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

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ClinicalTrials.gov Identifier: NCT02666664
Recruitment Status : Completed
First Posted : January 28, 2016
Results First Posted : April 20, 2020
Last Update Posted : May 11, 2020
Sponsor:
Information provided by (Responsible Party):
Esperion Therapeutics

Tracking Information
First Submitted Date  ICMJE January 20, 2016
First Posted Date  ICMJE January 28, 2016
Results First Submitted Date  ICMJE March 20, 2020
Results First Posted Date  ICMJE April 20, 2020
Last Update Posted Date May 11, 2020
Actual Study Start Date  ICMJE January 21, 2016
Actual Primary Completion Date February 21, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2020)
  • Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With the Indicated Event of Special Interest: Creatine Kinase Elevations [ Time Frame: Up to approximately 52 weeks ]
    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).
  • Percentage of Participants With the Indicated Event of Special Interest: Hepatic Disorders [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With the Indicated Event of Special Interest: Hypoglycemia [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With the Indicated Event of Special Interest: Metabolic Acidosis [ Time Frame: Up to approximately 52 weeks ]
    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).
  • Percentage of Participants With the Indicated Event of Special Interest: Muscular Disorder [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With the Indicated Event of Special Interest: Neurocognitive Disorder [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With the Indicated Event of Special Interest: New Onset or Worsening Diabetes Mellitus [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Percentage of Participants With the Indicated Event of Special Interest: Renal Disorder [ Time Frame: Up to approximately 52 weeks ]
    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.
  • Change From Baseline to Week 52 in Uric Acid (Urate) Level [ Time Frame: Baseline and Week 52 ]
    Blood samples were drawn at defined time points during the course of the study to monitor uric acid (urate) levels.
  • Change From Baseline to Week 52 in Creatinine Level [ Time Frame: Baseline and Week 52 ]
    Blood samples were drawn at defined time points during the course of the study to monitor creatinine levels.
  • Change From Baseline to Week 52 in Hemoglobin Level [ Time Frame: Baseline and Week 52 ]
    Blood samples were drawn at defined time points during the course of the study to monitor hemoglobin levels.
Original Primary Outcome Measures  ICMJE
 (submitted: January 25, 2016)
Number of participants with treatment-related adverse events as assessed by MedDRA 18.1 [ Time Frame: Baseline through 52 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2020)
  • Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline; Week 12 ]
    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.
  • Absolute Change From Baseline to Week 12 in LDL-C [ Time Frame: Baseline; Week 12 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 25, 2016)
  • Percent change in low-density lipoprotein cholesterol (LDL-C) [ Time Frame: 12, 24, and 52 weeks ]
  • Percent change in high-sensitivity C-reactive protein (hs-CRP) [ Time Frame: 12, 24, and 52 weeks ]
Current Other Pre-specified Outcome Measures
 (submitted: April 8, 2020)
  • Percent Change From Baseline to Week 24 in LDL-C [ Time Frame: Baseline; Week 24 ]
    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.
  • Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) [ Time Frame: Baseline; Week 12 ]
    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.
  • Percent Change From Baseline to Week 12 in Total Cholesterol (TC) [ Time Frame: Baseline; Week 12 ]
    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.
  • Percent Change From Baseline to Week 12 in Apolipoprotein B (apoB) [ Time Frame: Baseline; Week 12 ]
    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.
  • Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) [ Time Frame: Baseline; Week 12 ]
    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.
  • Percent Change From Baseline to Week 52 in LDL-C [ Time Frame: Baseline; Week 52 ]
    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.
  • Percent Change From Baseline to Week 24 in Non-HDL-C [ Time Frame: Baseline; Week 24 ]
    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.
  • Percent Change From Baseline to Week 52 in Non-HDL-C [ Time Frame: Baseline; Week 52 ]
    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.
  • Percent Change From Baseline to Week 24 in TC [ Time Frame: Baseline; Week 24 ]
    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.
  • Percent Change From Baseline to Week 52 in TC [ Time Frame: Baseline; Week 52 ]
    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.
  • Percent Change From Baseline to Week 24 in apoB [ Time Frame: Baseline; Week 24 ]
    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
  • Percent Change From Baseline to Week 52 in apoB [ Time Frame: Baseline; Week 52 ]
    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.
  • Percent Change From Baseline to Week 24 in hsCRP [ Time Frame: Baseline; Week 24 ]
    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.
  • Percent Change From Baseline to Week 52 in hsCRP [ Time Frame: Baseline; Week 52 ]
    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.
  • Percentage of Participants Achieving LDL-C <70 mg/dL at Week 12, 24, and 52 [ Time Frame: Week 12, Week 24, and Week 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.
Original Other Pre-specified Outcome Measures
 (submitted: January 25, 2016)
  • Percent change in non-high-density lipoprotein cholesterol (non-HDL-C) [ Time Frame: 12, 24, and 52 weeks ]
  • Percent change in total cholesterol (TC) [ Time Frame: 12, 24, and 52 weeks ]
  • Percent change in apolipoprotein B (apoB) [ Time Frame: 12, 24, and 52 weeks ]
 
Descriptive Information
Brief Title  ICMJE Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk (CLEAR Harmony)
Official Title  ICMJE 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
Brief 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypercholesterolemia
  • Atherosclerotic Cardiovascular Diseases
Intervention  ICMJE
  • Drug: ETC-1002
    ETC-1002 180 mg tablets taken orally, once per day. Patients remain on ongoing statin therapy (not study provided)
    Other Name: bempedoic acid
  • Drug: Placebo
    Matching placebo tablets taken orally, once per day. Patients remain on ongoing statin therapy (not study provided)
Study Arms  ICMJE
  • Experimental: ETC-1002
    ETC-1002 180 mg/day
    Intervention: Drug: ETC-1002
  • Placebo Comparator: Placebo
    Placebo control
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 23, 2018)
2230
Original Estimated Enrollment  ICMJE
 (submitted: January 25, 2016)
900
Actual Study Completion Date  ICMJE March 28, 2018
Actual Primary Completion Date February 21, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Germany,   Netherlands,   Poland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02666664
Other Study ID Numbers  ICMJE 1002-040
2015-004136-36 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Esperion Therapeutics
Study Sponsor  ICMJE Esperion Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Ron Haberman, MD Esperion Therapeutics
PRS Account Esperion Therapeutics
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP