Clinical trial NCT02434497: A Study to Evaluate the Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia
Official title: An Open-Label Long-Term Extension to the 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: 2015-05-05
Enrollment: 9
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate the safety of Rosuvastatin in Children and Adolescents with Homozygous Familial Hypercholesterolemia.

Detailed description: This is a long-term extension (LTE) to the randomized, double-blind, cross-over study of rosuvastatin 20 mg once daily (QD) versus placebo QD in children and adolescents (aged from 6 to \<18 years) with homozygous familial hypercholesterolemia (HoFH) (Study D3561C00004).

The study is designed to assess the long-term safety and tolerability of rosuvastatin 20 mg in pediatric patients with HoFH.

In this study all patients will receive rosuvastatin 20 mg QD. Investigators will also be permitted to titrate the dose of rosuvastatin from 20 to 40 mg per day if they feel it is warranted to more aggressively treat patients' elevated LDL-C levels. This up-titration will not be permitted in Asian patients. Pharmacokinetic data of the trough plasma exposure of rosuvastatin will also be assessed for the pediatric patients with HoFH taking a daily dose of rosuvastatin 40 mg.

The primary outcome measures to be assessed include 1) 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 2) Assessments of growth.

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 \[IEC\] 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:

     * Tendinous and/or cutaneous xanthoma prior to 10 years of age; or
     * 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.

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. 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: The Number of Participants Who Experianced Adverse Events and Serious Adverse Events
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Number of Participants Who Had Adverse Events, Discontinuations Due to Adverse Events
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Basophils/Leukocytes (%) >Upper Limite of Normal (ULN)
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Growth, Height
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormalitites in Sexual Maturation
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Growth, Height SD-score (or Z-score)
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Growth, Weight
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Alanine Aminotransferase (U/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Albumin (g/dL) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Aspartate Aminotransferase (U/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Bicarbonate (Mol/L) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Bicarbonate (Mol/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Ery. Mean Corpuscular HGB Concentration (g/dL) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Ery. Mean Corpuscular HGB (pg) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Ery. Mean Corpuscular Volume (fL) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Ery. Mean Corpuscular Volume (fL) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Erythrocytes (10^12/L) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Erythrocytes (10^12/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Hematocrit (%) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Hemoglobin (g/dL) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Leukocytes >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Lymphocytes/Leukocytes (%) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Lymphocytes/Leukocytes (%) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Monocytes/Leukocytes (%) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Platelets (10^9/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Blood Urea Nitrogen (mg/dL) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Chloride (mmol/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Creatine Kinase (U/L) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Glucose (mg/dL) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Lactate Dehydrogenase (U/L) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Phosphate (mg/dL) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Protein (g/dL) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Sodium (mmol/L) <LLN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Serum Laboratory Values, Urate (mg/dL) >ULN
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Urine Laboratory Values, Urine Ketones
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Urine Laboratory Values, Urine Occult Blood
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Urine Laboratory Values, Urine Protein
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal ECG, Abnormalities
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Physical Exams, Cardiovascular
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Physical Exams, General Appearance
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Physical Exams, Head and Neck
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Physical Exams, Musculoskeletal/Extremities
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Physical Exams, Skin
timeFrame: 96 weeks
measure: Safety and Tolerability in Terms of Abnormal Vital Signs
timeFrame: 96 weeks
Secondary outcomes:
measure: Percent Change in LDL-C From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in HDL-C From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in Total Cholesterol (TC) From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in Triglycerides (TG) From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in Non-HDL-C From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in LDL-C/HDL-C From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in TC/HDL-C From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in Non-HDL-C/HDL-C From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in ApoB From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in ApoA-1 From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Percent Change in ApoB/ApoA-1 From End of Placebo of D3561C00004 to the End of D356NC00001, Repeated Measures Analysis
timeFrame: Up to 22 months
measure: Pharmacokinetic Profile in Terms of Trough Concentrations in Pediatric HoFH Taking a Daily Dose of Rosuvastatin 40mg
timeFrame: Up to 22 months
Other outcomes:
Locations:
city: Brussels (Woluwé-St-Lambert)
country: Belgium
facility: Research Site
city: Chicoutimi
country: Canada
facility: Research Site
state: Quebec
city: Copenhagen
country: Denmark
facility: Research Site
city: Halfa
country: Israel
facility: Research Site
city: Kubang Kerian
country: Malaysia
facility: Research Site
city: Taipei City
country: Taiwan
facility: Research Site
Study officials:
References: