This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for 8-Week PK/PD Atorvastatin Study In Children And Adolescents With Heterozygous Familial Hypercholesterolemia (NCT00739999), a na phase 1 study. The primary outcome is Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00739999 |
| Phase | Phase 1 |
| Condition | Pediatric Heterozygous Hypercholesterolemia |
| Allocation | Not applicable (single group) |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 39 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Pfizer's Upjohn has merged with Mylan to form Viatris Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Children and adolescents with heterozygous familial hypercholesterolemia were studied. The trial enrolled 39 participants. The primary pharmacokinetic population is described as enrolled and treated participants with at least one pharmacokinetic concentration assessed. The count meeting that definition is not reported in the registry record.
Intervention
Participants received atorvastatin tablets in two age-based groups. The description for ages 6-10 says initial doses were based on age cohort. The description for ages 10-17 specifies a 10-mg daily dose. Adverse-event group labels separately identify Tanner Stage 1 groups receiving 5 mg or 10 mg and Tanner Stage 2+ groups receiving 10 mg or 20 mg; the registry record does not explain the relationship between all of these descriptions.
Comparator
There was no placebo or untreated control group described. Both groups received atorvastatin, and the allocation method is listed as not applicable. This was not a randomized, like-for-like treatment comparison; differences between groups cannot be separated from differences in age, developmental stage, or dose using the registry information.
Primary question
The primary endpoint concerned apparent clearance of atorvastatin, estimated with a parent-metabolite population pharmacokinetic model. The model used sparse blood samples collected at Weeks 2, 4, 6, and 8. The registry record describes how concentrations were measured and modeled, but gives no numerical clearance estimate or other numerical primary result. The study also listed pharmacodynamic changes in LDL-C and other lipid measures as secondary outcomes.
3. Trial Design
This was a Phase 1, open-label, parallel study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia. Masking was listed as none, and allocation was listed as not applicable. The registry therefore does not describe a blinded randomized comparison. Both groups received atorvastatin, with age-based dosing descriptions rather than a separate control intervention.
The study enrolled 39 participants and was planned as an 8-week evaluation of pharmacokinetics, pharmacodynamics, safety, and tolerability. The age descriptions identify a group aged 6-10 years, with starting doses based on age cohort, and a group aged 10-17 years, receiving a 10-mg daily dose. These age ranges overlap at age 10 as written. Adverse-event group labels also classify participants by Tanner stage and list dose levels; the record does not fully reconcile those labels with the age-based arm descriptions.
The registry lists the study start as 2008-12, primary completion as 2009-05, and status as completed. The primary pharmacokinetic endpoint used samples from Weeks 2, 4, 6, and 8. The sampling schedule was sparse and varied by visit: a single postdose sample was collected at Weeks 2 and 6, while predose and postdose samples were collected at Weeks 4 and 8. This design supports model-based estimation from concentration observations rather than a dense concentration-time profile for every participant.
The record does not report a randomized allocation procedure, a control arm, or a planned sample-size justification. It also does not report a numerical primary endpoint estimate. Accordingly, the design and posted results support a description of the study's purpose and methods, but not a controlled estimate of treatment differences.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Forty-five subjects were screened, and 39 subjects were assigned to study treatment.
Overall Study
| Stage | Atorvastatin (5 mg, 10 mg): Tanner Stage 1 | Atorvastatin (10 mg, 20 mg): Tanner Stage 2+ |
|---|---|---|
| STARTED | 15 | 24 |
| COMPLETED | 15 | 24 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: 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.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Atorvastatin (5 mg, 10 mg): Tanner Stage 1 | Atorvastatin (10 mg, 20 mg): Tanner Stage 2+ | Total |
|---|---|---|---|---|
| Participants analysed | 15 | 24 | 39 | |
| Age, Customized: 6-8 years | participants | 7 | 0 | 7 |
| Age, Customized: 9-10 years | participants | 6 | 3 | 9 |
| Age, Customized: 11-14 years | participants | 2 | 14 | 16 |
| Age, Customized: 15-17 years | participants | 0 | 7 | 7 |
| Sex: Female, Male: Female | Participants | 7 | 12 | 19 |
| Sex: Female, Male: Male | Participants | 8 | 12 | 20 |
6. Primary Endpoint
The registry lists the primary outcome as Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F), measured over Week 2, Week 4, Week 6, Week 8.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | L/hr |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was atorvastatin apparent clearance, denoted CL/F and measured in L/hr, estimated using a parent-metabolite population pharmacokinetic model. In general, clearance describes the rate at which drug is removed from the body relative to its concentration. The notation CL/F refers to apparent clearance after accounting for bioavailability; for an orally administered drug, clearance and the fraction reaching systemic circulation are not separately identified from concentration data without additional information.
The model used sparse blood samples from Tanner Stage 1 and Tanner Stage 2+ participants. Samples were collected at Weeks 2, 4, 6, and 8. The record says the model included atorvastatin and an active hydroxyacid metabolite, and describes plasma concentrations measured with a validated, sensitive, and specific high-performance liquid chromatography tandem mass spectrometric method.
In general, population pharmacokinetic modeling can combine concentration measurements from multiple participants to estimate typical drug disposition and variation between individuals, while making use of observations collected at different times. Such estimates depend on the model structure, sampling schedule, measured concentrations, and analysis population. The registry describes the endpoint and modeling approach but does not report the estimated CL/F value, its uncertainty, or model diagnostics. The endpoint therefore cannot be quantitatively interpreted from the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The primary endpoint is defined as a model-derived apparent clearance estimate, but no numerical estimate is reported in the registry record. There is consequently no posted value from which to assess the estimated magnitude, precision, or variability of atorvastatin clearance in this study. The record also does not give a confidence interval or another measure of uncertainty for the primary estimate. The stated endpoint definition and model description explain what was intended to be estimated, not what value the analysis produced.
The study's design matters when interpreting any comparison between its groups. Both groups received atorvastatin, allocation is listed as not applicable, and the study was open label. The record does not describe a randomized control group. The age-based dosing descriptions and Tanner-stage group labels also indicate that groups may differ in developmental stage and dose. A difference between groups, if reported elsewhere, could not be attributed to dose or developmental stage alone on the basis of this design description.
The registry lists 18 outcome measures and one analysis. It names secondary outcomes covering absolute and percent changes from baseline in LDL-C, total cholesterol, triglycerides, and HDL-C. Numerical values for those outcomes are not reported in the registry record represented by these results. No direction or magnitude of lipid change can therefore be described from the posted data. The study's stated aims include safety and tolerability, but outcome counts do not by themselves establish a treatment effect.
The adverse-event record reports no serious adverse events in either listed group: 0 among 15 Tanner Stage 1 participants and 0 among 24 Tanner Stage 2+ participants. It also reports events in the other adverse-event category for 9 of 15 and 13 of 24 participants, respectively. These are descriptive counts, not controlled estimates of comparative risk. The record does not list serious event terms or give further details about the other events.
Overall, the posted registry information characterizes a short, open-label pharmacokinetic and safety study and gives some adverse-event counts. It does not provide the numerical primary pharmacokinetic result or numerical secondary efficacy results. Conclusions about the size or precision of pharmacokinetic or lipid changes are therefore not supported by the numerical information in the registry record.
9. Statistical Methods Explained
In general, pharmacokinetics describes how drug concentrations change in the body over time. A population pharmacokinetic model uses concentration observations from a group of participants to estimate parameters such as apparent clearance. The primary endpoint in this study was model-derived CL/F for atorvastatin, with the model described as a parent-metabolite model. This is different from reporting a directly observed concentration or a simple average of individual clearance estimates.
Why use a population model?
In general, a population model is useful when each participant does not contribute a complete concentration-time profile. The model can use observations taken at different times across participants and estimate population-level parameters under stated structural and statistical assumptions. It may also represent variability between participants. Its reliability depends on the model being suitable for the data and on the amount and timing of information available. Sparse sampling can be appropriate for this approach, but it makes the model and sampling design especially important to interpretation.
The registry says samples were collected at Weeks 2, 4, 6, and 8. At Weeks 2 and 6, one sample was taken between 4 and 12 hours after dosing. At Weeks 4 and 8, samples were taken before dosing and at 1 hour and 2 hours after dosing. These schedules contribute different kinds of concentration information: a predose observation can characterize concentration before the next dose, while postdose observations capture concentrations after administration. The record does not provide participant-level concentrations, the model equations, parameter estimates, or diagnostic results.
What does apparent clearance represent?
In general, clearance relates drug concentration to the rate of drug removal. CL/F is termed apparent clearance because the model estimates clearance relative to bioavailability rather than identifying both quantities separately. A model-derived value is therefore conditional on the dosing and modeling framework. The registry gives the unit as L/hr but does not report an estimated value or its precision. Without that estimate, the endpoint's numerical size cannot be assessed.
The model description says plasma was analyzed for atorvastatin and the active hydroxyacid metabolite o-hydroxyatorvastatin using a validated, sensitive, and specific high-performance liquid chromatography tandem mass spectrometric method. A separate population note says p-hydroxyatorvastatin was not included in the model as originally planned because > 80% of samples were below the detectable level at the doses used. The difference between the metabolite names in these descriptions is present in the registry record; the record does not resolve it. The stated below-detection issue also means the planned inclusion of that metabolite could not be carried out as originally intended. General statistical practice treats concentrations below a detection limit as limited information about the true concentration, rather than as exact observed values, but the registry does not describe how such measurements were handled in the analysis.
How to read the study's group structure
In general, a parallel study assigns different groups to interventions that continue alongside one another during the study period. Here, the record lists two atorvastatin interventions and two age-based descriptions, but allocation is not applicable and masking is none. It is not a randomized comparison against an inactive control. The age bands are described as 6-10 years and 10-17 years; the adverse-event labels instead distinguish Tanner Stage 1 and Tanner Stage 2+ and list dose levels. Those labels should not be treated as proof that age, developmental stage, and dose are interchangeable classifications.
For a randomized controlled comparison, random allocation helps balance measured and unmeasured characteristics across groups on average. That general protection does not apply to a nonrandomized comparison in the same way. In this study, the registry does not identify a control group or provide an adjusted comparison. Group differences in an outcome, if available, could reflect differences in participant characteristics as well as treatment exposure.
Estimates, uncertainty, and reported outcomes
In general, a confidence interval describes a range of values compatible with an estimate under the statistical model and assumptions; it communicates precision as well as direction and magnitude. A p-value addresses compatibility with a specified null hypothesis under a statistical model, but it does not quantify the size or clinical importance of an effect. The registry record does not report a primary estimate, confidence interval, or p-value for the primary endpoint. It also does not describe the model's uncertainty estimates or diagnostic checks. Those omissions prevent an assessment of statistical precision and model adequacy from the registry information.
The listed secondary outcomes are absolute and percent changes from baseline in LDL-C, total cholesterol, triglycerides, and HDL-C. In general, an absolute change expresses movement in the outcome's measurement scale; a percent change expresses movement relative to a baseline value. Both can be informative, but their interpretation depends on the specific estimates, variability, analysis population, and time point. The registry names the outcomes but provides no numerical results for them in the record.
The record's sample-size illustration assumptions describe a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such calculations are planning illustrations, not evidence that a trial had a particular probability of detecting an effect. They are not the study's own design justification, and they are not observed power. A trial-specific sample-size justification is not reported in the registry record. In this case, the absence of a numerical primary effect also means that the registry information cannot support an independent assessment of the underlying effect size used in any illustration.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 18 outcome measures and one analysis. The listed secondary outcomes include absolute and percent changes from baseline in LDL-C, total cholesterol, triglycerides, and HDL-C. No numerical results for these outcomes are reported in the registry record. The record does not describe how analyses across multiple outcomes, measures, or time points were handled, and it does not report a multiplicity adjustment or a prespecified hierarchy of hypotheses.
In general, when many statistical hypotheses are tested, the chance of at least one apparently unusual result can increase if each is interpreted without accounting for the number of tests. A multiplicity strategy can define which outcomes are primary, control error rates, or distinguish confirmatory from exploratory analyses. The registry identifies a primary pharmacokinetic endpoint and names secondary lipid outcomes, but a detailed statistical plan for managing multiple analyses is not reported in the registry record. The number of listed outcomes alone does not establish how many tests were performed or how their results were interpreted.
Missing-data methods, imputation procedures, and the handling of participants without an evaluable outcome are not reported in the registry record. The primary pharmacokinetic population is described as enrolled and treated participants with at least one pharmacokinetic concentration assessed, but the number meeting that definition is not reported. The registry does not state whether all enrolled participants contributed to each secondary outcome or describe exclusions from those analyses.
In general, analysis-population definitions matter because estimates can depend on who is included and why observations are unavailable. A population requiring at least one concentration is an evaluable pharmacokinetic population, but its exact size and relationship to all enrolled participants cannot be determined from the record. No further analysis-population details or missing-data assumptions are reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| All Subjects (5 mg, 10 mg): Tanner Stage 1 | 0 | 15 | 0.0% |
| All Subjects (10 mg, 20 mg): Tanner Stage 2+ | 0 | 24 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| All Subjects (5 mg, 10 mg): Tanner Stage 1 | 9 of 15 |
| All Subjects (10 mg, 20 mg): Tanner Stage 2+ | 13 of 24 |
Most frequent non-serious adverse event terms
| Event term | Organ system | All Subjects (5 mg, 10 mg): Tanner Stage 1 | All Subjects (10 mg, 20 mg): Tanner Stage 2+ |
|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 1 of 15 | 2 of 24 |
| Viral upper respiratory tract infection | Infections and infestations | 3 of 15 | 0 of 24 |
| Headache | Nervous system disorders | 2 of 15 | 1 of 24 |
| Gastroenteritis | Infections and infestations | 1 of 15 | 1 of 24 |
| Alanine aminotransferase increased | Investigations | 0 of 15 | 2 of 24 |
| Abdominal pain | Gastrointestinal disorders | 1 of 15 | 0 of 24 |
| Nausea | Gastrointestinal disorders | 1 of 15 | 0 of 24 |
| Toothache | Gastrointestinal disorders | 0 of 15 | 1 of 24 |
| Vomiting | Gastrointestinal disorders | 1 of 15 | 0 of 24 |
| Pain | General disorders | 0 of 15 | 1 of 24 |
The registry reports serious adverse-event counts separately for two groups. In the group labeled All Subjects (5 mg, 10 mg): Tanner Stage 1, 0 serious adverse events were reported among 15 participants at risk. In the group labeled All Subjects (10 mg, 20 mg): Tanner Stage 2+, 0 serious adverse events were reported among 24 participants at risk. The serious-event term list is empty.
The record also lists 9 participants with events in the other adverse-event category among 15 at risk in the Tanner Stage 1 group, and 13 among 24 at risk in the Tanner Stage 2+ group. Those counts do not identify event types, severity beyond the category distinction, timing, or whether events were considered related to treatment. Further details are not reported in the registry record. Death counts are not reported in the registry record.
These are descriptive group counts from an open-label study without a control group. They do not establish whether event occurrence differs by dose, age, developmental stage, or treatment compared with no treatment. A zero count in a study group means no serious event was recorded in that group during the reported study; it does not show that serious events are impossible or that risk is absent. The registry does not provide enough detail to characterize individual events or to make a controlled safety comparison.
12. What the Result Does, and Does Not, Mean
The record establishes that the study was designed to evaluate atorvastatin pharmacokinetics, pharmacodynamics, safety, and tolerability in children and adolescents with heterozygous familial hypercholesterolemia. It identifies a model-based primary endpoint, CL/F, and describes sparse sampling at Weeks 2, 4, 6, and 8. It also names secondary lipid outcomes and provides adverse-event counts for two groups.
The record does not report a numerical primary clearance estimate, its uncertainty, or numerical results for the listed secondary lipid outcomes. It therefore does not show how large or precise any pharmacokinetic or lipid change was. A study objective and endpoint definition describe what investigators intended to assess; they are not themselves evidence of a particular result.
The design also limits what can be inferred from comparisons between groups. This was open label, allocation was not applicable, and both groups received atorvastatin. The record does not describe a randomized control group. The age-based dosing descriptions and Tanner-stage adverse-event labels do not provide a controlled contrast that isolates the effect of a specific dose or developmental stage.
The adverse-event counts show that no serious adverse events were reported in either listed group, alongside counts for events in the other category. These observations describe what was recorded in this study, not a comparison with an untreated group and not a complete characterization of safety. The serious-event term list is empty, and further event details are not reported in the registry record.
In general, statistical conclusions require estimates, uncertainty, an analysis plan, and a design suited to the question. The registry record supplies some design and outcome definitions, but not the numerical primary result or a detailed analysis plan. It supports a description of the study's scope and reported event counts, but not a quantitative conclusion about pharmacokinetic effects, lipid changes, or comparative safety.
13. Why This Trial Matters Statistically
This trial is statistically notable because its primary endpoint is a model-based pharmacokinetic quantity rather than a simple clinical outcome. Population pharmacokinetic models are often used when samples are sparse or collected at different times across participants. Understanding the sampling schedule and the model's assumptions is therefore central to interpreting an estimated clearance parameter. The registry describes the sampling times and assay, but does not report the estimate, its uncertainty, or model diagnostics.
The developmental setting also makes clear why group labels require careful reading. The record describes age-based groups and dosing, while adverse-event categories use Tanner stage and list different dose levels. These descriptions are not interchangeable, and the registry does not fully explain their correspondence. An unrandomized, open-label design cannot by itself separate differences associated with participant characteristics from differences associated with dose.
The record also illustrates the importance of documenting deviations from a planned measurement approach. A population note says a metabolite was not included in the model as originally planned because > 80% of its samples were below detectable level. The model description and population note use different metabolite names, an inconsistency not resolved in the registry record. Such details can affect how readers understand the model's scope and the information available to estimate parameters.
Finally, an outcome list is not the same as a report of outcome findings. The registry names pharmacodynamic lipid measures and records adverse-event counts, but does not report numerical primary or secondary efficacy results. For statistical interpretation, that distinction is essential: design details explain what could be studied, while estimates and uncertainty are needed to evaluate the observed findings.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The main limitation for statistical interpretation is the absence of a numerical result for the primary endpoint. The registry defines apparent clearance in L/hr and describes the population model, but does not give a clearance estimate, measure of uncertainty, or model diagnostics. Numerical results for the listed secondary lipid outcomes are also not reported in the registry record.
The study was open label, and allocation was listed as not applicable. Both groups received atorvastatin, so the registry does not describe a randomized control comparison. The age-based intervention descriptions and Tanner-stage adverse-event labels differ in how they define groups; the relationship between all ages, stages, and dose levels is not explained. The two age ranges also overlap at age 10 as written.
The concentration sampling schedule was sparse, with different timing at different study weeks. Population modeling can use such sampling, but interpretation depends on assumptions and diagnostics that are not reported. The record also notes that a planned metabolite was omitted because > 80% of samples were below detectable level. The model description and population note name different hydroxyacid metabolites, and the registry does not resolve that difference.
The number of participants meeting the pharmacokinetic population definition is not reported. Missing-data handling, exclusions, analysis populations for secondary outcomes, and the statistical plan for multiple outcomes are not reported in the registry record. Adverse-event information is limited to group counts; serious event terms are not listed, death counts are not reported, and further details about other events are absent. These gaps limit assessment of precision, model performance, outcome completeness, and comparative safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: 8-Week PK/PD Atorvastatin Study In Children And Adolescents With Heterozygous Familial Hypercholesterolemia — NCT00739999.
- Registry record last updated 2021-03-15; status last verified 2021-02.
- Results first posted 2010-08-20.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
NCT00739999 is a completed, open-label, Phase 1, parallel study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia. The study enrolled 39 participants and was planned for 8 weeks. It evaluated pharmacokinetics, pharmacodynamics, safety, and tolerability, with atorvastatin tablet regimens described by age cohort.
The primary endpoint was model-derived atorvastatin apparent clearance using a parent-metabolite population pharmacokinetic model and sparse samples collected at Weeks 2, 4, 6, and 8. The numerical primary result is not reported in the registry record. Secondary outcomes included absolute and percent changes from baseline in LDL-C, total cholesterol, triglycerides, and HDL-C; their numerical results are not reported in the registry record.
The adverse-event record reports 0 serious events among 15 Tanner Stage 1 participants and 0 among 24 Tanner Stage 2+ participants. Other-category event counts were 9 and 13, respectively. No randomized control group or detailed statistical plan is described.