A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia

Study Overview
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Brief Summary
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The purpose of the study is to establish the efficacy, safety and tolerability of rosuvastatin in children and adolescents with homozygous familial hypercholesterolemia.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, multi-center, cross-over study of the efficacy, safety and tolerability rosuvastatin in children and adolescents (aged 6 to <18 years) with homozygous familial hypercholesterolemia (HoFH). The study is designed to assess the efficacy of rosuvastatin 20 mg compared to placebo on lipids, lipoproteins and apolipoproteins in pediatric patients with HoFH. The outcome measures to be assessed include low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides, 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 following 6 weeks of treatment with rosuvastatin 20 mg or placebo. Pharmacokinetic data of the trough plasma exposure of rosuvastatin will also be assessed in these pediatric patients with HoFH.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multi-center, Cross-over Study of Rosuvastatin in Children and Adolescents (Aged 6 to <18 Years) With Homozygous Familial Hypercholesterolemia (HoFH)

Conditions
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Homozygous Familial Hypercholesterolemia (HoFH)

Intervention / Treatment
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* Drug: Rosuvastatin 20mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 [EC] 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. Male and female children and adolescents (aged 6 to <18 years) with at least 1 of the following criteria: 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 triglyceride (TG) <300 mg/dL (3.4 mmol/L) and at least 1 of the following criteria: Tendinous and/or cutaneous xanthoma prior to 10 years of age; or Documentation of HoFH in both parents by: genetic and/or clinical criteria 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 Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens. Exclusion Criteria History of statin inducted myopathy or serious hypersensitivity reaction to other HMG CoA reductase inhibitors (statins), including rosuvastatin, at Visit 1. Fasting serum glucose of >9.99 mmol/L (180 mg/dL) or glycosylated hemoglobin >9% at Visit 1 or patients with a history of diabetic ketoacidosis within the past year. Uncontrolled hypothyroidism defined as thyroid stimulating hormone (TSH) >1.5 times the upper limit of normal (ULN) at Visit 1 or patients whose thyroid replacement therapy was initiated or modified within the last 3 months prior to Visit 2. Current active liver disease or hepatic dysfunction (except a confirmed diagnosis of Gilbert's disease) as defined as elevations of 1.5 times the upper limit of normal (ULN) for any age in any of the following liver function tests at Visit 1: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), or bilirubin. 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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rosuvastatin<br>6-week treatment period, and after crossover finished a 12-week efficacy maintenance phase for all patients | Drug: Rosuvastatin 20mg<br>* Active drug will be taken taken orally, QD, either in the morning or in the evening<br>|
| Placebo Comparator: Placebo<br>6 weeks treatment during crossover | Drug: Placebo<br>* Will be taken taken orally, QD, either in the morning or in the evening<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LDL-Cholesterol (mg/dL) | Change in low density lipoprotein cholesterol (LDL C) following 6 weeks of rosuvastatin 20 mg compared to 6 weeks of placebo treatment | Samples taken on Day 42 (week 6) and on day 84 (week 12) | 
| LDL-Cholesterol (mmol/L) | Change in low density lipoprotein cholesterol (LDL C) following 6 weeks of rosuvastatin 20 mg compared to 6 weeks of placebo treatment | Samples taken on Day 42 (week 6) and on day 84 (week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TC (mg/dL) | Efficacy in terms of total cholesterol (TC) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| TC (mmol/L) | Efficacy in terms of total cholesterol (TC) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| Non-HDL C (mg/dL) | Efficacy in terms of non-high density lipoprotein cholesterol (non-HDL C) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| Non-HDL C (mmol/L) | Efficacy in terms of non-high density lipoprotein cholesterol (non-HDL C) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| ApoB (mg/dL) | Efficacy in terms of apolipoprotein B (ApoB) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| ApoB (g/L) | Efficacy in terms of apolipoprotein B (ApoB) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| HDL-C (mg/dL) | Efficacy in terms of high density lipoprotein cholesterol (HDL C) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| HDL-C (mmol/L) | Efficacy in terms of high density lipoprotein cholesterol (HDL C) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| LDL-C, Not on Apheresis (mg/dL) | Efficacy in terms of low density lipoprotein cholesterol (LDL C) following 6 weeks rosuvastatin 20 mg or placebo treatment in patients not treated with Apheresis | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| LDL-C, Not on Apheresis (mmol/L) | Efficacy in terms of low density lipoprotein cholesterol (LDL C) following 6 weeks rosuvastatin 20 mg or placebo treatment in patients not treated with Apheresis | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| LDL-C From End of Placebo (mg/dL) | Change in low density lipoprotein cholesterol (LDL C) from end of placebo period to 6, 12, and 18 weeks of therapy with rosuvastatin 20 mg | Samples taken at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) and Day 168 (week 24) | 
| LDL-C From End of Placebo (mmol/L) | Change in low density lipoprotein cholesterol (LDL C) from end of placebo period to 6, 12, and 18 weeks of therapy with rosuvastatin 20 mg | Samples taken at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) and Day 168 (week 24) | 
| Trough Concentrations | Pharmacokinetic profile in terms of trough concentrations. Cross-over phase results based on measurements taken after 6 weeks active treatment (rosuvastatin) in the cross-over phase. Maintenance phase results based on measurements taken after 6 weeks active treatment (rosuvastatin) in the maintenance phase. | Samples taken 24 hours post-dose at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) | 
| Adverse Events | Safety and tolerability will be described in terms of frequency and severity of adverse events | From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) | 
| AE's Leading to Discontinuation | Safety and tolerability will be described in terms of rate of discontinuations due to adverse events | From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) | 
| Abnormal Serum Levels | Safety and tolerability will be described in terms of abnormal serum laboratory values. The reported parameters are not the only ones measured, but rather those for which abnormailities were found | From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) | 
| Height | Safety and tolerability will be described in terms of growth, including height (linear growth [cm and standard deviation (SD) score]), and weight. | Week 0 (start of cross-over), weeks 6, week 12 and week 18 | 
| Height Z-score | Safety and tolerability will be described in terms of growth, including height (linear growth [cm and standard deviation (SD) score]), and weight. | Week 0 (start of cross-over), weeks 6, week 12 and week 18 | 
| Weight | Safety and tolerability will be described in terms of growth, including height (linear growth [cm and standard deviation (SD) score]), and weight. | Week 0 (start of cross-over), weeks 6, week 12 and week 18 | 
| Tanner Stage | Stages for fem (Pubic hair, Breasts): (Preadol,Preadol) (Sparse, lightly pigmented, medial border of labia,Breast and papilla elevated as small mound; areolar diam incr) (Darker, beginning to curl, incr amount, Breast and areola enlarged, no contour separation) (Course, curly, abundant but less amount in adult,Areola and papilla form secondary mound) (Adult fem triangle, spread to medial surface of thighs,Mature, nipple projects, areola part of general breast contour) For males (Pubic hair, Penis, Testes) 1=(None,Preadol,Preadol) 2=(Scanty, long, light pigm,Slight enl,Enl scrotum, pink texture alt) 3=(Darker, starts to curl, small amount,Longer,Larger) 4=(Resembles adult type, but less in quant; course, curly,Larger; glans and breadth increased in size,Larger, scrotum dark) 5=(Adult distr, spread to medial thighs,Adult size,Adult size). Progr at a normal rate is preferred. Regr is not preferred. | Week 0 (start of cross-over) | 
| TG (mg/dL) | Efficacy in terms of triglycerides (TG) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| TG (mmol/L) | Efficacy in terms of triglycerides (TG) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| LDL C/HDL C | Efficacy in terms of low density lipoprotein cholesterol (LDL C) / high density lipoprotein cholesterol (HDL C) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| TC/HDL C | Efficacy in terms of total cholesterol (TC) / high density lipoprotein cholesterol (HDL C) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| Non-HDL C/HDL C | Efficacy in terms of non-high density lipoprotein cholesterol (non-HDL C) / HDL C | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| ApoB/ApoA | Efficacy in terms of apolipoprotein B (ApoB) / apolipoprotein A (ApoA) | Samples taken at Day 42 (week 6) and Day 84 (week 12) | 
| Urinalysis Abnormalitites | Safety and tolerability will be described in terms of abnormal urine laboratory values | Week 0, week 6, week 12 and week 18 | 
| ECG Abnormalities | Safety and tolerability will be described in terms of abnormal electro cardio gram (ECG) | Week 0 | 
| Physical Exam Abnormalitites | Safety and tolerability will be described in terms of abnormal physical examinations. Only parameters for which abnormalities were found are reported. | Screening, Week 0, week 6, week 12 and week 18, week 24 | 
| Abnormal Vital Signs | Safety and tolerability will be described in terms of abnormal vital signs | From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LDL-C, HoFH, Hyperlipidemia