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

Hypercholesterolemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02666664
• Other study ID #: 1002-040
• Secondary ID: 2015-004136-36
• Status: Completed
• Phase: Phase 3
• Start date: January 21, 2016
• Est. completion date: March 28, 2018

Study information

• Verified date: April 2020
• Source: Esperion Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2230
• Est. completion date: March 28, 2018
• Est. primary completion date: February 21, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atherosclerosis
• Atherosclerotic Cardiovascular Diseases
• Cardiovascular Diseases
• Hypercholesterolemia
• Hyperlipidemias
• Hyperlipoproteinemias

Intervention

Drug:
• ETC-1002
ETC-1002 180 mg tablets taken orally, once per day. Patients remain on ongoing statin therapy (not study provided)
• Placebo
Matching placebo tablets taken orally, once per day. Patients remain on ongoing statin therapy (not study provided)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Esperion Therapeutics

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Netherlands,  Poland,  United Kingdom, 

References & Publications (6)

Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S1-8. doi: 10.1016/j.jacl.2011.04.003. Epub 2011 Apr 12. — View Citation

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. — View Citation

Pollex RL, Joy TR, Hegele RA. Emerging antidyslipidemic drugs. Expert Opin Emerg Drugs. 2008 Jun;13(2):363-81. doi: 10.1517/14728214.13.2.363 . Review. — View Citation

Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM; CLEAR Harmony Trial. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917. — View Citation

Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W; Atherosclerosis Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001 Sep 4;104(10):1108-13. — View Citation

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. Erratum in: Circulation. 2014 Jun 24;129(25 Suppl 2):S46-8. Erratum in: Circulation. 2015 Dec 22;132(25):e396. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent Change From Baseline to Week 24 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. 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.	Baseline; Week 24
Other	Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C)	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.	Baseline; Week 12
Other	Percent Change From Baseline to Week 12 in Total Cholesterol (TC)	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.	Baseline; Week 12
Other	Percent Change From Baseline to Week 12 in Apolipoprotein B (apoB)	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.	Baseline; Week 12
Other	Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP)	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.	Baseline; Week 12
Other	Percent Change From Baseline to Week 52 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. 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.	Baseline; Week 52
Other	Percent Change From Baseline to Week 24 in Non-HDL-C	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.	Baseline; Week 24
Other	Percent Change From Baseline to Week 52 in Non-HDL-C	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.	Baseline; Week 52
Other	Percent Change From Baseline to Week 24 in TC	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.	Baseline; Week 24
Other	Percent Change From Baseline to Week 52 in TC	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.	Baseline; Week 52
Other	Percent Change From Baseline to Week 24 in apoB	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	Baseline; Week 24
Other	Percent Change From Baseline to Week 52 in apoB	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.	Baseline; Week 52
Other	Percent Change From Baseline to Week 24 in hsCRP	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.	Baseline; Week 24
Other	Percent Change From Baseline to Week 52 in hsCRP	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.	Baseline; Week 52
Other	Percentage of Participants Achieving LDL-C <70 mg/dL at Week 12, 24, and 52	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.	Week 12, Week 24, and Week 52
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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

External Links

•   Familial Hypercholesterolemia Foundation
•   National Organization for Rare Disorders - Familial Hypercholesterolemia
•   World Health Organization Fact Sheet No. 317