Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to assess the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy and safety of ETC-1002(bempedoic acid) 60 mg, 120 mg and 180 mg versus placebo added to ongoing stable statin therapy or other lipid-modifying therapies in Japanese patients with hypercholesterolemia treated for 12 weeks.
Interventions
180mg, tablet, once daily, for 12 weeks
DRUG120mg of ETC-1002(bempedoic acid)
120mg, tablet, once daily, for 12 weeks
DRUG60mg of ETC-1002(bempedoic acid)
60mg, tablet, once daily, for 12 weeks
DRUGPlacebo
placebo, tablet, once daily, for 12 weeks
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Patients who have obtained informed consent to all of the observation/examination/evaluation items specified in the protocol * Patients must be on stable statin therapy defined as atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, or fluvastatin daily\[and other lipid-modifying therapies(LMTs) if needed\] at least 4 weeks(6 weeks for fibrates) prior to screening and above LDL-C control target. Or Patients for statin intolerant must be on stable LMT(s) at least 4 weeks prior to screening and above LDL-C control target. Statin intolerance defined as an inability to tolerate 1 or more statins due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued or decreased. Patients on the lowest or under the dosage of the approved dose of statin or unable to tolerate any statin at any dose were eligible. Patients could continue taking the lowest or under the dosage of the approved dose of statin therapy or taking other LMTs throughout the study provided that it was stable and well tolerated. * Fasting mean TG level \< 400 mg/dL from measurements at screening * Other protocol specific inclusion criteria may apply
Exclusion criteria
* Women who are pregnant or breastfeeding or who have a positive pregnancy test (urine) result at screening or baseline visits * Sexually active male subjects or sexually active female subjects of childbearing potential who do not agree to practice 2 different methods of birth control or to remain abstinent during the trial and for 30 days after final IMP administration test (urine) result at screening or baseline visits * Patients with homozygous familial hypercholesterolemia (HoFH) * Patients with a history or current symptoms of any of the following clinically significant cardiovascular diseases within 3 months prior to screening or before baseline visit * Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, coronary artery bypass graft, stroke, transient ischemic attack, symptomatic carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated heart failure * Abdominal aortic aneurysm * Unexplained syncope or long-QT syndrome, family history of long-QT syndrome, or risk factors for Torsade de Pointes, such as persistent hypokalemia or second- or third-degree atrioventricular block (except when controlled by medication, etc) * Uncontrolled hypertension, defined as follows: * Sitting systolic blood pressure after resting 5 minutes of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg at screening * Patients with uncontrolled and serious hematologic or coagulation disorders or with Hgb of \<10.0 g/dL at screening * Patients with type 1 diabetes or uncontrolled type 2 diabetes with hemoglobin A1c (HbA1c) of ≥9% at screening * Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone (TSH) of \>1.5 × ULN at screening * Patients with liver disease or dysfunction, including: * Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies at screening * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of ≥3 × ULN and/or total bilirubin of ≥2 × ULN * Patients with creatine kinase (CK) elevation( \>3 × ULN) at screening * Patients with renal dysfunction or nephritic syndrome or a history of nephritis and with estimated glomerular filtration rate (eGFR) of ≤30 mL/min/1.73m2 at screening * Other protocol specific inclusion criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in LDL-C From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. Baseline was defined as the mean of the values from Week -1 and Day 1. When LDL-C at Week 12 was missing, the missing value was imputed using the last observation carried forward from the start of the IMP administration to 2 days after the final IMP administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in HDL Cholesterol From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Percent Change in Non-HDL Cholesterol From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Percent Change in Total Cholesterol From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Percent Change in Triglycerides From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Percent Change in Apolipoprotein B From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Percent Change in High Sensitivity C Reactive Protein From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Percent Change in Hemoglobin A1c From Baseline to Week 12 | Baseline, week12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. |
| Proportion of Subjects Whose LDL-C Value Achieved the Lipid Management Goals Based on Risk Assessment at Week 12 | Baseline, week12 | The proportion of subjects whose LDL-C value achieves the lipid management goal at Week 12. |
| Proportion of Subjects Whose LDL-C Value Achieve < 70 mg/dL at Week 12 | Baseline, week12 | The proportion of subjects whose LDL-C value achieves \<70 mg/dL at Week 12. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ETC-1002 60 mg ETC-1002 60 mg tablet once daily for 12 weeks. | 45 |
| ETC-1002 120 mg ETC-1002 120 mg tablet once daily for 12 weeks. | 46 |
| ETC-1002 180 mg ETC-1002 180 mg tablet once daily for 12 weeks. | 48 |
| Placebo Placebo tablet once daily for 12 weeks. | 47 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 | 1 |
| Overall Study | Non-compliance with study drug | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | ETC-1002 60 mg | ETC-1002 120 mg | ETC-1002 180 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 19 Participants | 25 Participants | 27 Participants | 88 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 27 Participants | 23 Participants | 20 Participants | 98 Participants |
| Age, Continuous | 60.9 years STANDARD_DEVIATION 9.26 | 60.4 years STANDARD_DEVIATION 8.94 | 60.4 years STANDARD_DEVIATION 11.98 | 63.0 years STANDARD_DEVIATION 10.65 | 61.2 years STANDARD_DEVIATION 10.28 |
| Race/Ethnicity, Customized Asian | 45 Participants | 46 Participants | 48 Participants | 47 Participants | 186 Participants |
| Region of Enrollment Japan | 45 participants | 46 participants | 48 participants | 47 participants | 186 participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 16 Participants | 12 Participants | 60 Participants |
| Sex: Female, Male Male | 29 Participants | 30 Participants | 32 Participants | 35 Participants | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 46 | 0 / 47 | 0 / 48 |
| other Total, other adverse events | 23 / 47 | 17 / 46 | 21 / 48 | 9 / 47 |
| serious Total, serious adverse events | 0 / 47 | 0 / 46 | 1 / 47 | 1 / 48 |
Outcome results
Primary
Percent Change in LDL-C From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. Baseline was defined as the mean of the values from Week -1 and Day 1. When LDL-C at Week 12 was missing, the missing value was imputed using the last observation carried forward from the start of the IMP administration to 2 days after the final IMP administration.
Time frame: Baseline, week12
Population: The FAS included all subjects who receive at least one dose of IMP during the treatment period and for whom LDL-C values at baseline and at least one post-dose (up to 2 days after final IMP administration) are observed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in LDL-C From Baseline to Week 12 | -10.59 Percent Change | Standard Error 2.153 |
| ETC-1002 120 mg | Percent Change in LDL-C From Baseline to Week 12 | -21.85 Percent Change | Standard Error 2.156 |
| ETC-1002 180 mg | Percent Change in LDL-C From Baseline to Week 12 | -21.26 Percent Change | Standard Error 2.095 |
| Placebo | Percent Change in LDL-C From Baseline to Week 12 | -1.92 Percent Change | Standard Error 2.117 |
p-value: <0.00195% CI: [-24.81, -13.88]ANCOVA
p-value: <0.00195% CI: [-25.45, -14.41]ANCOVA
p-value: 0.00295% CI: [-14.22, -3.12]ANCOVA
Secondary
Percent Change in Apolipoprotein B From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in Apolipoprotein B From Baseline to Week 12 | -8.18 Percent Change | Standard Error 1.715 |
| ETC-1002 120 mg | Percent Change in Apolipoprotein B From Baseline to Week 12 | -14.59 Percent Change | Standard Error 1.709 |
| ETC-1002 180 mg | Percent Change in Apolipoprotein B From Baseline to Week 12 | -12.47 Percent Change | Standard Error 1.704 |
| Placebo | Percent Change in Apolipoprotein B From Baseline to Week 12 | -2.13 Percent Change | Standard Error 1.704 |
Secondary
Percent Change in HDL Cholesterol From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in HDL Cholesterol From Baseline to Week 12 | 0.16 Percent Change | Standard Error 2.208 |
| ETC-1002 120 mg | Percent Change in HDL Cholesterol From Baseline to Week 12 | -0.65 Percent Change | Standard Error 2.19 |
| ETC-1002 180 mg | Percent Change in HDL Cholesterol From Baseline to Week 12 | -7.29 Percent Change | Standard Error 2.139 |
| Placebo | Percent Change in HDL Cholesterol From Baseline to Week 12 | 3.08 Percent Change | Standard Error 2.155 |
Secondary
Percent Change in Hemoglobin A1c From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in Hemoglobin A1c From Baseline to Week 12 | 0.11 Percent Change | Standard Error 0.591 |
| ETC-1002 120 mg | Percent Change in Hemoglobin A1c From Baseline to Week 12 | -0.40 Percent Change | Standard Error 0.596 |
| ETC-1002 180 mg | Percent Change in Hemoglobin A1c From Baseline to Week 12 | -0.21 Percent Change | Standard Error 0.592 |
| Placebo | Percent Change in Hemoglobin A1c From Baseline to Week 12 | -0.05 Percent Change | Standard Error 0.578 |
Secondary
Percent Change in High Sensitivity C Reactive Protein From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in High Sensitivity C Reactive Protein From Baseline to Week 12 | 150.54 Percent Change | Standard Error 62.494 |
| ETC-1002 120 mg | Percent Change in High Sensitivity C Reactive Protein From Baseline to Week 12 | 1.02 Percent Change | Standard Error 62.418 |
| ETC-1002 180 mg | Percent Change in High Sensitivity C Reactive Protein From Baseline to Week 12 | -34.58 Percent Change | Standard Error 62.745 |
| Placebo | Percent Change in High Sensitivity C Reactive Protein From Baseline to Week 12 | 0.98 Percent Change | Standard Error 61.513 |
Secondary
Percent Change in Non-HDL Cholesterol From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in Non-HDL Cholesterol From Baseline to Week 12 | -8.86 Percent Change | Standard Error 2.019 |
| ETC-1002 120 mg | Percent Change in Non-HDL Cholesterol From Baseline to Week 12 | -18.29 Percent Change | Standard Error 2.021 |
| ETC-1002 180 mg | Percent Change in Non-HDL Cholesterol From Baseline to Week 12 | -16.01 Percent Change | Standard Error 1.956 |
| Placebo | Percent Change in Non-HDL Cholesterol From Baseline to Week 12 | -1.62 Percent Change | Standard Error 1.988 |
Secondary
Percent Change in Total Cholesterol From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in Total Cholesterol From Baseline to Week 12 | -6.42 Percent Change | Standard Error 1.665 |
| ETC-1002 120 mg | Percent Change in Total Cholesterol From Baseline to Week 12 | -13.61 Percent Change | Standard Error 1.65 |
| ETC-1002 180 mg | Percent Change in Total Cholesterol From Baseline to Week 12 | -13.56 Percent Change | Standard Error 1.599 |
| Placebo | Percent Change in Total Cholesterol From Baseline to Week 12 | -0.55 Percent Change | Standard Error 1.621 |
Secondary
Percent Change in Triglycerides From Baseline to Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100.
Time frame: Baseline, week12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETC-1002 60 mg | Percent Change in Triglycerides From Baseline to Week 12 | -9.09 Percent Change | Standard Error 6.286 |
| ETC-1002 120 mg | Percent Change in Triglycerides From Baseline to Week 12 | -5.62 Percent Change | Standard Error 6.29 |
| ETC-1002 180 mg | Percent Change in Triglycerides From Baseline to Week 12 | 9.17 Percent Change | Standard Error 6.151 |
| Placebo | Percent Change in Triglycerides From Baseline to Week 12 | -0.08 Percent Change | Standard Error 6.219 |
Secondary
Proportion of Subjects Whose LDL-C Value Achieve < 70 mg/dL at Week 12
The proportion of subjects whose LDL-C value achieves \<70 mg/dL at Week 12.
Time frame: Baseline, week12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ETC-1002 60 mg | Proportion of Subjects Whose LDL-C Value Achieve < 70 mg/dL at Week 12 | 0 Participants |
| ETC-1002 120 mg | Proportion of Subjects Whose LDL-C Value Achieve < 70 mg/dL at Week 12 | 1 Participants |
| ETC-1002 180 mg | Proportion of Subjects Whose LDL-C Value Achieve < 70 mg/dL at Week 12 | 0 Participants |
| Placebo | Proportion of Subjects Whose LDL-C Value Achieve < 70 mg/dL at Week 12 | 0 Participants |
Secondary
Proportion of Subjects Whose LDL-C Value Achieved the Lipid Management Goals Based on Risk Assessment at Week 12
The proportion of subjects whose LDL-C value achieves the lipid management goal at Week 12.
Time frame: Baseline, week12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ETC-1002 60 mg | Proportion of Subjects Whose LDL-C Value Achieved the Lipid Management Goals Based on Risk Assessment at Week 12 | 15 participants |
| ETC-1002 120 mg | Proportion of Subjects Whose LDL-C Value Achieved the Lipid Management Goals Based on Risk Assessment at Week 12 | 26 participants |
| ETC-1002 180 mg | Proportion of Subjects Whose LDL-C Value Achieved the Lipid Management Goals Based on Risk Assessment at Week 12 | 28 participants |
| Placebo | Proportion of Subjects Whose LDL-C Value Achieved the Lipid Management Goals Based on Risk Assessment at Week 12 | 1 participants |