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

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00739999
• Collaborator: (none)
• Enrollment: 39
• Locations: 3
• Arms: 2
• Duration (Months): 5
• Patients Per Site: 13
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Pediatric Heterozygous Hypercholesterolemia	Drug: Atorvastatin; Drug: Atorvastatin	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

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.
Other: 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.

Outcome Measures

Primary Outcome Measures

1. Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F) [Week 2, Week 4, Week 6, Week 8]

   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.

2. Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F) [Week 2, Week 4, Week 6, Week 8]

   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

1. Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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.

2. Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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]).

3. Absolute Change From Baseline in Total Cholesterol (TC) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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.

4. Percent Change From Baseline in Total Cholesterol (TC) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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]).

5. Absolute Change From Baseline in Triglycerides (TG) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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.

6. Percent Change From Baseline in Triglycerides (TG) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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]).

7. Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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.

8. Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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]).

9. Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1) [Baseline, Week 2, Week 4, Week 6, Week 8]

   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.

10. Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) [Baseline, Week 2, Week 4, Week 6, Week 8]

    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]).

11. Absolute Change From Baseline in Apolipoprotein B (Apo B) [Baseline, Week 2, Week 4, Week 6, Week 8]

    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.

12. Percent Change From Baseline in Apolipoprotein B (Apo B) [Baseline, Week 2, Week 4, Week 6, Week 8]

    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]).

13. Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) [Baseline, Week 2, Week 4, Week 6, Week 8]

    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]).

14. Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) [Baseline, Week 2, Week 4, Week 6, Week 8]

    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]).

15. Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8 [Baseline, 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.

16. Percent Change From Baseline in Flow-Mediated Dilatation at Week 8 [Baseline, Week 8]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Quebec		Canada	G1V 4G2
2	Pfizer Investigational Site	Athens		Greece	115 27
3	Pfizer Investigational Site	Oslo		Norway	0027

Sponsors and Collaborators

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

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT00739999
• Other Study ID Numbers: A2581172
• First Posted: Aug 22, 2008
• Last Update Posted: Mar 15, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.: heterozygous familial hypercholesterolemia (HeFH); atorvastatin; pediatric
• Additional relevant MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia; Atorvastatin

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at 3 medical centers and participated in the study between 02 December 2008 and 13 May 2009.
Pre-assignment Detail	Forty-five subjects were screened, and 39 subjects were assigned to study treatment.

Arm/Group Title	Atorvastatin (5 mg, 10 mg): Tanner Stage 1	Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
Arm/Group Description	Age 6 - 10 years, at Tanner Stage 1. Initial dose 5 mg/day through Week 4; after Week 4 dose may have been doubled to 10 mg/day if target low-density lipoprotein cholesterol (LDL-C) was not attained.	Age 10 - 17 years, at Tanner Stage 2+. Initial dose 10 mg/day through Week 4; after Week 4 dose may have been doubled to 20 mg/day if target LDL-C was not attained.
Period Title: Overall Study
STARTED	15	24
COMPLETED	15	24
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Atorvastatin (5 mg, 10 mg): Tanner Stage 1	Atorvastatin (10 mg, 20 mg): Tanner Stage 2+	Total
Arm/Group Description	Initial dose 5 mg/day through Week 4; after Week 4 dose may have been doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Initial dose 10 mg/day through Week 4; after Week 4 dose may have been doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.	Total of all reporting groups
Overall Participants	15	24	39
Age, Customized (participants) [Number]
6-8 years	7 46.7%	0 0%	7 17.9%
9-10 years	6 40%	3 12.5%	9 23.1%
11-14 years	2 13.3%	14 58.3%	16 41%
15-17 years	0 0%	7 29.2%	7 17.9%
Sex: Female, Male (Count of Participants)
Female	7 46.7%	12 50%	19 48.7%
Male	8 53.3%	12 50%	20 51.3%

Outcome Measures

1. Primary Outcome

Title	Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)
Description	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.
Time Frame	Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) concentration population: all enrolled and treated subjects who had ≥ 1 PK concentration assessed. Active hydroxyacid metabolite p-hydroxyatorvastatin was not included in the model as originally planned as > 80% of samples were below detectable level at the doses used in this trial.

Arm/Group Title	Atorvastatin (5 mg, 10 mg): Tanner Stage 1	Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
Arm/Group Description	Initial dose 5 mg/day through Week 4; after Week 4 dose may have been doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Initial dose 10 mg/day through Week 4; after Week 4 dose may have been doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	15	24
Number [L/hr]	553	543

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin (5 mg, 10 mg): Tanner Stage 1, Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
	Comments	Atorvastatin apparent clearance (CL/F) was described as a function of body weight using an allometric equation. The estimated parameter given is an extrapolation of the model for participants who weigh 70 kg.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Atorvastatin CL/F based on 70 kg BW
	Estimated Value	699
	Confidence Interval	(2-Sided) 95%; 570 to 881
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)
Description	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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis population: all enrolled subjects who received ≥ 1 dose of study drug and had ≥ 1 PD parameter measurement.

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	4.87 (0.48)	6.37 (1.10)	5.11 (0.65)	6.23 (1.00)
Week 2	-1.75 (0.72)	-1.62 (0.46)	-1.95 (0.52)	-1.90 (0.72)
Week 4	-2.07 (0.50)	-1.94 (0.56)	-2.24 (0.57)	-2.27 (1.04)
Week 6	-1.89 (0.42)	-2.57 (0.70)	-2.12 (0.74)	-2.55 (1.02)
Week 8	-1.80 (0.63)	-2.71 (0.60)	-1.99 (0.58)	-2.60 (1.01)

3. Secondary Outcome

Title	Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	-36.27 (14.72)	-25.70 (7.76)	-38.14 (9.35)	-30.27 (9.22)
Week 4	-42.33 (8.24)	-30.27 (5.72)	-43.66 (7.78)	-35.13 (12.01)
Week 6	-38.87 (7.84)	-40.01 (6.34)	-41.22 (11.34)	-39.73 (10.40)
Week 8	-36.78 (11.16)	-42.70 (6.45)	-38.45 (7.84)	-40.39 (11.71)

4. Secondary Outcome

Title	Absolute Change From Baseline in Total Cholesterol (TC)
Description	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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	6.76 (0.46)	8.58 (1.06)	6.92 (0.71)	8.40 (1.10)
Week 2	-1.89 (0.79)	-2.04 (0.69)	-2.11 (0.53)	-2.28 (0.82)
Week 4	-2.27 (0.63)	-2.24 (0.49)	-2.37 (0.61)	-2.66 (1.29)
Week 6	-2.03 (0.53)	-2.86 (0.79)	-2.28 (0.73)	-2.95 (1.19)
Week 8	-1.89 (0.44)	-3.20 (0.65)	-2.26 (0.69)	-3.22 (1.14)

5. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (TC)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	-28.06 (11.23)	-24.11 (8.97)	-30.60 (7.49)	-26.78 (7.59)
Week 4	-33.37 (7.81)	-26.12 (4.24)	-33.98 (7.13)	-30.54 (11.60)
Week 6	-29.99 (8.00)	-33.12 (6.83)	-32.80 (8.97)	-34.06 (9.94)
Week 8	-27.80 (5.56)	-37.17 (5.28)	-32.43 (8.53)	-37.45 (9.89)

6. Secondary Outcome

Title	Absolute Change From Baseline in Triglycerides (TG)
Description	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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	0.76 (0.15)	0.95 (0.27)	1.03 (0.37)	1.20 (0.50)
Week 2	0.05 (0.34)	-0.08 (0.28)	0.05 (0.68)	0.00 (0.47)
Week 4	-0.05 (0.29)	-0.26 (0.30)	-0.10 (0.51)	-0.10 (0.37)
Week 6	0.40 (0.62)	-0.04 (0.24)	-0.12 (0.42)	-0.04 (0.32)
Week 8	0.02 (0.28)	-0.16 (0.37)	-0.31 (0.43)	-0.28 (0.41)

7. Secondary Outcome

Title	Percent Change From Baseline in Triglycerides (TG)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	5.66 (38.26)	-6.87 (29.08)	28.37 (85.32)	-0.56 (32.19)
Week 4	-6.20 (32.55)	-21.43 (30.42)	1.27 (50.81)	-7.60 (25.75)
Week 6	57.06 (78.73)	-1.27 (23.91)	-4.43 (32.52)	-2.72 (24.80)
Week 8	1.69 (31.48)	-9.88 (33.31)	-20.94 (39.24)	-21.11 (23.85)

8. Secondary Outcome

Title	Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
Description	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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	1.35 (0.12)	1.45 (0.29)	1.17 (0.18)	1.18 (0.23)
Week 2	0.08 (0.24)	-0.10 (0.29)	-0.05 (0.26)	-0.01 (0.20)
Week 4	-0.02 (0.05)	0.00 (0.19)	0.02 (0.21)	-0.01 (0.28)
Week 6	-0.12 (0.29)	-0.01 (0.18)	0.04 (0.14)	-0.03 (0.23)
Week 8	0.04 (0.22)	-0.07 (0.21)	0.08 (0.25)	-0.08 (0.22)

9. Secondary Outcome

Title	Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	5.38 (17.32)	-6.45 (21.01)	-4.11 (19.96)	-0.77 (17.66)
Week 4	-1.99 (3.90)	1.59 (13.18)	1.04 (17.38)	1.77 (23.22)
Week 6	-10.18 (22.70)	-0.64 (10.35)	3.28 (11.63)	-2.78 (21.49)
Week 8	2.50 (15.02)	-2.84 (14.49)	5.99 (21.02)	-5.19 (17.76)

10. Secondary Outcome

Title	Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1)
Description	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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	1.42 (0.20)	1.45 (0.20)	1.29 (0.20)	1.24 (0.15)
Week 2	0.01 (0.17)	-0.08 (0.23)	-0.09 (0.22)	-0.01 (0.15)
Week 4	-0.09 (0.14)	-0.06 (0.13)	-0.06 (0.21)	0.07 (0.29)
Week 6	-0.14 (0.18)	-0.02 (0.11)	-0.07 (0.19)	-0.04 (0.23)
Week 8	-0.03 (0.12)	-0.05 (0.13)	-0.04 (0.24)	-0.07 (0.21)

11. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	1.69 (11.21)	-5.24 (15.86)	-5.96 (16.76)	-0.53 (11.90)
Week 4	-5.15 (8.20)	-3.30 (8.11)	-3.73 (16.43)	7.54 (25.24)
Week 6	-9.90 (14.01)	-0.97 (7.04)	-4.21 (14.81)	-2.82 (18.20)
Week 8	-1.24 (8.49)	-3.37 (9.35)	-2.60 (20.22)	-4.82 (16.13)

12. Secondary Outcome

Title	Absolute Change From Baseline in Apolipoprotein B (Apo B)
Description	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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	1.09 (0.13)	1.49 (0.24)	1.26 (0.14)	1.52 (0.18)
Week 2	-0.23 (0.13)	-0.31 (0.19)	-0.39 (0.14)	-0.42 (0.16)
Week 4	-0.33 (0.11)	-0.40 (0.13)	-0.44 (0.10)	-0.47 (0.22)
Week 6	-0.27 (0.15)	-0.53 (0.17)	-0.42 (0.15)	-0.52 (0.18)
Week 8	-0.30 (0.08)	-0.59 (0.15)	-0.41 (0.17)	-0.49 (0.30)

13. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein B (Apo B)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	-21.92 (13.97)	-19.88 (10.96)	-30.81 (10.27)	-27.46 (8.89)
Week 4	-29.89 (8.94)	-26.56 (5.33)	-34.69 (6.10)	-30.42 (11.86)
Week 6	-24.58 (12.96)	-35.26 (6.85)	-33.26 (10.38)	-33.61 (9.59)
Week 8	-27.39 (5.97)	-39.59 (5.83)	-31.94 (11.64)	-31.26 (18.57)

14. Secondary Outcome

Title	Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Baseline	0.54 (0.15)	0.76 (0.30)	0.65 (0.11)	0.99 (0.31)
Week 2	-0.22 (0.12)	-0.31 (0.38)	-0.12 (0.29)	-0.38 (0.33)
Week 4	-0.18 (0.24)	-0.30 (0.27)	-0.14 (0.24)	-0.39 (0.35)
Week 6	-0.01 (0.17)	-0.28 (0.32)	-0.20 (0.17)	-0.36 (0.28)
Week 8	-0.13 (0.32)	-0.42 (0.28)	-0.35 (0.14)	-0.55 (0.32)

15. Secondary Outcome

Title	Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)
Description	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]).
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	5	10	9	15
Week 2	-42.20 (25.17)	-28.49 (43.50)	-14.50 (41.19)	-39.95 (37.24)
Week 4	-30.66 (48.66)	-31.86 (37.62)	-21.10 (37.56)	-36.35 (28.79)
Week 6	4.10 (36.46)	-25.59 (44.90)	-29.20 (25.11)	-35.08 (25.06)
Week 8	-12.31 (57.38)	-50.29 (21.44)	-53.61 (19.21)	-52.38 (29.34)

16. Secondary Outcome

Title	Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8
Description	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.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population. Flow-mediated dilation (FMD) was measured at centers with established FMD facilities.

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	4	7	5	12
Baseline	4.34 (3.15)	7.41 (3.30)	5.05 (3.86)	3.67 (2.51)
Week 8	-0.16 (2.32)	-1.14 (1.47)	-0.32 (4.83)	1.35 (2.73)

17. Secondary Outcome

Title	Percent Change From Baseline in Flow-Mediated Dilatation at Week 8
Description	Brachial Flow-Mediated Dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%. .
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

PD analysis population. Flow-mediated dilation (FMD) was measured at centers with established FMD facilities.

Arm/Group Title	Stayed at 5 mg: Tanner Stage 1	Titrated to 10 mg: Tanner Stage 1	Stayed at 10 mg: Tanner Stage 2+	Titrated to 20 mg: Tanner Stage 2+
Arm/Group Description	Atorvastatin 5 mg/day	Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.	Atorvastatin 10 mg/day	Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	4	7	5	12
Mean (Standard Deviation) [percent change in FMD]	-17.19 (23.67)	-20.77 (37.03)	-9.77 (63.20)	1.49 (28.64)

18. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) concentration population: all enrolled and treated subjects who had ≥ 1 PK concentration assessed. Active hydroxyacid metabolite p-hydroxyatorvastatin was not included in the model as originally planned as > 80% of samples were below detectable level at the doses used in this trial.

Arm/Group Title	Atorvastatin (5 mg, 10 mg, 20 mg): Tanner Stages 1 and 2+
Arm/Group Description	Tanner Stage 1: Initial dose 5 mg/day through Week 4; after Week 4 dose may have been doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated; Tanner Stage 2+: Initial dose 10 mg/day through Week 4; after Week 4 dose may have been doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.
Measure Participants	39
Number (95% Confidence Interval) [liters]	1020

Adverse Events

Arm/Group Title	All Subjects (5 mg, 10 mg): Tanner Stage 1		All Subjects (10 mg, 20 mg): Tanner Stage 2+
Arm/Group Description	Atorvastatin: subjects who stayed at initial dose of 5 mg/day for duration of study and subjects who titrated after Week 4 to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.		Atorvastatin: subjects who stayed at initial dose of 10 mg/day for duration of study and subjects who titrated to 20 mg/day after Week 4 if target LDL-C was not attained and study drug was well tolerated.
All Cause Mortality
	All Subjects (5 mg, 10 mg): Tanner Stage 1		All Subjects (10 mg, 20 mg): Tanner Stage 2+
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	All Subjects (5 mg, 10 mg): Tanner Stage 1		All Subjects (10 mg, 20 mg): Tanner Stage 2+
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	All Subjects (5 mg, 10 mg): Tanner Stage 1		All Subjects (10 mg, 20 mg): Tanner Stage 2+
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/15 (60%)		13/24 (54.2%)
Gastrointestinal disorders
Abdominal pain	1/15 (6.7%)		0/24 (0%)
Nausea	1/15 (6.7%)		0/24 (0%)
Toothache	0/15 (0%)		1/24 (4.2%)
Vomiting	1/15 (6.7%)		0/24 (0%)
General disorders
Pain	0/15 (0%)		1/24 (4.2%)
Infections and infestations
Bronchopneumonia	1/15 (6.7%)		0/24 (0%)
Ear infection	0/15 (0%)		1/24 (4.2%)
Gastritis viral	1/15 (6.7%)		0/24 (0%)
Gastroenteritis	1/15 (6.7%)		1/24 (4.2%)
Influenza	0/15 (0%)		1/24 (4.2%)
Lower respiratory tract infection bacterial	0/15 (0%)		1/24 (4.2%)
Nasopharyngitis	1/15 (6.7%)		2/24 (8.3%)
Tonsillitis	0/15 (0%)		1/24 (4.2%)
Viral rhinitis	1/15 (6.7%)		0/24 (0%)
Viral upper respiratory tract infection	3/15 (20%)		0/24 (0%)
Injury, poisoning and procedural complications
Hand fracture	0/15 (0%)		1/24 (4.2%)
Investigations
Alanine aminotransferase increased	0/15 (0%)		2/24 (8.3%)
Blood creatinine increased	1/15 (6.7%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/15 (0%)		1/24 (4.2%)
Musculoskeletal pain	0/15 (0%)		1/24 (4.2%)
Pain in extremity	0/15 (0%)		1/24 (4.2%)
Nervous system disorders
Headache	2/15 (13.3%)		1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/15 (6.7%)		0/24 (0%)
Rhinitis allergic	0/15 (0%)		1/24 (4.2%)
Skin and subcutaneous tissue disorders
Urticaria	1/15 (6.7%)		0/24 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.