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 Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) (NCT00065806), a randomized phase 3 study. The primary outcome is Change in Mean-Mean Common Carotid IMT (CIMT).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00065806 |
| Phase | Phase 3 |
| Condition | Lupus Erythematosus, Systemic |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 221 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Laura Schanberg |
| Results posted | Yes |
2. Clinical Question
Population
Children and young adults with systemic lupus erythematosus were the focus of this study. The registry record describes the study as establishing a cohort of pediatric lupus patients, but does not report additional eligibility details in the posted results.
Intervention
Atorvastatin was given alongside dietary intervention, cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin and a multivitamin containing folate. The atorvastatin dose is not reported in the registry record.
Comparator
The comparator was placebo atorvastatin, alongside the same listed dietary and background measures. The registry record describes the trial as placebo-controlled and double-blind.
Primary question
Did mean-mean common carotid intima-media thickness change from baseline to 36 months in the atorvastatin arm, and how did that change compare with the placebo arm? The posted outcome estimates describe each arm; a direct between-arm estimate or test is not reported in the registry record.
The study also aimed to assess the safety of intermediate-term atorvastatin treatment and to characterize the course of systemic lupus erythematosus in children and young adults. Its broader aims included establishing a cohort for prospective follow-up and a mechanism for conducting trials in rare pediatric rheumatic diseases. These aims provide context for the trial, but the primary result presented in the record concerns change in carotid artery measurement, not a cardiovascular event or a measure of lupus activity.
The distinction between change within each arm and a comparison between arms matters. The arm-specific estimates show the mean change reported for participants in each treatment group. To answer the comparative question directly, readers would need an estimate of the difference between those changes, with its uncertainty and the relevant inferential test. Such a comparative result is not reported in the registry record.
3. Trial Design
APPLE (NCT00065806) is listed as a completed Phase 3 randomized, double-blind, parallel-group study. Its official title describes a multicenter, randomized, double-blind, placebo-controlled study of Lipitor (atorvastatin) and progression of carotid intima-media thickness in early childhood systemic lupus erythematosus. The registry lists enrollment as 221.
The intervention was atorvastatin and the comparator was placebo atorvastatin. Both arm descriptions include dietary intervention, cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin and a multivitamin containing folate. The placebo-arm description also says “placebo at 10 mg”; the atorvastatin dose is not reported in the registry record. The record does not provide further detail on how allocation was generated or concealed.
The primary outcome was change in mean-mean common carotid intima-media thickness from baseline to 36 months. The brief summary describes the safety aim as intermediate-term treatment of 36 months. The study start is listed as 2003-09 and primary completion as 2009-12. These dates describe the registry record and do not, by themselves, specify when each participant began or completed follow-up.
The study combined a vascular imaging endpoint with safety and cohort-building aims. Its randomized, blinded, placebo-controlled design supports a planned comparison of the assigned regimens, but interpreting that comparison requires the corresponding between-arm analysis and details of the analysis population. Those details are not reported in the registry record. The posted outcome values are arm-specific estimates, so they should not be treated as a reported randomized treatment contrast.
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.
Overall Study
| Stage | 1 Atorvastatin | 2 Placebo |
|---|---|---|
| STARTED | 113 | 108 |
| COMPLETED | 93 | 89 |
| NOT COMPLETED | 20 | 19 |
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 | 1 Atorvastatin | 2 Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 113 | 108 | 221 | |
| Age, Categorical: <=18 years | Participants | 87 | 87 | 174 |
| Age, Categorical: Between 18 and 65 years | Participants | 26 | 21 | 47 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Age Continuous | years | 15.7 (SD 2.8) | 15.8 (SD 2.5) | 15.7 (SD 2.6) |
| Sex: Female, Male: Female | Participants | 95 | 89 | 184 |
| Sex: Female, Male: Male | Participants | 18 | 19 | 37 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Mean-Mean Common Carotid IMT (CIMT), measured over Change from baseline to 36 months.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | mm |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change in mean-mean common carotid intima-media thickness (CIMT), measured in millimeters, from baseline to 36 months. CIMT is an ultrasound-based measure of the thickness of the inner layers of the carotid artery wall. The study used the common carotid segment and combined measurements across angles, sides and walls to obtain a single mean-mean common CIMT value for each participant visit.
In general, a continuous imaging measure can detect changes in a vascular feature without waiting for clinical events to occur. It can therefore serve as a marker of vascular structure over the study period. That role does not make CIMT itself a cardiovascular event, nor does a change in the measure establish what will happen to an individual later. The clinical interpretation of a surrogate or imaging marker depends on evidence beyond its observed change in a trial.
The endpoint’s definition matters because the registry lists several additional CIMT outcomes, including mean-max measures and measurements from other carotid segments. Those are not interchangeable with the primary mean-mean common CIMT outcome. The primary outcome is specifically the average of the common-segment summaries described in the registry record, assessed as change over the stated follow-up interval.
The record reports a mean and a 95% confidence interval for each arm. It does not report the number of participants contributing to the primary outcome at follow-up, the method used to handle missing measurements, or a direct treatment-effect estimate comparing arms.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
For mean-mean common CIMT change from baseline to 36 months, the atorvastatin arm has a reported mean of 0.001 mm, with a 95% confidence interval from -0.001 to 0.003. The placebo arm has a reported mean of 0.002 mm, with a 95% confidence interval from 0.001 to 0.004. These values describe the average change within each arm, with the intervals conveying uncertainty around each reported mean.
The intervals are not a confidence interval for the difference between treatment arms. The fact that the two arm-specific estimates and intervals differ does not by itself establish the size, precision or statistical significance of a treatment contrast. A direct between-arm estimate, its confidence interval and a test result are not reported in the registry record. The comparative question therefore cannot be answered from these arm-specific summaries alone.
For the atorvastatin arm, the reported interval extends across zero; for the placebo arm, the reported interval is above zero. This describes how each arm’s interval relates to no mean change. It is not a valid substitute for a randomized between-arm comparison. In general, separate within-arm tests do not determine whether two arms differ, because the uncertainty in their contrast must be evaluated directly.
The estimates are small in the measurement’s millimeter scale, but the registry record does not provide a threshold for a clinically meaningful CIMT change. It also does not report an interpretation linking the observed changes to future cardiovascular outcomes. The findings should therefore be read as estimates of change in the specified imaging measure, rather than as evidence about clinical events or an individual participant’s prognosis.
Precision is also relevant. A confidence interval gives a range of values compatible with the data under the statistical model used, rather than guaranteeing that the true value lies within that range. The arm-specific intervals indicate uncertainty around the respective means. The registry record does not identify the model or calculation used to construct them beyond labeling them 95% confidence intervals.
Other listed outcomes include additional CIMT summaries, but a result for the primary endpoint should not be conflated with those secondary measures. The registry record lists 18 secondary outcomes, while an analysis result for a direct arm comparison is not reported. Without the analysis details, missing-measurement information and multiplicity plan, the posted primary summaries offer a limited view of the trial’s statistical evidence.
9. Statistical Methods Explained
A mean is a measure of the center of a set of continuous observations. Here, each arm’s reported mean represents the average change in the specified CIMT measurement over the stated period. A mean helps summarize the group but can conceal variation among participants, so it is useful to read the estimate alongside its uncertainty interval and the definition of the outcome.
A 95% confidence interval describes uncertainty in an estimate under the method used to calculate it. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. The interval is not a range containing 95% of individual participant changes, and it is not a guarantee about the value of the underlying population mean. The registry record reports a 95% confidence interval for each arm but does not report the specific interval-construction method.
The primary outcome is continuous and measured in millimeters. Continuous outcomes can be summarized as means, although their analysis may depend on the distribution of the observations and on how repeated measurements are handled. The registry record describes the endpoint’s construction: measurements across angles were summarized by side and wall for the common carotid segment, then combined into a mean-mean value for each visit. It does not report the statistical model used to analyze change.
For a randomized trial, the central treatment-effect question is ordinarily expressed as a contrast between randomized arms. In general, comparing arm-specific means requires accounting for the uncertainty in both means and reporting the contrast on a meaningful scale. The posted values are the two arms’ separate mean changes. The record does not report a between-arm estimate, its confidence interval or a test statistic, so a recalculated contrast should not be presented as the sponsor’s analysis. The sponsor’s own analysis takes precedence when a recalculation differs, but no discrepancy is flagged in the record.
Zero is the reference point for no mean change in an arm. An interval that crosses zero is compatible, under its method, with both a decrease and an increase in the mean change. An interval that does not cross zero indicates that the arm-specific interval lies on one side of that reference. These observations concern within-arm change; they do not test whether the randomized arms differ. A treatment comparison needs its own contrast and uncertainty estimate.
General statistical practice also considers whether the outcome distribution is compatible with the chosen method. Over-dispersion, in a setting where a model assumes less variability than the data contain, can make standard errors too small and intervals too narrow. This is a general point, not a claim about the APPLE data: the registry record does not report an over-dispersion assessment or enough distributional detail to evaluate one.
The record lists sample-size planning illustrations as based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect defined as a stated fraction of the observed effect. Such illustrations are planning scenarios, not observed power and not proof that a trial was adequately powered for a particular effect. The record does not report a sample-size justification from the trial’s original design, or the numerical results of those illustrations in the registry record for this account.
Multiplicity arises when many outcomes or analyses are examined. In general, assessing several hypotheses increases the chance that at least one result appears notable by chance if no adjustment or other strategy is used. The registry record lists the primary CIMT outcome and 18 secondary outcomes, but does not report a multiplicity strategy or the analyses for those outcomes. It is therefore not possible to determine from the record whether or how multiplicity was addressed.
Missing data can affect estimates when measurements are unavailable at follow-up. In general, the consequences depend on how much information is missing, why it is missing, and what analysis assumptions are used. The registry record does not report the number with observed 36-month CIMT measurements, the handling of missing values, or the analysis population. Those omissions limit assessment of how representative the reported arm means are of all randomized participants.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 18 secondary outcomes in addition to the primary CIMT outcome. These include other mean-mean and mean-max CIMT summaries and measures from different carotid segments or walls. Examining several outcomes raises a general multiplicity concern: the chance of finding an apparently notable result can increase when many hypotheses are considered. The record does not report a multiplicity adjustment, a prespecified testing hierarchy or another strategy for handling multiple outcomes.
The registry lists no analyses. It therefore does not provide outcome-level analysis results for the secondary measures or the direct arm comparison for the primary endpoint. The arm-specific means and confidence intervals do not replace those missing comparative analyses.
The record does not report how missing 36-month measurements were handled, how many participants contributed data to the primary outcome at that time, or which analysis population was used. In general, complete-case analyses and methods that use incomplete repeated measurements can rely on different assumptions. If missingness is related to outcome or treatment, the interpretation of an estimate may depend on how it is addressed. These are general considerations; the registry record does not specify which situation applies.
The reported arm sizes do not establish the endpoint-specific sample size at follow-up. The number of participants with an outcome measurement may differ from the number assigned to an arm. Without the missing-data and analysis-population details, precision and potential selection effects cannot be fully assessed.
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 |
|---|---|---|---|
| 1 Atorvastatin | 34 | 113 | 30.1% |
| 2 Placebo | 40 | 108 | 37.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| 1 Atorvastatin | 94 of 113 |
| 2 Placebo | 95 of 108 |
Most frequent serious adverse event terms
| Event term | Organ system | 1 Atorvastatin | 2 Placebo |
|---|---|---|---|
| Systemic Lupus Erythematosus | Musculoskeletal and connective tissue disorders | 10 of 113 | 8 of 108 |
| Herpes Zoster | Infections and infestations | 1 of 113 | 5 of 108 |
| Pneumonia | Infections and infestations | 4 of 113 | 1 of 108 |
| Lupus Nephritis | Renal and urinary disorders | 1 of 113 | 3 of 108 |
| Uticaria | Skin and subcutaneous tissue disorders | 1 of 113 | 3 of 108 |
| Suicidal Ideation | Psychiatric disorders | 1 of 113 | 2 of 108 |
| Convulsion | Nervous system disorders | 0 of 113 | 3 of 108 |
| Thrombocytopenia | Blood and lymphatic system disorders | 2 of 113 | 1 of 108 |
| Hypertension | Vascular disorders | 1 of 113 | 2 of 108 |
| Appendicitis | Infections and infestations | 1 of 113 | 1 of 108 |
Most frequent non-serious adverse event terms
| Event term | Organ system | 1 Atorvastatin | 2 Placebo |
|---|---|---|---|
| Neurotoxicity | Nervous system disorders | 27 of 113 | 25 of 108 |
| Rash | Skin and subcutaneous tissue disorders | 19 of 113 | 28 of 108 |
| Upper Respiratory Tract Infection | Infections and infestations | 15 of 113 | 18 of 108 |
| Hypertension | Vascular disorders | 13 of 113 | 12 of 108 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 10 of 113 | 10 of 108 |
| Proteinuria | Renal and urinary disorders | 12 of 113 | 8 of 108 |
| Sinusitis | Infections and infestations | 11 of 113 | 7 of 108 |
| Urinary Tract Infection | Infections and infestations | 8 of 113 | 10 of 108 |
| Systemic Lupus Erythematosus | Musculoskeletal and connective tissue disorders | 10 of 113 | 8 of 108 |
| Gastrointestinal Disorder | Gastrointestinal disorders | 10 of 113 | 8 of 108 |
Serious events with the highest arm-level rate: systemic lupus erythematosus (8.8%), herpes zoster (4.6%), pneumonia (3.5%), convulsion (2.8%), lupus nephritis (2.8%).
The registry reports serious adverse events affecting 34 participants in the atorvastatin group, with 113 at risk, and 40 in the placebo group, with 108 at risk. It also reports other adverse events affecting 94 participants in the atorvastatin group, with 113 at risk, and 95 in the placebo group, with 108 at risk. These are arm-level participant counts as recorded; they do not provide a direct comparative safety estimate or an adjustment for differences in follow-up.
The listed leading serious adverse event terms are Systemic Lupus Erythematosus (8.8%), Herpes Zoster (4.6%), Pneumonia (3.5%), Convulsion (2.8%), Lupus Nephritis (2.8%) and Uticaria (2.8%). These percentages describe the registry’s reported terms and should not be read as a complete account of every event or as a treatment-effect comparison. The registry record does not report deaths.
In general, serious adverse events and other adverse events are different reporting categories. Counts of affected participants do not necessarily equal counts of event episodes, and one participant may experience more than one event. The record does not give event-level detail, exposure-adjusted rates, severity distributions beyond the serious-event category, or a causal assessment for individual events. The figures describe what was recorded, not whether an event was caused by the assigned treatment.
12. What the Result Does, and Does Not, Mean
The posted results describe mean change in mean-mean common CIMT from baseline to 36 months in the two randomized arms. The atorvastatin arm’s mean change is 0.001 mm, with a 95% confidence interval from -0.001 to 0.003. The placebo arm’s mean change is 0.002 mm, with a 95% confidence interval from 0.001 to 0.004. These are the central outcome estimates available in the registry record.
They do not, on their own, quantify the randomized treatment effect. A direct contrast would show how much the average change differed between arms and how uncertain that difference was. That contrast and its inferential test are not reported. It would be inappropriate to infer a comparative effect by visually comparing the two arm-specific intervals or by treating a within-arm interval as a test of treatment efficacy.
The endpoint is a measure of carotid artery structure. It is not a clinical cardiovascular event, and the record does not report whether the measured changes predict later events in this study population. The results therefore do not establish a clinical benefit or lack of benefit, nor do they determine what treatment an individual should receive. The registry’s safety counts likewise describe reported events but do not establish causation or comparative risk.
Interpretation is constrained by the absence of reported analysis details, endpoint-specific follow-up counts, missing-data methods and an analysis population. The record also does not report the trial’s multiplicity approach or results for the listed secondary outcomes. Those omissions leave uncertainty about the full analysis and how the primary result fits alongside the other planned or registered measures.
In general, trial findings are most informative when the endpoint, analysis population, treatment contrast, uncertainty and missing-data assumptions are considered together. For APPLE, the endpoint definition and arm-specific estimates are available, while several of those accompanying details are not reported in the registry record. The appropriate conclusion is limited to describing those posted summaries and their uncertainty, not making a broader claim about efficacy, safety or future cardiovascular outcomes.
13. Why This Trial Matters Statistically
APPLE addresses a difficult trial setting: systemic lupus erythematosus in children and young adults, a population the study summary describes as a rare pediatric rheumatic-disease context. The trial’s stated aims extended beyond evaluating a lipid-lowering agent. They included prospectively characterizing the course of pediatric lupus and establishing a mechanism for conducting trials through the Children’s Arthritis and Rheumatology Research Alliance.
Statistically, the study illustrates why a clear endpoint definition matters. The primary measure was not an unspecified carotid thickness value, but mean-mean common CIMT created from measurements across angles, sides and walls. That precision in the endpoint description helps distinguish the primary outcome from the additional CIMT measures listed as secondary outcomes.
The results also illustrate the difference between reporting change within each randomized group and reporting the treatment contrast. Arm-specific means and intervals are useful descriptive summaries, but the comparative question requires a direct estimate of the difference between arms and its uncertainty. The registry record does not report that analysis. This distinction is important whenever readers encounter outcomes reported separately by group.
The study’s 36-month outcome period and safety aim make follow-up and missingness relevant to interpretation. Yet the registry record does not report endpoint-specific follow-up counts or missing-data methods. This highlights how even a clearly defined outcome and randomized design leave important statistical questions unresolved when the analysis details are absent. The record’s limitations do not erase the value of the trial’s stated research aims, but they bound what can be concluded from the posted numerical summaries.
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 of the posted primary results is that they provide arm-specific means and confidence intervals but no direct between-arm treatment estimate or test. Those summaries cannot establish the magnitude or precision of a randomized contrast by themselves.
The registry record does not report the model used to analyze the primary outcome, the number of participants with measurements at 36 months, the missing-data approach or the analysis population. It is therefore not possible to assess from the posted information whether the primary analysis included all randomized participants or how incomplete follow-up may have affected the results.
Multiplicity handling is also not reported, despite the presence of 18 secondary outcomes. The record lists no analyses, so results for those outcomes and the statistical relationship between primary and secondary findings are unavailable. A sample-size justification from the original trial design is not reported in the registry record; the planning illustrations described in the record should not be treated as observed power.
The arm description does not report the atorvastatin dose. The safety summary supplies participant counts and leading serious-event terms but does not report event-level detail, exposure-adjusted rates or a causal assessment. The registry record does not report deaths. These limits make it difficult to assess safety patterns beyond the listed counts and terms.
Finally, the primary endpoint is an imaging measure. The registry record does not report a threshold for clinical importance or link the observed CIMT changes to cardiovascular events. This limits interpretation to the specified measurement and follow-up period, rather than broader clinical outcomes.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) — NCT00065806.
- Registry record last updated 2013-08-15; status last verified 2013-07.
- Results first posted 2013-08-15.
- 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
NCT00065806, titled Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE), is listed as a completed Phase 3 randomized, double-blind, parallel-group, placebo-controlled study. Enrollment is listed as 221. The study focused on children and young adults with systemic lupus erythematosus and compared atorvastatin with placebo, alongside the listed dietary and background measures.
The primary outcome was change in mean-mean common carotid IMT from baseline to 36 months. The registry reports arm-specific means and 95% confidence intervals, but not a direct between-arm estimate or test. It lists 18 secondary outcomes and no analyses. Missing-data methods, analysis population and the multiplicity approach are not reported in the registry record.
The record lists serious and other adverse-event participant counts by arm and leading serious-event terms. It does not report deaths. The study’s stated aims also included safety assessment and prospective characterization of pediatric lupus.