An Efficacy and 2-Year Safety Study of Open-label Rosuvastatin in Children and Adolescents (aged from 6 to less than 18 years) with Familial Hypercholesterolaemia

Phase 3

• Conditions: hypercholesterolaemia; 10027424; 10021605

• Registration Number: NL-OMON36759
• Lead Sponsor: Astra Zeneca

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 6 May 2024

Recruitment & Eligibility

• Status: Pending
• Sex: Not specified
• Target Recruitment: 72

Inclusion Criteria

For inclusion in the study, patients should fulfil the following 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 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, they must fulfil the following criteria:
- Documented absence of the genetic defect in LDL receptor or Apo B (by DNA analysis)
OR
- Historical documented LDL-C of <3.00 mmol/L, without lipid lowering medication.
*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).

Exclusion Criteria

Patients should not enter the study if any of the following exclusion criteria are fulfilled:
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. * 2+ proteinuria on urine dipstick at Visit 1 or Visit 2 (where applicable).
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

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Efficacy:<br /><br>* Percent change from baseline in low-density lipoprotein cholesterol following<br /><br>3 months, 12 months and 24 months of treatment with rosuvastatin 5 mg, 10 mg or<br /><br>20 mg.<br /><br><br /><br>Safety:<br /><br>* Assessments of growth by assessment of height (including linear growth [cm<br /><br>and standard deviation score]) and secondary characteristics of sexual<br /><br>maturation by Tanner staging at baseline, 12 months and 24 months.<br /><br><br /><br>Pharmacokinetics:<br /><br>* Single dose pharmacokinetics of rosuvastatin: Cmax, tmax, and AUC(0-24).<br /><br>* Population pharmacokinetics of rosuvastatin: CL/F and AUC(0-24) at steady<br /><br>state.</p><br>