Hypercholesterolemia
Conditions
Keywords
Pediatric, Heterozygous familial hypercholesterolemia, Low-density lipoprotein cholesterol (LDL-cholesterol), Bempedoic acid, ETC-1002, Adenosine triphosphate citrate lyase
Brief summary
Multiple-dose study to measure pharmacokinetics, pharmacodynamics and safety of bempedoic acid in pediatric participants 6 to 17 years of age with HeFH.
Detailed description
Dose-selection based on body weight will be determined for use in pediatric clinical development.
Interventions
DRUGBempedoic acid
Once daily oral dosing with oral tablets.
Sponsors
Esperion Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Participant's parent(s)/guardian(s) must be willing to provide written informed consent and the participant must provide informed assent before any study-specific procedures are performed; * Participant must be aged 6-17 years old and willing to swallow tablets; * Participant must weigh at least 16 kilograms (kg); * Participant must have a diagnosis of HeFH prior to receiving the first dose of study medication at Treatment Visit T1 per Make Early Diagnosis to Prevent Early Deaths project (MEDPED) criteria by meeting at least one of the following clinical criteria: 1. Documented diagnosis of HeFH determined by positive genetic testing; or 2. Documented LDL-C or TC meeting one or more of the following criteria: i. LDL-C \>200 milligrams per deciliter (mg/dL) (5.2 millimole per liter \[mmol/L\]) or TC \>270 mg/dL (7.0 mmol/L), with no first- second- or third-degree relative with documented FH diagnosis (general population); or ii. LDL-C \>155 mg/dL (4.0 mmol/L) or TC \>220 mg/dL (5.7 mmol/L), and also having a first-degree relative with documented familial hypercholesterolemia (FH) diagnosis; or iii. LDL-C \>165 mg/dL (4.3 mmol/L) or TC \>230 mg/dL (5.9 mmol/L), and also having a second-degree relative with documented FH diagnosis; or iv. LDL-C \>170 mg/dL (4.4 mmol/L) or TC \>240 mg/dL (6.2 mmol/L), and also having a third-degree relative with documented FH diagnosis * Current treatment with approved stable lipid-modifying therapy (LMT), including an optimal dose of statin with or without other LMT(s), at stable dose for at least 4 weeks prior to Treatment Visit T1 (6 weeks for fibrates; however, gemfibrozil is not allowed in participants taking a statin as per coadministration instructions defined in the statin label). Participants must remain on that stable dose throughout the duration of the trial. Optimal dose of statin will be determined by the investigator using their medical judgment and available sources, including the participant's self-reported history of LMT. A participant's optimal dose of statin is defined as meeting one of the following criteria: 1. the highest approved dose of statin prescribed for the age of the participant based on regional practice or local guidelines; or 2. less than the highest approved dose of statin, including no statin, prescribed for the age of the participant based on regional practice or local guidelines (including no statin) if: i. the participant has previously taken 2 or more statin therapies at any dose and not able to tolerate or unresponsive due to their mutations (null); or ii. the participant has previously taken 1 or more statin therapies at any dose and is unwilling to attempt another statin at any dose or advised by a physician to not attempt another statin at any dose. 3. Participant/parent and investigator attestation to the participant's unwillingness to attempt and/or physician advice to not attempt additional statin therapy will be recorded.
Exclusion criteria
* Participant has a diagnosis of homozygous familial hypercholesterolemia (HoFH) or compound HeFH; * Participant has a fasting triglyceride (TG) level ≥400 mg/dL (4.5 mmol/L); * Participant has uncontrolled hypothyroidism, including a value for thyroid-stimulating hormone (TSH) \< lower limit of normal (LLN) or \>1.5 × the upper limit of normal (ULN); * Participant has liver disease or dysfunction, including: 1. positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C virus antibodies (HCV-AB), or 2. serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value ≥2 × ULN and/or serum total bilirubin (TB) value ≥2 × ULN. If the serum TB value is ≥1.2 × ULN, a reflex indirect (unconjugated) bilirubin will be obtained and, if consistent with Gilbert's disease or if the participant has a history of Gilbert's disease, the participant may be enrolled in the study. * Participant has renal dysfunction or glomerulonephritis, including an estimated glomerular filtration rate (eGFR) \<75 milliliters/minute/1.73 square meter (mL/min/1.73 m\^2). Other protocol defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Observed Trough Plasma Concentration of ETC-1002 Following 8 Weeks of Steady State Dosing of Bempedoic Acid | Week 8 pre-dose | Blood plasma samples were collected and analyzed to determine the plasma trough concentration of ETC-1002 following 8 weeks of steady-state dosing of bempedoic acid. The data presented here is for participants who received tablet formulation only. |
| Model-based Steady State Area Under the Concentration-time Curve Over 24 Hours (AUC,24ss) of ETC-1002 | 24 hours | Blood plasma samples were collected and analyzed to determine the AUC,24ss of ETC-1002 over 24 hours. The data presented here is for participants who received tablet formulation only. |
| Model-based Steady State Average Plasma Concentration (Cavg,ss) of ETC-1002 | Week 8, 24 hours post-dose at steady state | Blood plasma samples were collected and analyzed to determine the Cavg,ss of ETC-1002. Cavg was calculated by empirical Bayesian estimated pediatric exposure over 24 hours divided by 24 (AUC24hr.ss / 24). The data presented here is for participants who received tablet formulation only. |
| Model-based Steady State Maximum Plasma Concentration (Cmax,ss) of ETC-1002 | Day 1: 1-hour and 4 hours post-dose; Week 4 pre-dose; Week 8 pre-dose | Blood plasma samples were collected and analyzed to determine the Cmax,ss of ETC-1002. The data presented here is for participants who received tablet formulation only. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Observed Trough Plasma Concentration of ESP15228 | Week 8 pre-dose | Blood plasma samples were collected and analyzed to determine the trough plasma concentration of active metabolite ESP15228 following 8 weeks of steady-state dosing of bempedoic acid. The data presented here is for participants who received tablet formulation only. |
| Observed Plasma Concentration at 4 Hours (C4hr) of ETC-1002 | Day 1: 4 hours post-dose | Blood plasma samples were collected and analyzed to determine the trough plasma concentration of ETC-1002 4 hours post-dose. The data presented here is for participants who received tablet formulation only. |
| Observed C4hr of ESP15228 | Day 1: 4 hours post-dose | Blood plasma samples were collected and analyzed to determine the trough plasma concentration of active metabolite ESP15228 4 hours post-dose on Day 1. The data presented here is for participants who received tablet formulation only. |
| Simulated Percent Change From Baseline in Exposure/ Low-Density Lipoprotein-Cholesterol (LDL-C) | Baseline and Week 12 | Blood samples were collected for the analysis of and exposure/LDL-C-lowering response relationship. |
| Observed Percent Change From Baseline in LDL-C | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of LDL-C levels. Baseline is defined as the last assessment measurements before the first dose of investigational medical product (IMP). Percent change from baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Absolute Change From Baseline in LDL-C (mg/dl) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of LDL-C levels. Baseline is defined as the last assessment measurements before the first dose of IMP. Change from baseline is defined as post- dose visit value minus baseline value. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of Non-HDL-C levels. Baseline is defined as the last assessment measurements before the first dose of IMP. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Absolute Change From Baseline in Non-HDL-C (mg/dL) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of Non-HDL-C levels. Baseline is defined as the last assessment measurements before the first dose of IMP. Change from Baseline is defined as post- dose visit value minus Baseline value. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Percent Change From Baseline in Total Cholesterol (TC) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of total cholesterol levels. Baseline is defined as the last assessment measurements before the first dose of IMP. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Absolute Change From Baseline in TC (mg/dL) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of TC levels. Baseline is defined as the last assessment measurements before the first dose of IMP. Change from Baseline is defined as post- dose visit value minus Baseline value. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Percent Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of hsCRP. Baseline is defined as the last assessment measurements before the first dose of IMP. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Observed Absolute Change From Baseline in hsCRP (mg/L) | Baseline and 8 Weeks post-treatment | Blood samples were collected for analysis of hsCRP levels. Baseline is defined as the last assessment measurements before the first dose of IMP. Change from Baseline is defined as post- dose visit value minus Baseline value. The treatment period for participants in cohort 1 (60 mg), cohort 2 (120 mg), and cohort 3 was weeks 1-8. The treatment period for participants in cohort 1 (90 mg) and cohort 2 (150 mg) was weeks 8-16. |
| Acceptability of Taste of Liquid Formulation Using a Dosing Acceptability Questionnaire | Days 1 and 2; Weeks 2, 4, 8, 8 (Phone), 10, 12, and 16 | Participant acceptance is defined as the overall ability of the participant to use a medicine as intended. The acceptability of overall flavor of IMP was recorded using a dosing acceptability questionnaire, where participants were asked 'Yes' or 'No', whether the flavor of the medication was acceptable. At Week 8 (Phone) participants in cohorts 1 and 2 were contacted by phone to collect questionnaire information. The number of participants who have responded at each time point have been presented. |
| Acceptability of Ease of Swallowing Tablet Formulation Using a Dosing Acceptability Questionnaire | Days 1 and 2; Weeks 2, 4, 8, 8 (Phone), 10, 12, and 16 | Participant acceptance is defined as the overall ability of the participant to use a medicine as intended. Acceptability of ease of swallowing was recorded using a dosing acceptability questionnaire where participants were asked if they were able to swallow the entire dose or not, by ticking 'yes' or 'no'. At Week 8 (Phone) participants in cohorts 1 and 2 were contacted by phone to collect questionnaire information. The number of participants who responded at each time point have been presented. |
| Number of Participants Reporting Serious Adverse Events (SAEs) and Non-SAEs | Up to Week 16 | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. A serious AE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the study medication that fulfills one or more of the following: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital abnormality or birth defect, is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above. |
Countries
Canada, Denmark, Germany, Netherlands, Spain, United States
Participant flow
Recruitment details
This was a multi-dose study to measure the pharmacokinetics (PK), pharmacodynamics (PD), and safety of bempedoic acid in pediatric participants aged 6 to 17 years with heterozygous familial hypercholesterolemia (HeFH).
Pre-assignment details
A total of 31 participants were enrolled in the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 12.6 years STANDARD_DEVIATION 3.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 16 | 0 / 14 | 0 / 11 |
| other Total, other adverse events | 3 / 4 | 3 / 3 | 10 / 16 | 10 / 14 | 9 / 11 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 16 | 0 / 14 | 0 / 11 |
Outcome results
None listed