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

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

Official Title
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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

Conditions
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Pediatric Heterozygous Hypercholesterolemia

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Atorvastatin


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1<br>6-10 years will be administered with atorvastatin tablet formulation with initial doses based on age cohort. | Drug: Atorvastatin<br>* 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.<br>|
| Other: 2<br>10-17 years will be administered 10-mg daily dose of atorvastatin tablet formulation. | Drug: Atorvastatin<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heterozygous familial hypercholesterolemia (HeFH); atorvastatin; pediatric