	A total of 779 participants were randomized 2:1 to receive either bempedoic acid or placebo.
Pre-assignment Details	The study consisted of 3 periods: a 1-week screening period; a 4-week single-blind, placebo run-in period; and a 52-week double-blind, randomized treatment period.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Period Title: Overall Study
Started	257	522
Completed	250	490
Not Completed	7	32
Reason Not Completed
Death	3	8
Protocol Violation	0	3
Physician Decision	0	1
Moved out of the country	0	1
Adverse Event	2	2
Withdrawal by Subject	1	7
Could not attend study visits	0	1
Lost to Follow-up	1	9

Baseline Characteristics

Arm/Group Title		Placebo	Bempedoic Acid	Total
Arm/Group Description		Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Total of all reporting groups
Overall Number of Baseline Participants		257	522	779
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	257 participants	522 participants	779 participants
		64.7 (8.73)	64.1 (8.82)	64.3 (8.79)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	257 participants	522 participants	779 participants
	Female	89 34.6%	194 37.2%	283 36.3%
	Male	168 65.4%	328 62.8%	496 63.7%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
American Indian or Alaska Native		1 0.4%	0 0.0%	1 0.1%
Asian		0 0.0%	4 0.8%	4 0.5%
Black or African American		12 4.7%	24 4.6%	36 4.6%
Native Hawaiian or Other Pacific Islander		0 0.0%	1 0.2%	1 0.1%
White		244 94.9%	491 94.1%	735 94.4%
Multiple		0 0.0%	2 0.4%	2 0.3%
Mean low-density lipoprotein cholesterol (LDL-C) [1]; Mean (Standard Deviation); Unit of measure: Milligrams per deciliter (mg/dL)
	Number Analyzed	257 participants	522 participants	779 participants
		122.4 (38.30)	119.4 (37.75)	120.43 (37.931)
		[1] Measure Description: Baseline was defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1.
LDL-C category; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
<130 mg/dL		173 67.3%	365 69.9%	538 69.1%
≥130 and <160 mg/dL		45 17.5%	89 17.0%	134 17.2%
≥160 mg/dL		39 15.2%	68 13.0%	107 13.7%
Mean non-high-density lipoprotein cholesterol (non-HDL-C) [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	257 participants	522 participants	779 participants
		153.7 (44.36)	150.7 (42.75)	151.7 (43.28)
		[1] Measure Description: 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.
Mean total cholesterol (TC) [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	257 participants	522 participants	779 participants
		204.8 (46.06)	202.1 (42.71)	203.0 (43.83)
		[1] Measure Description: Baseline was defined as the mean of the TC values from the last two non-missing values on or prior to Day 1.
Mean apolipoprotein B (apoB) [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	257 participants	522 participants	779 participants
		118.6 (30.53)	116.2 (29.58)	117.0 (29.90)
		[1] Measure Description: Baseline was defined as the last non-missing value on or prior to Day 1.
Median high-sensitivity C-reactive protein (hsCRP) [1]; Median (Inter-Quartile Range); Unit of measure: Milligrams per Liter
	Number Analyzed	257 participants	522 participants	779 participants
		1.880; (0.920 to 3.790)	1.610; (0.870 to 3.455)	1.700; (0.870 to 3.560)
		[1] Measure Description: Baseline was defined as the last non-missing value on or prior to Day 1. Dispersion data are reported as the first quartile and third quartile values.
Median triglycerides; Median (Inter-Quartile Range); Unit of measure: mg/dL
	Number Analyzed	257 participants	522 participants	779 participants
		143.00; (106.00 to 189.00)	139.25; (102.50 to 190.00)	140.00; (103.00 to 189.50)
Concomitant lipid-modifying therapy (LMT) medications [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
Statins		232 90.3%	478 91.6%	710 91.1%
Fibrates		17 6.6%	26 5.0%	43 5.5%
Nicotinic acid and derivatives		0 0.0%	1 0.2%	1 0.1%
Other lipidmodifying therapies		38 14.8%	63 12.1%	101 13.0%
Bile acid sequestrants		3 1.2%	5 1.0%	8 1.0%
		[1] Measure Description: Concomitant medications were defined as medications that were ongoing at the time of double-blind investigational medicinal product (IMP) initiation or new medications that started after double-blind IMP initiation and within 30 days following the date of the last dose of IMP. Other LMT included ezetimibe, fish oil, omega-3 fatty acids, omega-3-acid ethyl ester, alirocumab, evolocumab, and kolestop. Data are reported for participants who took at least one concomitant LMT.
History of atherosclerotic cardiovascular disease (ASCVD) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	257 participants	522 participants	779 participants
		241 93.8%	495 94.8%	736 94.5%
		[1] Measure Description: Data for participants with ASCVD only (without heterozygous familial hypercholesterolemia [HeFH]) are reported.
History of HeFH [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	257 participants	522 participants	779 participants
		16 6.2%	27 5.2%	43 5.5%
		[1] Measure Description: Data for participants with HeFH (with or without ASCVD) are reported.
History of impaired fasting glucose; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	257 participants	522 participants	779 participants
		5 1.9%	9 1.7%	14 1.8%
Background LMT; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
Statins with or without other LMTs		228 88.7%	470 90.0%	698 89.6%
Statins without other LMTs		196 76.3%	416 79.7%	612 78.6%
Statins with other LMTs		32 12.5%	54 10.3%	86 11.0%
Other LMTs without statins		15 5.8%	22 4.2%	37 4.7%
No LMT or statin		14 5.4%	30 5.7%	44 5.6%
Disease history [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
Hypertension		224 87.2%	438 83.9%	662 85.0%
Coronary heart disease		205 79.8%	432 82.8%	637 81.8%
Diabetes		81 31.5%	155 29.7%	236 30.3%
Impaired fasting glucose		5 1.9%	9 1.7%	14 1.8%
		[1] Measure Description: The presence of these conditions was determined by participant-reported medical history.
Body mass index (BMI) [1]; Mean (Standard Deviation); Unit of measure: Kilograms per meters squared (kg/m^2)
	Number Analyzed	257 participants	522 participants	779 participants
		30.64 (5.048)	30.01 (5.192)	30.22 (5.150)
		[1] Measure Description: BMI was calculated as weight in kilograms divided by height in meters squared.
Estimated glomerular filtration rate (eGFR) category [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
≥90 mL/min/1.73 m^2		56 21.8%	107 20.5%	163 20.9%
≥60 to <90 mL/min/1.73 m^2		164 63.8%	338 64.8%	502 64.4%
<60 mL/min/1.73 m^2		37 14.4%	77 14.8%	114 14.6%
		[1] Measure Description: eGFR was measured in milliliters per minutes per 1.73 meters squared (mL/min/1.73 m^2).
Statin intensity [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	257 participants	522 participants	779 participants
Low intensity or no statin		40 15.6%	78 14.9%	118 15.1%
Moderate intensity		82 31.9%	166 31.8%	248 31.8%
High intensity		135 52.5%	278 53.3%	413 53.0%
		[1] Measure Description: Baseline statin intensity were based on stratification at randomization. Low-intensity statins: simvastatin 10 milligrams (mg); pravastatin 10-20 mg; lovastatin 20 mg; fluvastatin 20-40 mg; pitavastatin 1 mg. Moderate-intensity statins: atorvastatin 10-20 mg; rosuvastatin 5-10 mg; simvastatin 20 mg; pravastatin 40-80 mg; lovastatin 40 mg; fluvastatin XL 80 mg; fluvastatin 40 mg twice a day; pitavastatin 2-4 mg. High-intensity statins: atorvastatin 40-80 mg; rosuvastatin 20-40 mg.
Numer of participants receiving ezetimibe; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	257 participants	522 participants	779 participants
		24 9.3%	39 7.5%	63 8.1%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C)
Description	Baseline is 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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in LDL-C was analyzed using an analysis of covariance (ANCOVA) model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (atherosclerotic cardiovascular diseases [ASCVD] and heterozygous familial hypercholesterolemia [HeFH]) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate. In the ANCOVA model, missing LDL-C data at Week 12 are imputed using multiple imputation method taking into account adherence to treatment.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	257	522
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.35 (1.446)	-15.07 (1.073)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-17.42
	Confidence Interval	(2-Sided) 95%; -20.951 to -13.896
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.800
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percent Change From Baseline to Week 24 in LDL-C
Description	Baseline is 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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in LDL-C was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate. In the ANCOVA model, missing LDL-C data at Week 24 were imputed using multiple imputation method taking into account adherence to treatment.
Time Frame	Baseline; Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	257	522
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.66 (1.910)	-12.10 (1.479)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-14.77
	Confidence Interval	(2-Sided) 95%; -19.504 to -10.027
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.418
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C)
Description	Baseline is 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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in non-HDL-C was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate. In the ANCOVA model, missing non-HDL-C data at Week 12 were imputed using multiple imputation method taking into account adherence to treatment.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	257	522
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.28 (1.351)	-10.75 (0.952)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-13.03
	Confidence Interval	(2-Sided) 95%; -16.270 to -9.794
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.652
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Percent Change From Baseline to Week 12 in Total Cholesterol (TC)
Description	Baseline is 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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in TC was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate. In the ANCOVA model, missing TC data at Week 12 were imputed using multiple imputation method taking into account adherence to treatment.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	257	522
Least Squares Mean (Standard Error); Unit of Measure: percent change
	1.26 (1.010)	-9.94 (0.688)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-11.20
	Confidence Interval	(2-Sided) 95%; -13.599 to -8.801
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.224
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Percent Change From Baseline to Week 12 in Apolipoprotein b (Apo B)
Description	Baseline for apo B was defined as the last non-missing value on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in apo B was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate. In the ANCOVA model, missing apo B data at Week 12 were imputed using multiple imputation method taking into account adherence to treatment.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	257	522
Least Squares Mean (Standard Error); Unit of Measure: percent change
	3.73 (1.340)	-9.29 (0.851)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-13.02
	Confidence Interval	(2-Sided) 95%; -16.130 to -9.907
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.587
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP)
Description	Baseline for hsCRP was defined as the last non-missing value on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	240	467
Median (Inter-Quartile Range); Unit of Measure: percent change
	-9.366; (-36.320 to 35.241)	-18.699; (-46.067 to 23.864)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.039
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Location shift
	Estimated Value	-8.733
	Confidence Interval	(2-Sided) 95%; -17.238 to -0.434
	Estimation Comments	The location shift and asymptotic 95% confidence interval are based on Hodges-Lehman estimation.

7. Secondary Outcome

Title	Change From Baseline to Week 12 in LDL-C
Description	Baseline is defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1. Change from Baseline is calculated as the post-baseline value minus the baseline value. Analysis was conducted using descriptive statistics by treatment group using observed data.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	253	498
Mean (Standard Deviation); Unit of Measure: mg/dL
	0.0 (30.62)	-21.2 (30.82)

8. Secondary Outcome

Title	Change From Baseline to Week 24 in LDL-C
Description	Baseline is defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1. Change from Baseline is calculated as the post-baseline value minus the baseline value. Analysis was conducted using descriptive statistics by treatment group using observed data.
Time Frame	Baseline; Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	247	485
Mean (Standard Deviation); Unit of Measure: mg/dL
	-1.0 (37.51)	-18.7 (35.76)

9. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 12 in Triglycerides (TGs)
Description	Baseline is defined as the mean of the TG values from the last two non-missing values on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in TG was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	253	499
Least Squares Mean (Standard Error); Unit of Measure: percent change
	6.12 (2.294)	11.01 (2.312)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.134
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	4.89
	Confidence Interval	(2-Sided) 95%; -1.504 to 11.292
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.258
	Estimation Comments	[Not Specified]

10. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 12 in HDL-C
Description	Baseline is 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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in HDL-C was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	253	499
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-0.25 (0.864)	-6.38 (0.741)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-6.13
	Confidence Interval	(2-Sided) 95%; -8.369 to -3.896
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.139
	Estimation Comments	[Not Specified]

11. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 52 in LDL-C
Description	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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in LDL-C was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	237	467
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-0.97 (1.830)	-13.24 (1.412)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-12.27
	Confidence Interval	(2-Sided) 95%; -16.813 to -7.722
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.314
	Estimation Comments	[Not Specified]

12. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 24 in Non-HDL-C
Description	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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in non-HDL-C was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	247	485
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.44 (1.611)	-10.19 (1.200)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-12.63
	Confidence Interval	(2-Sided) 95%; -16.580 to -8.682
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.010
	Estimation Comments	[Not Specified]

13. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 52 in Non-HDL-C
Description	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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in non-HDL-C was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	237	467
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-0.42 (1.605)	-10.34 (1.150)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-9.92
	Confidence Interval	(2-Sided) 95%; -13.803 to -6.037
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.976
	Estimation Comments	[Not Specified]

14. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 24 in TC
Description	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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in TC was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	247	486
Least Squares Mean (Standard Error); Unit of Measure: percent change
	1.52 (1.216)	-9.25 (0.857)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-10.77
	Confidence Interval	(2-Sided) 95%; -13.698 to -7.848
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.489
	Estimation Comments	[Not Specified]

15. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 52 in TC
Description	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 is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in TC was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	237	467
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-1.89 (1.199)	-10.25 (0.828)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-8.36
	Confidence Interval	(2-Sided) 95%; -11.223 to -5.493
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.458
	Estimation Comments	[Not Specified]

16. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 24 in Apo B
Description	Baseline for apo B was defined as the last non-missing value on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in apo B was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	144	294
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.39 (2.090)	-8.61 (1.267)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-13.00
	Confidence Interval	(2-Sided) 95%; -17.829 to -8.175
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.451
	Estimation Comments	[Not Specified]

17. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 52 in Apo B
Description	Baseline for apo B was defined as the last non-missing value on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100. Percent change from Baseline in apo B was analyzed using an ANCOVA model with percent change from Baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and Baseline as a covariate.
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	237	464
Least Squares Mean (Standard Error); Unit of Measure: percent change
	3.01 (1.502)	-6.56 (0.983)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-9.58
	Confidence Interval	(2-Sided) 95%; -13.107 to -6.047
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.796
	Estimation Comments	[Not Specified]

18. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 24 in hsCRP
Description	Baseline for hsCRP was defined as the last non-missing value on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100.
Time Frame	Baseline; Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	127	271
Median (Inter-Quartile Range); Unit of Measure: percent change
	1.563; (-32.174 to 47.500)	-24.107; (-51.502 to 14.035)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Location shift
	Estimated Value	-21.278
	Confidence Interval	(2-Sided) 95%; -32.250 to -10.034
	Estimation Comments	The location shift and asymptotic 95% confidence interval are based on Hodges-Lehman estimation.

19. Other Pre-specified Outcome

Title	Percent Change From Baseline to Week 52 in hsCRP
Description	Baseline for hsCRP was defined as the last non-missing value on or prior to Day 1. Percent change from Baseline is calculated as ([post-baseline value minus baseline value] divided by [baseline value]) multiplied by 100.
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	237	465
Median (Inter-Quartile Range); Unit of Measure: percent change
	-6.250; (-39.286 to 41.810)	-16.727; (-50.877 to 31.429)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.102
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Location shift
	Estimated Value	-7.587
	Confidence Interval	(2-Sided) 95%; -16.978 to 1.653
	Estimation Comments	The location shift and asymptotic 95% confidence interval are based on Hodges-Lehman estimation.

20. Other Pre-specified Outcome

Title	Change From Baseline to Week 52 in LDL-C
Description	Baseline was defined as the mean of the LDL-C values from the last two non-missing values on or prior to Day 1. Change from Baseline is calculated as the post-baseline value minus the baseline value. Analysis was conducted using descriptive statistics by treatment group using observed data. Change from Baseline in LDL-C was analyzed using an ANCOVA model with change from baseline as the dependent variable, treatment, cardiovascular risk (ASCVD and HeFH) crossed with Baseline statin intensity (low/moderate and high) as fixed effects and baseline as a covariate.
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only participants with available data were analyzed.

Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description:	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
Overall Number of Participants Analyzed	237	467
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
	-4.71 (2.216)	-19.78 (1.433)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bempedoic Acid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-15.07
	Confidence Interval	(2-Sided) 95%; -20.260 to -9.878
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.641
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	up to Week 52
Adverse Event Reporting Description	Treatment-emergent events, defined as those adverse events that began or worsened after the first dose of investigational medicinal product (IMP) until 30 days after the last dose of IMP, were collected and reported. The analysis was performed using the Safety Analysis Set, comprised of all randomized participants who received >=1 dose of IMP.
Arm/Group Title	Placebo	Bempedoic Acid
Arm/Group Description	Participants received placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received placebo once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.	Participants received a placebo tablet once daily by mouth for 4 weeks prior to the 52-week double-blind treatment period. During the treatment period, participants received a bempedoic acid 180 milligram (mg) tablet once daily by mouth for 52 weeks. Participants remained on ongoing lipid-modifying therapy (not study provided) throughout the study.
All-Cause Mortality
	Placebo	Bempedoic Acid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/257 (0.78%)	6/522 (1.15%)
Serious Adverse Events
	Placebo	Bempedoic Acid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	48/257 (18.68%)	106/522 (20.31%)
Blood and lymphatic system disorders
Microcytic anaemia † 1	1/257 (0.39%)	0/522 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	1/257 (0.39%)	0/522 (0.00%)
Acute left ventricular failure † 1	1/257 (0.39%)	0/522 (0.00%)
Acute myocardial infarction † 1	3/257 (1.17%)	2/522 (0.38%)
Angina pectoris † 1	1/257 (0.39%)	12/522 (2.30%)
Angina unstable † 1	6/257 (2.33%)	9/522 (1.72%)
Arteriosclerosis coronary artery † 1	0/257 (0.00%)	2/522 (0.38%)
Atrial fibrillation † 1	1/257 (0.39%)	4/522 (0.77%)
Atrioventricular block second degree † 1	1/257 (0.39%)	1/522 (0.19%)
Cardiac arrest † 1	2/257 (0.78%)	2/522 (0.38%)
Cardiac failure † 1	2/257 (0.78%)	0/522 (0.00%)
Cardiac failure chronic † 1	1/257 (0.39%)	4/522 (0.77%)
Cardiac failure congestive † 1	0/257 (0.00%)	2/522 (0.38%)
Cardiovascular disorder † 1	0/257 (0.00%)	1/522 (0.19%)
Coronary artery disease † 1	6/257 (2.33%)	7/522 (1.34%)
Coronary artery occlusion † 1	0/257 (0.00%)	1/522 (0.19%)
Coronary artery stenosis † 1	0/257 (0.00%)	1/522 (0.19%)
Myocardial infarction † 1	2/257 (0.78%)	2/522 (0.38%)
Myocardial ischaemia † 1	4/257 (1.56%)	2/522 (0.38%)
Ventricular arrhythmia † 1	1/257 (0.39%)	0/522 (0.00%)
Ventricular fibrillation † 1	0/257 (0.00%)	1/522 (0.19%)
Ear and labyrinth disorders
Vertigo † 1	0/257 (0.00%)	1/522 (0.19%)
Vertigo positional † 1	0/257 (0.00%)	1/522 (0.19%)
Gastrointestinal disorders
Abdominal pain upper † 1	1/257 (0.39%)	0/522 (0.00%)
Colitis ulcerative † 1	0/257 (0.00%)	1/522 (0.19%)
Dyspepsia † 1	0/257 (0.00%)	1/522 (0.19%)
Gastric antral vascular ectasia † 1	0/257 (0.00%)	1/522 (0.19%)
Gastritis † 1	0/257 (0.00%)	1/522 (0.19%)
Hiatus hernia † 1	1/257 (0.39%)	0/522 (0.00%)
Ileus † 1	0/257 (0.00%)	1/522 (0.19%)
Ileus paralytic † 1	0/257 (0.00%)	1/522 (0.19%)
Inguinal hernia † 1	0/257 (0.00%)	1/522 (0.19%)
Intestinal perforation † 1	0/257 (0.00%)	1/522 (0.19%)
Large intestine perforation † 1	0/257 (0.00%)	1/522 (0.19%)
Oesophageal obstruction † 1	0/257 (0.00%)	1/522 (0.19%)
Oesophagitis † 1	1/257 (0.39%)	0/522 (0.00%)
Peritoneal adhesions † 1	1/257 (0.39%)	0/522 (0.00%)
General disorders
Asthenia † 1	1/257 (0.39%)	0/522 (0.00%)
Chest pain † 1	0/257 (0.00%)	2/522 (0.38%)
Death † 1	0/257 (0.00%)	1/522 (0.19%)
Exercise tolerance decreased † 1	1/257 (0.39%)	0/522 (0.00%)
Non-cardiac chest pain † 1	2/257 (0.78%)	1/522 (0.19%)
Pain † 1	0/257 (0.00%)	1/522 (0.19%)
Vascular stent occlusion † 1	1/257 (0.39%)	1/522 (0.19%)
Hepatobiliary disorders
Cholecystitis acute † 1	0/257 (0.00%)	1/522 (0.19%)
Cholelithiasis † 1	1/257 (0.39%)	2/522 (0.38%)
Hepatic cirrhosis † 1	1/257 (0.39%)	0/522 (0.00%)
Infections and infestations
Cellulitis † 1	1/257 (0.39%)	0/522 (0.00%)
Clostridium difficile infection † 1	0/257 (0.00%)	1/522 (0.19%)
Cystitis † 1	0/257 (0.00%)	1/522 (0.19%)
Diverticulitis † 1	1/257 (0.39%)	1/522 (0.19%)
Fungal infection † 1	1/257 (0.39%)	0/522 (0.00%)
Gastroenteritis † 1	0/257 (0.00%)	1/522 (0.19%)
Lower respiratory tract infection † 1	1/257 (0.39%)	1/522 (0.19%)
Pneumonia † 1	1/257 (0.39%)	2/522 (0.38%)
Pneumonia bacterial † 1	0/257 (0.00%)	1/522 (0.19%)
Septic shock † 1	0/257 (0.00%)	1/522 (0.19%)
Urethral stricture post infection † 1	0/257 (0.00%)	1/522 (0.19%)
Urinary tract infection † 1	0/257 (0.00%)	3/522 (0.57%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence † 1	0/257 (0.00%)	1/522 (0.19%)
Brain contusion † 1	0/257 (0.00%)	1/522 (0.19%)
Contusion † 1	1/257 (0.39%)	0/522 (0.00%)
Coronary artery restenosis † 1	0/257 (0.00%)	1/522 (0.19%)
Femoral neck fracture † 1	1/257 (0.39%)	0/522 (0.00%)
Gas poisoning † 1	0/257 (0.00%)	1/522 (0.19%)
Kidney rupture † 1	0/257 (0.00%)	1/522 (0.19%)
Limb injury † 1	0/257 (0.00%)	1/522 (0.19%)
Meniscus injury † 1	0/257 (0.00%)	1/522 (0.19%)
Postoperative thoracic procedure complication † 1	0/257 (0.00%)	1/522 (0.19%)
Procedural pain † 1	0/257 (0.00%)	1/522 (0.19%)
Tendon rupture † 1	0/257 (0.00%)	3/522 (0.57%)
Vascular pseudoaneurysm † 1	0/257 (0.00%)	1/522 (0.19%)
Investigations
Ejection fraction decreased † 1	1/257 (0.39%)	0/522 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/257 (0.00%)	1/522 (0.19%)
Hyperkalaemia † 1	0/257 (0.00%)	1/522 (0.19%)
Hypokalaemia † 1	1/257 (0.39%)	0/522 (0.00%)
Lactic acidosis † 1	0/257 (0.00%)	1/522 (0.19%)
Musculoskeletal and connective tissue disorders
Back pain † 1	0/257 (0.00%)	2/522 (0.38%)
Intervertebral disc disorder † 1	0/257 (0.00%)	1/522 (0.19%)
Musculoskeletal chest pain † 1	0/257 (0.00%)	1/522 (0.19%)
Osteoarthritis † 1	2/257 (0.78%)	5/522 (0.96%)
Periostitis † 1	0/257 (0.00%)	1/522 (0.19%)
Spinal column stenosis † 1	0/257 (0.00%)	1/522 (0.19%)
Spondylitis † 1	0/257 (0.00%)	1/522 (0.19%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer † 1	1/257 (0.39%)	1/522 (0.19%)
Colon adenoma † 1	0/257 (0.00%)	1/522 (0.19%)
Lymphoma † 1	0/257 (0.00%)	1/522 (0.19%)
Malignant melanoma † 1	1/257 (0.39%)	0/522 (0.00%)
Neuroendocrine tumour of the lung † 1	0/257 (0.00%)	1/522 (0.19%)
Non-small cell lung cancer † 1	1/257 (0.39%)	0/522 (0.00%)
Renal cancer † 1	0/257 (0.00%)	1/522 (0.19%)
Squamous cell carcinoma of skin † 1	0/257 (0.00%)	1/522 (0.19%)
Nervous system disorders
Carotid artery stenosis † 1	0/257 (0.00%)	1/522 (0.19%)
Carpal tunnel syndrome † 1	1/257 (0.39%)	0/522 (0.00%)
Cervical radiculopathy † 1	0/257 (0.00%)	1/522 (0.19%)
Encephalopathy † 1	0/257 (0.00%)	1/522 (0.19%)
Hyporeflexia † 1	0/257 (0.00%)	1/522 (0.19%)
Ischaemic stroke † 1	2/257 (0.78%)	4/522 (0.77%)
Post stroke epilepsy † 1	0/257 (0.00%)	1/522 (0.19%)
Syncope † 1	0/257 (0.00%)	4/522 (0.77%)
Psychiatric disorders
Alcohol withdrawal syndrome † 1	0/257 (0.00%)	1/522 (0.19%)
Depression † 1	1/257 (0.39%)	0/522 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/257 (0.00%)	1/522 (0.19%)
Perinephritis † 1	0/257 (0.00%)	1/522 (0.19%)
Urinary incontinence † 1	0/257 (0.00%)	1/522 (0.19%)
Urinary retention † 1	0/257 (0.00%)	1/522 (0.19%)
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	0/257 (0.00%)	1/522 (0.19%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	0/257 (0.00%)	1/522 (0.19%)
Chronic obstructive pulmonary disease † 1	1/257 (0.39%)	1/522 (0.19%)
Dyspnoea † 1	4/257 (1.56%)	0/522 (0.00%)
Dyspnoea exertional † 1	1/257 (0.39%)	1/522 (0.19%)
Pulmonary embolism † 1	0/257 (0.00%)	1/522 (0.19%)
Skin and subcutaneous tissue disorders
Diabetic foot † 1	1/257 (0.39%)	0/522 (0.00%)
Skin necrosis † 1	0/257 (0.00%)	1/522 (0.19%)
Surgical and medical procedures
Supportive care † 1	0/257 (0.00%)	1/522 (0.19%)
Vascular disorders
Aortic aneurysm † 1	0/257 (0.00%)	1/522 (0.19%)
Deep vein thrombosis † 1	1/257 (0.39%)	0/522 (0.00%)
Iliac artery occlusion † 1	1/257 (0.39%)	0/522 (0.00%)
Peripheral arterial occlusive disease † 1	1/257 (0.39%)	2/522 (0.38%)
Peripheral artery stenosis † 1	0/257 (0.00%)	1/522 (0.19%)
Peripheral ischaemia † 1	0/257 (0.00%)	1/522 (0.19%)
Subclavian artery thrombosis † 1	1/257 (0.39%)	0/522 (0.00%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Placebo	Bempedoic Acid
	Affected / at Risk (%)	Affected / at Risk (%)
Total	88/257 (34.24%)	211/522 (40.42%)
Blood and lymphatic system disorders
Anaemia † 1	3/257 (1.17%)	14/522 (2.68%)
Gastrointestinal disorders
Diarrhoea † 1	7/257 (2.72%)	16/522 (3.07%)
General disorders
Fatigue † 1	9/257 (3.50%)	6/522 (1.15%)
Infections and infestations
Bronchitis † 1	6/257 (2.33%)	7/522 (1.34%)
Lower respiratory tract infection † 1	7/257 (2.72%)	7/522 (1.34%)
Nasopharyngitis † 1	13/257 (5.06%)	27/522 (5.17%)
Upper respiratory tract infection † 1	9/257 (3.50%)	19/522 (3.64%)
Urinary tract infection † 1	5/257 (1.95%)	24/522 (4.60%)
Investigations
Blood uric acid increased † 1	1/257 (0.39%)	14/522 (2.68%)
Metabolism and nutrition disorders
Diabetes mellitus † 1	6/257 (2.33%)	10/522 (1.92%)
Gout † 1	2/257 (0.78%)	11/522 (2.11%)
Hyperuricaemia † 1	5/257 (1.95%)	22/522 (4.21%)
Type 2 diabetes mellitus † 1	7/257 (2.72%)	10/522 (1.92%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	8/257 (3.11%)	18/522 (3.45%)
Muscle spasms † 1	3/257 (1.17%)	11/522 (2.11%)
Myalgia † 1	8/257 (3.11%)	15/522 (2.87%)
Osteoarthritis † 1	3/257 (1.17%)	11/522 (2.11%)
Pain in extremity † 1	1/257 (0.39%)	11/522 (2.11%)
Nervous system disorders
Dizziness † 1	9/257 (3.50%)	8/522 (1.53%)
Headache † 1	7/257 (2.72%)	10/522 (1.92%)
Vascular disorders
Hypertension † 1	6/257 (2.33%)	7/522 (1.34%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

If the Principal Investigator plans to publish information from the study, a copy of the manuscript should be provided to the Sponsor for review before submission for publication or presentation. The Sponsor may request that that publication be withheld.

Results Point of Contact

• Name/Title: Medical Director
• Organization: Esperion Therapeutics, Inc.
• Phone: 1-833-377-7633
• EMail: medinfo@esperion.com

Publications:

Goldberg AC, Leiter LA, Stroes ESG, Baum SJ, Hanselman JC, Bloedon LT, Lalwani ND, Patel PM, Zhao X, Duell PB. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019 Nov 12;322(18):1780-1788. doi: 10.1001/jama.2019.16585. Erratum In: JAMA. 2020 Jan 21;323(3):282.

Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, Birch CM, Smith BK, Filippov S, Groot PHE, Steinberg GR, Lalwani ND. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016 Nov 28;7:13457. doi: 10.1038/ncomms13457.

Cholesterol Treatment Trialists' (CTT) Collaboration; Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5. Epub 2010 Nov 8.

Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun 3.

Robinson JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm. 2013 Mar;19(2):139-49. doi: 10.18553/jmcp.2013.19.2.139.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45. doi: 10.1161/01.cir.0000437738.63853.7a. Epub 2013 Nov 12. No abstract available. Erratum In: Circulation. 2014 Jun 24;129(25 Suppl 2):S46-8. Circulation. 2015 Dec 22;132(25):e396.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ballantyne CM, Bays HE, Louie MJ, Smart J, Zhang Y, Ray KK. Factors Associated With Enhanced Low-Density Lipoprotein Cholesterol Lowering With Bempedoic Acid. J Am Heart Assoc. 2022 Aug 2;11(15):e024531. doi: 10.1161/JAHA.121.024531. Epub 2022 Aug 2.

Banach M, Duell PB, Gotto AM Jr, Laufs U, Leiter LA, Mancini GBJ, Ray KK, Flaim J, Ye Z, Catapano AL. Association of Bempedoic Acid Administration With Atherogenic Lipid Levels in Phase 3 Randomized Clinical Trials of Patients With Hypercholesterolemia. JAMA Cardiol. 2020 Oct 1;5(10):1124-1135. doi: 10.1001/jamacardio.2020.2314.

• Responsible Party: Esperion Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02991118
• Other Study ID Numbers: 1002-047; 2016-003486-26 ( EudraCT Number )
• First Submitted: December 9, 2016
• First Posted: December 13, 2016
• Results First Submitted: March 20, 2020
• Results First Posted: April 27, 2020
• Last Update Posted: April 27, 2020