E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypercholesterolemia - The current trial will study children with Homozygous Familial Hypercholesterolemia (HoFH). |
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E.1.1.1 | Medical condition in easily understood language |
The current trial will study children with a genetic disorder causing them to have high blood levels of bad cholesterol. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the long-term safety and tolerability of rosuvastatin 20 mg in pediatric patients with Homozygous Familial Hypercholesterolemia (HoFH). |
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E.2.2 | Secondary objectives of the trial |
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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). Study D3561C00004 participants who have had their 18th birthday (adults) will be required to provide written informed consent. Communication should take place 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 who were aged 6 to <18 years at the onset of Study D3561C00004 (even if they had their 18th birthday during that study) with:
Documentation of genetic testing confirming 2 mutated alleles of the LDL receptor gene locus; and/or Documented untreated LDL C >500 mg/dL (12.9 mmol/L) and TG <400 mg/dL (4.5 mmol/L) and at least 1 of the following criteria:
o Tendinous and/or cutaneous xanthoma prior to 10 years of age; or
o Documentation of HeFH in both parents by: genetic and/or clinical criteria;
3. Negative pregnancy test (b human chorionic gonadotropin analysis) 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 and 3 months following the last dose;
- Male patients should refrain from fathering a child (including sperm donation) during the study and up to 3 months following the last dose; and
4. Were taking study drug at the end of Study D3561C00004 and are willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens. |
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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 of Study D3561C00004;
2. Fasting serum glucose of >9.99 mmol/L (180 mg/dL) or glycosylated hemoglobin >9% during Study D3561C00004 or patients with a history of diabetic ketoacidosis within the past year;
3. Uncontrolled hypothyroidism defined as thyroid stimulating hormone >1.5 times the upper limit of normal (ULN) at any time during Study D3561C00004;
4. Evidence of active liver disease or hepatic dysfunction (except a confirmed diagnosis of Gilbert’s disease) as defined as non-transient elevations of ALT or AST elevations ≥3 times the ULN or non-transient total bilirubin ≥2 times the ULN during the Study D3561C00004;
5. Serum CK 3 times ULN (unless transient and/or explained by exercise) during Study D3561C00004;
6. Estimated glomerular filtration rate by Schwartz formula <50 mL/min at Visit 1 of Study D3561C00004;
7. A non-transient finding of ≥2 + proteinuria on urine dipstick during Study D3561C00004;
8. Stage 2 hypertension (non-transient systolic and/or diastolic blood pressure greater than 5 mmHg above the 99th percentile for age, gender, and height) during Study D3561C00004;
9. History of solid organ transplantation reported at any time;
10. Involvement in the planning and/or conduct of this study (applies to both AstraZeneca staff and/or staff at the study site);
11. Previous withdrawal from the present study;
12. Participation in clinical study (other than Study D3561C00004) where an investigational product was ingested within 30 days prior to the current study;
13. At the discretion of the Investigator: any new and clinically significant abnormalities in medical history, chemistry, hematology, or urinalysis results;
14. Definite or suspected personal history or family history of clinically significant adverse drug reactions (ADRs), or hypersensitivity to drugs with a similar chemical structure to rosuvastatin as well as other statins;
15. History or presence of gastrointestinal, hepatic, or renal disease or other conditions known to interfere with absorption, distribution, metabolism, or excretion of drugs;
16. Treatment in the previous 3 months with any drug known to have a well defined potential for hepatotoxicity (e.g., halothane);
17. Clinical judgment by the Investigator that the patient should not participate in the study;
18. Patients weighing <20 kg (44 lbs) or;
19. Pregnancy or lactating. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety
Adverse events, including:
• The frequency and severity of adverse events,
• Rate of discontinuations due to adverse events,
• Abnormal serum and urine laboratory values, electrocardiograms (ECGs), physical examinations, and vital signs; and
Assessments of growth, including height (linear growth [cm and standard deviation (SD) score]), weight, and secondary characteristics of sexual maturation by Tanner stage performed at Visit 1 (as part of the final assessments of Study D3561C00004), Visit 5, and the final visit of Study D356NC00001 (at least annually). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Samples taken at week 0, week 12, week 24, week 36, week 48, week 60, week 72, week 84, week 96 |
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E.5.2 | Secondary end point(s) |
Efficacy
Low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG), non-HDL-C, LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA 1), and ApoB/ApoA-1 at 12-week intervals during treatment with rosuvastatin 20 mg. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Samples taken at week 0, week 12, week 24, week 36, week 48, week 60, week 72, week 84, week 96 |
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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 | 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
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 | 6 |
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 |
Belgium |
Canada |
Denmark |
Germany |
Israel |
Lebanon |
Malaysia |
Netherlands |
Sweden |
Taiwan |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |