8-Week PK/PD Atorvastatin Study In Children And Adolescents With Heterozygous Familial Hypercholesterolemia

This study has been completed.
Sponsor:
Information provided by:
Pfizer
ClinicalTrials.gov Identifier:
NCT00739999
First received: August 21, 2008
Last updated: August 19, 2010
Last verified: June 2009
  Purpose

To evaluate pharmacokinetics, pharmacodynamics, safety and tolerability of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia


Condition Intervention Phase
Pediatric Heterozygous Hypercholesterolemia
Drug: Atorvastatin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: A 8-Week, Open-Label, Phase 1 Study To Evaluate Pharmacokinetics, Pharmacodynamics, Safety And Tolerability Of Atorvastatin In Children And Adolescents With Heterozygous Familial Hypercholesterolemia

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F) [ Time Frame: Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Parent-metabolite population PK model built using sparse blood samples from both Tanner Stage 1 and Tanner Stage 2+. Blood sampling times: Weeks 2 and 6: single sample between 4 and 12 hours postdose; Weeks 4 and 8: predose, 1 hour, and 2 hours postdose. Plasma samples were analyzed for atorvastatin and active hydroxyacid metabolite (o-hydroxyatorvastatin) concentrations using a validated, sensitive, and specific high-performance liquid chromatography tandem mass spectrometric method. Data presented are the result of the model used.

  • Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F) [ Time Frame: Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Parent-metabolite population PK model built using sparse blood samples from Tanner Stages 1 and 2+. Sampling times: Weeks 2 + 6: single sample between 4 -12 hours postdose; Weeks 4 + 8: predose, 1 + 2 hours postdose. Plasma samples analyzed for atorvastatin and active hydroxyacid metabolite (o-hydroxyatorvastatin) concentrations using validated, sensitive, specific high-performance liquid chromatography tandem mass spectrometric method. Vc/F value based on 70 kg body weight. Parameter estimation uncertainty (95% CI) by non-parametric bootstrap analysis. Data presented are result of model used.


Secondary Outcome Measures:
  • Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Low-density lipoprotein cholesterol (LDL-C) measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Low-density Lipoprotein Cholesterol (LDL-C): percent (%) change from baseline by treatment over time = [LDL-C at observation minus LDL-C at Week 0] divided by LDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in Total Cholesterol (TC) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Total Cholesterol measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in Total Cholesterol (TC) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Total cholesterol (TC): percent (%) change from baseline by treatment over time = [TC at observation minus TC at Week 0] divided by TC at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in Triglycerides (TG) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Change from baseline in triglycerides measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in Triglycerides (TG) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Triglycerides (TG): percent (%) change from baseline by treatment over time = [TG at observation minus TG at Week 0] divided by TG at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Change from baseline in high-density lipoprotein cholesterol measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    High-density lipoprotein cholesterol (HDL-C): percent (%) change by treatment over time = [HDL-C at observation minus HDL-C at Week 0] divided by HDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Change from baseline in Apolipoprotein A-1 measured in grams per liter (g/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Apolipoprotein A-1 (Apo A-1): percent (%) change from baseline by treatment over time = [Apo A-1 at observation minus Apo A-1 at Week 0] divided by Apo A-1 at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Change from baseline in Apolipoprotein B measured in grams per liter (g/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Apolipoprotein B (Apo B): percent (%) change from baseline by treatment over time = [Apo B at observation minus Apo B at Week 0] divided by Apo B at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Change from baseline in very low-density lipoprotein-cholesterol (VLDL-C) measured in millimoles per liter (mmol/L). Change from baseline = value at observation minus baseline value. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Very low-density lipoprotein-cholesterol (VLDL-C): percent (%) change from baseline by treatment over time = [VLDL-C at observation minus VLDL-C at Week 0] divided by VLDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).

  • Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8 [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]
    Brachial artery flow-mediated dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%. Standardized image acquisition: brachial artery images recorded for one minute at rest, blood pressure cuff inflated to 250 mm Hg for 5 minutes with brachial artery imaged continuously throughout cuff inflation, cuff released to produce reactive hyperaemia and the brachial artery imaged continuously for 3 minutes after release. Total duration of measurement approximately 25 minutes. Change from baseline = value at observation minus baseline value.

  • Percent Change From Baseline in Flow-Mediated Dilatation at Week 8 [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]

    Brachial Flow-Mediated Dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%.

    .



Enrollment: 39
Study Start Date: December 2008
Study Completion Date: May 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1
6-10 years will be administered with atorvastatin tablet formulation with initial doses based on age cohort.
Drug: Atorvastatin
6-10 years Tanner Stage 1 will be administered 5-mg daily dose of an atorvastatin pediatric tablet formulation. Dose may be doubled if subjects have not attained target LDL (<3.35 mmol/L) after 4-week treatment.
2
10-17 years will be administered 10-mg daily dose of atorvastatin tablet formulation.
Drug: Atorvastatin
10-17 years Tanner Stage 2 will be administered 10-mg daily dose of atorvastatin tablet formulation. Dose may be doubled if subjects have not attained target LDL (<3.35 mmol/L) after 4-week treatment.

  Eligibility

Ages Eligible for Study:   6 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Genetically confirmed heterozygous familial hypercholesterolemia (HeFH) with LDL greater or equal 4 mmol/L at baseline

Exclusion Criteria:

  • Evidence or history of clinically significant diseases, homozygous familial hypercholesterolemia (FH)
  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: NCT00739999

Locations
Canada
Pfizer Investigational Site
Quebec, Canada, G1V 4G2
Greece
Pfizer Investigational Site
Athens, Greece, 115 27
Norway
Pfizer Investigational Site
Oslo, Norway, 0027
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc.
ClinicalTrials.gov Identifier: NCT00739999     History of Changes
Other Study ID Numbers: A2581172
Study First Received: August 21, 2008
Results First Received: March 15, 2010
Last Updated: August 19, 2010
Health Authority: Canada: Ethics Review Committee

Keywords provided by Pfizer:
heterozygous familial hypercholesterolemia (HeFH); atorvastatin; pediatric

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
Atorvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 26, 2014