| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male and female children and adolescents (aged 6 to < 18 years) with FH* and at least 1 of the following criteria: 1. Fasting LDL-C>190 mg/dL (4.92 mmol/L) at baseline OR 2. Fasting LDL-C >160 mg/dL (4.10 mmol/L) at baseline in combination with evidence of other risk factors. *Familial hypercholesterolaemia is defined by a documented genetic defect in LDL receptor or Apo B or documented evidence of familial hypercholesterolaemia in a first-degree relative. |
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| E.1.1.1 | Medical condition in easily understood language |
| The constant high level of cholesterol in blood |
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| 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 |
To assess the efficacy of rosuvastatin in paediatric patients with FH.
To establish long-term safety, tolerability and efficacy of rosuvastatin in paediatric patients with FH.
To characterise the PK profile of rosuvastatin in paediatric patients with FH, aged from 6 to less tha Tanner Stage II, with familial hypercholesterolaemia. |
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| E.2.2 | Secondary objectives of the trial |
To assess cIMT by sonography at baseline and every year in patients and in healthy siblings.
To assess growth and maturation in children or adolescents with FH who are receiving long-term rosuvastatin treatment.
Assessment of adherence to rosuvastatin during a 2-year period of treatment.
To assess the feasibility and acceptability of the current marketed tablet formulation of rosuvastatin for use in children.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Prior to any study related procedures being performed, provision of written informed consent from a parent/both parents or guardian and statement of assent from the child or adolescent (if required by institutional review board [IRB] or independent ethics committee [IEC] according to local regulations and guidelines). Communication between the investigator, patient/guardian and child/adolescent to confirm understanding and required compliance with the requirements of the study.
2. Male and female children and adolescents (aged 6 to less than 18 years) with FH* and at least 1 of the following criteria:
-Fasting LDL-C >4.92 mmol/L (190 mg/dL) prior to Visit 3, per Visit 1 laboratory results (statin-naïve only) or Visit 2 laboratory results (previously treated).
or
-Fasting LDL-C >4.10 mmol/L (158 mg/dL) prior to Visit 3, per Visit 1 laboratory results (statin-naïve only) or Visit 2 laboratory results (previously treated) in combination with evidence of other risk factors, such as family history in first or second degree relatives of premature cardiovascular disease (CVD), defined as onset of clinical atherosclerotic disease before age 55 in males or age 65 in females at Visit 1.
*FH is defined by a documented genetic defect in LDL-R or ApoB (by DNA analysis) or documented evidence of FH in a first-degree relative (LDL C >4.90 mmol/L [189 mg/dL] in an adult; >4.10 mmol/L [158 mg/dL] in a child <18 years of age).
3. Patients aged between 6 and less than 10 years of age must be statin treatment naïve.
4. Negative serum pregnancy test (b-human chorionic gonadotropin analysis [b-HCG]) prior to baseline in females of child-bearing potential.
- Female patients of child-bearing potential must adhere to a pregnancy prevention method (abstinence, chemical or mechanical) during the study.
- Male patients should refrain from fathering a child (including sperm donation) during the study and up to 3 months following the last dose.
5. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws and compliance with study treatment regimens.
For inclusion of Healthy siblings in the study,
1. Documented absence of the genetic defect in LDL receptor or Apo B (by DNA analysis)
2. Historical documented LDL-C of <3.00 mmol/L without lipid lowering medication
Healthy siblings of non-participating patients must have a sibling with FH*.
*FH is defined by a documented genetic defect in LDL-R or ApoB (by DNA analysis) or documented evidence of FH in a first-degree relative (LDL�C >4.90 mmol/L [189 mg/dL] in an adult; >4.10 mmol/L [158 mg/dL] in a child <18 years of age).
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| E.4 | Principal exclusion criteria |
1. History of statin-inducted myopathy or serious hypersensitivity reaction to other HMG-CoA reductase inhibitors (statins), including rosuvastatin, at Visit 1.
2. Fasting TG ≥ 2.87 mmol/L (254 mg/dL) at Visit 1 for statin-naïve patients and at Visit 2 for patients who were on prior statin treatment.
3. Fasting serum glucose of >9.99 mmol/L (180 mg/dL) or glycosylated haemoglobin (HbA1c) >9% at Visit 1 or patients with a history of diabetic ketoacidosis within the past year.
4. Uncontrolled hypothyroidism defined as thyroid stimulating hormone (TSH) >1.5 times the upper limit of normal (ULN) at Visit 1 (Week –4) or patients whose thyroid replacement therapy was initiated or modified within the last 3 months prior to Visit 3 (Week 0).
5. Current active liver disease or hepatic dysfunction (except a confirmed diagnosis of Gilbert’s disease) as defined as elevations of 1.5 times the ULN for any age in any of the following liver functions test at Visit 1 or Visit 2: ALT, AST, or bilirubin.
6. Serum CK ≥ 3 times ULN (unless explained by exercise) at Visit 1.
7. Estimated glomerular filtration rate (GFR) by Schwartz formula <50 mL/min at Visit 1.
8. A ≥ 2+ proteinuria on urine dipstick at any of the screening visits: Visit 1 or Visit 2, will exclude the patient from participation.
9. Stage 2 hypertension (systolic and/or diastolic blood pressure [BP] greater than 5 mmHg above the 99th percentile for age, gender and height) at Visit 1 and Visit 2 (where applicable).
10. History of solid organ transplantation at Visit 1.
11. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
12. Previous enrolment in the present study.
13. Participation in a clinical study where an investigational product was ingested during the last 30 days before Visit 3 (Week 0) of the current study.
14. Any acute illness within 2 weeks before the start of the study (Visit 1).
15. Any clinically significant abnormalities in clinical chemistry and haematology or urinalysis results at the discretion of the investigator.
16. Any contraindication from the following: a detailed medical and drug history, a complete physical examination including vital signs, blood chemistry, haematology, coagulation factors and urinalysis.
17. Definite or suspected personal history or family history of adverse drug reactions (ADRs), or hypersensitivity to drugs with a similar chemical structure to rosuvastatin as well as other statins.
18. History or presence of gastrointestinal, hepatic or renal disease or other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
19. Treatment in the previous 3 months with any drug known to have a well-defined potential for hepatotoxicity (eg, halothane).
20. Treatment with any lipid lowering medications within 4 weeks or less of initial dosing.
21. Clinical judgement by the investigator that the volunteer should not participate in the study.
22. Patients weighing <20 kg (44 lbs).
Healthy siblings should not enter the study if the following exclusion criteria are fulfilled:
1. Participation in a study requiring ingestion of a lipid lowering therapy.
2. Under the care of a specialist if deemed exclusionary per investigator discretion.
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 5.3. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy parameter is the percentage reduction in LDL-C in patients from baseline to 3 months, 12 months and 24 months of treatment with 5 mg, 10 mg or 20 mg rosuvastatin.
To establish the long-term safety, tolerability and efficacy of rosuvastatin in psediatric patients with FH.
The assessment of growth by assessment of height (including linear growth [cm and standard deviationscore]) and secondary characteristics of sexual maturation by Tanner staging at baseline, 12 months and 24 months.
Single dose pharmacokinetics of rosuvastatin: Cmax, tmax, and AUC(0-24).
Population pharmacokinetics of rosuvastatin: CL/F and AUC(0-24) at steady state. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| baseline (week 0), 12 months and 24 months |
|
| E.5.2 | Secondary end point(s) |
to assess cIMT by sonography at baseline and every year in patients and healthy siblings;
to assess growth and maturation in children or adolescents with FH who are receiving long-term rosuvastatin treatment;
to assess adherence to rosuvastatine during a 2-year period of treatment;
to assess the feasibility and acceptability of the current marketed tablet formulation of rosuvastatine for use in children |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
week 0 (baseline) and every year
2-year period of treatment |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 |
| Belgium |
| Canada |
| Netherlands |
| Norway |
| United States |
|
| 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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| End of trial will be defined as data base lock. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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