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

Study Overview
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Brief Summary
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The purpose of this study is to see if ETC-1002 (bempedoic acid) is safe and well-tolerated versus placebo in patients with high cardiovascular risk and elevated LDL cholesterol that is not adequately controlled by their current therapy.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter Long-term Safety and Tolerability Study of ETC-1002 in Patients With Hyperlipidemia at High Cardiovascular Risk Who Are Not Adequately Controlled by Their Lipid-Modifying Therapy

Conditions
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Hypercholesterolemia, Atherosclerotic Cardiovascular Diseases

Intervention / Treatment
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* Drug: ETC-1002
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fasting LDL-C ≥ 70 mg/dL High cardiovascular risk (diagnosis of HeFH or ASCVD) Be on maximally tolerated lipid-modifying therapy Exclusion Criteria: Total fasting triglyceride ≥500 mg/dL Renal dysfunction or nephrotic syndrome or history of nephritis Body Mass Index (BMI) ≥50kg/m2 Significant cardiovascular disease or cardiovascular event in the past 3 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ETC-1002<br>ETC-1002 180 mg/day | Drug: ETC-1002<br>* ETC-1002 180 mg tablets taken orally, once per day. Patients remain on ongoing statin therapy (not study provided)<br>* Other names: bempedoic acid;|
| Placebo Comparator: Placebo<br>Placebo control | Drug: Placebo<br>* Matching placebo tablets taken orally, once per day. Patients remain on ongoing statin therapy (not study provided)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Creatine Kinase Elevations | 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). | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Hypoglycemia | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Metabolic Acidosis | 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). | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus | 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. | Up to approximately 52 weeks | 
| Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder | 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. | Up to approximately 52 weeks | 
| Change From Baseline to Week 52 in Uric Acid (Urate) Level | Blood samples were drawn at defined time points during the course of the study to monitor uric acid (urate) levels. | Baseline and Week 52 | 
| Change From Baseline to Week 52 in Creatinine Level | Blood samples were drawn at defined time points during the course of the study to monitor creatinine levels. | Baseline and Week 52 | 
| Change From Baseline to Week 52 in Hemoglobin Level | Blood samples were drawn at defined time points during the course of the study to monitor hemoglobin levels. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C) | 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. | Baseline; Week 12 | 
| Absolute Change From Baseline to Week 12 in LDL-C | 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. Absolute change from baseline was calculated as: LDL-C value at Week 12 minus Baseline value. Missing data were imputed with the use of a pattern-mixture model to account for adherence to the trial regimen. | Baseline; Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperlipidemia, cholesterol, heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease, ASCVD, HeFH, LDL