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

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

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

Study Overview

• Status: Completed
• Conditions: Pediatric Heterozygous Hypercholesterolemia
• Intervention / Treatment: Drug: Atorvastatin; Drug: Atorvastatin

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4G2
    • Pfizer Investigational Site
• Greece
  • Athens, Greece, 115 27
    • Pfizer Investigational Site
• Norway
  • Oslo, Norway, 0027
    • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.; 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.
Other: 2; 10-17 years will be administered 10-mg daily dose of atorvastatin tablet formulation.	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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)	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.	Week 2, Week 4, Week 6, Week 8
Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F)	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.	Week 2, Week 4, Week 6, Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)	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.	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Total Cholesterol (TC)	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.	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Total Cholesterol (TC)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Triglycerides (TG)	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.	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Triglycerides (TG)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)	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.	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1)	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.	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Apolipoprotein B (Apo B)	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.	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Apolipoprotein B (Apo B)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)	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]).	Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8	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.	Baseline, Week 8
Percent Change From Baseline in Flow-Mediated Dilatation at Week 8	Brachial Flow-Mediated Dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%. .	Baseline, Week 8

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: August 21, 2008
• First Submitted That Met QC Criteria: August 21, 2008
• First Posted (Estimate): August 22, 2008

Study Record Updates

• Last Update Posted (Actual): March 15, 2021
• Last Update Submitted That Met QC Criteria: February 17, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: heterozygous familial hypercholesterolemia (HeFH); atorvastatin; pediatric
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: A2581172