Trial Outcomes & Findings for Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk (CLEAR Harmony) (NCT NCT02666664)

Last Updated: 2020-05-11

Results Overview

TEAEs, defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2230 participants

Primary outcome timeframe

Up to approximately 52 weeks

Results posted on

2020-05-11

Participant Flow

A total of 2230 participants were randomized 2:1 to either bempedoic acid or placebo. One participant was randomized to bempedoic acid treatment, but never received any dose of investigational medicinal product (IMP) i.e. study drug.

The study consisted of 2 periods: a 2-week screening period and a 52-week double-blind, randomized treatment period.

Participant milestones

Participant milestones
Measure	Placebo During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Overall Study STARTED	742	1488
Overall Study COMPLETED	706	1404
Overall Study NOT COMPLETED	36	84

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Overall Study Physician Decision	0	1
Overall Study Protocol Violation	0	2
Overall Study Other	0	1
Overall Study Adverse Event	12	37
Overall Study Withdrawal by participant	23	40
Overall Study Sponsor decision	0	1
Overall Study Lost to Follow-up	1	2

Baseline Characteristics

Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk (CLEAR Harmony)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1488 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Total n=2230 Participants Total of all reporting groups
Age, Continuous	66.8 years STANDARD_DEVIATION 8.64 • n=5 Participants	65.8 years STANDARD_DEVIATION 9.11 • n=7 Participants	66.1 years STANDARD_DEVIATION 8.96 • n=5 Participants
Sex: Female, Male Female	213 Participants n=5 Participants	389 Participants n=7 Participants	602 Participants n=5 Participants
Sex: Female, Male Male	529 Participants n=5 Participants	1099 Participants n=7 Participants	1628 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=5 Participants	24 Participants n=7 Participants	35 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	731 Participants n=5 Participants	1464 Participants n=7 Participants	2195 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Asian	8 Participants n=5 Participants	14 Participants n=7 Participants	22 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	15 Participants n=5 Participants	42 Participants n=7 Participants	57 Participants n=5 Participants
Race (NIH/OMB) White	716 Participants n=5 Participants	1423 Participants n=7 Participants	2139 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Cardiovascular history: atherosclerotic cardiovascular disease (ASCVD) Yes	727 Participants n=5 Participants	1449 Participants n=7 Participants	2176 Participants n=5 Participants
Cardiovascular history: atherosclerotic cardiovascular disease (ASCVD) No	15 Participants n=5 Participants	39 Participants n=7 Participants	54 Participants n=5 Participants
Cardiovascular history: heterozygous familial hypercholesterolemia (HeFH) Yes	23 Participants n=5 Participants	56 Participants n=7 Participants	79 Participants n=5 Participants
Cardiovascular history: heterozygous familial hypercholesterolemia (HeFH) No	719 Participants n=5 Participants	1432 Participants n=7 Participants	2151 Participants n=5 Participants
History of diabetes Yes	212 Participants n=5 Participants	425 Participants n=7 Participants	637 Participants n=5 Participants
History of diabetes No	530 Participants n=5 Participants	1063 Participants n=7 Participants	1593 Participants n=5 Participants
History of hypertension Yes	594 Participants n=5 Participants	1174 Participants n=7 Participants	1768 Participants n=5 Participants
History of hypertension No	148 Participants n=5 Participants	314 Participants n=7 Participants	462 Participants n=5 Participants
Concomitant lipid-modifying therapy (LMT): Statin Yes	742 Participants n=5 Participants	1485 Participants n=7 Participants	2227 Participants n=5 Participants
Concomitant lipid-modifying therapy (LMT): Statin No	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Concomitant LMT: Ezetimibe Yes	56 Participants n=5 Participants	116 Participants n=7 Participants	172 Participants n=5 Participants
Concomitant LMT: Ezetimibe No	686 Participants n=5 Participants	1372 Participants n=7 Participants	2058 Participants n=5 Participants
Concomitant LMT: Fibrate Yes	26 Participants n=5 Participants	54 Participants n=7 Participants	80 Participants n=5 Participants
Concomitant LMT: Fibrate No	716 Participants n=5 Participants	1434 Participants n=7 Participants	2150 Participants n=5 Participants
Concomitant LMT: None Concomitant LMT: None	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Concomitant LMT: None Concomitant LMT: Yes	742 Participants n=5 Participants	1486 Participants n=7 Participants	2228 Participants n=5 Participants
Baseline statin intensity Low	48 Participants n=5 Participants	100 Participants n=7 Participants	148 Participants n=5 Participants
Baseline statin intensity Moderate	324 Participants n=5 Participants	646 Participants n=7 Participants	970 Participants n=5 Participants
Baseline statin intensity High	370 Participants n=5 Participants	742 Participants n=7 Participants	1112 Participants n=5 Participants
Estimated glomerular filtration rate (eGFR) Normal: ≥ 90 mL/min/1.73m^2	167 Participants n=5 Participants	320 Participants n=7 Participants	487 Participants n=5 Participants
Estimated glomerular filtration rate (eGFR) Mild Renal Impairment: 60-89 mL/min/1.73m^2	468 Participants n=5 Participants	946 Participants n=7 Participants	1414 Participants n=5 Participants
Estimated glomerular filtration rate (eGFR) Moderate Renal Impairment: 30-59 mL/min/1.73m^2	107 Participants n=5 Participants	222 Participants n=7 Participants	329 Participants n=5 Participants
Total cholesterol (TC)	178.64 mg/dL STANDARD_DEVIATION 35.645 • n=5 Participants	179.66 mg/dL STANDARD_DEVIATION 35.143 • n=7 Participants	179.32 mg/dL STANDARD_DEVIATION 35.306 • n=5 Participants
Low-density lipoprotein cholesterol (LDL-C)	102.30 mg/dL STANDARD_DEVIATION 30.048 • n=5 Participants	103.60 mg/dL STANDARD_DEVIATION 29.127 • n=7 Participants	103.16 mg/dL STANDARD_DEVIATION 29.436 • n=5 Participants
High-density lipoprotein cholesterol (HDL-C)	49.29 mg/dL STANDARD_DEVIATION 11.545 • n=5 Participants	48.71 mg/dL STANDARD_DEVIATION 11.853 • n=7 Participants	48.90 mg/dL STANDARD_DEVIATION 11.752 • n=5 Participants
Triglycerides (TG)	122.50 mg/dL n=5 Participants	126.25 mg/dL n=7 Participants	125.00 mg/dL n=5 Participants
Non-high-density lipoprotein cholesterol (non-HDL-C)	129.37 mg/dL STANDARD_DEVIATION 33.855 • n=5 Participants	130.92 mg/dL STANDARD_DEVIATION 33.677 • n=7 Participants	130.41 mg/dL STANDARD_DEVIATION 33.737 • n=5 Participants
Apolipoprotein B (apoB)	86.8 mg/dL STANDARD_DEVIATION 21.82 • n=5 Participants	88.5 mg/dL STANDARD_DEVIATION 21.57 • n=7 Participants	87.9 mg/dL STANDARD_DEVIATION 21.66 • n=5 Participants
High-sensitivity C-reactive protein (hsCRP)	1.51 mg/L n=5 Participants	1.49 mg/L n=7 Participants	1.49 mg/L n=5 Participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population: all randomized participants who received at least 1 dose of investigational medicinal product. Participants were included in the treatment group that they received, regardless of their randomized treatment.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Any TEAE	78.7 percentage of participants	78.5 percentage of participants
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Any serious TEAE	14.0 percentage of participants	14.5 percentage of participants
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Any fatal TEAE	0.3 percentage of participants	0.9 percentage of participants
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Any TEAE leading to discontinuation of study drug	7.1 percentage of participants	10.9 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

TEAEs, defined as AEs that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported. Cardiovascular events were considered as adverse events of special interest. Treatment-emergent = TE.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Any adjudicated major clinical event	5.7 percentage of participants	4.6 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Any TE death from cardiovascular causes	0.1 percentage of participants	0.4 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Any nonfatal myocardial infarction	1.8 percentage of participants	1.3 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Any nonfatal stroke	0.3 percentage of participants	0.3 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Any coronary revascularization	3.2 percentage of participants	2.6 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Any hospitalization for unstable angina	1.5 percentage of participants	0.9 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event TE death from noncardiovascular causes	0.1 percentage of participants	0.1 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Noncoronary arterial revascularization	0.8 percentage of participants	0.3 percentage of participants
Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event Hospitalization for heart failure	0.1 percentage of participants	0.6 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

TEAEs of special interest (AESIs) were predefined and monitored throughout the study. Creatine kinase elevations were assessed using the following preferred term: Blood creatine phosphokinase increased (system organ class: investigations).

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Creatine Kinase Elevations	1.8 percentage of participants	2.4 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population. The percentage of unique participants is reported in the "Overall hepatic disorder AESIs" category; a participant could have been represented in more than one of the individual hepatic disorder AESIs.

Treatment-emergent AESIs were predefined and monitored throughout the study. TEAEs potentially related to hepatic events were assessed using the following preferred terms and laboratory abnormalities: aspartate aminotransferase (AST) increased, Alanine aminotransferase (ALT) increased, Hepatic enzyme increased, Blood bilirubin increased, liver function test (LFT) abnormal, LFT increased, hepatic enzyme abnormal, transaminases increased, potential Hy's Law cases (PHLC) \[AST and (\&)/or ALT \>3 x upper limit of normal (ULN) with concurrent total bilirubin \>2 x ULN\], AST and/or ALT \>3 x ULN, and total bilirubin \>2 x ULN (system organ class: investigations). AST and ALT values were repeated and confirmed. "Repeated and confirmed" was defined as a participant having the last on-study LFT \> x ULN, the last on-treatment LFT \> x ULN, or LFT \> x ULN followed by another LFT \> x ULN.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Overall hepatic disorder AESIs	1.5 percentage of participants	2.5 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders AST increased	0.4 percentage of participants	1.5 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders ALT increased	0.3 percentage of participants	0.8 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Hepatic enzyme increased	0.0 percentage of participants	0.5 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Blood bilirubin increased	0.4 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Liver function test abnormal	0.3 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Liver function test increased	0.1 percentage of participants	0.2 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Hepatic enzyme abnormal	0.0 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Transaminases increased	0.1 percentage of participants	0.0 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders PHLC [AST &/or ALT>3 x ULN, concurrent TB>2 x ULN]	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders AST and/or ALT >3 x ULN	0.1 percentage of participants	0.5 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders Total bilirubin >2 x ULN	0.0 percentage of participants	0.0 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

Treatment-emergent AESIs were predefined and monitored throughout the study. Hypoglycemia was assessed using the following preferred terms: hypoglycaemia (system organ class: metabolism and nutrition disorders); blood glucose abnormal and blood glucose decreased (system organ class: investigations). The percentage of unique participants is reported in the "Overall hypoglycemia AESIs" category; a participant could have been represented in more than one of the individual hypoglycemia AESIs.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Hypoglycemia Overall hypoglycemia AESIs	3.1 percentage of participants	2.2 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hypoglycemia Hypoglycaemia	3.0 percentage of participants	2.2 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hypoglycemia Blood glucose abnormal	0.1 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Hypoglycemia Blood glucose decreased	0.0 percentage of participants	0.1 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

Treatment-emergent AESIs were predefined and monitored throughout the study. Metabolic acidosis was assessed using the preferred term metabolic acidosis (system organ class: metabolism and nutrition disorders).

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Metabolic Acidosis	0.0 percentage of participants	0.1 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

Treatment-emergent AESIs were predefined and monitored throughout the study. Muscular safety was assessed using the following preferred terms and laboratory abnormalities: myalgia, muscle spasms, pain in extremity, muscular weakness (system organ class: musculoskeletal and connective tissue disorders), and creatine kinase \>5 ULN (repeated and confirmed). The percentage of unique participants is reported in the "Overall muscular disorder AESIs" category; a participant could have been represented in more than one of the individual muscular disorder AESIs.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder Overall muscular disorder AESIs	10.1 percentage of participants	13.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder Myalgia	6.1 percentage of participants	6.0 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder Muscle spasms	2.7 percentage of participants	4.2 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder Pain in extremity	2.2 percentage of participants	3.4 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder Muscular weakness	0.5 percentage of participants	0.6 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder Creatine kinase >5 ULN	0.1 percentage of participants	0.5 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

Treatment-emergent AESIs were predefined and monitored throughout the study. Neurocognitive disorder was assessed using the following preferred terms: memory impairment, amnesia, and cognitive disorder (system organ class: nervous system disorders); confusional state and disorientation (system organ class: psychiatric disorders). The percentage of unique participants is reported in the "Overall neurocognitive disorder AESIs" category; a participant could have been represented in more than one of the individual neurocognitive disorder AESIs.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder Cognitive disorder	0.0 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder Overall neurocognitive disorder AESIs	0.9 percentage of participants	0.7 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder Memory impairment	0.5 percentage of participants	0.3 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder Amnesia	0.4 percentage of participants	0.2 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder Confusional state	0.0 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder Disorientation	0.0 percentage of participants	0.1 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

Treatment-emergent AESIs were predefined and monitored throughout the study. New onset or worsening diabetes was assessed using the following preferred terms: type 2 diabetes mellitus, diabetes mellitus, hyperglycaemia, glucose tolerance impaired, diabetes mellitus inadequate control, and impaired fasting glucose (system organ class: metabolism and nutrition disorders); blood glucose increased, glycosylated haemoglobin increased, blood glucose abnormal, and glucose urine present (system organ class: investigations); and glycosuria (system organ class: renal and urinary disorders). The percentage of unique participants is reported in the "Overall new onset/worsening diabetes mellitus AESIs" category; a participant could have been represented in more than one of the individual new onset/worsening diabetes mellitus AESIs.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Overall new onset/worsening diabetes mellitus AESI	5.4 percentage of participants	3.3 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Type 2 diabetes mellitus	0.9 percentage of participants	1.0 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Diabetes mellitus	0.9 percentage of participants	0.4 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Hyperglycaemia	0.7 percentage of participants	0.5 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Glucose tolerance impaired	0.1 percentage of participants	0.4 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Diabetes mellitus inadequate control	0.4 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Impaired fasting glucose	0.3 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Blood glucose increased	1.2 percentage of participants	0.7 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Glycosylated haemoglobin increased	0.5 percentage of participants	0.0 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Blood glucose abnormal	0.1 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Glucose urine present	0.1 percentage of participants	0.0 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus Glycosuria	0.3 percentage of participants	0.1 percentage of participants

PRIMARY outcome

Timeframe: Up to approximately 52 weeks

Population: Safety Population

Treatment-emergent AESIs were predefined and monitored throughout the study. TEAEs potentially related to renal events were assessed using the following preferred terms: renal failure, renal impairment, acute kidney injury (system organ class: renal and urinary disorders); blood creatinine increased, glomerular filtration rate decreased, blood urea increased, estimated glomerular filtration rate (eGFR) \<30 milliliter per minute per 1.73 square meter (ml/min/1.73m\^2), and change from baseline in creatinine \>1 mg/dL (system organ class: investigations); and gout (system organ class: metabolism and nutrition disorders). The percentage of unique participants is reported in the "Overall renal disorder AESIs" category; a participant could have been represented in more than one of the individual renal disorder AESIs.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Renal failure	0.1 percentage of participants	0.9 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Renal impairment	0.1 percentage of participants	0.4 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Acute kidney injury	0.3 percentage of participants	0.3 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Blood creatinine increased	0.4 percentage of participants	0.8 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Glomerular filtration rate decreased	0.0 percentage of participants	0.5 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Blood urea increased	0.1 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Gout	0.3 percentage of participants	1.2 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder Change from baseline in creatinine >1 mg/dL	0.0 percentage of participants	0.1 percentage of participants
Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder eGFR <30 mL/min/1.73 m^2	0.4 percentage of participants	0.9 percentage of participants

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: Safety Population. Only participants with available data were analyzed.

Blood samples were drawn at defined time points during the course of the study to monitor uric acid (urate) levels.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Change From Baseline to Week 52 in Uric Acid (Urate) Level Baseline	5.96 milligrams per deciliter (mg/dL) Standard Deviation 1.35	6.06 milligrams per deciliter (mg/dL) Standard Deviation 1.37
Change From Baseline to Week 52 in Uric Acid (Urate) Level Change from Baseline at Week 52	-0.06 milligrams per deciliter (mg/dL) Standard Deviation 0.87	0.73 milligrams per deciliter (mg/dL) Standard Deviation 1.11

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: Safety Population. Only participants with available data were analyzed.

Blood samples were drawn at defined time points during the course of the study to monitor creatinine levels.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Change From Baseline to Week 52 in Creatinine Level Baseline	0.96 mg/dL Standard Deviation 0.22	0.97 mg/dL Standard Deviation 0.22
Change From Baseline to Week 52 in Creatinine Level Change from Baseline at Week 52	-0.02 mg/dL Standard Deviation 0.12	0.02 mg/dL Standard Deviation 0.13

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: Safety Population. Only participants with available data were analyzed.

Blood samples were drawn at defined time points during the course of the study to monitor hemoglobin levels.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1487 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Change From Baseline to Week 52 in Hemoglobin Level Baseline	14.07 grams per deciliter (g/dL) Standard Deviation 1.26	14.22 grams per deciliter (g/dL) Standard Deviation 1.26
Change From Baseline to Week 52 in Hemoglobin Level Change from Baseline at Week 52	-0.23 grams per deciliter (g/dL) Standard Deviation 0.85	-0.58 grams per deciliter (g/dL) Standard Deviation 0.88

SECONDARY outcome

Timeframe: Baseline; Week 12

Population: Full Analysis Set: all randomized participants

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(LDL-C value at Week 12 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Missing data were imputed with the use of a pattern-mixture model to account for adherence to the trial regimen. Least Square mean= LS mean. Percent change was analyzed using the analysis of covariance (ANCOVA) method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1488 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C)	1.6 percent change Standard Error 0.86	-16.5 percent change Standard Error 0.52

SECONDARY outcome

Timeframe: Baseline; Week 12

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

Outcome measures

Outcome measures
Measure	Placebo n=725 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1424 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Absolute Change From Baseline to Week 12 in LDL-C	0.43 mg/dL Standard Deviation 27.04	-19.23 mg/dL Standard Deviation 24.01

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 24

Population: Full Analysis Set

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(LDL-C value at Week 24 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Missing data were imputed with the use of a pattern-mixture model to account for adherence to the trial regimen. Percent change was analyzed using the ANCOVA method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1488 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 24 in LDL-C	1.2 percent change Standard Error 0.88	-14.9 percent change Standard Error 0.60

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 12

Population: Full Analysis Set

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(non-HDL-C value at Week 12 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Missing data were imputed with the use of a pattern-mixture model to account for adherence to the trial regimen. Percent change was analyzed using the ANCOVA method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1488 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C)	1.5 percent change Standard Error 0.76	-11.9 percent change Standard Error 0.48

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 12

Population: Full Analysis Set

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(TC value at Week 12 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Missing data were imputed with the use of a pattern-mixture model to account for adherence to the trial regimen. Percent change was analyzed using the ANCOVA method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1488 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 12 in Total Cholesterol (TC)	0.8 percent change Standard Error 0.57	-10.3 percent change Standard Error 0.37

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 12

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

Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for apoB. Baseline was defined as the last value prior to first dose of study drug. Percent change from baseline was calculated as: \[(apoB value at Week 12 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Missing data were imputed with the use of a pattern-mixture model to account for adherence to the trial regimen. Percent change was analyzed using the ANCOVA method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=736 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1485 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 12 in Apolipoprotein B (apoB)	3.3 percent change Standard Error 0.70	-8.6 percent change Standard Error 0.47

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 12

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

Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for hsCRP. Baseline was defined as the last value prior to first dose of study drug. Percent change from baseline was calculated as: \[(hsCRP value at Week 12 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed. Percent change was analyzed using the ANCOVA method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=724 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1421 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP)	2.6 percent change Standard Error 91.9	-22.4 percent change Standard Error 72.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 52

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

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(LDL-C value at Week 52 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed. Percent change was analyzed using the ANCOVA method, which included treatment, randomization stratum as factors, and baseline value as covariate.

Outcome measures

Outcome measures
Measure	Placebo n=685 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1364 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 52 in LDL-C	1.0 percent change Standard Error 0.92	-12.6 percent change Standard Error 0.66

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 24

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

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(non-HDL-C value at Week 24 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=707 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1396 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 24 in Non-HDL-C	1.61 percent change Standard Deviation 20.91	-11.69 percent change Standard Deviation 19.80

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 52

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

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(non-HDL-C value at Week 52 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=685 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1364 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 52 in Non-HDL-C	0.65 percent change Standard Deviation 21.438	-10.07 percent change Standard Deviation 22.097

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 24

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

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(TC value at Week 24 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=708 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1396 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 24 in TC	1.15 percent change Standard Deviation 15.349	-9.86 percent change Standard Deviation 15.358

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 52

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

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 values at screening (Week -2) and predose Day 1/Week 0. Percent change from baseline was calculated as: \[(TC value at Week 52 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=685 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1365 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 52 in TC	0.38 percent change Standard Deviation 16.180	-8.92 percent change Standard Deviation 16.945

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 24

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

Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for apoB. Baseline was defined as the last value prior to first dose of study drug. Percent change from baseline was calculated as: \[(apoB value at Week 24 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed

Outcome measures

Outcome measures
Measure	Placebo n=699 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1381 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 24 in apoB	4.8 percent change Standard Deviation 20.41	-7.1 percent change Standard Deviation 20.01

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 52

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

Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for apoB. Baseline was defined as the last value prior to first dose of study drug. Percent change from baseline was calculated as: \[(apoB value at Week 52 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=676 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1342 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 52 in apoB	3.4 percent change Standard Deviation 20.24	-6.0 percent change Standard Deviation 22.54

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 24

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

Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for hsCRP. Baseline was defined as the last value prior to first dose of study drug. Percent change from baseline was calculated as: \[(hsCRP value at Week 24 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=706 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1392 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 24 in hsCRP	2.727 percent change Interval -33.028 to 59.016	-16.382 percent change Interval -51.329 to 34.436

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline; Week 52

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

Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for hsCRP. Baseline was defined as the last value prior to first dose of study drug. Percent change from baseline was calculated as: \[(hsCRP value at Week 52 minus Baseline value) divided by (Baseline Value)\] multiplied by 100. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=681 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1358 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percent Change From Baseline to Week 52 in hsCRP	1.818 percent change Interval -36.508 to 60.952	-14.445 percent change Interval -50.0 to 43.889

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12, Week 24, and Week 52

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

The percentage of participants who achieved lowering in lipid values of LDL-C below 70 mg/dL have been reported. Baseline was defined as the mean of the values at screening (Week -2) and predose Day 1/Week 0. Observed data was used for the analysis, no imputation for the missing data was performed.

Outcome measures

Outcome measures
Measure	Placebo n=742 Participants During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Bempedoic Acid n=1488 Participants During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Percentage of Participants Achieving LDL-C <70 mg/dL at Week 12, 24, and 52 Week 52	9.5 Percentage of participants	28.2 Percentage of participants
Percentage of Participants Achieving LDL-C <70 mg/dL at Week 12, 24, and 52 Week 12	9.0 Percentage of participants	32.4 Percentage of participants
Percentage of Participants Achieving LDL-C <70 mg/dL at Week 12, 24, and 52 Week 24	10.2 Percentage of participants	32.0 Percentage of participants

Adverse Events

Bempedoic Acid

Serious events: 216 serious events

Other events: 792 other events

Deaths: 13 deaths

Placebo

Serious events: 104 serious events

Other events: 381 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director

Esperion Therapeutics, Inc.

Phone: 1-833-377-7633

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Bempedoic Acid n=1487 participants at risk During the double-blind treatment period, participants received bempedoic acid 180 mg tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.	Placebo n=742 participants at risk During the double-blind treatment period, participants received placebo tablet, once daily by mouth for 52 weeks. In addition, participants received stable background lipid-modifying therapy(ies) including a maximally tolerated statin throughout the study.
Blood and lymphatic system disorders Anaemia	2.8% 41/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.0% 15/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Cardiac disorders Angina pectoris	1.6% 24/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.6% 19/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Gastrointestinal disorders Nausea	2.9% 43/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.6% 19/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Gastrointestinal disorders Constipation	1.7% 26/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.4% 18/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Gastrointestinal disorders Diarrhoea	4.0% 60/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	4.0% 30/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Infections and infestations Bronchitis	3.5% 52/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.6% 19/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Infections and infestations Lower respiratory tract infection	2.8% 41/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.6% 19/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
General disorders Fatigue	2.6% 38/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	3.4% 25/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Infections and infestations Sinusitis	1.7% 26/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.4% 18/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Infections and infestations Nasopharyngitis	9.8% 146/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	11.7% 87/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Infections and infestations Urinary tract infection	4.7% 70/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	6.3% 47/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Infections and infestations Upper respiratory tract infection	4.8% 72/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	4.2% 31/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Investigations Blood creatine phosphokinase increased	2.4% 35/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	1.8% 13/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Metabolism and nutrition disorders Hypoglycaemia	2.2% 32/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	3.0% 22/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Arthralgia	4.3% 64/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	5.9% 44/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Back pain	3.7% 55/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.4% 18/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Muscle spasms	4.2% 62/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.7% 20/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Osteoarthritis	2.0% 30/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	3.1% 23/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Myalgia	6.0% 89/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	6.1% 45/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.7% 40/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.6% 19/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Nervous system disorders Dizziness	4.4% 65/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	4.2% 31/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Musculoskeletal and connective tissue disorders Pain in extremity	3.4% 50/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.2% 16/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Respiratory, thoracic and mediastinal disorders Cough	3.2% 47/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	3.1% 23/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Nervous system disorders Headache	3.0% 45/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	3.2% 24/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.3% 19/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	2.2% 16/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.
Vascular disorders Hypertension	2.8% 42/1487 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.	3.5% 26/742 • Up to approximately 52 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began or worsened in severity after the first dose of double-blind study drug and up to 30 days after receiving the last dose of double-blind study drug, were collected and reported.