Clinical trial NCT02226198: A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Homozygous Familial Hypercholesterolemia (HoFH)
Keywords: LDL-C
HoFH
Hyperlipidemia
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-08-27
Enrollment: 20
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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 \[EC\] 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.
2. 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:
   1. Tendinous and/or cutaneous xanthoma prior to 10 years of age; or
   2. Documentation of HoFH 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. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens.

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 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.
3. 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.
4. 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.
5. 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.

Primary outcomes:
measure: LDL-Cholesterol (mg/dL)
timeFrame: Samples taken on Day 42 (week 6) and on day 84 (week 12)
measure: LDL-Cholesterol (mmol/L)
timeFrame: Samples taken on Day 42 (week 6) and on day 84 (week 12)
Secondary outcomes:
measure: TC (mg/dL)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: TC (mmol/L)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: Non-HDL C (mg/dL)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: Non-HDL C (mmol/L)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: ApoB (mg/dL)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: ApoB (g/L)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: HDL-C (mg/dL)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: HDL-C (mmol/L)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: LDL-C, Not on Apheresis (mg/dL)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: LDL-C, Not on Apheresis (mmol/L)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: LDL-C From End of Placebo (mg/dL)
timeFrame: Samples taken at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) and Day 168 (week 24)
measure: LDL-C From End of Placebo (mmol/L)
timeFrame: Samples taken at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) and Day 168 (week 24)
measure: Trough Concentrations
timeFrame: Samples taken 24 hours post-dose at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18)
measure: Adverse Events
timeFrame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening)
measure: AE's Leading to Discontinuation
timeFrame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening)
measure: Abnormal Serum Levels
timeFrame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening)
measure: Height
timeFrame: Week 0 (start of cross-over), weeks 6, week 12 and week 18
measure: Height Z-score
timeFrame: Week 0 (start of cross-over), weeks 6, week 12 and week 18
measure: Weight
timeFrame: Week 0 (start of cross-over), weeks 6, week 12 and week 18
measure: Tanner Stage
timeFrame: Week 0 (start of cross-over)
measure: TG (mg/dL)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: TG (mmol/L)
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: LDL C/HDL C
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: TC/HDL C
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: Non-HDL C/HDL C
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: ApoB/ApoA
timeFrame: Samples taken at Day 42 (week 6) and Day 84 (week 12)
measure: Urinalysis Abnormalitites
timeFrame: Week 0, week 6, week 12 and week 18
measure: ECG Abnormalities
timeFrame: Week 0
measure: Physical Exam Abnormalitites
timeFrame: Screening, Week 0, week 6, week 12 and week 18, week 24
measure: Abnormal Vital Signs
timeFrame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening)
Other outcomes:
Locations:
city: Brussels (Woluwé-St-Lambert)
country: Belgium
facility: Research Site
city: Chicoutimi
country: Canada
facility: Research Site
state: Quebec
city: København Ø
country: Denmark
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kubang Kerian
country: Malaysia
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Goteborg
country: Netherlands
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
Study officials:
References:
citation: Stein EA, Dann EJ, Wiegman A, Skovby F, Gaudet D, Sokal E, Charng MJ, Mohamed M, Luirink I, Raichlen JS, Sunden M, Carlsson SC, Raal FJ, Kastelein JJP. Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations. J Am Coll Cardiol. 2017 Aug 29;70(9):1162-1170. doi: 10.1016/j.jacc.2017.06.058.