Cholesterolemia, Diabetes, Diabetes Mellitus, Type 2
Conditions
Keywords
diabetes, cholesterolemia, type 2 diabetes, LDL-C, T2D, diabetes mellitus
Brief summary
12 week study to assess the LDL-C lowering efficacy, other lipid and glycemic measures, and safety of bempedoic acid/ezetimibe FDC compared to ezetimibe and placebo in patients with type 2 diabetes (T2D) and elevated LDL-C
Detailed description
Assess efficacy of FDC vs. ezetimibe vs. placebo for 12 week LDL-C lowering, changes in atherogenic lipids, hsCRP and exploratory glycemic measures as well as safety in patients with type 2 diabetes and elevated LDL-C.
Interventions
DRUGBempedoic acid + Ezetimibe FDC Oral Tablet
Experimental therapy of bempedoic acid 180 mg + ezetimibe 10 mg FDC tablet
DRUGEzetimibe 10 mg Oral Tablet
Ezetimibe 10 mg tablet, overencapsulated for blinding purposes
DRUGPlacebo Oral Tablet
Placebo tablet, matched for the FDC product for blinding purposes
DRUGPlacebo oral capsule
Placebo over-encapsulated for blinding purposes
Sponsors
Esperion Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes for 6 months or greater * Currently taking stable diabetes medication for 3 months or greater * HbA1c between 7-10% * LDL-cholesterol greater than 70 mg/dL * Women must not be pregnant, lactating, or planning to become pregnant within 30 days after last dose of study medication; and must be postmenopausal, surgically sterile, or willing to use 1 acceptable form of birth control during the study through 30 days after the last dose of study medication
Exclusion criteria
* Body mass index \> 40 kg/m2 * History of documented clinically significant cardiovascular disease * Fasting triglycerides \> 400 mg/dL * History of Type 1 diabetes * Uncontrolled hypothyroidism, liver dysfunction, renal dysfunction, gastrointestinal condition that may affect drug absorption, hematologic or coagulation disorder or active malignancy * History of drug or alcohol abuse within 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 12/End of Study (EOS) in Low-density Lipoprotein Cholesterol (LDL-C) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the average of LDL-C values at the Screening Visit 3 (Visit S3) and the Treatment Visit 1 (Visit T1) (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for LDL-C was analyzed using analysis of covariance (ANCOVA), with treatment as factor and Baseline lipid parameter as a covariate. Missing data for LDL-C was imputed using the last observation carried forward (LOCF) method. Percent change from Baseline was calculated as: (\[LDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 12 in Apolipoprotein B (Apo B) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for apo B. Baseline was defined as the last value prior to the first dose of IMP. Percent change from Baseline for TC was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for apo B was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[apo B value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For apo B, if a measured apo B value was available, measured apo B was used. |
| Number of Participants With LDL-C <70 Milligrams Per Deciliter (mg/dL) at Week 12 | Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used. |
| Secondary Outcome Measure: Number of Participants With an LDL-C Reduction of ≥50% From Baseline at Week 12 | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the average of LDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. LDL-C reduction from Baseline was calculated as the LDL-C value at Week 12 minus the Baseline value. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used. |
| Change From Baseline to Week 12 in Hemoglobin A1C (HbA1c) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for HbA1c. Baseline was defined as the last value prior to the first dose of IMP (on or before Visit T1). Change from Baseline was calculated as the HbA1c value at Week 12 minus the Baseline value. For HbA1c, if a measured HbA1c value was available, measured HbA1c was used. |
| Percent Change From Baseline to Week 12 in HbA1c | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for HbA1c. Baseline was defined as the last value prior to the first dose of IMP (on or before Visit T1). Percent change from Baseline for HbA1C was analyzed using ANCOVA, with treatment as factor and Baseline HbA1C value as a covariate. Percent change from Baseline for HbA1c was calculated as: (\[HbA1c value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For HbA1c, if a measured HbA1c value was available, measured HbA1c was used. |
| Percent Change From Baseline to Week 12/EOS in LDL-C (Comparing Ezetimibe With Placebo) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the average of LDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for LDL-C was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for LDL-C was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[LDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used. |
| Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for hsCRP. Baseline was defined as the last value prior to the first dose of investigational medicinal product (IMP). Percent change from Baseline for hsCRP was analyzed using a non-parametric approach. Percent change from Baseline was calculated as: (\[hsCRP value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For hsCRP, if a measured hsCRP value was available, measured hsCRP was used. |
| Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for non-HDL-C. Baseline was defined as the average of non-HDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for non-HDL-C was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for non-HDL-C was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[non-HDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For non-HDL-C, if a measured non-HDL-C value was available, measured non-HDL-C was used. |
| Percent Change From Baseline to Week 12 in Total Cholesterol (TC) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for TC. Baseline was defined as the average of TC values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for TC was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for TC was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[TC value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For TC, if a measured TC value was available, measured TC was used. |
| Percent Change From Baseline to Week 12 in Triglycerides (TGs) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for TGs. Baseline was defined as the average of TG values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for TGs was analyzed using a non-parametric approach. Percent change from Baseline was calculated as: (\[TG value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For TGs, if a measured TG value was available, measured TG was used. |
| Percent Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C) | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for HDL-C. Baseline was defined as the average of HDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for HDL-C was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for HDL-C was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[HDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For HDL-C, if a measured HDL-C value was available, measured HDL-C was used. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 12 in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Index | Baseline; Week 12 | The HOMA-IR index was calculated from the fasting glucose and insulin values that were obtained at each clinic visit (Day 1/Visit T1, Week 4/Visit T2, and Week 12/Visit T3) during the double-blind treatment period, using the formula: (fasting glucose \[millimoles per milliliter {mmol/ml}\] x fasting insulin \[micro International Units per milliliter {μIU/ml}\]) divided by 22.5. Percent change from Baseline for HOMA-IR index was analyzed using ANCOVA, with treatment as factor and Baseline HOMA-IR index as a covariate. Baseline was defined as the last value prior to the first dose of study drug (on or before T1). Percent change from Baseline for HOMA-IR index was calculated as: (\[HOMA-IR index value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to approximately 16 weeks | Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) that began or worsened in severity on or after the first dose of double-blind IMP through 30 days after the last dose of double-blind IMP. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, including control, and which does not necessarily have a causal relationship with treatment. An AE is: any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; any deterioration in non-protocol-required measurements of a laboratory value or other clinical test (e.g., electrocardiogram or x-ray) that results in symptoms, a change in treatment, or discontinuation from IMP; or an adverse drug reaction. |
| Percent Change From Baseline to Week 12 in Fasting Plasma Glucose | Baseline; Week 12 | Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for fasting plasma glucose. Baseline was defined as the last value prior to the first dose of study drug (on or before T1). Percent change from Baseline for fasting plasma glucose was analyzed using ANCOVA, with treatment as factor and Baseline fasting plasma glucose as a covariate. Percent change from Baseline for fasting plasma glucose was calculated as: (\[fasting plasma glucose value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For fasting plasma glucose, if a measured fasting plasma glucose value was available, measured fasting plasma glucose was used. |
| Percent Change From Baseline to Week 12 in 2-hour Post Prandial Plasma Glucose (PPG) | Baseline; Week 12 | Blood samples were drawn 2 hours ± 5 minutes after the start of the meal. Samples were collected and analyzed for PPG. Baseline was defined as the last value prior to the first dose of study drug (on or before T1). Percent change from Baseline for PPG was calculated as: (\[PPG value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For PPG, if a measured PPG value was available, measured PPG was used. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC Participants received bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 milligrams (mg)/10 mg tablets orally once daily for 12 weeks. | 81 |
| Ezetimibe 10 mg Participants received ezetimibe 10 mg overencapsulated tablets orally once daily for 12 weeks. | 81 |
| Placebo Participants received placebo to match the FDC 180 mg/10 mg tablet or the ezetimibe 10 mg overencapsulated tablet, taken orally, once daily for 12 weeks. | 80 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Could not speak with the participant | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 1 |
| Overall Study | Participant was out of town | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 2 |
Baseline characteristics
| Characteristic | Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Ezetimibe 10 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 8.65 | 61.0 years STANDARD_DEVIATION 8 | 62.1 years STANDARD_DEVIATION 8.63 | 61.4 years STANDARD_DEVIATION 8.41 |
| Apolipoprotein B (Apo B) | 121.6 mg/dL STANDARD_DEVIATION 22.95 | 117.3 mg/dL STANDARD_DEVIATION 22.96 | 120.8 mg/dL STANDARD_DEVIATION 18.53 | 119.9 mg/dL STANDARD_DEVIATION 21.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 38 Participants | 30 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 43 Participants | 50 Participants | 142 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting plasma glucose | 162.4 mg/dL STANDARD_DEVIATION 46.1 | 153.3 mg/dL STANDARD_DEVIATION 46.73 | 174.2 mg/dL STANDARD_DEVIATION 57.53 | 163.2 mg/dL STANDARD_DEVIATION 50.78 |
| Hemoglobin A1C (HbA1c) | 7.86 Percent STANDARD_DEVIATION 0.927 | 7.96 Percent STANDARD_DEVIATION 1.279 | 8.02 Percent STANDARD_DEVIATION 0.773 | 7.95 Percent STANDARD_DEVIATION 1.013 |
| High-density lipoprotein cholesterol (HDL-C) | 48.73 mg/dL STANDARD_DEVIATION 13.067 | 47.95 mg/dL STANDARD_DEVIATION 10.847 | 48.53 mg/dL STANDARD_DEVIATION 13.482 | 48.40 mg/dL STANDARD_DEVIATION 12.447 |
| High-sensitivity C-reactive protein (hsCRP) | 2.570 milligrams per liter (mg/ L) | 2.420 milligrams per liter (mg/ L) | 3.480 milligrams per liter (mg/ L) | 2.610 milligrams per liter (mg/ L) |
| HOMA-IR index | 6.709 units on a scale STANDARD_DEVIATION 6.2 | 10.847 units on a scale STANDARD_DEVIATION 18.074 | 13.267 units on a scale STANDARD_DEVIATION 21.305 | 10.199 units on a scale STANDARD_DEVIATION 16.503 |
| Low-density lipoprotein cholesterol (LDL-C) | 145.06 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 31.504 | 139.24 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 28.121 | 143.36 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 26.421 | 142.55 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 28.715 |
| Non-high-density lipoprotein cholesterol (non-HDL-C) | 181.69 mg/dL STANDARD_DEVIATION 36.659 | 172.87 mg/dL STANDARD_DEVIATION 33.277 | 177.38 mg/dL STANDARD_DEVIATION 29.116 | 177.31 mg/dL STANDARD_DEVIATION 33.194 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 15 Participants | 16 Participants | 46 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 61 Participants | 65 Participants | 62 Participants | 188 Participants |
| Sex: Female, Male Female | 36 Participants | 39 Participants | 42 Participants | 117 Participants |
| Sex: Female, Male Male | 45 Participants | 42 Participants | 38 Participants | 125 Participants |
| Total cholesterol (TC) | 230.34 mg/dL STANDARD_DEVIATION 37.234 | 221.33 mg/dL STANDARD_DEVIATION 33.592 | 225.94 mg/dL STANDARD_DEVIATION 32.83 | 225.87 mg/dL STANDARD_DEVIATION 34.619 |
| Triglycerides (TGs) | 172.25 mg/dL | 159.25 mg/dL | 163.00 mg/dL | 163.00 mg/dL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 81 | 0 / 81 | 0 / 80 |
| other Total, other adverse events | 8 / 81 | 6 / 81 | 7 / 80 |
| serious Total, serious adverse events | 0 / 81 | 1 / 81 | 1 / 80 |
Outcome results
Primary
Percent Change From Baseline to Week 12/End of Study (EOS) in Low-density Lipoprotein Cholesterol (LDL-C)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the average of LDL-C values at the Screening Visit 3 (Visit S3) and the Treatment Visit 1 (Visit T1) (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for LDL-C was analyzed using analysis of covariance (ANCOVA), with treatment as factor and Baseline lipid parameter as a covariate. Missing data for LDL-C was imputed using the last observation carried forward (LOCF) method. Percent change from Baseline was calculated as: (\[LDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used.
Time frame: Baseline; Week 12
Population: Efficacy Analysis Set (EAS): all randomized participants who received at least one dose of investigational medicinal product (Full Analysis Set), excluding participants at three study sites. Only participants with available data were analyzed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12/End of Study (EOS) in Low-density Lipoprotein Cholesterol (LDL-C) | -38.8 Percent change | Standard Error 2.24 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12/End of Study (EOS) in Low-density Lipoprotein Cholesterol (LDL-C) | -19.2 Percent change | Standard Error 2.16 |
| Placebo | Percent Change From Baseline to Week 12/End of Study (EOS) in Low-density Lipoprotein Cholesterol (LDL-C) | 0.9 Percent change | Standard Error 2.2 |
p-value: <0.00195% CI: [-45.8, -33.4]ANCOVA
p-value: <0.00195% CI: [-25.7, -13.4]ANCOVA
p-value: <0.00195% CI: [-26.2, -14]ANCOVA
Secondary
Change From Baseline to Week 12 in Hemoglobin A1C (HbA1c)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for HbA1c. Baseline was defined as the last value prior to the first dose of IMP (on or before Visit T1). Change from Baseline was calculated as the HbA1c value at Week 12 minus the Baseline value. For HbA1c, if a measured HbA1c value was available, measured HbA1c was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Change From Baseline to Week 12 in Hemoglobin A1C (HbA1c) | 0.01 mg/dL | Standard Deviation 0.849 |
| Ezetimibe 10 mg | Change From Baseline to Week 12 in Hemoglobin A1C (HbA1c) | -0.06 mg/dL | Standard Deviation 0.851 |
| Placebo | Change From Baseline to Week 12 in Hemoglobin A1C (HbA1c) | 0.03 mg/dL | Standard Deviation 0.667 |
Secondary
Number of Participants With LDL-C <70 Milligrams Per Deciliter (mg/dL) at Week 12
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used.
Time frame: Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Number of Participants With LDL-C <70 Milligrams Per Deciliter (mg/dL) at Week 12 | 21 Participants |
| Ezetimibe 10 mg | Number of Participants With LDL-C <70 Milligrams Per Deciliter (mg/dL) at Week 12 | 3 Participants |
| Placebo | Number of Participants With LDL-C <70 Milligrams Per Deciliter (mg/dL) at Week 12 | 0 Participants |
p-value: <0.001Fisher Exact
p-value: 0.118Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Percent Change From Baseline to Week 12/EOS in LDL-C (Comparing Ezetimibe With Placebo)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the average of LDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for LDL-C was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for LDL-C was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[LDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12/EOS in LDL-C (Comparing Ezetimibe With Placebo) | -19.2 Percent change | Standard Error 2.16 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12/EOS in LDL-C (Comparing Ezetimibe With Placebo) | 0.9 Percent change | Standard Error 2.2 |
p-value: <0.00195% CI: [-26.2, -14]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in Apolipoprotein B (Apo B)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for apo B. Baseline was defined as the last value prior to the first dose of IMP. Percent change from Baseline for TC was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for apo B was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[apo B value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For apo B, if a measured apo B value was available, measured apo B was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in Apolipoprotein B (Apo B) | -27.5 Percent change | Standard Error 1.94 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in Apolipoprotein B (Apo B) | -14.8 Percent change | Standard Error 1.88 |
| Placebo | Percent Change From Baseline to Week 12 in Apolipoprotein B (Apo B) | -0.3 Percent change | Standard Error 1.91 |
p-value: <0.00195% CI: [-32.6, -21.8]ANCOVA
p-value: <0.00195% CI: [-18.1, -7.4]ANCOVA
p-value: <0.00195% CI: [-19.7, -9.1]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in HbA1c
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for HbA1c. Baseline was defined as the last value prior to the first dose of IMP (on or before Visit T1). Percent change from Baseline for HbA1C was analyzed using ANCOVA, with treatment as factor and Baseline HbA1C value as a covariate. Percent change from Baseline for HbA1c was calculated as: (\[HbA1c value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For HbA1c, if a measured HbA1c value was available, measured HbA1c was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in HbA1c | 0.1 Percent change | Standard Error 1.31 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in HbA1c | -0.7 Percent change | Standard Error 1.28 |
| Placebo | Percent Change From Baseline to Week 12 in HbA1c | 0.4 Percent change | Standard Error 1.27 |
p-value: 0.87795% CI: [-3.9, 3.3]ANCOVA
p-value: 0.66995% CI: [-2.8, 4.4]ANCOVA
p-value: 0.55695% CI: [-4.6, 2.5]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for HDL-C. Baseline was defined as the average of HDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for HDL-C was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for HDL-C was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[HDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For HDL-C, if a measured HDL-C value was available, measured HDL-C was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C) | -5.1 Percent change | Standard Error 1.53 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C) | 2.1 Percent change | Standard Error 1.48 |
| Placebo | Percent Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C) | 0.8 Percent change | Standard Error 1.5 |
p-value: 0.00795% CI: [-10.1, -1.7]ANCOVA
p-value: <0.00195% CI: [-11.5, -3.1]ANCOVA
p-value: 0.51795% CI: [-2.8, 5.5]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for hsCRP. Baseline was defined as the last value prior to the first dose of investigational medicinal product (IMP). Percent change from Baseline for hsCRP was analyzed using a non-parametric approach. Percent change from Baseline was calculated as: (\[hsCRP value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For hsCRP, if a measured hsCRP value was available, measured hsCRP was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) | -25.347 Percent change |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) | 2.078 Percent change |
| Placebo | Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) | 14.085 Percent change |
p-value: <0.00195% CI: [-55.97, -17.67]Wilcoxon rank sum test
p-value: 0.00595% CI: [-48.92, -9.62]Wilcoxon rank sum test
p-value: 0.4895% CI: [-30.51, 13.76]Wilcoxon rank sum test
Secondary
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 at pre-specified intervals. Samples were collected and analyzed for non-HDL-C. Baseline was defined as the average of non-HDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for non-HDL-C was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for non-HDL-C was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[non-HDL-C value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For non-HDL-C, if a measured non-HDL-C value was available, measured non-HDL-C was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | -33.0 Percent change | Standard Error 2.01 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | -17.8 Percent change | Standard Error 1.94 |
| Placebo | Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | 0.1 Percent change | Standard Error 1.97 |
p-value: <0.00195% CI: [-38.6, -27.5]ANCOVA
p-value: <0.00195% CI: [-20.8, -9.7]ANCOVA
p-value: <0.00195% CI: [-23.3, -12.4]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in Total Cholesterol (TC)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for TC. Baseline was defined as the average of TC values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for TC was analyzed using ANCOVA, with treatment as factor and Baseline lipid parameter as a covariate. Missing data for TC was imputed using the LOCF method. Percent change from Baseline was calculated as: (\[TC value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For TC, if a measured TC value was available, measured TC was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in Total Cholesterol (TC) | -27.3 Percent change | Standard Error 1.61 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in Total Cholesterol (TC) | -13.9 Percent change | Standard Error 1.55 |
| Placebo | Percent Change From Baseline to Week 12 in Total Cholesterol (TC) | -0.1 Percent change | Standard Error 1.57 |
p-value: <0.00195% CI: [-31.7, -22.8]ANCOVA
p-value: <0.00195% CI: [-17.8, -9]ANCOVA
p-value: <0.00195% CI: [-18.2, -9.5]ANCOVA
Secondary
Percent Change From Baseline to Week 12 in Triglycerides (TGs)
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for TGs. Baseline was defined as the average of TG values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. Percent change from Baseline for TGs was analyzed using a non-parametric approach. Percent change from Baseline was calculated as: (\[TG value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For TGs, if a measured TG value was available, measured TG was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in Triglycerides (TGs) | -9.20 Percent change |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in Triglycerides (TGs) | -13.59 Percent change |
| Placebo | Percent Change From Baseline to Week 12 in Triglycerides (TGs) | -5.11 Percent change |
p-value: 0.45795% CI: [-14.55, 6.79]Wilcoxon rank sum test
p-value: 0.35195% CI: [-4.93, 15.63]ANCOVA
p-value: 0.06895% CI: [-17.92, 0.68]ANCOVA
Secondary
Secondary Outcome Measure: Number of Participants With an LDL-C Reduction of ≥50% From Baseline at Week 12
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the average of LDL-C values at Visit S3 and Visit T1 (last 2 non-missing values on or prior to Day 1). If only 1 value was available, the single value was used as Baseline. LDL-C reduction from Baseline was calculated as the LDL-C value at Week 12 minus the Baseline value. For LDL-C, if a measured LDL-C value was available, measured LDL-C was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Secondary Outcome Measure: Number of Participants With an LDL-C Reduction of ≥50% From Baseline at Week 12 | 22 Participants |
| Ezetimibe 10 mg | Secondary Outcome Measure: Number of Participants With an LDL-C Reduction of ≥50% From Baseline at Week 12 | 0 Participants |
| Placebo | Secondary Outcome Measure: Number of Participants With an LDL-C Reduction of ≥50% From Baseline at Week 12 | 0 Participants |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Other Pre-specified
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) that began or worsened in severity on or after the first dose of double-blind IMP through 30 days after the last dose of double-blind IMP. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, including control, and which does not necessarily have a causal relationship with treatment. An AE is: any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; any deterioration in non-protocol-required measurements of a laboratory value or other clinical test (e.g., electrocardiogram or x-ray) that results in symptoms, a change in treatment, or discontinuation from IMP; or an adverse drug reaction.
Time frame: up to approximately 16 weeks
Population: Safety Analysis Set: all randomized participants who received at least one dose of IMP
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 55 Participants |
| Ezetimibe 10 mg | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 45 Participants |
| Placebo | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 46 Participants |
Other Pre-specified
Percent Change From Baseline to Week 12 in 2-hour Post Prandial Plasma Glucose (PPG)
Blood samples were drawn 2 hours ± 5 minutes after the start of the meal. Samples were collected and analyzed for PPG. Baseline was defined as the last value prior to the first dose of study drug (on or before T1). Percent change from Baseline for PPG was calculated as: (\[PPG value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For PPG, if a measured PPG value was available, measured PPG was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in 2-hour Post Prandial Plasma Glucose (PPG) | 1.9 Percent change | Standard Deviation 24.25 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in 2-hour Post Prandial Plasma Glucose (PPG) | 0.2 Percent change | Standard Deviation 31.88 |
| Placebo | Percent Change From Baseline to Week 12 in 2-hour Post Prandial Plasma Glucose (PPG) | 2.2 Percent change | Standard Deviation 25.39 |
Other Pre-specified
Percent Change From Baseline to Week 12 in Fasting Plasma Glucose
Blood samples were drawn after a minimum 10-hour fast at pre-specified intervals. Samples were collected and analyzed for fasting plasma glucose. Baseline was defined as the last value prior to the first dose of study drug (on or before T1). Percent change from Baseline for fasting plasma glucose was analyzed using ANCOVA, with treatment as factor and Baseline fasting plasma glucose as a covariate. Percent change from Baseline for fasting plasma glucose was calculated as: (\[fasting plasma glucose value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100. For fasting plasma glucose, if a measured fasting plasma glucose value was available, measured fasting plasma glucose was used.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in Fasting Plasma Glucose | 4.2 Percent change | Standard Error 3.29 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in Fasting Plasma Glucose | 3.7 Percent change | Standard Error 3.28 |
| Placebo | Percent Change From Baseline to Week 12 in Fasting Plasma Glucose | 1.7 Percent change | Standard Error 3.27 |
p-value: 0.58995% CI: [-6.7, 11.7]ANCOVA
p-value: 0.90495% CI: [-8.6, 9.7]ANCOVA
p-value: 0.67695% CI: [-7.3, 11.2]ANCOVA
Other Pre-specified
Percent Change From Baseline to Week 12 in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Index
The HOMA-IR index was calculated from the fasting glucose and insulin values that were obtained at each clinic visit (Day 1/Visit T1, Week 4/Visit T2, and Week 12/Visit T3) during the double-blind treatment period, using the formula: (fasting glucose \[millimoles per milliliter {mmol/ml}\] x fasting insulin \[micro International Units per milliliter {μIU/ml}\]) divided by 22.5. Percent change from Baseline for HOMA-IR index was analyzed using ANCOVA, with treatment as factor and Baseline HOMA-IR index as a covariate. Baseline was defined as the last value prior to the first dose of study drug (on or before T1). Percent change from Baseline for HOMA-IR index was calculated as: (\[HOMA-IR index value at Week 12 minus Baseline value\] divided by \[Baseline value\]) multiplied by 100.
Time frame: Baseline; Week 12
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid 180 mg + Ezetimibe 10 mg FDC | Percent Change From Baseline to Week 12 in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Index | 3.0 Percent change | Standard Error 9.85 |
| Ezetimibe 10 mg | Percent Change From Baseline to Week 12 in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Index | 2.5 Percent change | Standard Error 9.59 |
| Placebo | Percent Change From Baseline to Week 12 in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Index | 18.9 Percent change | Standard Error 9.79 |
p-value: 0.25895% CI: [-43.4, 11.7]ANCOVA
p-value: 0.97295% CI: [-26.8, 27.7]ANCOVA
p-value: 0.23595% CI: [-43.3, 10.7]ANCOVA