| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA |
|
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004861 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054380 |
| E.1.2 | Term | Familial hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057079 |
| E.1.2 | Term | Heterozygous familial hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the pharmacokinetics (PK) of bempedoic acid (ETC-1002 and ESP15228)in pediatric patients (6 to 17 years of age) with HeFH treated for 8 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess bempedoic acid exposure/LDL-C-lowering response relationship;
•To assess the absolute and percent change from baseline to Weeks 8 and 16 inLDL-C, total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C)and high-sensitivity C-reactive protein (hsCRP);
•To monitor the acceptability (taste and ease of swallowing) of the age-appropriateformulations;
•To assess the safety and tolerability of bempedoic acid in pediatric patients withHeFH treated with escalating, multiple oral doses of bempedoic acid based on bodyweight for 8 and 16 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient’s parent(s)/guardian(s) must be willing to provide written informed consent and the patient must provide informed assent before any study-specific procedures are performed;
2. The patient must be aged 6-17 years old;
3. The patient must weigh at least 16 kg;
4. The patient must have a diagnosis of HeFH per MEDPED criteria by meeting at least one of the following clinical criteria*:
a. Documented diagnosis of HeFH determined by positive genetic testing; or
b. Documented LDL-C or TC meeting one or more of the following criteria:
i. LDL-C >200 mg/dL (5.2 mmol/L) or total cholesterol (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
5. Current treatment with approved stable LMTs, including optimal dose of statin +/- other LMT(s), at stable dose for at least 4 weeks prior to screening Visit S1 (6 weeks for fibrates; however, gemfibrozil is not allowed in patients taking a statin as per co-administration instructions defined in the statin label) and must remain on that stable dose throughout the duration of the trial.
A patient’s optimal dose of statin is defined as the highest approved dose prescribed for the age of the patient based on regional practice or local guidelines; or is the dose that is maximally tolerated due to adverse effects on higher doses. If a patient is not receiving the highest approved statin dose for the age based on regional and local requirements, the Investigator should consider escalation of the statin dose for the management of the patient’s hypercholesterolemia prior to enrollment in this non-statin bempedoic acid trial. Optimal dose of statin or other LMT(s) will be determined by the investigator using their medical judgment and available sources, including the patient’s self-reported history of LMT.
Patients where the optimal dose of statin is not the highest approved dose for the age based on regional or local guidelines must have documented inability to tolerate the highest approved statin dosing due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued.
Patients not taking any statin must have documented failure to tolerate at least two statins, including one at its lowest dose, and patient/parent and investigator attestation.
6. The patient must have a fasting LDL-C level ≥130 mg/dL (3.4 mmol/L);
7. The patient may be male or female. Females must not be pregnant (or planning to become pregnant within 30 days after the last dose of investigational medicinal product [IMP])
breastfeeding and must be sexually inactive or willing to use 1 acceptable method of birth control. The minimal requirement for use of acceptable contraception is from the time the informed consent form (ICF) is signed, during the study period, and for at least 30 days after the last dose of IMP. Acceptable methods of birth control include:
a. placement of an intrauterine device (IUD) with or without hormones,
b. established use of oral, implanted, topical, or injectable, or hormonal method of contraception associated with inhibition of ovulation, or
c. barrier methods, including condom or occlusive cap with spermicidal foam or spermicidal jelly,
There are no protocol-specific birth control requirements for males who have partners that can become pregnant. |
|
| E.4 | Principal exclusion criteria |
1. The patient has a diagnosis of HoFH or compound HeFH;
2. The patient has a fasting triglyceride (TG) level ≥400 mg/dL (4.5 mmol/L);
3. The patient 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);
4. The patient has liver disease or dysfunction, including:
a. positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C virus antibodies (HCV-AB), or
b. 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 patient has a history of Gilbert’s disease, the patient may be enrolled in the study.
5. The patient has renal dysfunction or glomerulonephritis, including an estimated glomerular filtration rate (eGFR) <75 mL/min/1.73 m2 (as determined by the central laboratory using the Revised [“Bedside”] Schwartz formula);
6. The patient has Stage 2 hypertension (based on gender, age and height; see Appendix 4);
7. The patient has a gastrointestinal condition that may affect drug absorption;
8. The patient has a history of hematologic or coagulation disorders, anemia, or a hemoglobin (Hgb) level <11.5 g/dL;
9. The patient has type 1 or type 2 diabetes, or newly diagnosed impaired glucose tolerance (within 3 months of Screening);
10.The patient had an active malignancy, including those requiring surgery, chemotherapy, and/or radiation, in the past 5 years. Nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed;
11.The patient has an unexplained (ie, not associated with recent trauma or physically strenuous activity) serum creatine kinase (CK) value >3 × ULN at any time before randomization. Patients with an explained elevation in serum CK must have single repeat serum CK value ≤3 × ULN before enrollment;
12.The patient has a history of drug or alcohol abuse within the last 2 years or is unwilling to refrain from alcohol consumption for the duration of the study, or uses any illicit drugs, or has a history of amphetamine or derivatives abuse or cocaine abuse. Patients who are using amphetamine derivatives prescribed by and who are under the care of a health care practitioner can be enrolled after evaluation by the Investigator;
13.The patient has donated blood, undergone multiple blood draws in a clinical study, experienced major trauma, received a blood transfusion, or undergone surgery, with or without blood loss, within 30 days before enrollment;
14.The patient has used any experimental or investigational drugs within 30 days before screening and throughout the trial;
15.The patient has previously participated in a clinical study of bempedoic acid;
16.The patient is taking any of the following medications or therapies, except as indicated below:
a. Mipomersen or lomitapide (current or within 6 months of Screening).
b.PCKS9 inhibitors including evolocumab or alirocumab (current or within 3 months of Screening).
c. Lipid apheresis (current or within 8 weeks of Screening or intends to have lipidapheresis treatments throughout the trial).
d. Systemic corticosteroids (current or within 4 weeks prior to enrollment; topical and inhaled corticosteroids are allowed).
e. Red yeast rice extract (also known as monascus purpureus extract or Cholestin)containing products (current or within 4 weeks of Screening);
f. Lipid altering nutritional supplements including berberine, psyllium (Metamucil®),green tea extract, sitostanol (found in oral nutritional supplements and some margarines, such as Benecol), beta-sitosterol (found in oral nutritional supplements and some margarines, such as Promise Activ), pantothine and policosanol (current or within 4 weeks of Screening);
g. Bile acid sequestrants, fibrates, omega 3 fatty acids, or niacin, unless the dose has been stable for ≥6 weeks and will remain stable throughout the trial.
h. Simvastatin >20 mg or pravastatin >40 mg (current or within 4 weeks of Screening).
17.The patient has a history or evidence of any other clinically significant condition, or planned or expected procedure that in the opinion of the Investigator, may compromise the patient’s safety or ability to complete the study;
18. The patient has a situational (ie, geographical) finding that, in the Investigator’s opinion, may compromise the patient’s safety or ability to complete the study;
19. The patient is an employee or contractor of the facility that is conducting the study or is a family member of the Investigator, sub-Investigator, or any Sponsor personnel. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•Observed trough plasma concentration of ETC-1002 following 8 weeks of steady-state dosing of bempedoic acid;
•Model-based PK parameters including steady-state estimates of:
−area under the plasma concentration-time curve (AUCss),
−average plasma concentration (Cavg,ss) and
−maximum plasma concentration (Cmax,ss). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 8 weeks of steady-state dosing of bempedoic acid |
|
| E.5.2 | Secondary end point(s) |
•Observed trough plasma concentration of ESP15228 (active metabolite) following 8 weeks of steady-state dosing of bempedoic acid;
•Plasma concentration at 4 hours (C4hr) of ETC-1002 and ESP15228 following first dose;
•ETC-1002 dose and exposure/LDL-C-lowering response relationship;
•Percent and absolute from baseline to Weeks 8 and 16 in LDL-C, TC, non-HDL-C, and hsCRP;
•Evaluation of acceptability (taste and ease of swallowing) of the age-appropriate formulations. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- following 8 weeks of steady-state dosing of bempedoic acid
- following first dose
- weeks 8 and 16 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
| Denmark |
| Germany |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 13 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 13 |
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