E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
-Primary Hypercholesterolemia (Heterozygous Familial [HeFH]) -Primary Hypercholesterolemia (Nonfamilial) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057079 |
E.1.2 | Term | Heterozygous familial hypercholesterolemia |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
|
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 |
Determine the effect of ezetimibe 10mg/day compared to placebo on the reduction of LDL-C from baseline to 12 weeks of treatment in children ≥6 to ≤10 years old with primary hypercholesterolemia (HeFH and nonfamilial) |
|
E.2.2 | Secondary objectives of the trial |
Key secondary objective: Determine effect of ezetimibe 10mg/day compared to placebo on TC, Apo B, HDL-C, non-HDL-C, & TG from baseline (BL) to 12 weeks of treatment
Other secondary objectives: Determine effect of ezetimibe 10mg/day compared to placebo on: -LDL-C, TC, HDL-C, non-HDL-C, TG, and ratios LDL-C:HDL-C and TC:HDL-C from baseline to 2, 4 and 8 weeks of treatment -apolipoprotein A1 (Apo A1), and ratios of LDL-C:HDL-C, TC:HDL-C, and Apo B: Apo A1 from baseline to 12 weeks of treatment -Plasma hs-CRP from BL to 4 & 12 weeks of treatment -Plasma plant sterols/stanols, sitosterol, campesterol, and cholestanol & lathosterol from BL to 2, 4, 8, & 12 weeks of treatment
Determine safety of ezetimibe 10 mg/day as assessed by AEs, physical examinations, lab parameters (chemistry, hematology, urinalysis, & steroid hormone levels), & effects on liver and muscle
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A PK substudy will be conducted in a subset of patients to explore and provide a descriptive analysis of the PK profile of ezetimibe in this population.
Full title, date & version of sub-study: N/A
Other Secondary Objective: To assess the PK parameters & to provide a descriptive analysis of ezetimibe 10 mg/day in a subset of study participants. |
|
E.3 | Principal inclusion criteria |
1. Each subject may be of either sex and of any race/ethnicity, and must be ≥6 and ≤10 years of age, with a diagnosis of primary hypercholesterolemia (heterozygous familial or nonfamilial) despite being on a lipid-lowering diet for at least 3 months
2. Any subject meeting at least one of the following clinical criteria items, a-e below, will be considered to have heterozygous familial hypercholesterolemia: a. genotype-confirmed HeFH with written documentation of the genetic diagnosis prior to or at the time of screening & LDL-C >159 mg/dL(4.1 mmol/L) & <400 mg/dL (10.3 mmol/L) b. LDL-C >159 mg/dL (4.1 mmol/L) & <400 mg/dL (10.3 mmol/L) with at least one biological parent with genotype-confirmed HeFH & a historical untreated LDL-C of >159 mg/dL c. LDL-C >159 mg/dL (4.1 mmol/L) & <400 mg/dL (10.3 mmol/L) with at least one biological parent with an untreated LDL-C value of at least 210 mg/dL (5.4 mmol/L) not associated with a disorder known to produce secondary elevation of LDL-C d. LDL-C >159 mg/dL (4.1 mmol/L) & <400 mg/dL (10.3 mmol/L) with tendinous xanthomas, not associated with a disorder known to produce secondary elevation of LDL-C e. LDL-C >189 mg/dL (4.9 mmol/L) & <400 mg/dL (10.3 mmol/L) & a family history of hypercholesterolemia consistent with dominant autosomal transmission
3. Each subject with nonfamilial primary hypercholesterolemia must have a LDL-C of > 159mg/dL (4.1 mmol/L) and < 400mg/dL (10.3 mmol/L) at Visit 1 and Visit 3
4. Each subject must have been on a diet in accordance with the American Heart Association/American Academy of Pediatric guidelines
5. Each subject’s complete blood count [CBC], blood chemistry, urinalysis, & steroid hormone levels must be within normal limits or clinically acceptable to the investigator
6. Each subject must be free of any clinically significant disease, other than hypercholesterolemia, that would interfere with the study evaluations
7. Each subject must be willing to participate in the study & to complete all study-related procedures
8. Each subject’s parent/guardian must be willing to give written informed consent on his/her behalf
9. Each subject must be able to adhere to dosing requirements & visit schedules
10. All females of child-bearing potential must have a negative serum pregnancy test (beta-hCG) at screening
|
|
E.4 | Principal exclusion criteria |
Each subject must not: 1. have known hypersensitivity or any contraindication to ezetimibe 2. have BMI above the 97th percentile for age & sex (using accepted standards, such as Centers for Disease Control (CDC) & Prevention charts and/or World Health Organization (WHO) 3. have a height below the 3rd percentile for age & sex (using accepted standards) 4. be in a situation or have any condition that, in the opinion of the investigator, may interfere with optimal participation in the study 5. have an underlying disease likely to limit life span to less than 1 year 6. have use of any investigational drugs within 30 days of study entry 7. have participation in any other clinical study, unless permission is given by this sponsor 8. be a member or a family member of the personnel of the investigational or sponsor staff directly involved with this trial 9. be a female of child-bearing potential who is pregnant, intends to become pregnant, or is nursing 10. be a female of child-bearing potential who will not abstain from sex or use a medically acceptable method of birth control in the opinion of the investigator
Exclusionary Concomitant Illness: Each subject must not: 1. have known congenital cardiac disorder 2. have any cardiac disorder that may limit participation in the study 3. have documented or laboratory values consistent with homozygous familial hypercholesterolemia (HoFH) 4. have disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease, anorexia nervosa, & degenerative disease that would limit study evaluation or participation 5. have Type 1 diabetes mellitus 6. have Type 2 diabetes mellitus 7. have uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins 8. be on unstable thyroid hormone replacement therapy with TSH levels outside the normal range 9. have known clinically significant impairment of renal function, dysproteinemia, nephrotic syndrome, or other renal disease 10. have fasting plasma triglyceride that is >150 mg/dL (>1.69 mmol/L) at Visit 1 and/or Visit 3 11. have serum creatinine ≥ 2.0 mg/dL 12. have active or chronic hepatic or biliary disease 13. have AST and/or ALT >1.5 times the upper limit of normal (ULN) of the central laboratory reference range 14. have blood creatine phosphokinase or creatine kinase (CPK) >1.5 times the ULN of the central laboratory reference range 15. be known to be HIV positive 16. have known coagulopathy 17. be undergoing LDL apheresis or plasma apheresis 18. have a history of a partial ileal bypass or disease that affects significant function of ileum 19. have a history of mental instability, or be an individual who has been treated, or is being treated, for severe psychiatric illness that, in the opinion of the investigator, may interfere with optimal participation in the study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The percent change from baseline in LDL-C to 12 weeks in the ezetimibe group compared to the placebo group. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 | Information not present in EudraCT |
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 |
|
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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |