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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02226198
First received: August 14, 2014
Last updated: July 1, 2016
Last verified: July 2016
  Purpose
The purpose of the study is to establish the efficacy, safety and tolerability of rosuvastatin in children and adolescents with homozygous familial hypercholesterolemia.

Condition Intervention Phase
Homozygous Familial Hypercholesterolemia (HoFH)
Drug: Rosuvastatin 20mg
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • LDL-Cholesterol (mg/dL) [ Time Frame: Samples taken on Day 42 (week 6) and on day 84 (week 12) ] [ Designated as safety issue: No ]
    Change in low density lipoprotein cholesterol (LDL C) following 6 weeks of rosuvastatin 20 mg compared to 6 weeks of placebo treatment

  • LDL-Cholesterol (mmol/L) [ Time Frame: Samples taken on Day 42 (week 6) and on day 84 (week 12) ] [ Designated as safety issue: No ]
    Change in low density lipoprotein cholesterol (LDL C) following 6 weeks of rosuvastatin 20 mg compared to 6 weeks of placebo treatment


Secondary Outcome Measures:
  • TC (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of total cholesterol (TC)

  • TC (mmol/L) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of total cholesterol (TC)

  • Non-HDL C (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of non-high density lipoprotein cholesterol (non-HDL C)

  • Non-HDL C (mmol/L) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of non-high density lipoprotein cholesterol (non-HDL C)

  • ApoB (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of apolipoprotein B (ApoB)

  • ApoB (g/L) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of apolipoprotein B (ApoB)

  • HDL-C (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of high density lipoprotein cholesterol (HDL C)

  • HDL-C (mmol/L) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of high density lipoprotein cholesterol (HDL C)

  • LDL-C, Not on Apheresis (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    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

  • LDL-C, Not on Apheresis (mmol/L) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    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

  • LDL-C From End of Placebo (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) and Day 168 (week 24) ] [ Designated as safety issue: No ]
    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

  • LDL-C From End of Placebo (mmol/L) [ Time Frame: Samples taken at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) and Day 168 (week 24) ] [ Designated as safety issue: No ]
    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

  • Trough Concentrations [ Time Frame: Samples taken 24 hours post-dose at Day 42 (week 6), Day 84 (week 12), Day 126 (week 18) ] [ Designated as safety issue: No ]
    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.

  • Adverse Events [ Time Frame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of frequency and severity of adverse events

  • AE's Leading to Discontinuation [ Time Frame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of rate of discontinuations due to adverse events

  • Abnormal Serum Levels [ Time Frame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) ] [ Designated as safety issue: Yes ]
    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

  • Height [ Time Frame: Week 0 (start of cross-over), weeks 6, week 12 and week 18 ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of growth, including height (linear growth [cm and standard deviation (SD) score]), and weight.

  • Height Z-score [ Time Frame: Week 0 (start of cross-over), weeks 6, week 12 and week 18 ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of growth, including height (linear growth [cm and standard deviation (SD) score]), and weight.

  • Weight [ Time Frame: Week 0 (start of cross-over), weeks 6, week 12 and week 18 ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of growth, including height (linear growth [cm and standard deviation (SD) score]), and weight.

  • Tanner Stage [ Time Frame: Week 0 (start of cross-over) ] [ Designated as safety issue: Yes ]

    Stages for fem (Pubic hair, Breasts):

    1. (Preadol,Preadol)
    2. (Sparse, lightly pigmented, medial border of labia,Breast and papilla elevated as small mound; areolar diam incr)
    3. (Darker, beginning to curl, incr amount, Breast and areola enlarged, no contour separation)
    4. (Course, curly, abundant but less amount in adult,Areola and papilla form secondary mound)
    5. (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.


  • TG (mg/dL) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of triglycerides (TG)

  • TG (mmol/L) [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of triglycerides (TG)

  • LDL C/HDL C [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of low density lipoprotein cholesterol (LDL C) / high density lipoprotein cholesterol (HDL C)

  • TC/HDL C [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of total cholesterol (TC) / high density lipoprotein cholesterol (HDL C)

  • Non-HDL C/HDL C [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of non-high density lipoprotein cholesterol (non-HDL C) / HDL C

  • ApoB/ApoA [ Time Frame: Samples taken at Day 42 (week 6) and Day 84 (week 12) ] [ Designated as safety issue: No ]
    Efficacy in terms of apolipoprotein B (ApoB) / apolipoprotein A (ApoA)

  • Urinalysis Abnormalitites [ Time Frame: Week 0, week 6, week 12 and week 18 ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of abnormal urine laboratory values

  • ECG Abnormalities [ Time Frame: Week 0 ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of abnormal electro cardio gram (ECG)

  • Physical Exam Abnormalitites [ Time Frame: Screening, Week 0, week 6, week 12 and week 18, week 24 ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of abnormal physical examinations. Only parameters for which abnormalities were found are reported.

  • Abnormal Vital Signs [ Time Frame: From screening (5-6weeks before dose) up to the last visit Day 168 (approximately 30 weeks after screening) ] [ Designated as safety issue: Yes ]
    Safety and tolerability will be described in terms of abnormal vital signs


Enrollment: 20
Study Start Date: November 2014
Study Completion Date: July 2015
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rosuvastatin
6-week treatment period, and after crossover finished a 12-week efficacy maintenance phase for all patients
Drug: Rosuvastatin 20mg
Active drug will be taken taken orally, QD, either in the morning or in the evening
Placebo Comparator: Placebo
6 weeks treatment during crossover
Drug: Placebo
Will be taken taken orally, QD, either in the morning or in the evening

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

Ages Eligible for Study:   6 Years to 17 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02226198

Locations
Belgium
Research Site
Brussels (Woluwé-St-Lambert), Belgium
Canada, Quebec
Research Site
Chicoutimi, Quebec, Canada
Denmark
Research Site
København Ø, Denmark
Israel
Research Site
Haifa, Israel
Malaysia
Research Site
Kuala Lumpur, Malaysia
Research Site
Kubang Kerian, Malaysia
Netherlands
Research Site
Amsterdam, Netherlands
Research Site
Goteborg, Netherlands
Taiwan
Research Site
Taipei, Taiwan
Sponsors and Collaborators
AstraZeneca
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02226198     History of Changes
Other Study ID Numbers: D3561C00004 
Study First Received: August 14, 2014
Results First Received: December 18, 2015
Last Updated: July 1, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by AstraZeneca:
LDL-C
HoFH
Hyperlipidemia

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipoproteinemia Type II
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias
Rosuvastatin Calcium
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents

ClinicalTrials.gov processed this record on August 25, 2016