| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heterozygous familial hypercholesterolemia (HeFH) is a frequent, inherited disorderof lipoprotein metabolism caused by mutations in the LDL receptor gene. The risk of CHD is approximately 50% by 50 years of age in untreated HeFH. Morphological and functional changes of the arteries are present in hypercholesterolemic children and can predict future CHD, underscoring the importance of aggressive and early treatment of dyslipidemia to prevent premature events in HeFH. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| 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 |
| The primary objective of this study is to determine the efficacy of once-daily rosuvastatin in reducing LDL-C in children and adolescents aged 10-17 years with HeFH from baseline (Day 0) to the end of the 12-week double-blind treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
1.The percent change in LDL-C from baseline to Week 6
2.The percent change in HDL-C, TC, TG, non-HDL-C, LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, ApoB, ApoB/ApoA-1, and ApoA-1 for each assigned dose level from baseline to Week 6, and to the end of the double-blind treatment period as compared to placebo
3.The efficacy of rosuvastatin in achieving the LDL-C goal of <110 mg/dL (percent response rate) after 40 weeks of titration-to-goal dosing.
4.The safety of each dose level by assessing the incidence and severity of adverse events, abnormal serum laboratory values, and rate of discontinuations due to AEs at Week 12 (vs. placebo) and during the 40-week open label treatment
5.The effects on urinary protein excretion and estimated glomerular filtration rate
6.The effect on growth by assessment of height (including linear growth [cm and Standard Deviation Score]) and secondary characteristics of sexual maturation by Tanner Staging at baseline and 52 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study dietary lead in and double-blind period, patients must fulfill all of the following criteria:
1. Provision of written informed consent from a parent or guardian. Communication with the investigator and understanding and compliance with the requirements of the study by the patient and parent or guardian. Statement of assent from the child or adolescent as required by the IRB or IEC according to local regulations and guidelines
2. Male or female (Tanner stage II to V, at least 1 year post-menarche) children and adolescents (aged 10 –17 years) with heterozygous familial hypercholesterolemia (HeFH)* and at least one of the following criteria:
- Fasting LDL-C >190 mg/dL (4.9 mmol/L) at Visit 2
or
- Fasting LDL-C >160 mg/dL (4.1 mmol/L) at Visit 2 and either of the following:
- Family history of premature cardiovascular disease (CVD) defined as onset of clinical atherosclerotic disease before age 55 in males or age 65 in females
or
- 2 or more other CVD risk factors (HDL-C <35 mg/dL; hypertension; cigarette smoking; severe obesity; diabetes mellitus; physical inactivity) present after vigorous attempts have been made to control these risk factors during 6 weeks dietary lead-in
*HeFH defined as:
· Documented genetic defect in LDL receptor or ApoB by DNA analysis
or
· Documented evidence of FH in a first degree relative (LDL-C >190 mg/dL (4.9mmol/L) in an adult not receiving a statin or LDL-C >95mg/dL (2.5mmol/L) in an adult receiving statin treatment; LDL-C >160 mg/dL (4.1mmol/L) in a child <18 years of age not receiving a statin or LDL-C >80mg/dL (2.1mmol/L) in a child <18 years of age receiving statin treatment)
3. Negative serum pregnancy test (b-human chorionic gonadotropin analysis [b-HCG]) prior to randomization and thereafter in females
· Female patients must adhere to a pregnancy prevention method (abstinence, chemical or mechanical) during the study
4. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws and compliance with study treatment regimen
|
|
| E.4 | Principal exclusion criteria |
Any of the following is regarded as a criterion for exclusion from the study:
1. History of statin induced myopathy or serious hypersensitivity reaction to other HMG-CoA reductase inhibitors (statins), including rosuvastatin
2. Fasting TG ³250 mg/dL (2.87 mmol/L) at Visit 2
3. Fasting serum glucose of 180 mg/dL (9.99 mmol/L) or HbA1c >9% at Visit 1 or patients with a history of diabetic ketoacidosis within the past 1 year
4. Uncontrolled hypothyroidism defined as thyroid stimulating hormone (TSH) > 1.5 times the upper limit of normal (ULN) at Visit 1 (Week -6) or patients whose thyroid replacement therapy was initiated or modified within the last 3 months
5. Use of specified disallowed concomitant medications
6. History of alcohol abuse and/or drug abuse
7. Current active liver disease or hepatic dysfunction (excluding a confirmed diagnosis of Gilbert’s disease) as defined by elevations of 1.5 times the ULN for any age in any of the following liver functions tests: ALT, AST, or bilirubin at Visit 1
8. Serum creatine kinase (CK) ³3 times ULN (unless explained by exercise) at Visit 1
9. Estimated GFR by Schwartz formula < 50 ml/min at Visit 1 (Schwartz, 1985)
10. ³2+ proteinuria on urine dipstick at Visit 1 or Visit 2
11. Stage 2 Hypertension (systolic and/or diastolic blood pressure greater than 5 mmHg above the 99th percentile for age, gender and height, see Appendix H)
12. History of solid organ transplantation
13. Patients previously screened for this study and/or patients randomized to treatment who subsequently withdraw consent
14. Participation in another investigational drug study <4 weeks before enrolment into the dietary lead-in period
15. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the patient’s safety or successful participation in the study
16. Documented history of malignancy with the exception of basal or squamous cell carcinoma of the skin
17. Patients who are Tanner Stage 1
18. Boys > 12 years of age with testicular volume <3 cc
19. Patients with height <3rd percentile for age and sex (See Appendix I)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the percent change from the baseline in LDL-C at 12 weeks of treatment from each rosuvastatin dose as compared to placebo. Statistically significant results for any dose (without multiplicity adjustment) will be considered acceptable evidence of efficacy if a trend toward dose response is evident. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Percent of patients achieving a LDL-C target of <2.85 mmol/L during double-blind dose treatment at dose of 5 mg up to 20 mg (week 12)
- Percent change in LDL-C from baseline to week 6
- Percent change from baseline in HDL-C, TC, TG, non-HDL-C, LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, ApoB, ApoB/ApoA-1 and ApoA-1 to weeks 6 and 12
- Assessment of growth and secondary characteristics of sexual maturation at baseline and 52 weeks |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| After double blind will become open label |
|
| 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.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA 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.8.9.2 | 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 |
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